5212018

1

Disclosures

ConsultingMyriad Genetics

SciBase

Superficial Atypical Melanocytic Proliferations

SSM LMM and (some of) their Simulants

5212018

2

Melanomas and Nevi

bull Nevi are important mainly in relation to melanomandash Precursors ndash but risk for individual lesions is low

ndash Risk markers ndash important mainly in high risk situations

ndash Simulants ndash important in everyday clinical decision-making

bull Makes sense to consider attributes of melanomas before discussing nevi

Low UV

Pathway I

Low-CSD MelanomaSupertpficial Spreading Melanoma

Banal Acquired Nevus (junctional compound dermal)

Low Grade Dysplasia Bap-1

Deficiency Melanocytoma

Deep penetrating

nevus (DPN) Melanocytoma

PigmentedEpithelioid

Melanocytoma (PEM)High Grade

Dysplasia

Superficial Spreading Melanoma

Melanoma in BPDM (rare)

Melanoma in DPN (rare)

Melanoma in PEM (rare)

BRAF V600E NRAS

(BRAF or NRAS)+BAP1

(BRAF MEK1 or NRAS) +(CBNN1 or APC)

(BRAF+PRKAR1A) or PRKCA

TERT CDKN2A TP53 PTEN

Lentiginous junctional nevus

Compound dysplastic nevus

Superficial spreading or ldquopagetoidrdquo melanoma

5212018

3

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed nevoid

Poor circumscription common less common uncommon

Nested variable predominant predominant

Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Superficial Melanoma and Mimics in Low CSD Skin

bull Superficial Spreading (ldquoPagetoidrdquo) Melanoma

bull Junctional and superficial Compound nevi

bull Dysplastic Nevi

bull Recurrent and Traumatized Nevi

bull Pagetoid Spitz and other pagetoid proliferatons

bull Superficial Atypical Melanocytic Proliferations (SAMPUS)

5212018

4

Case 1

DEE-10253

History M50 Lesion of BackReason for Consultation Is this a melanoma or a severely dysplastic nevus

bull Broad moderately to highly cellular asymmetric

bull Cells at periphery of lesion- predominantly in nests- predominantly near the DEJ - some nests bridging between adjacent elongated rete ridges

bull Pattern of melanocytic dysplasia with severe cytologic atypia and moderate architectural disorder

5212018

5

bull Adjacent component more highly cellular

bull More severe uniform atypia

bull Pagetoid scatterbull Diffuse fibroplasiabull Bandlike

lymphocytic infiltrate

bull Few clusters of immature cells in dermis

bull Adjacent component more highly cellular

bull More severe uniform atypia

bull Pagetoid scatterbull Diffuse fibroplasiabull Bandlike lymphocytic

infiltratebull Few clusters of

immature cells in dermis

bull Localized clusters of mature nevoid cells (precursorassociated nevus)

Your Diagnosis

Melanoma

Nevus

5212018

6

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed nevoid

Poor circumscription common less common uncommon

Distribution of Nests variable irregular predominant predominant regular

Pattern of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe (gt15x) mild-moderate

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 1 M50

bull Malignant melanoma superficial spreading type nonulcerated non-tumorigenic and nonmitogenic invasive radial growth phase only Clark level II greatest Breslow thickness 028 mm see comment

Commentndash Dermal mitotic rate is zero tumor infiltrating lymphocytes are absent (with

moderate noninfiltrating lymphocytes) there is no radial growth phase regression there is no ulcer there are no microscopic satellites and there is no evidence of vascular lymphatic or neural invasion

ndash Age lt 56ndash Associated compound dysplastic nevus ndash Appears to be minimally excised ndash MPATH-Dx 4 ndash 100 5 year survival

Case 2

Clinical InformationLesion of left shin with a mottled color in a 26-year-old woman

Reason for ConsultationI am enclosing for your consultation a melanocytic lesion

present for many years from the right shin of a 27-year-old woman Though the lesion had not changed (according to the patient) her clinician decided to remove it because he ldquodidnrsquot

like the mottled colorrdquo

5212018

7

Description

A relatively broad moderately cellular plaque-like lesion

Comprised mainly of nested large epithelioid melanocytes with abundant cytoplasm that contains finely divided ldquodustyrdquo melanin pigment

Some bridging nests between adjacent rete - possible junctional melanocytic dysplasia of the epithelioid type

bull Nests somewhat haphazardly distributed along the interface

bull Poor circumscription

bull Patchy to bandlike lymphocytic infiltrate

bull Diffuse fibroplasia

bull Nests somewhat haphazardly distributed along the interface

bull Poor circumscription

bull Patchy to bandlike lymphocytic infiltrate

bull Diffuse fibroplasia

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8

bull Nests somewhat haphazardly distributed along the interface

bull Tendency to confluence of nests

bull Patchy to bandlike lymphocytic infiltrate

bull Diffuse fibroplasia

bull Nests somewhat haphazardly distributed along the interface

bull Nests in dermis not larger than largest in epidermis

bull Tendency to confluence of nests

bull Focal pagetoid scatter

Your Diagnosis

Melanoma

Nevus

5212018

9

1125 Dermal mitotic activity in atypical cells that resemble those in epidermis

The mitosis on the right could be considered junctional however there seems to be a wisp of collagen between the nest which is predominantly located in the dermis and the overlying junctional nest

Non tumorigenic mitogenic VGP

Nests in the dermis are smaller than the largest nests in the epidermisCount dermal mitoses in 1 sq mm even if not fully occupied by tumor express rate as a whole number

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed nevoid

Poor circumscription common less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe (gt15x) mild-moderate

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

5212018

10

Diagnosis Case 2 F26

bull Skin right shin Malignant melanoma superficial spreading type nonulcerated with non-tumorigenic but mitogenic early vertical growth phase Clarkrsquos level II greatest Breslow thickness 051 mm see description and comment

bull Comment Differential diagnosis could include severe dermal and epidermal melanocytic dysplasia however dermal (or even epidermal) mitotic activity essentially rules out this diagnosis The lesion is not a Spitz nevustumor because it is not comprised of large spindle andor epithelioid cells

bull Dermal mitotic rate 2 per square millimeterbull Tumor-infiltrating lymphocytes essentially absent in the invasive component with brisk

noninfiltrating lymphocytes nearbybull Focal radial growth phase regression presentbull No ulcer no microscopic satellites and no evidence of vascular lymphatic or neural invasionbull Associated junctional dysplastic nevus of the epithelioid subtypebull Actinic elastosis in the adjacent dermis is present and mild bull Lesion is completely excised with a closest border of approximately 1 mm

Superficial Melanoma and Mimics in Low CSD Skin

bull Superficial Spreading (ldquoPagetoidrdquo) Melanoma

bull Junctional and superficial Compound nevi

bull Dysplastic Nevi

bull Recurrent and Traumatized Nevi

bull Pagetoid Spitz and other pagetoid proliferations

bull Superficial Atypical Melanocytic Proliferations (SAMPUS)

Case 3

Clinical InformationA macular slightly variegated lesion from the back of a 37-year-old

womanReason for ConsultationIs this a dysplastic nevus

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11

bull 25451bull Clinical Informationbull A 3 mm macular slightly variegated lesion from the back of a 37-year-old

womanbull Reason for Consultationbull Is this a dysplastic nevus

bull Smallbull Poorly circumscribedbull Nest predominate discretebull Patchy lymphocytes scant fibroplasia numerous melanophages (clinically

atypical)

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12

bull Slightabsent cytologic atypia

bull No mitoses

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

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13

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed nevoid

Poor circumscription cannot assess less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 2-1 F37

bull Diagnosisbull Skin abdomen bull Lentiginous junctional nevus with mild dysplasia see description and commentbull OR Lentiginous junctional nevus

bull Comment bull Mild dysplasia is not an independent risk factor for melanoma however if this patient should

have other clinically atypical nevi andor a family or personal history of melanoma or other melanoma risk factors consideration of periodic surveillance may be appropriate

bull The lesion appears to be excised however even if this were not the case reexcision might not be necessary if this biopsy was considered representative of the lesion and especially if the patient were to be followed

bull Since mild dysplasia is not an independent risk factor for melanoma lesions of this type might be better given a descriptive name such as ldquolentiginous junctional nevusrdquo

bull It is important to distinguish these lesions from nevoid lentigo maligna which can also be characterized by slight degrees of cytologic atypia

bull This is an MPATH Category 1 lesion (no need for reexcision even if margins are positive)

Superficial Atypical Nevi

bull Nevi are important mainly in relation to melanoma

ndash Precursors ndash but risk for individual lesions is low (one in thousands)

ndash Risk markers ndash important mainly in high risk situations (patients with multiple atypical nevi family history high CSD etc)

ndash Simulants ndash important in everyday clinical decision-making

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14

Grading of atypia in nevi correlation with melanoma risk Arumi-Uria McNutt Finnerty 2003

bull Grading of nevi with architectural disorder (dysplastic nevi) involves architectural and cytological features

bull Grades of atypia are related to patient history of melanoma ndash personal history of melanoma present in 57 of 2504 patients with mild

81 of 1657 with moderate and 197 of 320 patients with severe atypia

bull Odds ratio as a measure of association between NAD and history of melanomandash 408 for severe versus mild ndash 281 for severe versus moderate and ndash 145 for moderate versus mild dysplasia

bull ldquoMelanoma risk is greater in persons whose nevi have higher grade histological atypiardquo

Dysplasia Grading Criteria helliphellip Arumi-Uria et al Mod Pathol 2003

Mild Moderate Severe

bull The clinically most atypical macular nevus was biopsied from 80 newly incident cases of melanoma and spouse controls

bull Histological dysplasia was assigned on a subjective 0-4 point scale by a 13-member panel of dermatopathologists (International Melanoma Pathology Group)

bull Subjects with panel ratings gt 1 had increased relative risk of melanoma

bull Odds ratio after adjustment for confounders = 399 95 CI 102-1571

bull kappa statistic was 028 for the panel histological diagnoses indicating poor interobserver reproducibilityndash Repeating study agreed but found size to be a good surrogatecorrelate for

atypiandash Evidence-based criteria for histologic dysplasia as a risk marker

5212018

15

Xiong Rabkin Piepkorn Barnhill et al JAAD 2014

ldquoGiven that measuring diameter tends to be more objective than grading dysplasia these results could provide increased consistency when assessing risk of melanoma among patients with dysplastic nevirdquo

Rabkin Piepkorn Barnhill et al JAAD

Mild Dysplasia

bull Poorly reproducible diagnosis (vs nevus)bull Not associated with melanoma riskbull Not a high risk precursorbull Not a strong simulant of melanomabull UNCERTAINTY vs Moderate dysplasia No dysplasia

bull Should be considered in the spectrum of banal nevi (junctional or compound nevus eg lentiginous junctional nevus)

bull Complete excision is not necessary even when margins are positive

bull TERM ldquoMILD DYSPLASIArdquo SHOULD NO LONGER BE USED

bull (Lentiginous) Junctional Nevus

lt 4 mm diameter

minimal cytologic atypia

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16

Moderate Dysplasia

bull Controversialbull Poorly reproducible diagnosis (vs mild severe)bull UNCERTAINTY vs Mild dysplasia MISbull Associated with melanoma riskbull Probably not a high risk precursorbull A weak simulant of melanoma (at least

histologically)

bull Complete excision is a consideration observation is an option

Severe Dysplasia

bull Reasonably reproducible diagnosis

bull UNCERTAINTY vs MIS

bull Associated with melanoma risk

bull Probably a high risk precursor

bull A strong simulant of melanoma (at least histologically)

bull Should be managed by complete excision and consideration of follow-up similar to MIS

Proposal for Grading Dysplasia

bull Junctionalcompound nevus

ndash Includes former mild dysplasia and ldquoClarkrsquos nevusrdquo

bull Low Grade Dysplasia (LGD)

ndash Former moderate dysplasia

bull High Grade Dysplasia (HGD)

ndash Former severe dysplasia

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17

Case 4

Part 2-2 5475Clinical Information

Please find enclosed slides on a 36-year-old male with multiple dysplastic nevi removed Reason for Consultation

I have also enclosed a prior pathology report of other lesions removed My diagnosis is compound melanocytic nevus with architectural disorder and moderate cytologic atypia However

I am concerned that this lesion may be severely dysplastic Would you recommend a reexcision procedure

bull Broadbull Symmetricbull Moderately cellular bull Poorly circumscribed

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18

bull Broadbull Symmetricbull Moderately

cellular bull Poorly

circumscribedbull Slight low

level pagetoid scatter

bull Moderate random atypia

bull Nuclear size 1-15x

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

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19

Your Diagnosis

Low Grade

High Grade

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription cannot assess less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis (Part 2 Case 3)

Skin back (M36) Compound nevus with moderate dysplasia completely excised see description and comment

OR Compound dysplastic nevus low grade

Comment bull Patient presents with multiple lesions some of which are

dysplastic nevi with moderate dysplasia bull Benign lesions with little or no potential for recurrence and no

potential for metastasis bull Periodic follow-up may be appropriate for this patient

especially if there are other clinically atypical nevi andor a family or personal history of melanoma

bull Although the lesion extends close to the specimen margin there is no essential indication for reexcision especially if the patient is to be followed

This is an MPATH DX Category 1 or perhaps Category 2 lesion depending on clinical correlation and preference

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20

Case 5

Part 2-3Clinical Information

A lesion from the back of a 54 year old manReason for consultation

The clinician was concerned about a melanoma but I favor a dysplastic nevus

Description

Very broad

Moderately cellular

Reasonably symmetrical

Uniformly elongated rete

Patchy infiltrate in dermis

5212018

21

5212018

22

bull Descriptionbull Very broad Moderate pagetoid scatter low

levelbull Moderately cellular Mild to moderate cytologic atypiabull Reasonably symmetrical Mild to moderate solar elastosisbull Uniformly elongated retebull Patchy infiltrate in dermis

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

23

Your Diagnosis

Low Grade

High Grade

Compound nevus with severe dysplasia(Severe architectural disorder moderate cytological atypia)

Feature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Cellularity high intermediate lower

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription common less common uncommon

Nested variable predominant predominant

Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate (1-15X) mild

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells Absent uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 5

bull Junctional nevus with severe melanocytic dysplasia completely excised see note

bull vs Junctional dysplastic nevus high grade

bull vs Intraepidermal atypical melanocytic proliferation (IAMPUS) cannot ro MISndash Diagnosis is based on ldquosevererdquo architectural features

(single cell predominance low level pagetoid scatter) with mild to moderate cytologic atypia

ndash MPATH-Dx Category III (consider excision with up to 5 mm margins if present at the margin)

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24

Next Case

Part 2-5 35728Clinical Information

An irregular pigmented lesion on the back of a 59 year old manReason for Consultation

Is this a nevoid melanoma

Broad focally highly cellular asymmetric diffuse fibroplasia and variably sized nests in dermis

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25

bull Only minimal pagetoid scatter

bull Moderate cytologic atypia

bull No mitosesbull Cells in dermal

nests are small nevoid

bull No confluent sheetlike growth

HMB46 staining is ldquotop-heavyrdquo(stratified)

bull Ki-67 proliferation is minimal in dermis

5212018

26

bull p16 staining is positive in a checkerboard pattern with nuclear and cytoplasmic positivity

Helpful Markers in Nevus vs Melanoma

bull HM45 stratificationndash J Invest Dermatol 1993 Mar100(3)313S-317S Immunophenotyping of compound and spitz nevi and vertical growth-phase

melanomas using a panel of monoclonal antibodies reactive in paraffin sectionsLazzaro B1 Elder DE Rebers A Power L Herlyn M Menrad A Johnson B

bull Low Ki-67 proliferation ratendash A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions

Li LX Crotty KA McCarthy SW Palmer AA Kril JJAm J Dermatopathol 2000 Dec22(6)489-95

bull Preservation of p16 protein expressionndash More problematical presence in an atypical tumor at

least precludes homozygous loss of 9p21 and is therefore reassuring but does not preclude diagnosis of melanoma

9p21 Locus

bull Contains p16 p14 and p15 all suppressor genes

bull Presumably all lost together in cases of homozygous 9p21 loss

bull Appears to have special significance in Spitzoid lesions

5212018

2

Melanomas and Nevi

bull Nevi are important mainly in relation to melanomandash Precursors ndash but risk for individual lesions is low

ndash Risk markers ndash important mainly in high risk situations

ndash Simulants ndash important in everyday clinical decision-making

bull Makes sense to consider attributes of melanomas before discussing nevi

Low UV

Pathway I

Low-CSD MelanomaSupertpficial Spreading Melanoma

Banal Acquired Nevus (junctional compound dermal)

Low Grade Dysplasia Bap-1

Deficiency Melanocytoma

Deep penetrating

nevus (DPN) Melanocytoma

PigmentedEpithelioid

Melanocytoma (PEM)High Grade

Dysplasia

Superficial Spreading Melanoma

Melanoma in BPDM (rare)

Melanoma in DPN (rare)

Melanoma in PEM (rare)

BRAF V600E NRAS

(BRAF or NRAS)+BAP1

(BRAF MEK1 or NRAS) +(CBNN1 or APC)

(BRAF+PRKAR1A) or PRKCA

TERT CDKN2A TP53 PTEN

Lentiginous junctional nevus

Compound dysplastic nevus

Superficial spreading or ldquopagetoidrdquo melanoma

5212018

3

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed nevoid

Poor circumscription common less common uncommon

Nested variable predominant predominant

Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Superficial Melanoma and Mimics in Low CSD Skin

bull Superficial Spreading (ldquoPagetoidrdquo) Melanoma

bull Junctional and superficial Compound nevi

bull Dysplastic Nevi

bull Recurrent and Traumatized Nevi

bull Pagetoid Spitz and other pagetoid proliferatons

bull Superficial Atypical Melanocytic Proliferations (SAMPUS)

5212018

4

Case 1

DEE-10253

History M50 Lesion of BackReason for Consultation Is this a melanoma or a severely dysplastic nevus

bull Broad moderately to highly cellular asymmetric

bull Cells at periphery of lesion- predominantly in nests- predominantly near the DEJ - some nests bridging between adjacent elongated rete ridges

bull Pattern of melanocytic dysplasia with severe cytologic atypia and moderate architectural disorder

5212018

5

bull Adjacent component more highly cellular

bull More severe uniform atypia

bull Pagetoid scatterbull Diffuse fibroplasiabull Bandlike

lymphocytic infiltrate

bull Few clusters of immature cells in dermis

bull Adjacent component more highly cellular

bull More severe uniform atypia

bull Pagetoid scatterbull Diffuse fibroplasiabull Bandlike lymphocytic

infiltratebull Few clusters of

immature cells in dermis

bull Localized clusters of mature nevoid cells (precursorassociated nevus)

Your Diagnosis

Melanoma

Nevus

5212018

6

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed nevoid

Poor circumscription common less common uncommon

Distribution of Nests variable irregular predominant predominant regular

Pattern of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe (gt15x) mild-moderate

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 1 M50

bull Malignant melanoma superficial spreading type nonulcerated non-tumorigenic and nonmitogenic invasive radial growth phase only Clark level II greatest Breslow thickness 028 mm see comment

Commentndash Dermal mitotic rate is zero tumor infiltrating lymphocytes are absent (with

moderate noninfiltrating lymphocytes) there is no radial growth phase regression there is no ulcer there are no microscopic satellites and there is no evidence of vascular lymphatic or neural invasion

ndash Age lt 56ndash Associated compound dysplastic nevus ndash Appears to be minimally excised ndash MPATH-Dx 4 ndash 100 5 year survival

Case 2

Clinical InformationLesion of left shin with a mottled color in a 26-year-old woman

Reason for ConsultationI am enclosing for your consultation a melanocytic lesion

present for many years from the right shin of a 27-year-old woman Though the lesion had not changed (according to the patient) her clinician decided to remove it because he ldquodidnrsquot

like the mottled colorrdquo

5212018

7

Description

A relatively broad moderately cellular plaque-like lesion

Comprised mainly of nested large epithelioid melanocytes with abundant cytoplasm that contains finely divided ldquodustyrdquo melanin pigment

Some bridging nests between adjacent rete - possible junctional melanocytic dysplasia of the epithelioid type

bull Nests somewhat haphazardly distributed along the interface

bull Poor circumscription

bull Patchy to bandlike lymphocytic infiltrate

bull Diffuse fibroplasia

bull Nests somewhat haphazardly distributed along the interface

bull Poor circumscription

bull Patchy to bandlike lymphocytic infiltrate

bull Diffuse fibroplasia

5212018

8

bull Nests somewhat haphazardly distributed along the interface

bull Tendency to confluence of nests

bull Patchy to bandlike lymphocytic infiltrate

bull Diffuse fibroplasia

bull Nests somewhat haphazardly distributed along the interface

bull Nests in dermis not larger than largest in epidermis

bull Tendency to confluence of nests

bull Focal pagetoid scatter

Your Diagnosis

Melanoma

Nevus

5212018

9

1125 Dermal mitotic activity in atypical cells that resemble those in epidermis

The mitosis on the right could be considered junctional however there seems to be a wisp of collagen between the nest which is predominantly located in the dermis and the overlying junctional nest

Non tumorigenic mitogenic VGP

Nests in the dermis are smaller than the largest nests in the epidermisCount dermal mitoses in 1 sq mm even if not fully occupied by tumor express rate as a whole number

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed nevoid

Poor circumscription common less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe (gt15x) mild-moderate

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

5212018

10

Diagnosis Case 2 F26

bull Skin right shin Malignant melanoma superficial spreading type nonulcerated with non-tumorigenic but mitogenic early vertical growth phase Clarkrsquos level II greatest Breslow thickness 051 mm see description and comment

bull Comment Differential diagnosis could include severe dermal and epidermal melanocytic dysplasia however dermal (or even epidermal) mitotic activity essentially rules out this diagnosis The lesion is not a Spitz nevustumor because it is not comprised of large spindle andor epithelioid cells

bull Dermal mitotic rate 2 per square millimeterbull Tumor-infiltrating lymphocytes essentially absent in the invasive component with brisk

noninfiltrating lymphocytes nearbybull Focal radial growth phase regression presentbull No ulcer no microscopic satellites and no evidence of vascular lymphatic or neural invasionbull Associated junctional dysplastic nevus of the epithelioid subtypebull Actinic elastosis in the adjacent dermis is present and mild bull Lesion is completely excised with a closest border of approximately 1 mm

Superficial Melanoma and Mimics in Low CSD Skin

bull Superficial Spreading (ldquoPagetoidrdquo) Melanoma

bull Junctional and superficial Compound nevi

bull Dysplastic Nevi

bull Recurrent and Traumatized Nevi

bull Pagetoid Spitz and other pagetoid proliferations

bull Superficial Atypical Melanocytic Proliferations (SAMPUS)

Case 3

Clinical InformationA macular slightly variegated lesion from the back of a 37-year-old

womanReason for ConsultationIs this a dysplastic nevus

5212018

11

bull 25451bull Clinical Informationbull A 3 mm macular slightly variegated lesion from the back of a 37-year-old

womanbull Reason for Consultationbull Is this a dysplastic nevus

bull Smallbull Poorly circumscribedbull Nest predominate discretebull Patchy lymphocytes scant fibroplasia numerous melanophages (clinically

atypical)

5212018

12

bull Slightabsent cytologic atypia

bull No mitoses

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

13

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed nevoid

Poor circumscription cannot assess less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 2-1 F37

bull Diagnosisbull Skin abdomen bull Lentiginous junctional nevus with mild dysplasia see description and commentbull OR Lentiginous junctional nevus

bull Comment bull Mild dysplasia is not an independent risk factor for melanoma however if this patient should

have other clinically atypical nevi andor a family or personal history of melanoma or other melanoma risk factors consideration of periodic surveillance may be appropriate

bull The lesion appears to be excised however even if this were not the case reexcision might not be necessary if this biopsy was considered representative of the lesion and especially if the patient were to be followed

bull Since mild dysplasia is not an independent risk factor for melanoma lesions of this type might be better given a descriptive name such as ldquolentiginous junctional nevusrdquo

bull It is important to distinguish these lesions from nevoid lentigo maligna which can also be characterized by slight degrees of cytologic atypia

bull This is an MPATH Category 1 lesion (no need for reexcision even if margins are positive)

Superficial Atypical Nevi

bull Nevi are important mainly in relation to melanoma

ndash Precursors ndash but risk for individual lesions is low (one in thousands)

ndash Risk markers ndash important mainly in high risk situations (patients with multiple atypical nevi family history high CSD etc)

ndash Simulants ndash important in everyday clinical decision-making

5212018

14

Grading of atypia in nevi correlation with melanoma risk Arumi-Uria McNutt Finnerty 2003

bull Grading of nevi with architectural disorder (dysplastic nevi) involves architectural and cytological features

bull Grades of atypia are related to patient history of melanoma ndash personal history of melanoma present in 57 of 2504 patients with mild

81 of 1657 with moderate and 197 of 320 patients with severe atypia

bull Odds ratio as a measure of association between NAD and history of melanomandash 408 for severe versus mild ndash 281 for severe versus moderate and ndash 145 for moderate versus mild dysplasia

bull ldquoMelanoma risk is greater in persons whose nevi have higher grade histological atypiardquo

Dysplasia Grading Criteria helliphellip Arumi-Uria et al Mod Pathol 2003

Mild Moderate Severe

bull The clinically most atypical macular nevus was biopsied from 80 newly incident cases of melanoma and spouse controls

bull Histological dysplasia was assigned on a subjective 0-4 point scale by a 13-member panel of dermatopathologists (International Melanoma Pathology Group)

bull Subjects with panel ratings gt 1 had increased relative risk of melanoma

bull Odds ratio after adjustment for confounders = 399 95 CI 102-1571

bull kappa statistic was 028 for the panel histological diagnoses indicating poor interobserver reproducibilityndash Repeating study agreed but found size to be a good surrogatecorrelate for

atypiandash Evidence-based criteria for histologic dysplasia as a risk marker

5212018

15

Xiong Rabkin Piepkorn Barnhill et al JAAD 2014

ldquoGiven that measuring diameter tends to be more objective than grading dysplasia these results could provide increased consistency when assessing risk of melanoma among patients with dysplastic nevirdquo

Rabkin Piepkorn Barnhill et al JAAD

Mild Dysplasia

bull Poorly reproducible diagnosis (vs nevus)bull Not associated with melanoma riskbull Not a high risk precursorbull Not a strong simulant of melanomabull UNCERTAINTY vs Moderate dysplasia No dysplasia

bull Should be considered in the spectrum of banal nevi (junctional or compound nevus eg lentiginous junctional nevus)

bull Complete excision is not necessary even when margins are positive

bull TERM ldquoMILD DYSPLASIArdquo SHOULD NO LONGER BE USED

bull (Lentiginous) Junctional Nevus

lt 4 mm diameter

minimal cytologic atypia

5212018

16

Moderate Dysplasia

bull Controversialbull Poorly reproducible diagnosis (vs mild severe)bull UNCERTAINTY vs Mild dysplasia MISbull Associated with melanoma riskbull Probably not a high risk precursorbull A weak simulant of melanoma (at least

histologically)

bull Complete excision is a consideration observation is an option

Severe Dysplasia

bull Reasonably reproducible diagnosis

bull UNCERTAINTY vs MIS

bull Associated with melanoma risk

bull Probably a high risk precursor

bull A strong simulant of melanoma (at least histologically)

bull Should be managed by complete excision and consideration of follow-up similar to MIS

Proposal for Grading Dysplasia

bull Junctionalcompound nevus

ndash Includes former mild dysplasia and ldquoClarkrsquos nevusrdquo

bull Low Grade Dysplasia (LGD)

ndash Former moderate dysplasia

bull High Grade Dysplasia (HGD)

ndash Former severe dysplasia

5212018

17

Case 4

Part 2-2 5475Clinical Information

Please find enclosed slides on a 36-year-old male with multiple dysplastic nevi removed Reason for Consultation

I have also enclosed a prior pathology report of other lesions removed My diagnosis is compound melanocytic nevus with architectural disorder and moderate cytologic atypia However

I am concerned that this lesion may be severely dysplastic Would you recommend a reexcision procedure

bull Broadbull Symmetricbull Moderately cellular bull Poorly circumscribed

5212018

18

bull Broadbull Symmetricbull Moderately

cellular bull Poorly

circumscribedbull Slight low

level pagetoid scatter

bull Moderate random atypia

bull Nuclear size 1-15x

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

19

Your Diagnosis

Low Grade

High Grade

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription cannot assess less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis (Part 2 Case 3)

Skin back (M36) Compound nevus with moderate dysplasia completely excised see description and comment

OR Compound dysplastic nevus low grade

Comment bull Patient presents with multiple lesions some of which are

dysplastic nevi with moderate dysplasia bull Benign lesions with little or no potential for recurrence and no

potential for metastasis bull Periodic follow-up may be appropriate for this patient

especially if there are other clinically atypical nevi andor a family or personal history of melanoma

bull Although the lesion extends close to the specimen margin there is no essential indication for reexcision especially if the patient is to be followed

This is an MPATH DX Category 1 or perhaps Category 2 lesion depending on clinical correlation and preference

5212018

20

Case 5

Part 2-3Clinical Information

A lesion from the back of a 54 year old manReason for consultation

The clinician was concerned about a melanoma but I favor a dysplastic nevus

Description

Very broad

Moderately cellular

Reasonably symmetrical

Uniformly elongated rete

Patchy infiltrate in dermis

5212018

21

5212018

22

bull Descriptionbull Very broad Moderate pagetoid scatter low

levelbull Moderately cellular Mild to moderate cytologic atypiabull Reasonably symmetrical Mild to moderate solar elastosisbull Uniformly elongated retebull Patchy infiltrate in dermis

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

23

Your Diagnosis

Low Grade

High Grade

Compound nevus with severe dysplasia(Severe architectural disorder moderate cytological atypia)

Feature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Cellularity high intermediate lower

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription common less common uncommon

Nested variable predominant predominant

Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate (1-15X) mild

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells Absent uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 5

bull Junctional nevus with severe melanocytic dysplasia completely excised see note

bull vs Junctional dysplastic nevus high grade

bull vs Intraepidermal atypical melanocytic proliferation (IAMPUS) cannot ro MISndash Diagnosis is based on ldquosevererdquo architectural features

(single cell predominance low level pagetoid scatter) with mild to moderate cytologic atypia

ndash MPATH-Dx Category III (consider excision with up to 5 mm margins if present at the margin)

5212018

24

Next Case

Part 2-5 35728Clinical Information

An irregular pigmented lesion on the back of a 59 year old manReason for Consultation

Is this a nevoid melanoma

Broad focally highly cellular asymmetric diffuse fibroplasia and variably sized nests in dermis

5212018

25

bull Only minimal pagetoid scatter

bull Moderate cytologic atypia

bull No mitosesbull Cells in dermal

nests are small nevoid

bull No confluent sheetlike growth

HMB46 staining is ldquotop-heavyrdquo(stratified)

bull Ki-67 proliferation is minimal in dermis

5212018

26

bull p16 staining is positive in a checkerboard pattern with nuclear and cytoplasmic positivity

Helpful Markers in Nevus vs Melanoma

bull HM45 stratificationndash J Invest Dermatol 1993 Mar100(3)313S-317S Immunophenotyping of compound and spitz nevi and vertical growth-phase

melanomas using a panel of monoclonal antibodies reactive in paraffin sectionsLazzaro B1 Elder DE Rebers A Power L Herlyn M Menrad A Johnson B

bull Low Ki-67 proliferation ratendash A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions

Li LX Crotty KA McCarthy SW Palmer AA Kril JJAm J Dermatopathol 2000 Dec22(6)489-95

bull Preservation of p16 protein expressionndash More problematical presence in an atypical tumor at

least precludes homozygous loss of 9p21 and is therefore reassuring but does not preclude diagnosis of melanoma

9p21 Locus

bull Contains p16 p14 and p15 all suppressor genes

bull Presumably all lost together in cases of homozygous 9p21 loss

bull Appears to have special significance in Spitzoid lesions

5212018

3

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed nevoid

Poor circumscription common less common uncommon

Nested variable predominant predominant

Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Superficial Melanoma and Mimics in Low CSD Skin

bull Superficial Spreading (ldquoPagetoidrdquo) Melanoma

bull Junctional and superficial Compound nevi

bull Dysplastic Nevi

bull Recurrent and Traumatized Nevi

bull Pagetoid Spitz and other pagetoid proliferatons

bull Superficial Atypical Melanocytic Proliferations (SAMPUS)

5212018

4

Case 1

DEE-10253

History M50 Lesion of BackReason for Consultation Is this a melanoma or a severely dysplastic nevus

bull Broad moderately to highly cellular asymmetric

bull Cells at periphery of lesion- predominantly in nests- predominantly near the DEJ - some nests bridging between adjacent elongated rete ridges

bull Pattern of melanocytic dysplasia with severe cytologic atypia and moderate architectural disorder

5212018

5

bull Adjacent component more highly cellular

bull More severe uniform atypia

bull Pagetoid scatterbull Diffuse fibroplasiabull Bandlike

lymphocytic infiltrate

bull Few clusters of immature cells in dermis

bull Adjacent component more highly cellular

bull More severe uniform atypia

bull Pagetoid scatterbull Diffuse fibroplasiabull Bandlike lymphocytic

infiltratebull Few clusters of

immature cells in dermis

bull Localized clusters of mature nevoid cells (precursorassociated nevus)

Your Diagnosis

Melanoma

Nevus

5212018

6

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed nevoid

Poor circumscription common less common uncommon

Distribution of Nests variable irregular predominant predominant regular

Pattern of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe (gt15x) mild-moderate

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 1 M50

bull Malignant melanoma superficial spreading type nonulcerated non-tumorigenic and nonmitogenic invasive radial growth phase only Clark level II greatest Breslow thickness 028 mm see comment

Commentndash Dermal mitotic rate is zero tumor infiltrating lymphocytes are absent (with

moderate noninfiltrating lymphocytes) there is no radial growth phase regression there is no ulcer there are no microscopic satellites and there is no evidence of vascular lymphatic or neural invasion

ndash Age lt 56ndash Associated compound dysplastic nevus ndash Appears to be minimally excised ndash MPATH-Dx 4 ndash 100 5 year survival

Case 2

Clinical InformationLesion of left shin with a mottled color in a 26-year-old woman

Reason for ConsultationI am enclosing for your consultation a melanocytic lesion

present for many years from the right shin of a 27-year-old woman Though the lesion had not changed (according to the patient) her clinician decided to remove it because he ldquodidnrsquot

like the mottled colorrdquo

5212018

7

Description

A relatively broad moderately cellular plaque-like lesion

Comprised mainly of nested large epithelioid melanocytes with abundant cytoplasm that contains finely divided ldquodustyrdquo melanin pigment

Some bridging nests between adjacent rete - possible junctional melanocytic dysplasia of the epithelioid type

bull Nests somewhat haphazardly distributed along the interface

bull Poor circumscription

bull Patchy to bandlike lymphocytic infiltrate

bull Diffuse fibroplasia

bull Nests somewhat haphazardly distributed along the interface

bull Poor circumscription

bull Patchy to bandlike lymphocytic infiltrate

bull Diffuse fibroplasia

5212018

8

bull Nests somewhat haphazardly distributed along the interface

bull Tendency to confluence of nests

bull Patchy to bandlike lymphocytic infiltrate

bull Diffuse fibroplasia

bull Nests somewhat haphazardly distributed along the interface

bull Nests in dermis not larger than largest in epidermis

bull Tendency to confluence of nests

bull Focal pagetoid scatter

Your Diagnosis

Melanoma

Nevus

5212018

9

1125 Dermal mitotic activity in atypical cells that resemble those in epidermis

The mitosis on the right could be considered junctional however there seems to be a wisp of collagen between the nest which is predominantly located in the dermis and the overlying junctional nest

Non tumorigenic mitogenic VGP

Nests in the dermis are smaller than the largest nests in the epidermisCount dermal mitoses in 1 sq mm even if not fully occupied by tumor express rate as a whole number

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed nevoid

Poor circumscription common less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe (gt15x) mild-moderate

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

5212018

10

Diagnosis Case 2 F26

bull Skin right shin Malignant melanoma superficial spreading type nonulcerated with non-tumorigenic but mitogenic early vertical growth phase Clarkrsquos level II greatest Breslow thickness 051 mm see description and comment

bull Comment Differential diagnosis could include severe dermal and epidermal melanocytic dysplasia however dermal (or even epidermal) mitotic activity essentially rules out this diagnosis The lesion is not a Spitz nevustumor because it is not comprised of large spindle andor epithelioid cells

bull Dermal mitotic rate 2 per square millimeterbull Tumor-infiltrating lymphocytes essentially absent in the invasive component with brisk

noninfiltrating lymphocytes nearbybull Focal radial growth phase regression presentbull No ulcer no microscopic satellites and no evidence of vascular lymphatic or neural invasionbull Associated junctional dysplastic nevus of the epithelioid subtypebull Actinic elastosis in the adjacent dermis is present and mild bull Lesion is completely excised with a closest border of approximately 1 mm

Superficial Melanoma and Mimics in Low CSD Skin

bull Superficial Spreading (ldquoPagetoidrdquo) Melanoma

bull Junctional and superficial Compound nevi

bull Dysplastic Nevi

bull Recurrent and Traumatized Nevi

bull Pagetoid Spitz and other pagetoid proliferations

bull Superficial Atypical Melanocytic Proliferations (SAMPUS)

Case 3

Clinical InformationA macular slightly variegated lesion from the back of a 37-year-old

womanReason for ConsultationIs this a dysplastic nevus

5212018

11

bull 25451bull Clinical Informationbull A 3 mm macular slightly variegated lesion from the back of a 37-year-old

womanbull Reason for Consultationbull Is this a dysplastic nevus

bull Smallbull Poorly circumscribedbull Nest predominate discretebull Patchy lymphocytes scant fibroplasia numerous melanophages (clinically

atypical)

5212018

12

bull Slightabsent cytologic atypia

bull No mitoses

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

13

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed nevoid

Poor circumscription cannot assess less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 2-1 F37

bull Diagnosisbull Skin abdomen bull Lentiginous junctional nevus with mild dysplasia see description and commentbull OR Lentiginous junctional nevus

bull Comment bull Mild dysplasia is not an independent risk factor for melanoma however if this patient should

have other clinically atypical nevi andor a family or personal history of melanoma or other melanoma risk factors consideration of periodic surveillance may be appropriate

bull The lesion appears to be excised however even if this were not the case reexcision might not be necessary if this biopsy was considered representative of the lesion and especially if the patient were to be followed

bull Since mild dysplasia is not an independent risk factor for melanoma lesions of this type might be better given a descriptive name such as ldquolentiginous junctional nevusrdquo

bull It is important to distinguish these lesions from nevoid lentigo maligna which can also be characterized by slight degrees of cytologic atypia

bull This is an MPATH Category 1 lesion (no need for reexcision even if margins are positive)

Superficial Atypical Nevi

bull Nevi are important mainly in relation to melanoma

ndash Precursors ndash but risk for individual lesions is low (one in thousands)

ndash Risk markers ndash important mainly in high risk situations (patients with multiple atypical nevi family history high CSD etc)

ndash Simulants ndash important in everyday clinical decision-making

5212018

14

Grading of atypia in nevi correlation with melanoma risk Arumi-Uria McNutt Finnerty 2003

bull Grading of nevi with architectural disorder (dysplastic nevi) involves architectural and cytological features

bull Grades of atypia are related to patient history of melanoma ndash personal history of melanoma present in 57 of 2504 patients with mild

81 of 1657 with moderate and 197 of 320 patients with severe atypia

bull Odds ratio as a measure of association between NAD and history of melanomandash 408 for severe versus mild ndash 281 for severe versus moderate and ndash 145 for moderate versus mild dysplasia

bull ldquoMelanoma risk is greater in persons whose nevi have higher grade histological atypiardquo

Dysplasia Grading Criteria helliphellip Arumi-Uria et al Mod Pathol 2003

Mild Moderate Severe

bull The clinically most atypical macular nevus was biopsied from 80 newly incident cases of melanoma and spouse controls

bull Histological dysplasia was assigned on a subjective 0-4 point scale by a 13-member panel of dermatopathologists (International Melanoma Pathology Group)

bull Subjects with panel ratings gt 1 had increased relative risk of melanoma

bull Odds ratio after adjustment for confounders = 399 95 CI 102-1571

bull kappa statistic was 028 for the panel histological diagnoses indicating poor interobserver reproducibilityndash Repeating study agreed but found size to be a good surrogatecorrelate for

atypiandash Evidence-based criteria for histologic dysplasia as a risk marker

5212018

15

Xiong Rabkin Piepkorn Barnhill et al JAAD 2014

ldquoGiven that measuring diameter tends to be more objective than grading dysplasia these results could provide increased consistency when assessing risk of melanoma among patients with dysplastic nevirdquo

Rabkin Piepkorn Barnhill et al JAAD

Mild Dysplasia

bull Poorly reproducible diagnosis (vs nevus)bull Not associated with melanoma riskbull Not a high risk precursorbull Not a strong simulant of melanomabull UNCERTAINTY vs Moderate dysplasia No dysplasia

bull Should be considered in the spectrum of banal nevi (junctional or compound nevus eg lentiginous junctional nevus)

bull Complete excision is not necessary even when margins are positive

bull TERM ldquoMILD DYSPLASIArdquo SHOULD NO LONGER BE USED

bull (Lentiginous) Junctional Nevus

lt 4 mm diameter

minimal cytologic atypia

5212018

16

Moderate Dysplasia

bull Controversialbull Poorly reproducible diagnosis (vs mild severe)bull UNCERTAINTY vs Mild dysplasia MISbull Associated with melanoma riskbull Probably not a high risk precursorbull A weak simulant of melanoma (at least

histologically)

bull Complete excision is a consideration observation is an option

Severe Dysplasia

bull Reasonably reproducible diagnosis

bull UNCERTAINTY vs MIS

bull Associated with melanoma risk

bull Probably a high risk precursor

bull A strong simulant of melanoma (at least histologically)

bull Should be managed by complete excision and consideration of follow-up similar to MIS

Proposal for Grading Dysplasia

bull Junctionalcompound nevus

ndash Includes former mild dysplasia and ldquoClarkrsquos nevusrdquo

bull Low Grade Dysplasia (LGD)

ndash Former moderate dysplasia

bull High Grade Dysplasia (HGD)

ndash Former severe dysplasia

5212018

17

Case 4

Part 2-2 5475Clinical Information

Please find enclosed slides on a 36-year-old male with multiple dysplastic nevi removed Reason for Consultation

I have also enclosed a prior pathology report of other lesions removed My diagnosis is compound melanocytic nevus with architectural disorder and moderate cytologic atypia However

I am concerned that this lesion may be severely dysplastic Would you recommend a reexcision procedure

bull Broadbull Symmetricbull Moderately cellular bull Poorly circumscribed

5212018

18

bull Broadbull Symmetricbull Moderately

cellular bull Poorly

circumscribedbull Slight low

level pagetoid scatter

bull Moderate random atypia

bull Nuclear size 1-15x

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

19

Your Diagnosis

Low Grade

High Grade

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription cannot assess less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis (Part 2 Case 3)

Skin back (M36) Compound nevus with moderate dysplasia completely excised see description and comment

OR Compound dysplastic nevus low grade

Comment bull Patient presents with multiple lesions some of which are

dysplastic nevi with moderate dysplasia bull Benign lesions with little or no potential for recurrence and no

potential for metastasis bull Periodic follow-up may be appropriate for this patient

especially if there are other clinically atypical nevi andor a family or personal history of melanoma

bull Although the lesion extends close to the specimen margin there is no essential indication for reexcision especially if the patient is to be followed

This is an MPATH DX Category 1 or perhaps Category 2 lesion depending on clinical correlation and preference

5212018

20

Case 5

Part 2-3Clinical Information

A lesion from the back of a 54 year old manReason for consultation

The clinician was concerned about a melanoma but I favor a dysplastic nevus

Description

Very broad

Moderately cellular

Reasonably symmetrical

Uniformly elongated rete

Patchy infiltrate in dermis

5212018

21

5212018

22

bull Descriptionbull Very broad Moderate pagetoid scatter low

levelbull Moderately cellular Mild to moderate cytologic atypiabull Reasonably symmetrical Mild to moderate solar elastosisbull Uniformly elongated retebull Patchy infiltrate in dermis

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

23

Your Diagnosis

Low Grade

High Grade

Compound nevus with severe dysplasia(Severe architectural disorder moderate cytological atypia)

Feature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Cellularity high intermediate lower

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription common less common uncommon

Nested variable predominant predominant

Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate (1-15X) mild

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells Absent uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 5

bull Junctional nevus with severe melanocytic dysplasia completely excised see note

bull vs Junctional dysplastic nevus high grade

bull vs Intraepidermal atypical melanocytic proliferation (IAMPUS) cannot ro MISndash Diagnosis is based on ldquosevererdquo architectural features

(single cell predominance low level pagetoid scatter) with mild to moderate cytologic atypia

ndash MPATH-Dx Category III (consider excision with up to 5 mm margins if present at the margin)

5212018

24

Next Case

Part 2-5 35728Clinical Information

An irregular pigmented lesion on the back of a 59 year old manReason for Consultation

Is this a nevoid melanoma

Broad focally highly cellular asymmetric diffuse fibroplasia and variably sized nests in dermis

5212018

25

bull Only minimal pagetoid scatter

bull Moderate cytologic atypia

bull No mitosesbull Cells in dermal

nests are small nevoid

bull No confluent sheetlike growth

HMB46 staining is ldquotop-heavyrdquo(stratified)

bull Ki-67 proliferation is minimal in dermis

5212018

26

bull p16 staining is positive in a checkerboard pattern with nuclear and cytoplasmic positivity

Helpful Markers in Nevus vs Melanoma

bull HM45 stratificationndash J Invest Dermatol 1993 Mar100(3)313S-317S Immunophenotyping of compound and spitz nevi and vertical growth-phase

melanomas using a panel of monoclonal antibodies reactive in paraffin sectionsLazzaro B1 Elder DE Rebers A Power L Herlyn M Menrad A Johnson B

bull Low Ki-67 proliferation ratendash A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions

Li LX Crotty KA McCarthy SW Palmer AA Kril JJAm J Dermatopathol 2000 Dec22(6)489-95

bull Preservation of p16 protein expressionndash More problematical presence in an atypical tumor at

least precludes homozygous loss of 9p21 and is therefore reassuring but does not preclude diagnosis of melanoma

9p21 Locus

bull Contains p16 p14 and p15 all suppressor genes

bull Presumably all lost together in cases of homozygous 9p21 loss

bull Appears to have special significance in Spitzoid lesions

5212018

4

Case 1

DEE-10253

History M50 Lesion of BackReason for Consultation Is this a melanoma or a severely dysplastic nevus

bull Broad moderately to highly cellular asymmetric

bull Cells at periphery of lesion- predominantly in nests- predominantly near the DEJ - some nests bridging between adjacent elongated rete ridges

bull Pattern of melanocytic dysplasia with severe cytologic atypia and moderate architectural disorder

5212018

5

bull Adjacent component more highly cellular

bull More severe uniform atypia

bull Pagetoid scatterbull Diffuse fibroplasiabull Bandlike

lymphocytic infiltrate

bull Few clusters of immature cells in dermis

bull Adjacent component more highly cellular

bull More severe uniform atypia

bull Pagetoid scatterbull Diffuse fibroplasiabull Bandlike lymphocytic

infiltratebull Few clusters of

immature cells in dermis

bull Localized clusters of mature nevoid cells (precursorassociated nevus)

Your Diagnosis

Melanoma

Nevus

5212018

6

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed nevoid

Poor circumscription common less common uncommon

Distribution of Nests variable irregular predominant predominant regular

Pattern of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe (gt15x) mild-moderate

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 1 M50

bull Malignant melanoma superficial spreading type nonulcerated non-tumorigenic and nonmitogenic invasive radial growth phase only Clark level II greatest Breslow thickness 028 mm see comment

Commentndash Dermal mitotic rate is zero tumor infiltrating lymphocytes are absent (with

moderate noninfiltrating lymphocytes) there is no radial growth phase regression there is no ulcer there are no microscopic satellites and there is no evidence of vascular lymphatic or neural invasion

ndash Age lt 56ndash Associated compound dysplastic nevus ndash Appears to be minimally excised ndash MPATH-Dx 4 ndash 100 5 year survival

Case 2

Clinical InformationLesion of left shin with a mottled color in a 26-year-old woman

Reason for ConsultationI am enclosing for your consultation a melanocytic lesion

present for many years from the right shin of a 27-year-old woman Though the lesion had not changed (according to the patient) her clinician decided to remove it because he ldquodidnrsquot

like the mottled colorrdquo

5212018

7

Description

A relatively broad moderately cellular plaque-like lesion

Comprised mainly of nested large epithelioid melanocytes with abundant cytoplasm that contains finely divided ldquodustyrdquo melanin pigment

Some bridging nests between adjacent rete - possible junctional melanocytic dysplasia of the epithelioid type

bull Nests somewhat haphazardly distributed along the interface

bull Poor circumscription

bull Patchy to bandlike lymphocytic infiltrate

bull Diffuse fibroplasia

bull Nests somewhat haphazardly distributed along the interface

bull Poor circumscription

bull Patchy to bandlike lymphocytic infiltrate

bull Diffuse fibroplasia

5212018

8

bull Nests somewhat haphazardly distributed along the interface

bull Tendency to confluence of nests

bull Patchy to bandlike lymphocytic infiltrate

bull Diffuse fibroplasia

bull Nests somewhat haphazardly distributed along the interface

bull Nests in dermis not larger than largest in epidermis

bull Tendency to confluence of nests

bull Focal pagetoid scatter

Your Diagnosis

Melanoma

Nevus

5212018

9

1125 Dermal mitotic activity in atypical cells that resemble those in epidermis

The mitosis on the right could be considered junctional however there seems to be a wisp of collagen between the nest which is predominantly located in the dermis and the overlying junctional nest

Non tumorigenic mitogenic VGP

Nests in the dermis are smaller than the largest nests in the epidermisCount dermal mitoses in 1 sq mm even if not fully occupied by tumor express rate as a whole number

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed nevoid

Poor circumscription common less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe (gt15x) mild-moderate

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

5212018

10

Diagnosis Case 2 F26

bull Skin right shin Malignant melanoma superficial spreading type nonulcerated with non-tumorigenic but mitogenic early vertical growth phase Clarkrsquos level II greatest Breslow thickness 051 mm see description and comment

bull Comment Differential diagnosis could include severe dermal and epidermal melanocytic dysplasia however dermal (or even epidermal) mitotic activity essentially rules out this diagnosis The lesion is not a Spitz nevustumor because it is not comprised of large spindle andor epithelioid cells

bull Dermal mitotic rate 2 per square millimeterbull Tumor-infiltrating lymphocytes essentially absent in the invasive component with brisk

noninfiltrating lymphocytes nearbybull Focal radial growth phase regression presentbull No ulcer no microscopic satellites and no evidence of vascular lymphatic or neural invasionbull Associated junctional dysplastic nevus of the epithelioid subtypebull Actinic elastosis in the adjacent dermis is present and mild bull Lesion is completely excised with a closest border of approximately 1 mm

Superficial Melanoma and Mimics in Low CSD Skin

bull Superficial Spreading (ldquoPagetoidrdquo) Melanoma

bull Junctional and superficial Compound nevi

bull Dysplastic Nevi

bull Recurrent and Traumatized Nevi

bull Pagetoid Spitz and other pagetoid proliferations

bull Superficial Atypical Melanocytic Proliferations (SAMPUS)

Case 3

Clinical InformationA macular slightly variegated lesion from the back of a 37-year-old

womanReason for ConsultationIs this a dysplastic nevus

5212018

11

bull 25451bull Clinical Informationbull A 3 mm macular slightly variegated lesion from the back of a 37-year-old

womanbull Reason for Consultationbull Is this a dysplastic nevus

bull Smallbull Poorly circumscribedbull Nest predominate discretebull Patchy lymphocytes scant fibroplasia numerous melanophages (clinically

atypical)

5212018

12

bull Slightabsent cytologic atypia

bull No mitoses

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

13

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed nevoid

Poor circumscription cannot assess less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 2-1 F37

bull Diagnosisbull Skin abdomen bull Lentiginous junctional nevus with mild dysplasia see description and commentbull OR Lentiginous junctional nevus

bull Comment bull Mild dysplasia is not an independent risk factor for melanoma however if this patient should

have other clinically atypical nevi andor a family or personal history of melanoma or other melanoma risk factors consideration of periodic surveillance may be appropriate

bull The lesion appears to be excised however even if this were not the case reexcision might not be necessary if this biopsy was considered representative of the lesion and especially if the patient were to be followed

bull Since mild dysplasia is not an independent risk factor for melanoma lesions of this type might be better given a descriptive name such as ldquolentiginous junctional nevusrdquo

bull It is important to distinguish these lesions from nevoid lentigo maligna which can also be characterized by slight degrees of cytologic atypia

bull This is an MPATH Category 1 lesion (no need for reexcision even if margins are positive)

Superficial Atypical Nevi

bull Nevi are important mainly in relation to melanoma

ndash Precursors ndash but risk for individual lesions is low (one in thousands)

ndash Risk markers ndash important mainly in high risk situations (patients with multiple atypical nevi family history high CSD etc)

ndash Simulants ndash important in everyday clinical decision-making

5212018

14

Grading of atypia in nevi correlation with melanoma risk Arumi-Uria McNutt Finnerty 2003

bull Grading of nevi with architectural disorder (dysplastic nevi) involves architectural and cytological features

bull Grades of atypia are related to patient history of melanoma ndash personal history of melanoma present in 57 of 2504 patients with mild

81 of 1657 with moderate and 197 of 320 patients with severe atypia

bull Odds ratio as a measure of association between NAD and history of melanomandash 408 for severe versus mild ndash 281 for severe versus moderate and ndash 145 for moderate versus mild dysplasia

bull ldquoMelanoma risk is greater in persons whose nevi have higher grade histological atypiardquo

Dysplasia Grading Criteria helliphellip Arumi-Uria et al Mod Pathol 2003

Mild Moderate Severe

bull The clinically most atypical macular nevus was biopsied from 80 newly incident cases of melanoma and spouse controls

bull Histological dysplasia was assigned on a subjective 0-4 point scale by a 13-member panel of dermatopathologists (International Melanoma Pathology Group)

bull Subjects with panel ratings gt 1 had increased relative risk of melanoma

bull Odds ratio after adjustment for confounders = 399 95 CI 102-1571

bull kappa statistic was 028 for the panel histological diagnoses indicating poor interobserver reproducibilityndash Repeating study agreed but found size to be a good surrogatecorrelate for

atypiandash Evidence-based criteria for histologic dysplasia as a risk marker

5212018

15

Xiong Rabkin Piepkorn Barnhill et al JAAD 2014

ldquoGiven that measuring diameter tends to be more objective than grading dysplasia these results could provide increased consistency when assessing risk of melanoma among patients with dysplastic nevirdquo

Rabkin Piepkorn Barnhill et al JAAD

Mild Dysplasia

bull Poorly reproducible diagnosis (vs nevus)bull Not associated with melanoma riskbull Not a high risk precursorbull Not a strong simulant of melanomabull UNCERTAINTY vs Moderate dysplasia No dysplasia

bull Should be considered in the spectrum of banal nevi (junctional or compound nevus eg lentiginous junctional nevus)

bull Complete excision is not necessary even when margins are positive

bull TERM ldquoMILD DYSPLASIArdquo SHOULD NO LONGER BE USED

bull (Lentiginous) Junctional Nevus

lt 4 mm diameter

minimal cytologic atypia

5212018

16

Moderate Dysplasia

bull Controversialbull Poorly reproducible diagnosis (vs mild severe)bull UNCERTAINTY vs Mild dysplasia MISbull Associated with melanoma riskbull Probably not a high risk precursorbull A weak simulant of melanoma (at least

histologically)

bull Complete excision is a consideration observation is an option

Severe Dysplasia

bull Reasonably reproducible diagnosis

bull UNCERTAINTY vs MIS

bull Associated with melanoma risk

bull Probably a high risk precursor

bull A strong simulant of melanoma (at least histologically)

bull Should be managed by complete excision and consideration of follow-up similar to MIS

Proposal for Grading Dysplasia

bull Junctionalcompound nevus

ndash Includes former mild dysplasia and ldquoClarkrsquos nevusrdquo

bull Low Grade Dysplasia (LGD)

ndash Former moderate dysplasia

bull High Grade Dysplasia (HGD)

ndash Former severe dysplasia

5212018

17

Case 4

Part 2-2 5475Clinical Information

Please find enclosed slides on a 36-year-old male with multiple dysplastic nevi removed Reason for Consultation

I have also enclosed a prior pathology report of other lesions removed My diagnosis is compound melanocytic nevus with architectural disorder and moderate cytologic atypia However

I am concerned that this lesion may be severely dysplastic Would you recommend a reexcision procedure

bull Broadbull Symmetricbull Moderately cellular bull Poorly circumscribed

5212018

18

bull Broadbull Symmetricbull Moderately

cellular bull Poorly

circumscribedbull Slight low

level pagetoid scatter

bull Moderate random atypia

bull Nuclear size 1-15x

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

19

Your Diagnosis

Low Grade

High Grade

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription cannot assess less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis (Part 2 Case 3)

Skin back (M36) Compound nevus with moderate dysplasia completely excised see description and comment

OR Compound dysplastic nevus low grade

Comment bull Patient presents with multiple lesions some of which are

dysplastic nevi with moderate dysplasia bull Benign lesions with little or no potential for recurrence and no

potential for metastasis bull Periodic follow-up may be appropriate for this patient

especially if there are other clinically atypical nevi andor a family or personal history of melanoma

bull Although the lesion extends close to the specimen margin there is no essential indication for reexcision especially if the patient is to be followed

This is an MPATH DX Category 1 or perhaps Category 2 lesion depending on clinical correlation and preference

5212018

20

Case 5

Part 2-3Clinical Information

A lesion from the back of a 54 year old manReason for consultation

The clinician was concerned about a melanoma but I favor a dysplastic nevus

Description

Very broad

Moderately cellular

Reasonably symmetrical

Uniformly elongated rete

Patchy infiltrate in dermis

5212018

21

5212018

22

bull Descriptionbull Very broad Moderate pagetoid scatter low

levelbull Moderately cellular Mild to moderate cytologic atypiabull Reasonably symmetrical Mild to moderate solar elastosisbull Uniformly elongated retebull Patchy infiltrate in dermis

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

23

Your Diagnosis

Low Grade

High Grade

Compound nevus with severe dysplasia(Severe architectural disorder moderate cytological atypia)

Feature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Cellularity high intermediate lower

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription common less common uncommon

Nested variable predominant predominant

Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate (1-15X) mild

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells Absent uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 5

bull Junctional nevus with severe melanocytic dysplasia completely excised see note

bull vs Junctional dysplastic nevus high grade

bull vs Intraepidermal atypical melanocytic proliferation (IAMPUS) cannot ro MISndash Diagnosis is based on ldquosevererdquo architectural features

(single cell predominance low level pagetoid scatter) with mild to moderate cytologic atypia

ndash MPATH-Dx Category III (consider excision with up to 5 mm margins if present at the margin)

5212018

24

Next Case

Part 2-5 35728Clinical Information

An irregular pigmented lesion on the back of a 59 year old manReason for Consultation

Is this a nevoid melanoma

Broad focally highly cellular asymmetric diffuse fibroplasia and variably sized nests in dermis

5212018

25

bull Only minimal pagetoid scatter

bull Moderate cytologic atypia

bull No mitosesbull Cells in dermal

nests are small nevoid

bull No confluent sheetlike growth

HMB46 staining is ldquotop-heavyrdquo(stratified)

bull Ki-67 proliferation is minimal in dermis

5212018

26

bull p16 staining is positive in a checkerboard pattern with nuclear and cytoplasmic positivity

Helpful Markers in Nevus vs Melanoma

bull HM45 stratificationndash J Invest Dermatol 1993 Mar100(3)313S-317S Immunophenotyping of compound and spitz nevi and vertical growth-phase

melanomas using a panel of monoclonal antibodies reactive in paraffin sectionsLazzaro B1 Elder DE Rebers A Power L Herlyn M Menrad A Johnson B

bull Low Ki-67 proliferation ratendash A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions

Li LX Crotty KA McCarthy SW Palmer AA Kril JJAm J Dermatopathol 2000 Dec22(6)489-95

bull Preservation of p16 protein expressionndash More problematical presence in an atypical tumor at

least precludes homozygous loss of 9p21 and is therefore reassuring but does not preclude diagnosis of melanoma

9p21 Locus

bull Contains p16 p14 and p15 all suppressor genes

bull Presumably all lost together in cases of homozygous 9p21 loss

bull Appears to have special significance in Spitzoid lesions

5212018

5

bull Adjacent component more highly cellular

bull More severe uniform atypia

bull Pagetoid scatterbull Diffuse fibroplasiabull Bandlike

lymphocytic infiltrate

bull Few clusters of immature cells in dermis

bull Adjacent component more highly cellular

bull More severe uniform atypia

bull Pagetoid scatterbull Diffuse fibroplasiabull Bandlike lymphocytic

infiltratebull Few clusters of

immature cells in dermis

bull Localized clusters of mature nevoid cells (precursorassociated nevus)

Your Diagnosis

Melanoma

Nevus

5212018

6

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed nevoid

Poor circumscription common less common uncommon

Distribution of Nests variable irregular predominant predominant regular

Pattern of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe (gt15x) mild-moderate

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 1 M50

bull Malignant melanoma superficial spreading type nonulcerated non-tumorigenic and nonmitogenic invasive radial growth phase only Clark level II greatest Breslow thickness 028 mm see comment

Commentndash Dermal mitotic rate is zero tumor infiltrating lymphocytes are absent (with

moderate noninfiltrating lymphocytes) there is no radial growth phase regression there is no ulcer there are no microscopic satellites and there is no evidence of vascular lymphatic or neural invasion

ndash Age lt 56ndash Associated compound dysplastic nevus ndash Appears to be minimally excised ndash MPATH-Dx 4 ndash 100 5 year survival

Case 2

Clinical InformationLesion of left shin with a mottled color in a 26-year-old woman

Reason for ConsultationI am enclosing for your consultation a melanocytic lesion

present for many years from the right shin of a 27-year-old woman Though the lesion had not changed (according to the patient) her clinician decided to remove it because he ldquodidnrsquot

like the mottled colorrdquo

5212018

7

Description

A relatively broad moderately cellular plaque-like lesion

Comprised mainly of nested large epithelioid melanocytes with abundant cytoplasm that contains finely divided ldquodustyrdquo melanin pigment

Some bridging nests between adjacent rete - possible junctional melanocytic dysplasia of the epithelioid type

bull Nests somewhat haphazardly distributed along the interface

bull Poor circumscription

bull Patchy to bandlike lymphocytic infiltrate

bull Diffuse fibroplasia

bull Nests somewhat haphazardly distributed along the interface

bull Poor circumscription

bull Patchy to bandlike lymphocytic infiltrate

bull Diffuse fibroplasia

5212018

8

bull Nests somewhat haphazardly distributed along the interface

bull Tendency to confluence of nests

bull Patchy to bandlike lymphocytic infiltrate

bull Diffuse fibroplasia

bull Nests somewhat haphazardly distributed along the interface

bull Nests in dermis not larger than largest in epidermis

bull Tendency to confluence of nests

bull Focal pagetoid scatter

Your Diagnosis

Melanoma

Nevus

5212018

9

1125 Dermal mitotic activity in atypical cells that resemble those in epidermis

The mitosis on the right could be considered junctional however there seems to be a wisp of collagen between the nest which is predominantly located in the dermis and the overlying junctional nest

Non tumorigenic mitogenic VGP

Nests in the dermis are smaller than the largest nests in the epidermisCount dermal mitoses in 1 sq mm even if not fully occupied by tumor express rate as a whole number

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed nevoid

Poor circumscription common less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe (gt15x) mild-moderate

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

5212018

10

Diagnosis Case 2 F26

bull Skin right shin Malignant melanoma superficial spreading type nonulcerated with non-tumorigenic but mitogenic early vertical growth phase Clarkrsquos level II greatest Breslow thickness 051 mm see description and comment

bull Comment Differential diagnosis could include severe dermal and epidermal melanocytic dysplasia however dermal (or even epidermal) mitotic activity essentially rules out this diagnosis The lesion is not a Spitz nevustumor because it is not comprised of large spindle andor epithelioid cells

bull Dermal mitotic rate 2 per square millimeterbull Tumor-infiltrating lymphocytes essentially absent in the invasive component with brisk

noninfiltrating lymphocytes nearbybull Focal radial growth phase regression presentbull No ulcer no microscopic satellites and no evidence of vascular lymphatic or neural invasionbull Associated junctional dysplastic nevus of the epithelioid subtypebull Actinic elastosis in the adjacent dermis is present and mild bull Lesion is completely excised with a closest border of approximately 1 mm

Superficial Melanoma and Mimics in Low CSD Skin

bull Superficial Spreading (ldquoPagetoidrdquo) Melanoma

bull Junctional and superficial Compound nevi

bull Dysplastic Nevi

bull Recurrent and Traumatized Nevi

bull Pagetoid Spitz and other pagetoid proliferations

bull Superficial Atypical Melanocytic Proliferations (SAMPUS)

Case 3

Clinical InformationA macular slightly variegated lesion from the back of a 37-year-old

womanReason for ConsultationIs this a dysplastic nevus

5212018

11

bull 25451bull Clinical Informationbull A 3 mm macular slightly variegated lesion from the back of a 37-year-old

womanbull Reason for Consultationbull Is this a dysplastic nevus

bull Smallbull Poorly circumscribedbull Nest predominate discretebull Patchy lymphocytes scant fibroplasia numerous melanophages (clinically

atypical)

5212018

12

bull Slightabsent cytologic atypia

bull No mitoses

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

13

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed nevoid

Poor circumscription cannot assess less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 2-1 F37

bull Diagnosisbull Skin abdomen bull Lentiginous junctional nevus with mild dysplasia see description and commentbull OR Lentiginous junctional nevus

bull Comment bull Mild dysplasia is not an independent risk factor for melanoma however if this patient should

have other clinically atypical nevi andor a family or personal history of melanoma or other melanoma risk factors consideration of periodic surveillance may be appropriate

bull The lesion appears to be excised however even if this were not the case reexcision might not be necessary if this biopsy was considered representative of the lesion and especially if the patient were to be followed

bull Since mild dysplasia is not an independent risk factor for melanoma lesions of this type might be better given a descriptive name such as ldquolentiginous junctional nevusrdquo

bull It is important to distinguish these lesions from nevoid lentigo maligna which can also be characterized by slight degrees of cytologic atypia

bull This is an MPATH Category 1 lesion (no need for reexcision even if margins are positive)

Superficial Atypical Nevi

bull Nevi are important mainly in relation to melanoma

ndash Precursors ndash but risk for individual lesions is low (one in thousands)

ndash Risk markers ndash important mainly in high risk situations (patients with multiple atypical nevi family history high CSD etc)

ndash Simulants ndash important in everyday clinical decision-making

5212018

14

Grading of atypia in nevi correlation with melanoma risk Arumi-Uria McNutt Finnerty 2003

bull Grading of nevi with architectural disorder (dysplastic nevi) involves architectural and cytological features

bull Grades of atypia are related to patient history of melanoma ndash personal history of melanoma present in 57 of 2504 patients with mild

81 of 1657 with moderate and 197 of 320 patients with severe atypia

bull Odds ratio as a measure of association between NAD and history of melanomandash 408 for severe versus mild ndash 281 for severe versus moderate and ndash 145 for moderate versus mild dysplasia

bull ldquoMelanoma risk is greater in persons whose nevi have higher grade histological atypiardquo

Dysplasia Grading Criteria helliphellip Arumi-Uria et al Mod Pathol 2003

Mild Moderate Severe

bull The clinically most atypical macular nevus was biopsied from 80 newly incident cases of melanoma and spouse controls

bull Histological dysplasia was assigned on a subjective 0-4 point scale by a 13-member panel of dermatopathologists (International Melanoma Pathology Group)

bull Subjects with panel ratings gt 1 had increased relative risk of melanoma

bull Odds ratio after adjustment for confounders = 399 95 CI 102-1571

bull kappa statistic was 028 for the panel histological diagnoses indicating poor interobserver reproducibilityndash Repeating study agreed but found size to be a good surrogatecorrelate for

atypiandash Evidence-based criteria for histologic dysplasia as a risk marker

5212018

15

Xiong Rabkin Piepkorn Barnhill et al JAAD 2014

ldquoGiven that measuring diameter tends to be more objective than grading dysplasia these results could provide increased consistency when assessing risk of melanoma among patients with dysplastic nevirdquo

Rabkin Piepkorn Barnhill et al JAAD

Mild Dysplasia

bull Poorly reproducible diagnosis (vs nevus)bull Not associated with melanoma riskbull Not a high risk precursorbull Not a strong simulant of melanomabull UNCERTAINTY vs Moderate dysplasia No dysplasia

bull Should be considered in the spectrum of banal nevi (junctional or compound nevus eg lentiginous junctional nevus)

bull Complete excision is not necessary even when margins are positive

bull TERM ldquoMILD DYSPLASIArdquo SHOULD NO LONGER BE USED

bull (Lentiginous) Junctional Nevus

lt 4 mm diameter

minimal cytologic atypia

5212018

16

Moderate Dysplasia

bull Controversialbull Poorly reproducible diagnosis (vs mild severe)bull UNCERTAINTY vs Mild dysplasia MISbull Associated with melanoma riskbull Probably not a high risk precursorbull A weak simulant of melanoma (at least

histologically)

bull Complete excision is a consideration observation is an option

Severe Dysplasia

bull Reasonably reproducible diagnosis

bull UNCERTAINTY vs MIS

bull Associated with melanoma risk

bull Probably a high risk precursor

bull A strong simulant of melanoma (at least histologically)

bull Should be managed by complete excision and consideration of follow-up similar to MIS

Proposal for Grading Dysplasia

bull Junctionalcompound nevus

ndash Includes former mild dysplasia and ldquoClarkrsquos nevusrdquo

bull Low Grade Dysplasia (LGD)

ndash Former moderate dysplasia

bull High Grade Dysplasia (HGD)

ndash Former severe dysplasia

5212018

17

Case 4

Part 2-2 5475Clinical Information

Please find enclosed slides on a 36-year-old male with multiple dysplastic nevi removed Reason for Consultation

I have also enclosed a prior pathology report of other lesions removed My diagnosis is compound melanocytic nevus with architectural disorder and moderate cytologic atypia However

I am concerned that this lesion may be severely dysplastic Would you recommend a reexcision procedure

bull Broadbull Symmetricbull Moderately cellular bull Poorly circumscribed

5212018

18

bull Broadbull Symmetricbull Moderately

cellular bull Poorly

circumscribedbull Slight low

level pagetoid scatter

bull Moderate random atypia

bull Nuclear size 1-15x

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

19

Your Diagnosis

Low Grade

High Grade

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription cannot assess less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis (Part 2 Case 3)

Skin back (M36) Compound nevus with moderate dysplasia completely excised see description and comment

OR Compound dysplastic nevus low grade

Comment bull Patient presents with multiple lesions some of which are

dysplastic nevi with moderate dysplasia bull Benign lesions with little or no potential for recurrence and no

potential for metastasis bull Periodic follow-up may be appropriate for this patient

especially if there are other clinically atypical nevi andor a family or personal history of melanoma

bull Although the lesion extends close to the specimen margin there is no essential indication for reexcision especially if the patient is to be followed

This is an MPATH DX Category 1 or perhaps Category 2 lesion depending on clinical correlation and preference

5212018

20

Case 5

Part 2-3Clinical Information

A lesion from the back of a 54 year old manReason for consultation

The clinician was concerned about a melanoma but I favor a dysplastic nevus

Description

Very broad

Moderately cellular

Reasonably symmetrical

Uniformly elongated rete

Patchy infiltrate in dermis

5212018

21

5212018

22

bull Descriptionbull Very broad Moderate pagetoid scatter low

levelbull Moderately cellular Mild to moderate cytologic atypiabull Reasonably symmetrical Mild to moderate solar elastosisbull Uniformly elongated retebull Patchy infiltrate in dermis

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

23

Your Diagnosis

Low Grade

High Grade

Compound nevus with severe dysplasia(Severe architectural disorder moderate cytological atypia)

Feature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Cellularity high intermediate lower

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription common less common uncommon

Nested variable predominant predominant

Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate (1-15X) mild

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells Absent uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 5

bull Junctional nevus with severe melanocytic dysplasia completely excised see note

bull vs Junctional dysplastic nevus high grade

bull vs Intraepidermal atypical melanocytic proliferation (IAMPUS) cannot ro MISndash Diagnosis is based on ldquosevererdquo architectural features

(single cell predominance low level pagetoid scatter) with mild to moderate cytologic atypia

ndash MPATH-Dx Category III (consider excision with up to 5 mm margins if present at the margin)

5212018

24

Next Case

Part 2-5 35728Clinical Information

An irregular pigmented lesion on the back of a 59 year old manReason for Consultation

Is this a nevoid melanoma

Broad focally highly cellular asymmetric diffuse fibroplasia and variably sized nests in dermis

5212018

25

bull Only minimal pagetoid scatter

bull Moderate cytologic atypia

bull No mitosesbull Cells in dermal

nests are small nevoid

bull No confluent sheetlike growth

HMB46 staining is ldquotop-heavyrdquo(stratified)

bull Ki-67 proliferation is minimal in dermis

5212018

26

bull p16 staining is positive in a checkerboard pattern with nuclear and cytoplasmic positivity

Helpful Markers in Nevus vs Melanoma

bull HM45 stratificationndash J Invest Dermatol 1993 Mar100(3)313S-317S Immunophenotyping of compound and spitz nevi and vertical growth-phase

melanomas using a panel of monoclonal antibodies reactive in paraffin sectionsLazzaro B1 Elder DE Rebers A Power L Herlyn M Menrad A Johnson B

bull Low Ki-67 proliferation ratendash A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions

Li LX Crotty KA McCarthy SW Palmer AA Kril JJAm J Dermatopathol 2000 Dec22(6)489-95

bull Preservation of p16 protein expressionndash More problematical presence in an atypical tumor at

least precludes homozygous loss of 9p21 and is therefore reassuring but does not preclude diagnosis of melanoma

9p21 Locus

bull Contains p16 p14 and p15 all suppressor genes

bull Presumably all lost together in cases of homozygous 9p21 loss

bull Appears to have special significance in Spitzoid lesions

5212018

6

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed nevoid

Poor circumscription common less common uncommon

Distribution of Nests variable irregular predominant predominant regular

Pattern of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe (gt15x) mild-moderate

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 1 M50

bull Malignant melanoma superficial spreading type nonulcerated non-tumorigenic and nonmitogenic invasive radial growth phase only Clark level II greatest Breslow thickness 028 mm see comment

Commentndash Dermal mitotic rate is zero tumor infiltrating lymphocytes are absent (with

moderate noninfiltrating lymphocytes) there is no radial growth phase regression there is no ulcer there are no microscopic satellites and there is no evidence of vascular lymphatic or neural invasion

ndash Age lt 56ndash Associated compound dysplastic nevus ndash Appears to be minimally excised ndash MPATH-Dx 4 ndash 100 5 year survival

Case 2

Clinical InformationLesion of left shin with a mottled color in a 26-year-old woman

Reason for ConsultationI am enclosing for your consultation a melanocytic lesion

present for many years from the right shin of a 27-year-old woman Though the lesion had not changed (according to the patient) her clinician decided to remove it because he ldquodidnrsquot

like the mottled colorrdquo

5212018

7

Description

A relatively broad moderately cellular plaque-like lesion

Comprised mainly of nested large epithelioid melanocytes with abundant cytoplasm that contains finely divided ldquodustyrdquo melanin pigment

Some bridging nests between adjacent rete - possible junctional melanocytic dysplasia of the epithelioid type

bull Nests somewhat haphazardly distributed along the interface

bull Poor circumscription

bull Patchy to bandlike lymphocytic infiltrate

bull Diffuse fibroplasia

bull Nests somewhat haphazardly distributed along the interface

bull Poor circumscription

bull Patchy to bandlike lymphocytic infiltrate

bull Diffuse fibroplasia

5212018

8

bull Nests somewhat haphazardly distributed along the interface

bull Tendency to confluence of nests

bull Patchy to bandlike lymphocytic infiltrate

bull Diffuse fibroplasia

bull Nests somewhat haphazardly distributed along the interface

bull Nests in dermis not larger than largest in epidermis

bull Tendency to confluence of nests

bull Focal pagetoid scatter

Your Diagnosis

Melanoma

Nevus

5212018

9

1125 Dermal mitotic activity in atypical cells that resemble those in epidermis

The mitosis on the right could be considered junctional however there seems to be a wisp of collagen between the nest which is predominantly located in the dermis and the overlying junctional nest

Non tumorigenic mitogenic VGP

Nests in the dermis are smaller than the largest nests in the epidermisCount dermal mitoses in 1 sq mm even if not fully occupied by tumor express rate as a whole number

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed nevoid

Poor circumscription common less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe (gt15x) mild-moderate

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

5212018

10

Diagnosis Case 2 F26

bull Skin right shin Malignant melanoma superficial spreading type nonulcerated with non-tumorigenic but mitogenic early vertical growth phase Clarkrsquos level II greatest Breslow thickness 051 mm see description and comment

bull Comment Differential diagnosis could include severe dermal and epidermal melanocytic dysplasia however dermal (or even epidermal) mitotic activity essentially rules out this diagnosis The lesion is not a Spitz nevustumor because it is not comprised of large spindle andor epithelioid cells

bull Dermal mitotic rate 2 per square millimeterbull Tumor-infiltrating lymphocytes essentially absent in the invasive component with brisk

noninfiltrating lymphocytes nearbybull Focal radial growth phase regression presentbull No ulcer no microscopic satellites and no evidence of vascular lymphatic or neural invasionbull Associated junctional dysplastic nevus of the epithelioid subtypebull Actinic elastosis in the adjacent dermis is present and mild bull Lesion is completely excised with a closest border of approximately 1 mm

Superficial Melanoma and Mimics in Low CSD Skin

bull Superficial Spreading (ldquoPagetoidrdquo) Melanoma

bull Junctional and superficial Compound nevi

bull Dysplastic Nevi

bull Recurrent and Traumatized Nevi

bull Pagetoid Spitz and other pagetoid proliferations

bull Superficial Atypical Melanocytic Proliferations (SAMPUS)

Case 3

Clinical InformationA macular slightly variegated lesion from the back of a 37-year-old

womanReason for ConsultationIs this a dysplastic nevus

5212018

11

bull 25451bull Clinical Informationbull A 3 mm macular slightly variegated lesion from the back of a 37-year-old

womanbull Reason for Consultationbull Is this a dysplastic nevus

bull Smallbull Poorly circumscribedbull Nest predominate discretebull Patchy lymphocytes scant fibroplasia numerous melanophages (clinically

atypical)

5212018

12

bull Slightabsent cytologic atypia

bull No mitoses

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

13

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed nevoid

Poor circumscription cannot assess less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 2-1 F37

bull Diagnosisbull Skin abdomen bull Lentiginous junctional nevus with mild dysplasia see description and commentbull OR Lentiginous junctional nevus

bull Comment bull Mild dysplasia is not an independent risk factor for melanoma however if this patient should

have other clinically atypical nevi andor a family or personal history of melanoma or other melanoma risk factors consideration of periodic surveillance may be appropriate

bull The lesion appears to be excised however even if this were not the case reexcision might not be necessary if this biopsy was considered representative of the lesion and especially if the patient were to be followed

bull Since mild dysplasia is not an independent risk factor for melanoma lesions of this type might be better given a descriptive name such as ldquolentiginous junctional nevusrdquo

bull It is important to distinguish these lesions from nevoid lentigo maligna which can also be characterized by slight degrees of cytologic atypia

bull This is an MPATH Category 1 lesion (no need for reexcision even if margins are positive)

Superficial Atypical Nevi

bull Nevi are important mainly in relation to melanoma

ndash Precursors ndash but risk for individual lesions is low (one in thousands)

ndash Risk markers ndash important mainly in high risk situations (patients with multiple atypical nevi family history high CSD etc)

ndash Simulants ndash important in everyday clinical decision-making

5212018

14

Grading of atypia in nevi correlation with melanoma risk Arumi-Uria McNutt Finnerty 2003

bull Grading of nevi with architectural disorder (dysplastic nevi) involves architectural and cytological features

bull Grades of atypia are related to patient history of melanoma ndash personal history of melanoma present in 57 of 2504 patients with mild

81 of 1657 with moderate and 197 of 320 patients with severe atypia

bull Odds ratio as a measure of association between NAD and history of melanomandash 408 for severe versus mild ndash 281 for severe versus moderate and ndash 145 for moderate versus mild dysplasia

bull ldquoMelanoma risk is greater in persons whose nevi have higher grade histological atypiardquo

Dysplasia Grading Criteria helliphellip Arumi-Uria et al Mod Pathol 2003

Mild Moderate Severe

bull The clinically most atypical macular nevus was biopsied from 80 newly incident cases of melanoma and spouse controls

bull Histological dysplasia was assigned on a subjective 0-4 point scale by a 13-member panel of dermatopathologists (International Melanoma Pathology Group)

bull Subjects with panel ratings gt 1 had increased relative risk of melanoma

bull Odds ratio after adjustment for confounders = 399 95 CI 102-1571

bull kappa statistic was 028 for the panel histological diagnoses indicating poor interobserver reproducibilityndash Repeating study agreed but found size to be a good surrogatecorrelate for

atypiandash Evidence-based criteria for histologic dysplasia as a risk marker

5212018

15

Xiong Rabkin Piepkorn Barnhill et al JAAD 2014

ldquoGiven that measuring diameter tends to be more objective than grading dysplasia these results could provide increased consistency when assessing risk of melanoma among patients with dysplastic nevirdquo

Rabkin Piepkorn Barnhill et al JAAD

Mild Dysplasia

bull Poorly reproducible diagnosis (vs nevus)bull Not associated with melanoma riskbull Not a high risk precursorbull Not a strong simulant of melanomabull UNCERTAINTY vs Moderate dysplasia No dysplasia

bull Should be considered in the spectrum of banal nevi (junctional or compound nevus eg lentiginous junctional nevus)

bull Complete excision is not necessary even when margins are positive

bull TERM ldquoMILD DYSPLASIArdquo SHOULD NO LONGER BE USED

bull (Lentiginous) Junctional Nevus

lt 4 mm diameter

minimal cytologic atypia

5212018

16

Moderate Dysplasia

bull Controversialbull Poorly reproducible diagnosis (vs mild severe)bull UNCERTAINTY vs Mild dysplasia MISbull Associated with melanoma riskbull Probably not a high risk precursorbull A weak simulant of melanoma (at least

histologically)

bull Complete excision is a consideration observation is an option

Severe Dysplasia

bull Reasonably reproducible diagnosis

bull UNCERTAINTY vs MIS

bull Associated with melanoma risk

bull Probably a high risk precursor

bull A strong simulant of melanoma (at least histologically)

bull Should be managed by complete excision and consideration of follow-up similar to MIS

Proposal for Grading Dysplasia

bull Junctionalcompound nevus

ndash Includes former mild dysplasia and ldquoClarkrsquos nevusrdquo

bull Low Grade Dysplasia (LGD)

ndash Former moderate dysplasia

bull High Grade Dysplasia (HGD)

ndash Former severe dysplasia

5212018

17

Case 4

Part 2-2 5475Clinical Information

Please find enclosed slides on a 36-year-old male with multiple dysplastic nevi removed Reason for Consultation

I have also enclosed a prior pathology report of other lesions removed My diagnosis is compound melanocytic nevus with architectural disorder and moderate cytologic atypia However

I am concerned that this lesion may be severely dysplastic Would you recommend a reexcision procedure

bull Broadbull Symmetricbull Moderately cellular bull Poorly circumscribed

5212018

18

bull Broadbull Symmetricbull Moderately

cellular bull Poorly

circumscribedbull Slight low

level pagetoid scatter

bull Moderate random atypia

bull Nuclear size 1-15x

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

19

Your Diagnosis

Low Grade

High Grade

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription cannot assess less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis (Part 2 Case 3)

Skin back (M36) Compound nevus with moderate dysplasia completely excised see description and comment

OR Compound dysplastic nevus low grade

Comment bull Patient presents with multiple lesions some of which are

dysplastic nevi with moderate dysplasia bull Benign lesions with little or no potential for recurrence and no

potential for metastasis bull Periodic follow-up may be appropriate for this patient

especially if there are other clinically atypical nevi andor a family or personal history of melanoma

bull Although the lesion extends close to the specimen margin there is no essential indication for reexcision especially if the patient is to be followed

This is an MPATH DX Category 1 or perhaps Category 2 lesion depending on clinical correlation and preference

5212018

20

Case 5

Part 2-3Clinical Information

A lesion from the back of a 54 year old manReason for consultation

The clinician was concerned about a melanoma but I favor a dysplastic nevus

Description

Very broad

Moderately cellular

Reasonably symmetrical

Uniformly elongated rete

Patchy infiltrate in dermis

5212018

21

5212018

22

bull Descriptionbull Very broad Moderate pagetoid scatter low

levelbull Moderately cellular Mild to moderate cytologic atypiabull Reasonably symmetrical Mild to moderate solar elastosisbull Uniformly elongated retebull Patchy infiltrate in dermis

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

23

Your Diagnosis

Low Grade

High Grade

Compound nevus with severe dysplasia(Severe architectural disorder moderate cytological atypia)

Feature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Cellularity high intermediate lower

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription common less common uncommon

Nested variable predominant predominant

Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate (1-15X) mild

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells Absent uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 5

bull Junctional nevus with severe melanocytic dysplasia completely excised see note

bull vs Junctional dysplastic nevus high grade

bull vs Intraepidermal atypical melanocytic proliferation (IAMPUS) cannot ro MISndash Diagnosis is based on ldquosevererdquo architectural features

(single cell predominance low level pagetoid scatter) with mild to moderate cytologic atypia

ndash MPATH-Dx Category III (consider excision with up to 5 mm margins if present at the margin)

5212018

24

Next Case

Part 2-5 35728Clinical Information

An irregular pigmented lesion on the back of a 59 year old manReason for Consultation

Is this a nevoid melanoma

Broad focally highly cellular asymmetric diffuse fibroplasia and variably sized nests in dermis

5212018

25

bull Only minimal pagetoid scatter

bull Moderate cytologic atypia

bull No mitosesbull Cells in dermal

nests are small nevoid

bull No confluent sheetlike growth

HMB46 staining is ldquotop-heavyrdquo(stratified)

bull Ki-67 proliferation is minimal in dermis

5212018

26

bull p16 staining is positive in a checkerboard pattern with nuclear and cytoplasmic positivity

Helpful Markers in Nevus vs Melanoma

bull HM45 stratificationndash J Invest Dermatol 1993 Mar100(3)313S-317S Immunophenotyping of compound and spitz nevi and vertical growth-phase

melanomas using a panel of monoclonal antibodies reactive in paraffin sectionsLazzaro B1 Elder DE Rebers A Power L Herlyn M Menrad A Johnson B

bull Low Ki-67 proliferation ratendash A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions

Li LX Crotty KA McCarthy SW Palmer AA Kril JJAm J Dermatopathol 2000 Dec22(6)489-95

bull Preservation of p16 protein expressionndash More problematical presence in an atypical tumor at

least precludes homozygous loss of 9p21 and is therefore reassuring but does not preclude diagnosis of melanoma

9p21 Locus

bull Contains p16 p14 and p15 all suppressor genes

bull Presumably all lost together in cases of homozygous 9p21 loss

bull Appears to have special significance in Spitzoid lesions

5212018

7

Description

A relatively broad moderately cellular plaque-like lesion

Comprised mainly of nested large epithelioid melanocytes with abundant cytoplasm that contains finely divided ldquodustyrdquo melanin pigment

Some bridging nests between adjacent rete - possible junctional melanocytic dysplasia of the epithelioid type

bull Nests somewhat haphazardly distributed along the interface

bull Poor circumscription

bull Patchy to bandlike lymphocytic infiltrate

bull Diffuse fibroplasia

bull Nests somewhat haphazardly distributed along the interface

bull Poor circumscription

bull Patchy to bandlike lymphocytic infiltrate

bull Diffuse fibroplasia

5212018

8

bull Nests somewhat haphazardly distributed along the interface

bull Tendency to confluence of nests

bull Patchy to bandlike lymphocytic infiltrate

bull Diffuse fibroplasia

bull Nests somewhat haphazardly distributed along the interface

bull Nests in dermis not larger than largest in epidermis

bull Tendency to confluence of nests

bull Focal pagetoid scatter

Your Diagnosis

Melanoma

Nevus

5212018

9

1125 Dermal mitotic activity in atypical cells that resemble those in epidermis

The mitosis on the right could be considered junctional however there seems to be a wisp of collagen between the nest which is predominantly located in the dermis and the overlying junctional nest

Non tumorigenic mitogenic VGP

Nests in the dermis are smaller than the largest nests in the epidermisCount dermal mitoses in 1 sq mm even if not fully occupied by tumor express rate as a whole number

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed nevoid

Poor circumscription common less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe (gt15x) mild-moderate

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

5212018

10

Diagnosis Case 2 F26

bull Skin right shin Malignant melanoma superficial spreading type nonulcerated with non-tumorigenic but mitogenic early vertical growth phase Clarkrsquos level II greatest Breslow thickness 051 mm see description and comment

bull Comment Differential diagnosis could include severe dermal and epidermal melanocytic dysplasia however dermal (or even epidermal) mitotic activity essentially rules out this diagnosis The lesion is not a Spitz nevustumor because it is not comprised of large spindle andor epithelioid cells

bull Dermal mitotic rate 2 per square millimeterbull Tumor-infiltrating lymphocytes essentially absent in the invasive component with brisk

noninfiltrating lymphocytes nearbybull Focal radial growth phase regression presentbull No ulcer no microscopic satellites and no evidence of vascular lymphatic or neural invasionbull Associated junctional dysplastic nevus of the epithelioid subtypebull Actinic elastosis in the adjacent dermis is present and mild bull Lesion is completely excised with a closest border of approximately 1 mm

Superficial Melanoma and Mimics in Low CSD Skin

bull Superficial Spreading (ldquoPagetoidrdquo) Melanoma

bull Junctional and superficial Compound nevi

bull Dysplastic Nevi

bull Recurrent and Traumatized Nevi

bull Pagetoid Spitz and other pagetoid proliferations

bull Superficial Atypical Melanocytic Proliferations (SAMPUS)

Case 3

Clinical InformationA macular slightly variegated lesion from the back of a 37-year-old

womanReason for ConsultationIs this a dysplastic nevus

5212018

11

bull 25451bull Clinical Informationbull A 3 mm macular slightly variegated lesion from the back of a 37-year-old

womanbull Reason for Consultationbull Is this a dysplastic nevus

bull Smallbull Poorly circumscribedbull Nest predominate discretebull Patchy lymphocytes scant fibroplasia numerous melanophages (clinically

atypical)

5212018

12

bull Slightabsent cytologic atypia

bull No mitoses

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

13

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed nevoid

Poor circumscription cannot assess less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 2-1 F37

bull Diagnosisbull Skin abdomen bull Lentiginous junctional nevus with mild dysplasia see description and commentbull OR Lentiginous junctional nevus

bull Comment bull Mild dysplasia is not an independent risk factor for melanoma however if this patient should

have other clinically atypical nevi andor a family or personal history of melanoma or other melanoma risk factors consideration of periodic surveillance may be appropriate

bull The lesion appears to be excised however even if this were not the case reexcision might not be necessary if this biopsy was considered representative of the lesion and especially if the patient were to be followed

bull Since mild dysplasia is not an independent risk factor for melanoma lesions of this type might be better given a descriptive name such as ldquolentiginous junctional nevusrdquo

bull It is important to distinguish these lesions from nevoid lentigo maligna which can also be characterized by slight degrees of cytologic atypia

bull This is an MPATH Category 1 lesion (no need for reexcision even if margins are positive)

Superficial Atypical Nevi

bull Nevi are important mainly in relation to melanoma

ndash Precursors ndash but risk for individual lesions is low (one in thousands)

ndash Risk markers ndash important mainly in high risk situations (patients with multiple atypical nevi family history high CSD etc)

ndash Simulants ndash important in everyday clinical decision-making

5212018

14

Grading of atypia in nevi correlation with melanoma risk Arumi-Uria McNutt Finnerty 2003

bull Grading of nevi with architectural disorder (dysplastic nevi) involves architectural and cytological features

bull Grades of atypia are related to patient history of melanoma ndash personal history of melanoma present in 57 of 2504 patients with mild

81 of 1657 with moderate and 197 of 320 patients with severe atypia

bull Odds ratio as a measure of association between NAD and history of melanomandash 408 for severe versus mild ndash 281 for severe versus moderate and ndash 145 for moderate versus mild dysplasia

bull ldquoMelanoma risk is greater in persons whose nevi have higher grade histological atypiardquo

Dysplasia Grading Criteria helliphellip Arumi-Uria et al Mod Pathol 2003

Mild Moderate Severe

bull The clinically most atypical macular nevus was biopsied from 80 newly incident cases of melanoma and spouse controls

bull Histological dysplasia was assigned on a subjective 0-4 point scale by a 13-member panel of dermatopathologists (International Melanoma Pathology Group)

bull Subjects with panel ratings gt 1 had increased relative risk of melanoma

bull Odds ratio after adjustment for confounders = 399 95 CI 102-1571

bull kappa statistic was 028 for the panel histological diagnoses indicating poor interobserver reproducibilityndash Repeating study agreed but found size to be a good surrogatecorrelate for

atypiandash Evidence-based criteria for histologic dysplasia as a risk marker

5212018

15

Xiong Rabkin Piepkorn Barnhill et al JAAD 2014

ldquoGiven that measuring diameter tends to be more objective than grading dysplasia these results could provide increased consistency when assessing risk of melanoma among patients with dysplastic nevirdquo

Rabkin Piepkorn Barnhill et al JAAD

Mild Dysplasia

bull Poorly reproducible diagnosis (vs nevus)bull Not associated with melanoma riskbull Not a high risk precursorbull Not a strong simulant of melanomabull UNCERTAINTY vs Moderate dysplasia No dysplasia

bull Should be considered in the spectrum of banal nevi (junctional or compound nevus eg lentiginous junctional nevus)

bull Complete excision is not necessary even when margins are positive

bull TERM ldquoMILD DYSPLASIArdquo SHOULD NO LONGER BE USED

bull (Lentiginous) Junctional Nevus

lt 4 mm diameter

minimal cytologic atypia

5212018

16

Moderate Dysplasia

bull Controversialbull Poorly reproducible diagnosis (vs mild severe)bull UNCERTAINTY vs Mild dysplasia MISbull Associated with melanoma riskbull Probably not a high risk precursorbull A weak simulant of melanoma (at least

histologically)

bull Complete excision is a consideration observation is an option

Severe Dysplasia

bull Reasonably reproducible diagnosis

bull UNCERTAINTY vs MIS

bull Associated with melanoma risk

bull Probably a high risk precursor

bull A strong simulant of melanoma (at least histologically)

bull Should be managed by complete excision and consideration of follow-up similar to MIS

Proposal for Grading Dysplasia

bull Junctionalcompound nevus

ndash Includes former mild dysplasia and ldquoClarkrsquos nevusrdquo

bull Low Grade Dysplasia (LGD)

ndash Former moderate dysplasia

bull High Grade Dysplasia (HGD)

ndash Former severe dysplasia

5212018

17

Case 4

Part 2-2 5475Clinical Information

Please find enclosed slides on a 36-year-old male with multiple dysplastic nevi removed Reason for Consultation

I have also enclosed a prior pathology report of other lesions removed My diagnosis is compound melanocytic nevus with architectural disorder and moderate cytologic atypia However

I am concerned that this lesion may be severely dysplastic Would you recommend a reexcision procedure

bull Broadbull Symmetricbull Moderately cellular bull Poorly circumscribed

5212018

18

bull Broadbull Symmetricbull Moderately

cellular bull Poorly

circumscribedbull Slight low

level pagetoid scatter

bull Moderate random atypia

bull Nuclear size 1-15x

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

19

Your Diagnosis

Low Grade

High Grade

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription cannot assess less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis (Part 2 Case 3)

Skin back (M36) Compound nevus with moderate dysplasia completely excised see description and comment

OR Compound dysplastic nevus low grade

Comment bull Patient presents with multiple lesions some of which are

dysplastic nevi with moderate dysplasia bull Benign lesions with little or no potential for recurrence and no

potential for metastasis bull Periodic follow-up may be appropriate for this patient

especially if there are other clinically atypical nevi andor a family or personal history of melanoma

bull Although the lesion extends close to the specimen margin there is no essential indication for reexcision especially if the patient is to be followed

This is an MPATH DX Category 1 or perhaps Category 2 lesion depending on clinical correlation and preference

5212018

20

Case 5

Part 2-3Clinical Information

A lesion from the back of a 54 year old manReason for consultation

The clinician was concerned about a melanoma but I favor a dysplastic nevus

Description

Very broad

Moderately cellular

Reasonably symmetrical

Uniformly elongated rete

Patchy infiltrate in dermis

5212018

21

5212018

22

bull Descriptionbull Very broad Moderate pagetoid scatter low

levelbull Moderately cellular Mild to moderate cytologic atypiabull Reasonably symmetrical Mild to moderate solar elastosisbull Uniformly elongated retebull Patchy infiltrate in dermis

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

23

Your Diagnosis

Low Grade

High Grade

Compound nevus with severe dysplasia(Severe architectural disorder moderate cytological atypia)

Feature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Cellularity high intermediate lower

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription common less common uncommon

Nested variable predominant predominant

Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate (1-15X) mild

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells Absent uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 5

bull Junctional nevus with severe melanocytic dysplasia completely excised see note

bull vs Junctional dysplastic nevus high grade

bull vs Intraepidermal atypical melanocytic proliferation (IAMPUS) cannot ro MISndash Diagnosis is based on ldquosevererdquo architectural features

(single cell predominance low level pagetoid scatter) with mild to moderate cytologic atypia

ndash MPATH-Dx Category III (consider excision with up to 5 mm margins if present at the margin)

5212018

24

Next Case

Part 2-5 35728Clinical Information

An irregular pigmented lesion on the back of a 59 year old manReason for Consultation

Is this a nevoid melanoma

Broad focally highly cellular asymmetric diffuse fibroplasia and variably sized nests in dermis

5212018

25

bull Only minimal pagetoid scatter

bull Moderate cytologic atypia

bull No mitosesbull Cells in dermal

nests are small nevoid

bull No confluent sheetlike growth

HMB46 staining is ldquotop-heavyrdquo(stratified)

bull Ki-67 proliferation is minimal in dermis

5212018

26

bull p16 staining is positive in a checkerboard pattern with nuclear and cytoplasmic positivity

Helpful Markers in Nevus vs Melanoma

bull HM45 stratificationndash J Invest Dermatol 1993 Mar100(3)313S-317S Immunophenotyping of compound and spitz nevi and vertical growth-phase

melanomas using a panel of monoclonal antibodies reactive in paraffin sectionsLazzaro B1 Elder DE Rebers A Power L Herlyn M Menrad A Johnson B

bull Low Ki-67 proliferation ratendash A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions

Li LX Crotty KA McCarthy SW Palmer AA Kril JJAm J Dermatopathol 2000 Dec22(6)489-95

bull Preservation of p16 protein expressionndash More problematical presence in an atypical tumor at

least precludes homozygous loss of 9p21 and is therefore reassuring but does not preclude diagnosis of melanoma

9p21 Locus

bull Contains p16 p14 and p15 all suppressor genes

bull Presumably all lost together in cases of homozygous 9p21 loss

bull Appears to have special significance in Spitzoid lesions

5212018

8

bull Nests somewhat haphazardly distributed along the interface

bull Tendency to confluence of nests

bull Patchy to bandlike lymphocytic infiltrate

bull Diffuse fibroplasia

bull Nests somewhat haphazardly distributed along the interface

bull Nests in dermis not larger than largest in epidermis

bull Tendency to confluence of nests

bull Focal pagetoid scatter

Your Diagnosis

Melanoma

Nevus

5212018

9

1125 Dermal mitotic activity in atypical cells that resemble those in epidermis

The mitosis on the right could be considered junctional however there seems to be a wisp of collagen between the nest which is predominantly located in the dermis and the overlying junctional nest

Non tumorigenic mitogenic VGP

Nests in the dermis are smaller than the largest nests in the epidermisCount dermal mitoses in 1 sq mm even if not fully occupied by tumor express rate as a whole number

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed nevoid

Poor circumscription common less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe (gt15x) mild-moderate

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

5212018

10

Diagnosis Case 2 F26

bull Skin right shin Malignant melanoma superficial spreading type nonulcerated with non-tumorigenic but mitogenic early vertical growth phase Clarkrsquos level II greatest Breslow thickness 051 mm see description and comment

bull Comment Differential diagnosis could include severe dermal and epidermal melanocytic dysplasia however dermal (or even epidermal) mitotic activity essentially rules out this diagnosis The lesion is not a Spitz nevustumor because it is not comprised of large spindle andor epithelioid cells

bull Dermal mitotic rate 2 per square millimeterbull Tumor-infiltrating lymphocytes essentially absent in the invasive component with brisk

noninfiltrating lymphocytes nearbybull Focal radial growth phase regression presentbull No ulcer no microscopic satellites and no evidence of vascular lymphatic or neural invasionbull Associated junctional dysplastic nevus of the epithelioid subtypebull Actinic elastosis in the adjacent dermis is present and mild bull Lesion is completely excised with a closest border of approximately 1 mm

Superficial Melanoma and Mimics in Low CSD Skin

bull Superficial Spreading (ldquoPagetoidrdquo) Melanoma

bull Junctional and superficial Compound nevi

bull Dysplastic Nevi

bull Recurrent and Traumatized Nevi

bull Pagetoid Spitz and other pagetoid proliferations

bull Superficial Atypical Melanocytic Proliferations (SAMPUS)

Case 3

Clinical InformationA macular slightly variegated lesion from the back of a 37-year-old

womanReason for ConsultationIs this a dysplastic nevus

5212018

11

bull 25451bull Clinical Informationbull A 3 mm macular slightly variegated lesion from the back of a 37-year-old

womanbull Reason for Consultationbull Is this a dysplastic nevus

bull Smallbull Poorly circumscribedbull Nest predominate discretebull Patchy lymphocytes scant fibroplasia numerous melanophages (clinically

atypical)

5212018

12

bull Slightabsent cytologic atypia

bull No mitoses

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

13

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed nevoid

Poor circumscription cannot assess less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 2-1 F37

bull Diagnosisbull Skin abdomen bull Lentiginous junctional nevus with mild dysplasia see description and commentbull OR Lentiginous junctional nevus

bull Comment bull Mild dysplasia is not an independent risk factor for melanoma however if this patient should

have other clinically atypical nevi andor a family or personal history of melanoma or other melanoma risk factors consideration of periodic surveillance may be appropriate

bull The lesion appears to be excised however even if this were not the case reexcision might not be necessary if this biopsy was considered representative of the lesion and especially if the patient were to be followed

bull Since mild dysplasia is not an independent risk factor for melanoma lesions of this type might be better given a descriptive name such as ldquolentiginous junctional nevusrdquo

bull It is important to distinguish these lesions from nevoid lentigo maligna which can also be characterized by slight degrees of cytologic atypia

bull This is an MPATH Category 1 lesion (no need for reexcision even if margins are positive)

Superficial Atypical Nevi

bull Nevi are important mainly in relation to melanoma

ndash Precursors ndash but risk for individual lesions is low (one in thousands)

ndash Risk markers ndash important mainly in high risk situations (patients with multiple atypical nevi family history high CSD etc)

ndash Simulants ndash important in everyday clinical decision-making

5212018

14

Grading of atypia in nevi correlation with melanoma risk Arumi-Uria McNutt Finnerty 2003

bull Grading of nevi with architectural disorder (dysplastic nevi) involves architectural and cytological features

bull Grades of atypia are related to patient history of melanoma ndash personal history of melanoma present in 57 of 2504 patients with mild

81 of 1657 with moderate and 197 of 320 patients with severe atypia

bull Odds ratio as a measure of association between NAD and history of melanomandash 408 for severe versus mild ndash 281 for severe versus moderate and ndash 145 for moderate versus mild dysplasia

bull ldquoMelanoma risk is greater in persons whose nevi have higher grade histological atypiardquo

Dysplasia Grading Criteria helliphellip Arumi-Uria et al Mod Pathol 2003

Mild Moderate Severe

bull The clinically most atypical macular nevus was biopsied from 80 newly incident cases of melanoma and spouse controls

bull Histological dysplasia was assigned on a subjective 0-4 point scale by a 13-member panel of dermatopathologists (International Melanoma Pathology Group)

bull Subjects with panel ratings gt 1 had increased relative risk of melanoma

bull Odds ratio after adjustment for confounders = 399 95 CI 102-1571

bull kappa statistic was 028 for the panel histological diagnoses indicating poor interobserver reproducibilityndash Repeating study agreed but found size to be a good surrogatecorrelate for

atypiandash Evidence-based criteria for histologic dysplasia as a risk marker

5212018

15

Xiong Rabkin Piepkorn Barnhill et al JAAD 2014

ldquoGiven that measuring diameter tends to be more objective than grading dysplasia these results could provide increased consistency when assessing risk of melanoma among patients with dysplastic nevirdquo

Rabkin Piepkorn Barnhill et al JAAD

Mild Dysplasia

bull Poorly reproducible diagnosis (vs nevus)bull Not associated with melanoma riskbull Not a high risk precursorbull Not a strong simulant of melanomabull UNCERTAINTY vs Moderate dysplasia No dysplasia

bull Should be considered in the spectrum of banal nevi (junctional or compound nevus eg lentiginous junctional nevus)

bull Complete excision is not necessary even when margins are positive

bull TERM ldquoMILD DYSPLASIArdquo SHOULD NO LONGER BE USED

bull (Lentiginous) Junctional Nevus

lt 4 mm diameter

minimal cytologic atypia

5212018

16

Moderate Dysplasia

bull Controversialbull Poorly reproducible diagnosis (vs mild severe)bull UNCERTAINTY vs Mild dysplasia MISbull Associated with melanoma riskbull Probably not a high risk precursorbull A weak simulant of melanoma (at least

histologically)

bull Complete excision is a consideration observation is an option

Severe Dysplasia

bull Reasonably reproducible diagnosis

bull UNCERTAINTY vs MIS

bull Associated with melanoma risk

bull Probably a high risk precursor

bull A strong simulant of melanoma (at least histologically)

bull Should be managed by complete excision and consideration of follow-up similar to MIS

Proposal for Grading Dysplasia

bull Junctionalcompound nevus

ndash Includes former mild dysplasia and ldquoClarkrsquos nevusrdquo

bull Low Grade Dysplasia (LGD)

ndash Former moderate dysplasia

bull High Grade Dysplasia (HGD)

ndash Former severe dysplasia

5212018

17

Case 4

Part 2-2 5475Clinical Information

Please find enclosed slides on a 36-year-old male with multiple dysplastic nevi removed Reason for Consultation

I have also enclosed a prior pathology report of other lesions removed My diagnosis is compound melanocytic nevus with architectural disorder and moderate cytologic atypia However

I am concerned that this lesion may be severely dysplastic Would you recommend a reexcision procedure

bull Broadbull Symmetricbull Moderately cellular bull Poorly circumscribed

5212018

18

bull Broadbull Symmetricbull Moderately

cellular bull Poorly

circumscribedbull Slight low

level pagetoid scatter

bull Moderate random atypia

bull Nuclear size 1-15x

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

19

Your Diagnosis

Low Grade

High Grade

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription cannot assess less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis (Part 2 Case 3)

Skin back (M36) Compound nevus with moderate dysplasia completely excised see description and comment

OR Compound dysplastic nevus low grade

Comment bull Patient presents with multiple lesions some of which are

dysplastic nevi with moderate dysplasia bull Benign lesions with little or no potential for recurrence and no

potential for metastasis bull Periodic follow-up may be appropriate for this patient

especially if there are other clinically atypical nevi andor a family or personal history of melanoma

bull Although the lesion extends close to the specimen margin there is no essential indication for reexcision especially if the patient is to be followed

This is an MPATH DX Category 1 or perhaps Category 2 lesion depending on clinical correlation and preference

5212018

20

Case 5

Part 2-3Clinical Information

A lesion from the back of a 54 year old manReason for consultation

The clinician was concerned about a melanoma but I favor a dysplastic nevus

Description

Very broad

Moderately cellular

Reasonably symmetrical

Uniformly elongated rete

Patchy infiltrate in dermis

5212018

21

5212018

22

bull Descriptionbull Very broad Moderate pagetoid scatter low

levelbull Moderately cellular Mild to moderate cytologic atypiabull Reasonably symmetrical Mild to moderate solar elastosisbull Uniformly elongated retebull Patchy infiltrate in dermis

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

23

Your Diagnosis

Low Grade

High Grade

Compound nevus with severe dysplasia(Severe architectural disorder moderate cytological atypia)

Feature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Cellularity high intermediate lower

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription common less common uncommon

Nested variable predominant predominant

Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate (1-15X) mild

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells Absent uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 5

bull Junctional nevus with severe melanocytic dysplasia completely excised see note

bull vs Junctional dysplastic nevus high grade

bull vs Intraepidermal atypical melanocytic proliferation (IAMPUS) cannot ro MISndash Diagnosis is based on ldquosevererdquo architectural features

(single cell predominance low level pagetoid scatter) with mild to moderate cytologic atypia

ndash MPATH-Dx Category III (consider excision with up to 5 mm margins if present at the margin)

5212018

24

Next Case

Part 2-5 35728Clinical Information

An irregular pigmented lesion on the back of a 59 year old manReason for Consultation

Is this a nevoid melanoma

Broad focally highly cellular asymmetric diffuse fibroplasia and variably sized nests in dermis

5212018

25

bull Only minimal pagetoid scatter

bull Moderate cytologic atypia

bull No mitosesbull Cells in dermal

nests are small nevoid

bull No confluent sheetlike growth

HMB46 staining is ldquotop-heavyrdquo(stratified)

bull Ki-67 proliferation is minimal in dermis

5212018

26

bull p16 staining is positive in a checkerboard pattern with nuclear and cytoplasmic positivity

Helpful Markers in Nevus vs Melanoma

bull HM45 stratificationndash J Invest Dermatol 1993 Mar100(3)313S-317S Immunophenotyping of compound and spitz nevi and vertical growth-phase

melanomas using a panel of monoclonal antibodies reactive in paraffin sectionsLazzaro B1 Elder DE Rebers A Power L Herlyn M Menrad A Johnson B

bull Low Ki-67 proliferation ratendash A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions

Li LX Crotty KA McCarthy SW Palmer AA Kril JJAm J Dermatopathol 2000 Dec22(6)489-95

bull Preservation of p16 protein expressionndash More problematical presence in an atypical tumor at

least precludes homozygous loss of 9p21 and is therefore reassuring but does not preclude diagnosis of melanoma

9p21 Locus

bull Contains p16 p14 and p15 all suppressor genes

bull Presumably all lost together in cases of homozygous 9p21 loss

bull Appears to have special significance in Spitzoid lesions

5212018

9

1125 Dermal mitotic activity in atypical cells that resemble those in epidermis

The mitosis on the right could be considered junctional however there seems to be a wisp of collagen between the nest which is predominantly located in the dermis and the overlying junctional nest

Non tumorigenic mitogenic VGP

Nests in the dermis are smaller than the largest nests in the epidermisCount dermal mitoses in 1 sq mm even if not fully occupied by tumor express rate as a whole number

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed nevoid

Poor circumscription common less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe (gt15x) mild-moderate

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

5212018

10

Diagnosis Case 2 F26

bull Skin right shin Malignant melanoma superficial spreading type nonulcerated with non-tumorigenic but mitogenic early vertical growth phase Clarkrsquos level II greatest Breslow thickness 051 mm see description and comment

bull Comment Differential diagnosis could include severe dermal and epidermal melanocytic dysplasia however dermal (or even epidermal) mitotic activity essentially rules out this diagnosis The lesion is not a Spitz nevustumor because it is not comprised of large spindle andor epithelioid cells

bull Dermal mitotic rate 2 per square millimeterbull Tumor-infiltrating lymphocytes essentially absent in the invasive component with brisk

noninfiltrating lymphocytes nearbybull Focal radial growth phase regression presentbull No ulcer no microscopic satellites and no evidence of vascular lymphatic or neural invasionbull Associated junctional dysplastic nevus of the epithelioid subtypebull Actinic elastosis in the adjacent dermis is present and mild bull Lesion is completely excised with a closest border of approximately 1 mm

Superficial Melanoma and Mimics in Low CSD Skin

bull Superficial Spreading (ldquoPagetoidrdquo) Melanoma

bull Junctional and superficial Compound nevi

bull Dysplastic Nevi

bull Recurrent and Traumatized Nevi

bull Pagetoid Spitz and other pagetoid proliferations

bull Superficial Atypical Melanocytic Proliferations (SAMPUS)

Case 3

Clinical InformationA macular slightly variegated lesion from the back of a 37-year-old

womanReason for ConsultationIs this a dysplastic nevus

5212018

11

bull 25451bull Clinical Informationbull A 3 mm macular slightly variegated lesion from the back of a 37-year-old

womanbull Reason for Consultationbull Is this a dysplastic nevus

bull Smallbull Poorly circumscribedbull Nest predominate discretebull Patchy lymphocytes scant fibroplasia numerous melanophages (clinically

atypical)

5212018

12

bull Slightabsent cytologic atypia

bull No mitoses

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

13

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed nevoid

Poor circumscription cannot assess less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 2-1 F37

bull Diagnosisbull Skin abdomen bull Lentiginous junctional nevus with mild dysplasia see description and commentbull OR Lentiginous junctional nevus

bull Comment bull Mild dysplasia is not an independent risk factor for melanoma however if this patient should

have other clinically atypical nevi andor a family or personal history of melanoma or other melanoma risk factors consideration of periodic surveillance may be appropriate

bull The lesion appears to be excised however even if this were not the case reexcision might not be necessary if this biopsy was considered representative of the lesion and especially if the patient were to be followed

bull Since mild dysplasia is not an independent risk factor for melanoma lesions of this type might be better given a descriptive name such as ldquolentiginous junctional nevusrdquo

bull It is important to distinguish these lesions from nevoid lentigo maligna which can also be characterized by slight degrees of cytologic atypia

bull This is an MPATH Category 1 lesion (no need for reexcision even if margins are positive)

Superficial Atypical Nevi

bull Nevi are important mainly in relation to melanoma

ndash Precursors ndash but risk for individual lesions is low (one in thousands)

ndash Risk markers ndash important mainly in high risk situations (patients with multiple atypical nevi family history high CSD etc)

ndash Simulants ndash important in everyday clinical decision-making

5212018

14

Grading of atypia in nevi correlation with melanoma risk Arumi-Uria McNutt Finnerty 2003

bull Grading of nevi with architectural disorder (dysplastic nevi) involves architectural and cytological features

bull Grades of atypia are related to patient history of melanoma ndash personal history of melanoma present in 57 of 2504 patients with mild

81 of 1657 with moderate and 197 of 320 patients with severe atypia

bull Odds ratio as a measure of association between NAD and history of melanomandash 408 for severe versus mild ndash 281 for severe versus moderate and ndash 145 for moderate versus mild dysplasia

bull ldquoMelanoma risk is greater in persons whose nevi have higher grade histological atypiardquo

Dysplasia Grading Criteria helliphellip Arumi-Uria et al Mod Pathol 2003

Mild Moderate Severe

bull The clinically most atypical macular nevus was biopsied from 80 newly incident cases of melanoma and spouse controls

bull Histological dysplasia was assigned on a subjective 0-4 point scale by a 13-member panel of dermatopathologists (International Melanoma Pathology Group)

bull Subjects with panel ratings gt 1 had increased relative risk of melanoma

bull Odds ratio after adjustment for confounders = 399 95 CI 102-1571

bull kappa statistic was 028 for the panel histological diagnoses indicating poor interobserver reproducibilityndash Repeating study agreed but found size to be a good surrogatecorrelate for

atypiandash Evidence-based criteria for histologic dysplasia as a risk marker

5212018

15

Xiong Rabkin Piepkorn Barnhill et al JAAD 2014

ldquoGiven that measuring diameter tends to be more objective than grading dysplasia these results could provide increased consistency when assessing risk of melanoma among patients with dysplastic nevirdquo

Rabkin Piepkorn Barnhill et al JAAD

Mild Dysplasia

bull Poorly reproducible diagnosis (vs nevus)bull Not associated with melanoma riskbull Not a high risk precursorbull Not a strong simulant of melanomabull UNCERTAINTY vs Moderate dysplasia No dysplasia

bull Should be considered in the spectrum of banal nevi (junctional or compound nevus eg lentiginous junctional nevus)

bull Complete excision is not necessary even when margins are positive

bull TERM ldquoMILD DYSPLASIArdquo SHOULD NO LONGER BE USED

bull (Lentiginous) Junctional Nevus

lt 4 mm diameter

minimal cytologic atypia

5212018

16

Moderate Dysplasia

bull Controversialbull Poorly reproducible diagnosis (vs mild severe)bull UNCERTAINTY vs Mild dysplasia MISbull Associated with melanoma riskbull Probably not a high risk precursorbull A weak simulant of melanoma (at least

histologically)

bull Complete excision is a consideration observation is an option

Severe Dysplasia

bull Reasonably reproducible diagnosis

bull UNCERTAINTY vs MIS

bull Associated with melanoma risk

bull Probably a high risk precursor

bull A strong simulant of melanoma (at least histologically)

bull Should be managed by complete excision and consideration of follow-up similar to MIS

Proposal for Grading Dysplasia

bull Junctionalcompound nevus

ndash Includes former mild dysplasia and ldquoClarkrsquos nevusrdquo

bull Low Grade Dysplasia (LGD)

ndash Former moderate dysplasia

bull High Grade Dysplasia (HGD)

ndash Former severe dysplasia

5212018

17

Case 4

Part 2-2 5475Clinical Information

Please find enclosed slides on a 36-year-old male with multiple dysplastic nevi removed Reason for Consultation

I have also enclosed a prior pathology report of other lesions removed My diagnosis is compound melanocytic nevus with architectural disorder and moderate cytologic atypia However

I am concerned that this lesion may be severely dysplastic Would you recommend a reexcision procedure

bull Broadbull Symmetricbull Moderately cellular bull Poorly circumscribed

5212018

18

bull Broadbull Symmetricbull Moderately

cellular bull Poorly

circumscribedbull Slight low

level pagetoid scatter

bull Moderate random atypia

bull Nuclear size 1-15x

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

19

Your Diagnosis

Low Grade

High Grade

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription cannot assess less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis (Part 2 Case 3)

Skin back (M36) Compound nevus with moderate dysplasia completely excised see description and comment

OR Compound dysplastic nevus low grade

Comment bull Patient presents with multiple lesions some of which are

dysplastic nevi with moderate dysplasia bull Benign lesions with little or no potential for recurrence and no

potential for metastasis bull Periodic follow-up may be appropriate for this patient

especially if there are other clinically atypical nevi andor a family or personal history of melanoma

bull Although the lesion extends close to the specimen margin there is no essential indication for reexcision especially if the patient is to be followed

This is an MPATH DX Category 1 or perhaps Category 2 lesion depending on clinical correlation and preference

5212018

20

Case 5

Part 2-3Clinical Information

A lesion from the back of a 54 year old manReason for consultation

The clinician was concerned about a melanoma but I favor a dysplastic nevus

Description

Very broad

Moderately cellular

Reasonably symmetrical

Uniformly elongated rete

Patchy infiltrate in dermis

5212018

21

5212018

22

bull Descriptionbull Very broad Moderate pagetoid scatter low

levelbull Moderately cellular Mild to moderate cytologic atypiabull Reasonably symmetrical Mild to moderate solar elastosisbull Uniformly elongated retebull Patchy infiltrate in dermis

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

23

Your Diagnosis

Low Grade

High Grade

Compound nevus with severe dysplasia(Severe architectural disorder moderate cytological atypia)

Feature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Cellularity high intermediate lower

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription common less common uncommon

Nested variable predominant predominant

Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate (1-15X) mild

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells Absent uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 5

bull Junctional nevus with severe melanocytic dysplasia completely excised see note

bull vs Junctional dysplastic nevus high grade

bull vs Intraepidermal atypical melanocytic proliferation (IAMPUS) cannot ro MISndash Diagnosis is based on ldquosevererdquo architectural features

(single cell predominance low level pagetoid scatter) with mild to moderate cytologic atypia

ndash MPATH-Dx Category III (consider excision with up to 5 mm margins if present at the margin)

5212018

24

Next Case

Part 2-5 35728Clinical Information

An irregular pigmented lesion on the back of a 59 year old manReason for Consultation

Is this a nevoid melanoma

Broad focally highly cellular asymmetric diffuse fibroplasia and variably sized nests in dermis

5212018

25

bull Only minimal pagetoid scatter

bull Moderate cytologic atypia

bull No mitosesbull Cells in dermal

nests are small nevoid

bull No confluent sheetlike growth

HMB46 staining is ldquotop-heavyrdquo(stratified)

bull Ki-67 proliferation is minimal in dermis

5212018

26

bull p16 staining is positive in a checkerboard pattern with nuclear and cytoplasmic positivity

Helpful Markers in Nevus vs Melanoma

bull HM45 stratificationndash J Invest Dermatol 1993 Mar100(3)313S-317S Immunophenotyping of compound and spitz nevi and vertical growth-phase

melanomas using a panel of monoclonal antibodies reactive in paraffin sectionsLazzaro B1 Elder DE Rebers A Power L Herlyn M Menrad A Johnson B

bull Low Ki-67 proliferation ratendash A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions

Li LX Crotty KA McCarthy SW Palmer AA Kril JJAm J Dermatopathol 2000 Dec22(6)489-95

bull Preservation of p16 protein expressionndash More problematical presence in an atypical tumor at

least precludes homozygous loss of 9p21 and is therefore reassuring but does not preclude diagnosis of melanoma

9p21 Locus

bull Contains p16 p14 and p15 all suppressor genes

bull Presumably all lost together in cases of homozygous 9p21 loss

bull Appears to have special significance in Spitzoid lesions

5212018

10

Diagnosis Case 2 F26

bull Skin right shin Malignant melanoma superficial spreading type nonulcerated with non-tumorigenic but mitogenic early vertical growth phase Clarkrsquos level II greatest Breslow thickness 051 mm see description and comment

bull Comment Differential diagnosis could include severe dermal and epidermal melanocytic dysplasia however dermal (or even epidermal) mitotic activity essentially rules out this diagnosis The lesion is not a Spitz nevustumor because it is not comprised of large spindle andor epithelioid cells

bull Dermal mitotic rate 2 per square millimeterbull Tumor-infiltrating lymphocytes essentially absent in the invasive component with brisk

noninfiltrating lymphocytes nearbybull Focal radial growth phase regression presentbull No ulcer no microscopic satellites and no evidence of vascular lymphatic or neural invasionbull Associated junctional dysplastic nevus of the epithelioid subtypebull Actinic elastosis in the adjacent dermis is present and mild bull Lesion is completely excised with a closest border of approximately 1 mm

Superficial Melanoma and Mimics in Low CSD Skin

bull Superficial Spreading (ldquoPagetoidrdquo) Melanoma

bull Junctional and superficial Compound nevi

bull Dysplastic Nevi

bull Recurrent and Traumatized Nevi

bull Pagetoid Spitz and other pagetoid proliferations

bull Superficial Atypical Melanocytic Proliferations (SAMPUS)

Case 3

Clinical InformationA macular slightly variegated lesion from the back of a 37-year-old

womanReason for ConsultationIs this a dysplastic nevus

5212018

11

bull 25451bull Clinical Informationbull A 3 mm macular slightly variegated lesion from the back of a 37-year-old

womanbull Reason for Consultationbull Is this a dysplastic nevus

bull Smallbull Poorly circumscribedbull Nest predominate discretebull Patchy lymphocytes scant fibroplasia numerous melanophages (clinically

atypical)

5212018

12

bull Slightabsent cytologic atypia

bull No mitoses

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

13

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed nevoid

Poor circumscription cannot assess less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 2-1 F37

bull Diagnosisbull Skin abdomen bull Lentiginous junctional nevus with mild dysplasia see description and commentbull OR Lentiginous junctional nevus

bull Comment bull Mild dysplasia is not an independent risk factor for melanoma however if this patient should

have other clinically atypical nevi andor a family or personal history of melanoma or other melanoma risk factors consideration of periodic surveillance may be appropriate

bull The lesion appears to be excised however even if this were not the case reexcision might not be necessary if this biopsy was considered representative of the lesion and especially if the patient were to be followed

bull Since mild dysplasia is not an independent risk factor for melanoma lesions of this type might be better given a descriptive name such as ldquolentiginous junctional nevusrdquo

bull It is important to distinguish these lesions from nevoid lentigo maligna which can also be characterized by slight degrees of cytologic atypia

bull This is an MPATH Category 1 lesion (no need for reexcision even if margins are positive)

Superficial Atypical Nevi

bull Nevi are important mainly in relation to melanoma

ndash Precursors ndash but risk for individual lesions is low (one in thousands)

ndash Risk markers ndash important mainly in high risk situations (patients with multiple atypical nevi family history high CSD etc)

ndash Simulants ndash important in everyday clinical decision-making

5212018

14

Grading of atypia in nevi correlation with melanoma risk Arumi-Uria McNutt Finnerty 2003

bull Grading of nevi with architectural disorder (dysplastic nevi) involves architectural and cytological features

bull Grades of atypia are related to patient history of melanoma ndash personal history of melanoma present in 57 of 2504 patients with mild

81 of 1657 with moderate and 197 of 320 patients with severe atypia

bull Odds ratio as a measure of association between NAD and history of melanomandash 408 for severe versus mild ndash 281 for severe versus moderate and ndash 145 for moderate versus mild dysplasia

bull ldquoMelanoma risk is greater in persons whose nevi have higher grade histological atypiardquo

Dysplasia Grading Criteria helliphellip Arumi-Uria et al Mod Pathol 2003

Mild Moderate Severe

bull The clinically most atypical macular nevus was biopsied from 80 newly incident cases of melanoma and spouse controls

bull Histological dysplasia was assigned on a subjective 0-4 point scale by a 13-member panel of dermatopathologists (International Melanoma Pathology Group)

bull Subjects with panel ratings gt 1 had increased relative risk of melanoma

bull Odds ratio after adjustment for confounders = 399 95 CI 102-1571

bull kappa statistic was 028 for the panel histological diagnoses indicating poor interobserver reproducibilityndash Repeating study agreed but found size to be a good surrogatecorrelate for

atypiandash Evidence-based criteria for histologic dysplasia as a risk marker

5212018

15

Xiong Rabkin Piepkorn Barnhill et al JAAD 2014

ldquoGiven that measuring diameter tends to be more objective than grading dysplasia these results could provide increased consistency when assessing risk of melanoma among patients with dysplastic nevirdquo

Rabkin Piepkorn Barnhill et al JAAD

Mild Dysplasia

bull Poorly reproducible diagnosis (vs nevus)bull Not associated with melanoma riskbull Not a high risk precursorbull Not a strong simulant of melanomabull UNCERTAINTY vs Moderate dysplasia No dysplasia

bull Should be considered in the spectrum of banal nevi (junctional or compound nevus eg lentiginous junctional nevus)

bull Complete excision is not necessary even when margins are positive

bull TERM ldquoMILD DYSPLASIArdquo SHOULD NO LONGER BE USED

bull (Lentiginous) Junctional Nevus

lt 4 mm diameter

minimal cytologic atypia

5212018

16

Moderate Dysplasia

bull Controversialbull Poorly reproducible diagnosis (vs mild severe)bull UNCERTAINTY vs Mild dysplasia MISbull Associated with melanoma riskbull Probably not a high risk precursorbull A weak simulant of melanoma (at least

histologically)

bull Complete excision is a consideration observation is an option

Severe Dysplasia

bull Reasonably reproducible diagnosis

bull UNCERTAINTY vs MIS

bull Associated with melanoma risk

bull Probably a high risk precursor

bull A strong simulant of melanoma (at least histologically)

bull Should be managed by complete excision and consideration of follow-up similar to MIS

Proposal for Grading Dysplasia

bull Junctionalcompound nevus

ndash Includes former mild dysplasia and ldquoClarkrsquos nevusrdquo

bull Low Grade Dysplasia (LGD)

ndash Former moderate dysplasia

bull High Grade Dysplasia (HGD)

ndash Former severe dysplasia

5212018

17

Case 4

Part 2-2 5475Clinical Information

Please find enclosed slides on a 36-year-old male with multiple dysplastic nevi removed Reason for Consultation

I have also enclosed a prior pathology report of other lesions removed My diagnosis is compound melanocytic nevus with architectural disorder and moderate cytologic atypia However

I am concerned that this lesion may be severely dysplastic Would you recommend a reexcision procedure

bull Broadbull Symmetricbull Moderately cellular bull Poorly circumscribed

5212018

18

bull Broadbull Symmetricbull Moderately

cellular bull Poorly

circumscribedbull Slight low

level pagetoid scatter

bull Moderate random atypia

bull Nuclear size 1-15x

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

19

Your Diagnosis

Low Grade

High Grade

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription cannot assess less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis (Part 2 Case 3)

Skin back (M36) Compound nevus with moderate dysplasia completely excised see description and comment

OR Compound dysplastic nevus low grade

Comment bull Patient presents with multiple lesions some of which are

dysplastic nevi with moderate dysplasia bull Benign lesions with little or no potential for recurrence and no

potential for metastasis bull Periodic follow-up may be appropriate for this patient

especially if there are other clinically atypical nevi andor a family or personal history of melanoma

bull Although the lesion extends close to the specimen margin there is no essential indication for reexcision especially if the patient is to be followed

This is an MPATH DX Category 1 or perhaps Category 2 lesion depending on clinical correlation and preference

5212018

20

Case 5

Part 2-3Clinical Information

A lesion from the back of a 54 year old manReason for consultation

The clinician was concerned about a melanoma but I favor a dysplastic nevus

Description

Very broad

Moderately cellular

Reasonably symmetrical

Uniformly elongated rete

Patchy infiltrate in dermis

5212018

21

5212018

22

bull Descriptionbull Very broad Moderate pagetoid scatter low

levelbull Moderately cellular Mild to moderate cytologic atypiabull Reasonably symmetrical Mild to moderate solar elastosisbull Uniformly elongated retebull Patchy infiltrate in dermis

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

23

Your Diagnosis

Low Grade

High Grade

Compound nevus with severe dysplasia(Severe architectural disorder moderate cytological atypia)

Feature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Cellularity high intermediate lower

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription common less common uncommon

Nested variable predominant predominant

Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate (1-15X) mild

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells Absent uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 5

bull Junctional nevus with severe melanocytic dysplasia completely excised see note

bull vs Junctional dysplastic nevus high grade

bull vs Intraepidermal atypical melanocytic proliferation (IAMPUS) cannot ro MISndash Diagnosis is based on ldquosevererdquo architectural features

(single cell predominance low level pagetoid scatter) with mild to moderate cytologic atypia

ndash MPATH-Dx Category III (consider excision with up to 5 mm margins if present at the margin)

5212018

24

Next Case

Part 2-5 35728Clinical Information

An irregular pigmented lesion on the back of a 59 year old manReason for Consultation

Is this a nevoid melanoma

Broad focally highly cellular asymmetric diffuse fibroplasia and variably sized nests in dermis

5212018

25

bull Only minimal pagetoid scatter

bull Moderate cytologic atypia

bull No mitosesbull Cells in dermal

nests are small nevoid

bull No confluent sheetlike growth

HMB46 staining is ldquotop-heavyrdquo(stratified)

bull Ki-67 proliferation is minimal in dermis

5212018

26

bull p16 staining is positive in a checkerboard pattern with nuclear and cytoplasmic positivity

Helpful Markers in Nevus vs Melanoma

bull HM45 stratificationndash J Invest Dermatol 1993 Mar100(3)313S-317S Immunophenotyping of compound and spitz nevi and vertical growth-phase

melanomas using a panel of monoclonal antibodies reactive in paraffin sectionsLazzaro B1 Elder DE Rebers A Power L Herlyn M Menrad A Johnson B

bull Low Ki-67 proliferation ratendash A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions

Li LX Crotty KA McCarthy SW Palmer AA Kril JJAm J Dermatopathol 2000 Dec22(6)489-95

bull Preservation of p16 protein expressionndash More problematical presence in an atypical tumor at

least precludes homozygous loss of 9p21 and is therefore reassuring but does not preclude diagnosis of melanoma

9p21 Locus

bull Contains p16 p14 and p15 all suppressor genes

bull Presumably all lost together in cases of homozygous 9p21 loss

bull Appears to have special significance in Spitzoid lesions

5212018

11

bull 25451bull Clinical Informationbull A 3 mm macular slightly variegated lesion from the back of a 37-year-old

womanbull Reason for Consultationbull Is this a dysplastic nevus

bull Smallbull Poorly circumscribedbull Nest predominate discretebull Patchy lymphocytes scant fibroplasia numerous melanophages (clinically

atypical)

5212018

12

bull Slightabsent cytologic atypia

bull No mitoses

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

13

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed nevoid

Poor circumscription cannot assess less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 2-1 F37

bull Diagnosisbull Skin abdomen bull Lentiginous junctional nevus with mild dysplasia see description and commentbull OR Lentiginous junctional nevus

bull Comment bull Mild dysplasia is not an independent risk factor for melanoma however if this patient should

have other clinically atypical nevi andor a family or personal history of melanoma or other melanoma risk factors consideration of periodic surveillance may be appropriate

bull The lesion appears to be excised however even if this were not the case reexcision might not be necessary if this biopsy was considered representative of the lesion and especially if the patient were to be followed

bull Since mild dysplasia is not an independent risk factor for melanoma lesions of this type might be better given a descriptive name such as ldquolentiginous junctional nevusrdquo

bull It is important to distinguish these lesions from nevoid lentigo maligna which can also be characterized by slight degrees of cytologic atypia

bull This is an MPATH Category 1 lesion (no need for reexcision even if margins are positive)

Superficial Atypical Nevi

bull Nevi are important mainly in relation to melanoma

ndash Precursors ndash but risk for individual lesions is low (one in thousands)

ndash Risk markers ndash important mainly in high risk situations (patients with multiple atypical nevi family history high CSD etc)

ndash Simulants ndash important in everyday clinical decision-making

5212018

14

Grading of atypia in nevi correlation with melanoma risk Arumi-Uria McNutt Finnerty 2003

bull Grading of nevi with architectural disorder (dysplastic nevi) involves architectural and cytological features

bull Grades of atypia are related to patient history of melanoma ndash personal history of melanoma present in 57 of 2504 patients with mild

81 of 1657 with moderate and 197 of 320 patients with severe atypia

bull Odds ratio as a measure of association between NAD and history of melanomandash 408 for severe versus mild ndash 281 for severe versus moderate and ndash 145 for moderate versus mild dysplasia

bull ldquoMelanoma risk is greater in persons whose nevi have higher grade histological atypiardquo

Dysplasia Grading Criteria helliphellip Arumi-Uria et al Mod Pathol 2003

Mild Moderate Severe

bull The clinically most atypical macular nevus was biopsied from 80 newly incident cases of melanoma and spouse controls

bull Histological dysplasia was assigned on a subjective 0-4 point scale by a 13-member panel of dermatopathologists (International Melanoma Pathology Group)

bull Subjects with panel ratings gt 1 had increased relative risk of melanoma

bull Odds ratio after adjustment for confounders = 399 95 CI 102-1571

bull kappa statistic was 028 for the panel histological diagnoses indicating poor interobserver reproducibilityndash Repeating study agreed but found size to be a good surrogatecorrelate for

atypiandash Evidence-based criteria for histologic dysplasia as a risk marker

5212018

15

Xiong Rabkin Piepkorn Barnhill et al JAAD 2014

ldquoGiven that measuring diameter tends to be more objective than grading dysplasia these results could provide increased consistency when assessing risk of melanoma among patients with dysplastic nevirdquo

Rabkin Piepkorn Barnhill et al JAAD

Mild Dysplasia

bull Poorly reproducible diagnosis (vs nevus)bull Not associated with melanoma riskbull Not a high risk precursorbull Not a strong simulant of melanomabull UNCERTAINTY vs Moderate dysplasia No dysplasia

bull Should be considered in the spectrum of banal nevi (junctional or compound nevus eg lentiginous junctional nevus)

bull Complete excision is not necessary even when margins are positive

bull TERM ldquoMILD DYSPLASIArdquo SHOULD NO LONGER BE USED

bull (Lentiginous) Junctional Nevus

lt 4 mm diameter

minimal cytologic atypia

5212018

16

Moderate Dysplasia

bull Controversialbull Poorly reproducible diagnosis (vs mild severe)bull UNCERTAINTY vs Mild dysplasia MISbull Associated with melanoma riskbull Probably not a high risk precursorbull A weak simulant of melanoma (at least

histologically)

bull Complete excision is a consideration observation is an option

Severe Dysplasia

bull Reasonably reproducible diagnosis

bull UNCERTAINTY vs MIS

bull Associated with melanoma risk

bull Probably a high risk precursor

bull A strong simulant of melanoma (at least histologically)

bull Should be managed by complete excision and consideration of follow-up similar to MIS

Proposal for Grading Dysplasia

bull Junctionalcompound nevus

ndash Includes former mild dysplasia and ldquoClarkrsquos nevusrdquo

bull Low Grade Dysplasia (LGD)

ndash Former moderate dysplasia

bull High Grade Dysplasia (HGD)

ndash Former severe dysplasia

5212018

17

Case 4

Part 2-2 5475Clinical Information

Please find enclosed slides on a 36-year-old male with multiple dysplastic nevi removed Reason for Consultation

I have also enclosed a prior pathology report of other lesions removed My diagnosis is compound melanocytic nevus with architectural disorder and moderate cytologic atypia However

I am concerned that this lesion may be severely dysplastic Would you recommend a reexcision procedure

bull Broadbull Symmetricbull Moderately cellular bull Poorly circumscribed

5212018

18

bull Broadbull Symmetricbull Moderately

cellular bull Poorly

circumscribedbull Slight low

level pagetoid scatter

bull Moderate random atypia

bull Nuclear size 1-15x

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

19

Your Diagnosis

Low Grade

High Grade

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription cannot assess less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis (Part 2 Case 3)

Skin back (M36) Compound nevus with moderate dysplasia completely excised see description and comment

OR Compound dysplastic nevus low grade

Comment bull Patient presents with multiple lesions some of which are

dysplastic nevi with moderate dysplasia bull Benign lesions with little or no potential for recurrence and no

potential for metastasis bull Periodic follow-up may be appropriate for this patient

especially if there are other clinically atypical nevi andor a family or personal history of melanoma

bull Although the lesion extends close to the specimen margin there is no essential indication for reexcision especially if the patient is to be followed

This is an MPATH DX Category 1 or perhaps Category 2 lesion depending on clinical correlation and preference

5212018

20

Case 5

Part 2-3Clinical Information

A lesion from the back of a 54 year old manReason for consultation

The clinician was concerned about a melanoma but I favor a dysplastic nevus

Description

Very broad

Moderately cellular

Reasonably symmetrical

Uniformly elongated rete

Patchy infiltrate in dermis

5212018

21

5212018

22

bull Descriptionbull Very broad Moderate pagetoid scatter low

levelbull Moderately cellular Mild to moderate cytologic atypiabull Reasonably symmetrical Mild to moderate solar elastosisbull Uniformly elongated retebull Patchy infiltrate in dermis

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

23

Your Diagnosis

Low Grade

High Grade

Compound nevus with severe dysplasia(Severe architectural disorder moderate cytological atypia)

Feature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Cellularity high intermediate lower

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription common less common uncommon

Nested variable predominant predominant

Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate (1-15X) mild

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells Absent uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 5

bull Junctional nevus with severe melanocytic dysplasia completely excised see note

bull vs Junctional dysplastic nevus high grade

bull vs Intraepidermal atypical melanocytic proliferation (IAMPUS) cannot ro MISndash Diagnosis is based on ldquosevererdquo architectural features

(single cell predominance low level pagetoid scatter) with mild to moderate cytologic atypia

ndash MPATH-Dx Category III (consider excision with up to 5 mm margins if present at the margin)

5212018

24

Next Case

Part 2-5 35728Clinical Information

An irregular pigmented lesion on the back of a 59 year old manReason for Consultation

Is this a nevoid melanoma

Broad focally highly cellular asymmetric diffuse fibroplasia and variably sized nests in dermis

5212018

25

bull Only minimal pagetoid scatter

bull Moderate cytologic atypia

bull No mitosesbull Cells in dermal

nests are small nevoid

bull No confluent sheetlike growth

HMB46 staining is ldquotop-heavyrdquo(stratified)

bull Ki-67 proliferation is minimal in dermis

5212018

26

bull p16 staining is positive in a checkerboard pattern with nuclear and cytoplasmic positivity

Helpful Markers in Nevus vs Melanoma

bull HM45 stratificationndash J Invest Dermatol 1993 Mar100(3)313S-317S Immunophenotyping of compound and spitz nevi and vertical growth-phase

melanomas using a panel of monoclonal antibodies reactive in paraffin sectionsLazzaro B1 Elder DE Rebers A Power L Herlyn M Menrad A Johnson B

bull Low Ki-67 proliferation ratendash A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions

Li LX Crotty KA McCarthy SW Palmer AA Kril JJAm J Dermatopathol 2000 Dec22(6)489-95

bull Preservation of p16 protein expressionndash More problematical presence in an atypical tumor at

least precludes homozygous loss of 9p21 and is therefore reassuring but does not preclude diagnosis of melanoma

9p21 Locus

bull Contains p16 p14 and p15 all suppressor genes

bull Presumably all lost together in cases of homozygous 9p21 loss

bull Appears to have special significance in Spitzoid lesions

5212018

12

bull Slightabsent cytologic atypia

bull No mitoses

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

13

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed nevoid

Poor circumscription cannot assess less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 2-1 F37

bull Diagnosisbull Skin abdomen bull Lentiginous junctional nevus with mild dysplasia see description and commentbull OR Lentiginous junctional nevus

bull Comment bull Mild dysplasia is not an independent risk factor for melanoma however if this patient should

have other clinically atypical nevi andor a family or personal history of melanoma or other melanoma risk factors consideration of periodic surveillance may be appropriate

bull The lesion appears to be excised however even if this were not the case reexcision might not be necessary if this biopsy was considered representative of the lesion and especially if the patient were to be followed

bull Since mild dysplasia is not an independent risk factor for melanoma lesions of this type might be better given a descriptive name such as ldquolentiginous junctional nevusrdquo

bull It is important to distinguish these lesions from nevoid lentigo maligna which can also be characterized by slight degrees of cytologic atypia

bull This is an MPATH Category 1 lesion (no need for reexcision even if margins are positive)

Superficial Atypical Nevi

bull Nevi are important mainly in relation to melanoma

ndash Precursors ndash but risk for individual lesions is low (one in thousands)

ndash Risk markers ndash important mainly in high risk situations (patients with multiple atypical nevi family history high CSD etc)

ndash Simulants ndash important in everyday clinical decision-making

5212018

14

Grading of atypia in nevi correlation with melanoma risk Arumi-Uria McNutt Finnerty 2003

bull Grading of nevi with architectural disorder (dysplastic nevi) involves architectural and cytological features

bull Grades of atypia are related to patient history of melanoma ndash personal history of melanoma present in 57 of 2504 patients with mild

81 of 1657 with moderate and 197 of 320 patients with severe atypia

bull Odds ratio as a measure of association between NAD and history of melanomandash 408 for severe versus mild ndash 281 for severe versus moderate and ndash 145 for moderate versus mild dysplasia

bull ldquoMelanoma risk is greater in persons whose nevi have higher grade histological atypiardquo

Dysplasia Grading Criteria helliphellip Arumi-Uria et al Mod Pathol 2003

Mild Moderate Severe

bull The clinically most atypical macular nevus was biopsied from 80 newly incident cases of melanoma and spouse controls

bull Histological dysplasia was assigned on a subjective 0-4 point scale by a 13-member panel of dermatopathologists (International Melanoma Pathology Group)

bull Subjects with panel ratings gt 1 had increased relative risk of melanoma

bull Odds ratio after adjustment for confounders = 399 95 CI 102-1571

bull kappa statistic was 028 for the panel histological diagnoses indicating poor interobserver reproducibilityndash Repeating study agreed but found size to be a good surrogatecorrelate for

atypiandash Evidence-based criteria for histologic dysplasia as a risk marker

5212018

15

Xiong Rabkin Piepkorn Barnhill et al JAAD 2014

ldquoGiven that measuring diameter tends to be more objective than grading dysplasia these results could provide increased consistency when assessing risk of melanoma among patients with dysplastic nevirdquo

Rabkin Piepkorn Barnhill et al JAAD

Mild Dysplasia

bull Poorly reproducible diagnosis (vs nevus)bull Not associated with melanoma riskbull Not a high risk precursorbull Not a strong simulant of melanomabull UNCERTAINTY vs Moderate dysplasia No dysplasia

bull Should be considered in the spectrum of banal nevi (junctional or compound nevus eg lentiginous junctional nevus)

bull Complete excision is not necessary even when margins are positive

bull TERM ldquoMILD DYSPLASIArdquo SHOULD NO LONGER BE USED

bull (Lentiginous) Junctional Nevus

lt 4 mm diameter

minimal cytologic atypia

5212018

16

Moderate Dysplasia

bull Controversialbull Poorly reproducible diagnosis (vs mild severe)bull UNCERTAINTY vs Mild dysplasia MISbull Associated with melanoma riskbull Probably not a high risk precursorbull A weak simulant of melanoma (at least

histologically)

bull Complete excision is a consideration observation is an option

Severe Dysplasia

bull Reasonably reproducible diagnosis

bull UNCERTAINTY vs MIS

bull Associated with melanoma risk

bull Probably a high risk precursor

bull A strong simulant of melanoma (at least histologically)

bull Should be managed by complete excision and consideration of follow-up similar to MIS

Proposal for Grading Dysplasia

bull Junctionalcompound nevus

ndash Includes former mild dysplasia and ldquoClarkrsquos nevusrdquo

bull Low Grade Dysplasia (LGD)

ndash Former moderate dysplasia

bull High Grade Dysplasia (HGD)

ndash Former severe dysplasia

5212018

17

Case 4

Part 2-2 5475Clinical Information

Please find enclosed slides on a 36-year-old male with multiple dysplastic nevi removed Reason for Consultation

I have also enclosed a prior pathology report of other lesions removed My diagnosis is compound melanocytic nevus with architectural disorder and moderate cytologic atypia However

I am concerned that this lesion may be severely dysplastic Would you recommend a reexcision procedure

bull Broadbull Symmetricbull Moderately cellular bull Poorly circumscribed

5212018

18

bull Broadbull Symmetricbull Moderately

cellular bull Poorly

circumscribedbull Slight low

level pagetoid scatter

bull Moderate random atypia

bull Nuclear size 1-15x

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

19

Your Diagnosis

Low Grade

High Grade

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription cannot assess less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis (Part 2 Case 3)

Skin back (M36) Compound nevus with moderate dysplasia completely excised see description and comment

OR Compound dysplastic nevus low grade

Comment bull Patient presents with multiple lesions some of which are

dysplastic nevi with moderate dysplasia bull Benign lesions with little or no potential for recurrence and no

potential for metastasis bull Periodic follow-up may be appropriate for this patient

especially if there are other clinically atypical nevi andor a family or personal history of melanoma

bull Although the lesion extends close to the specimen margin there is no essential indication for reexcision especially if the patient is to be followed

This is an MPATH DX Category 1 or perhaps Category 2 lesion depending on clinical correlation and preference

5212018

20

Case 5

Part 2-3Clinical Information

A lesion from the back of a 54 year old manReason for consultation

The clinician was concerned about a melanoma but I favor a dysplastic nevus

Description

Very broad

Moderately cellular

Reasonably symmetrical

Uniformly elongated rete

Patchy infiltrate in dermis

5212018

21

5212018

22

bull Descriptionbull Very broad Moderate pagetoid scatter low

levelbull Moderately cellular Mild to moderate cytologic atypiabull Reasonably symmetrical Mild to moderate solar elastosisbull Uniformly elongated retebull Patchy infiltrate in dermis

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

23

Your Diagnosis

Low Grade

High Grade

Compound nevus with severe dysplasia(Severe architectural disorder moderate cytological atypia)

Feature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Cellularity high intermediate lower

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription common less common uncommon

Nested variable predominant predominant

Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate (1-15X) mild

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells Absent uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 5

bull Junctional nevus with severe melanocytic dysplasia completely excised see note

bull vs Junctional dysplastic nevus high grade

bull vs Intraepidermal atypical melanocytic proliferation (IAMPUS) cannot ro MISndash Diagnosis is based on ldquosevererdquo architectural features

(single cell predominance low level pagetoid scatter) with mild to moderate cytologic atypia

ndash MPATH-Dx Category III (consider excision with up to 5 mm margins if present at the margin)

5212018

24

Next Case

Part 2-5 35728Clinical Information

An irregular pigmented lesion on the back of a 59 year old manReason for Consultation

Is this a nevoid melanoma

Broad focally highly cellular asymmetric diffuse fibroplasia and variably sized nests in dermis

5212018

25

bull Only minimal pagetoid scatter

bull Moderate cytologic atypia

bull No mitosesbull Cells in dermal

nests are small nevoid

bull No confluent sheetlike growth

HMB46 staining is ldquotop-heavyrdquo(stratified)

bull Ki-67 proliferation is minimal in dermis

5212018

26

bull p16 staining is positive in a checkerboard pattern with nuclear and cytoplasmic positivity

Helpful Markers in Nevus vs Melanoma

bull HM45 stratificationndash J Invest Dermatol 1993 Mar100(3)313S-317S Immunophenotyping of compound and spitz nevi and vertical growth-phase

melanomas using a panel of monoclonal antibodies reactive in paraffin sectionsLazzaro B1 Elder DE Rebers A Power L Herlyn M Menrad A Johnson B

bull Low Ki-67 proliferation ratendash A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions

Li LX Crotty KA McCarthy SW Palmer AA Kril JJAm J Dermatopathol 2000 Dec22(6)489-95

bull Preservation of p16 protein expressionndash More problematical presence in an atypical tumor at

least precludes homozygous loss of 9p21 and is therefore reassuring but does not preclude diagnosis of melanoma

9p21 Locus

bull Contains p16 p14 and p15 all suppressor genes

bull Presumably all lost together in cases of homozygous 9p21 loss

bull Appears to have special significance in Spitzoid lesions

5212018

13

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed nevoid

Poor circumscription cannot assess less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 2-1 F37

bull Diagnosisbull Skin abdomen bull Lentiginous junctional nevus with mild dysplasia see description and commentbull OR Lentiginous junctional nevus

bull Comment bull Mild dysplasia is not an independent risk factor for melanoma however if this patient should

have other clinically atypical nevi andor a family or personal history of melanoma or other melanoma risk factors consideration of periodic surveillance may be appropriate

bull The lesion appears to be excised however even if this were not the case reexcision might not be necessary if this biopsy was considered representative of the lesion and especially if the patient were to be followed

bull Since mild dysplasia is not an independent risk factor for melanoma lesions of this type might be better given a descriptive name such as ldquolentiginous junctional nevusrdquo

bull It is important to distinguish these lesions from nevoid lentigo maligna which can also be characterized by slight degrees of cytologic atypia

bull This is an MPATH Category 1 lesion (no need for reexcision even if margins are positive)

Superficial Atypical Nevi

bull Nevi are important mainly in relation to melanoma

ndash Precursors ndash but risk for individual lesions is low (one in thousands)

ndash Risk markers ndash important mainly in high risk situations (patients with multiple atypical nevi family history high CSD etc)

ndash Simulants ndash important in everyday clinical decision-making

5212018

14

Grading of atypia in nevi correlation with melanoma risk Arumi-Uria McNutt Finnerty 2003

bull Grading of nevi with architectural disorder (dysplastic nevi) involves architectural and cytological features

bull Grades of atypia are related to patient history of melanoma ndash personal history of melanoma present in 57 of 2504 patients with mild

81 of 1657 with moderate and 197 of 320 patients with severe atypia

bull Odds ratio as a measure of association between NAD and history of melanomandash 408 for severe versus mild ndash 281 for severe versus moderate and ndash 145 for moderate versus mild dysplasia

bull ldquoMelanoma risk is greater in persons whose nevi have higher grade histological atypiardquo

Dysplasia Grading Criteria helliphellip Arumi-Uria et al Mod Pathol 2003

Mild Moderate Severe

bull The clinically most atypical macular nevus was biopsied from 80 newly incident cases of melanoma and spouse controls

bull Histological dysplasia was assigned on a subjective 0-4 point scale by a 13-member panel of dermatopathologists (International Melanoma Pathology Group)

bull Subjects with panel ratings gt 1 had increased relative risk of melanoma

bull Odds ratio after adjustment for confounders = 399 95 CI 102-1571

bull kappa statistic was 028 for the panel histological diagnoses indicating poor interobserver reproducibilityndash Repeating study agreed but found size to be a good surrogatecorrelate for

atypiandash Evidence-based criteria for histologic dysplasia as a risk marker

5212018

15

Xiong Rabkin Piepkorn Barnhill et al JAAD 2014

ldquoGiven that measuring diameter tends to be more objective than grading dysplasia these results could provide increased consistency when assessing risk of melanoma among patients with dysplastic nevirdquo

Rabkin Piepkorn Barnhill et al JAAD

Mild Dysplasia

bull Poorly reproducible diagnosis (vs nevus)bull Not associated with melanoma riskbull Not a high risk precursorbull Not a strong simulant of melanomabull UNCERTAINTY vs Moderate dysplasia No dysplasia

bull Should be considered in the spectrum of banal nevi (junctional or compound nevus eg lentiginous junctional nevus)

bull Complete excision is not necessary even when margins are positive

bull TERM ldquoMILD DYSPLASIArdquo SHOULD NO LONGER BE USED

bull (Lentiginous) Junctional Nevus

lt 4 mm diameter

minimal cytologic atypia

5212018

16

Moderate Dysplasia

bull Controversialbull Poorly reproducible diagnosis (vs mild severe)bull UNCERTAINTY vs Mild dysplasia MISbull Associated with melanoma riskbull Probably not a high risk precursorbull A weak simulant of melanoma (at least

histologically)

bull Complete excision is a consideration observation is an option

Severe Dysplasia

bull Reasonably reproducible diagnosis

bull UNCERTAINTY vs MIS

bull Associated with melanoma risk

bull Probably a high risk precursor

bull A strong simulant of melanoma (at least histologically)

bull Should be managed by complete excision and consideration of follow-up similar to MIS

Proposal for Grading Dysplasia

bull Junctionalcompound nevus

ndash Includes former mild dysplasia and ldquoClarkrsquos nevusrdquo

bull Low Grade Dysplasia (LGD)

ndash Former moderate dysplasia

bull High Grade Dysplasia (HGD)

ndash Former severe dysplasia

5212018

17

Case 4

Part 2-2 5475Clinical Information

Please find enclosed slides on a 36-year-old male with multiple dysplastic nevi removed Reason for Consultation

I have also enclosed a prior pathology report of other lesions removed My diagnosis is compound melanocytic nevus with architectural disorder and moderate cytologic atypia However

I am concerned that this lesion may be severely dysplastic Would you recommend a reexcision procedure

bull Broadbull Symmetricbull Moderately cellular bull Poorly circumscribed

5212018

18

bull Broadbull Symmetricbull Moderately

cellular bull Poorly

circumscribedbull Slight low

level pagetoid scatter

bull Moderate random atypia

bull Nuclear size 1-15x

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

19

Your Diagnosis

Low Grade

High Grade

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription cannot assess less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis (Part 2 Case 3)

Skin back (M36) Compound nevus with moderate dysplasia completely excised see description and comment

OR Compound dysplastic nevus low grade

Comment bull Patient presents with multiple lesions some of which are

dysplastic nevi with moderate dysplasia bull Benign lesions with little or no potential for recurrence and no

potential for metastasis bull Periodic follow-up may be appropriate for this patient

especially if there are other clinically atypical nevi andor a family or personal history of melanoma

bull Although the lesion extends close to the specimen margin there is no essential indication for reexcision especially if the patient is to be followed

This is an MPATH DX Category 1 or perhaps Category 2 lesion depending on clinical correlation and preference

5212018

20

Case 5

Part 2-3Clinical Information

A lesion from the back of a 54 year old manReason for consultation

The clinician was concerned about a melanoma but I favor a dysplastic nevus

Description

Very broad

Moderately cellular

Reasonably symmetrical

Uniformly elongated rete

Patchy infiltrate in dermis

5212018

21

5212018

22

bull Descriptionbull Very broad Moderate pagetoid scatter low

levelbull Moderately cellular Mild to moderate cytologic atypiabull Reasonably symmetrical Mild to moderate solar elastosisbull Uniformly elongated retebull Patchy infiltrate in dermis

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

23

Your Diagnosis

Low Grade

High Grade

Compound nevus with severe dysplasia(Severe architectural disorder moderate cytological atypia)

Feature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Cellularity high intermediate lower

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription common less common uncommon

Nested variable predominant predominant

Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate (1-15X) mild

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells Absent uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 5

bull Junctional nevus with severe melanocytic dysplasia completely excised see note

bull vs Junctional dysplastic nevus high grade

bull vs Intraepidermal atypical melanocytic proliferation (IAMPUS) cannot ro MISndash Diagnosis is based on ldquosevererdquo architectural features

(single cell predominance low level pagetoid scatter) with mild to moderate cytologic atypia

ndash MPATH-Dx Category III (consider excision with up to 5 mm margins if present at the margin)

5212018

24

Next Case

Part 2-5 35728Clinical Information

An irregular pigmented lesion on the back of a 59 year old manReason for Consultation

Is this a nevoid melanoma

Broad focally highly cellular asymmetric diffuse fibroplasia and variably sized nests in dermis

5212018

25

bull Only minimal pagetoid scatter

bull Moderate cytologic atypia

bull No mitosesbull Cells in dermal

nests are small nevoid

bull No confluent sheetlike growth

HMB46 staining is ldquotop-heavyrdquo(stratified)

bull Ki-67 proliferation is minimal in dermis

5212018

26

bull p16 staining is positive in a checkerboard pattern with nuclear and cytoplasmic positivity

Helpful Markers in Nevus vs Melanoma

bull HM45 stratificationndash J Invest Dermatol 1993 Mar100(3)313S-317S Immunophenotyping of compound and spitz nevi and vertical growth-phase

melanomas using a panel of monoclonal antibodies reactive in paraffin sectionsLazzaro B1 Elder DE Rebers A Power L Herlyn M Menrad A Johnson B

bull Low Ki-67 proliferation ratendash A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions

Li LX Crotty KA McCarthy SW Palmer AA Kril JJAm J Dermatopathol 2000 Dec22(6)489-95

bull Preservation of p16 protein expressionndash More problematical presence in an atypical tumor at

least precludes homozygous loss of 9p21 and is therefore reassuring but does not preclude diagnosis of melanoma

9p21 Locus

bull Contains p16 p14 and p15 all suppressor genes

bull Presumably all lost together in cases of homozygous 9p21 loss

bull Appears to have special significance in Spitzoid lesions

5212018

14

Grading of atypia in nevi correlation with melanoma risk Arumi-Uria McNutt Finnerty 2003

bull Grading of nevi with architectural disorder (dysplastic nevi) involves architectural and cytological features

bull Grades of atypia are related to patient history of melanoma ndash personal history of melanoma present in 57 of 2504 patients with mild

81 of 1657 with moderate and 197 of 320 patients with severe atypia

bull Odds ratio as a measure of association between NAD and history of melanomandash 408 for severe versus mild ndash 281 for severe versus moderate and ndash 145 for moderate versus mild dysplasia

bull ldquoMelanoma risk is greater in persons whose nevi have higher grade histological atypiardquo

Dysplasia Grading Criteria helliphellip Arumi-Uria et al Mod Pathol 2003

Mild Moderate Severe

bull The clinically most atypical macular nevus was biopsied from 80 newly incident cases of melanoma and spouse controls

bull Histological dysplasia was assigned on a subjective 0-4 point scale by a 13-member panel of dermatopathologists (International Melanoma Pathology Group)

bull Subjects with panel ratings gt 1 had increased relative risk of melanoma

bull Odds ratio after adjustment for confounders = 399 95 CI 102-1571

bull kappa statistic was 028 for the panel histological diagnoses indicating poor interobserver reproducibilityndash Repeating study agreed but found size to be a good surrogatecorrelate for

atypiandash Evidence-based criteria for histologic dysplasia as a risk marker

5212018

15

Xiong Rabkin Piepkorn Barnhill et al JAAD 2014

ldquoGiven that measuring diameter tends to be more objective than grading dysplasia these results could provide increased consistency when assessing risk of melanoma among patients with dysplastic nevirdquo

Rabkin Piepkorn Barnhill et al JAAD

Mild Dysplasia

bull Poorly reproducible diagnosis (vs nevus)bull Not associated with melanoma riskbull Not a high risk precursorbull Not a strong simulant of melanomabull UNCERTAINTY vs Moderate dysplasia No dysplasia

bull Should be considered in the spectrum of banal nevi (junctional or compound nevus eg lentiginous junctional nevus)

bull Complete excision is not necessary even when margins are positive

bull TERM ldquoMILD DYSPLASIArdquo SHOULD NO LONGER BE USED

bull (Lentiginous) Junctional Nevus

lt 4 mm diameter

minimal cytologic atypia

5212018

16

Moderate Dysplasia

bull Controversialbull Poorly reproducible diagnosis (vs mild severe)bull UNCERTAINTY vs Mild dysplasia MISbull Associated with melanoma riskbull Probably not a high risk precursorbull A weak simulant of melanoma (at least

histologically)

bull Complete excision is a consideration observation is an option

Severe Dysplasia

bull Reasonably reproducible diagnosis

bull UNCERTAINTY vs MIS

bull Associated with melanoma risk

bull Probably a high risk precursor

bull A strong simulant of melanoma (at least histologically)

bull Should be managed by complete excision and consideration of follow-up similar to MIS

Proposal for Grading Dysplasia

bull Junctionalcompound nevus

ndash Includes former mild dysplasia and ldquoClarkrsquos nevusrdquo

bull Low Grade Dysplasia (LGD)

ndash Former moderate dysplasia

bull High Grade Dysplasia (HGD)

ndash Former severe dysplasia

5212018

17

Case 4

Part 2-2 5475Clinical Information

Please find enclosed slides on a 36-year-old male with multiple dysplastic nevi removed Reason for Consultation

I have also enclosed a prior pathology report of other lesions removed My diagnosis is compound melanocytic nevus with architectural disorder and moderate cytologic atypia However

I am concerned that this lesion may be severely dysplastic Would you recommend a reexcision procedure

bull Broadbull Symmetricbull Moderately cellular bull Poorly circumscribed

5212018

18

bull Broadbull Symmetricbull Moderately

cellular bull Poorly

circumscribedbull Slight low

level pagetoid scatter

bull Moderate random atypia

bull Nuclear size 1-15x

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

19

Your Diagnosis

Low Grade

High Grade

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription cannot assess less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis (Part 2 Case 3)

Skin back (M36) Compound nevus with moderate dysplasia completely excised see description and comment

OR Compound dysplastic nevus low grade

Comment bull Patient presents with multiple lesions some of which are

dysplastic nevi with moderate dysplasia bull Benign lesions with little or no potential for recurrence and no

potential for metastasis bull Periodic follow-up may be appropriate for this patient

especially if there are other clinically atypical nevi andor a family or personal history of melanoma

bull Although the lesion extends close to the specimen margin there is no essential indication for reexcision especially if the patient is to be followed

This is an MPATH DX Category 1 or perhaps Category 2 lesion depending on clinical correlation and preference

5212018

20

Case 5

Part 2-3Clinical Information

A lesion from the back of a 54 year old manReason for consultation

The clinician was concerned about a melanoma but I favor a dysplastic nevus

Description

Very broad

Moderately cellular

Reasonably symmetrical

Uniformly elongated rete

Patchy infiltrate in dermis

5212018

21

5212018

22

bull Descriptionbull Very broad Moderate pagetoid scatter low

levelbull Moderately cellular Mild to moderate cytologic atypiabull Reasonably symmetrical Mild to moderate solar elastosisbull Uniformly elongated retebull Patchy infiltrate in dermis

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

23

Your Diagnosis

Low Grade

High Grade

Compound nevus with severe dysplasia(Severe architectural disorder moderate cytological atypia)

Feature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Cellularity high intermediate lower

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription common less common uncommon

Nested variable predominant predominant

Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate (1-15X) mild

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells Absent uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 5

bull Junctional nevus with severe melanocytic dysplasia completely excised see note

bull vs Junctional dysplastic nevus high grade

bull vs Intraepidermal atypical melanocytic proliferation (IAMPUS) cannot ro MISndash Diagnosis is based on ldquosevererdquo architectural features

(single cell predominance low level pagetoid scatter) with mild to moderate cytologic atypia

ndash MPATH-Dx Category III (consider excision with up to 5 mm margins if present at the margin)

5212018

24

Next Case

Part 2-5 35728Clinical Information

An irregular pigmented lesion on the back of a 59 year old manReason for Consultation

Is this a nevoid melanoma

Broad focally highly cellular asymmetric diffuse fibroplasia and variably sized nests in dermis

5212018

25

bull Only minimal pagetoid scatter

bull Moderate cytologic atypia

bull No mitosesbull Cells in dermal

nests are small nevoid

bull No confluent sheetlike growth

HMB46 staining is ldquotop-heavyrdquo(stratified)

bull Ki-67 proliferation is minimal in dermis

5212018

26

bull p16 staining is positive in a checkerboard pattern with nuclear and cytoplasmic positivity

Helpful Markers in Nevus vs Melanoma

bull HM45 stratificationndash J Invest Dermatol 1993 Mar100(3)313S-317S Immunophenotyping of compound and spitz nevi and vertical growth-phase

melanomas using a panel of monoclonal antibodies reactive in paraffin sectionsLazzaro B1 Elder DE Rebers A Power L Herlyn M Menrad A Johnson B

bull Low Ki-67 proliferation ratendash A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions

Li LX Crotty KA McCarthy SW Palmer AA Kril JJAm J Dermatopathol 2000 Dec22(6)489-95

bull Preservation of p16 protein expressionndash More problematical presence in an atypical tumor at

least precludes homozygous loss of 9p21 and is therefore reassuring but does not preclude diagnosis of melanoma

9p21 Locus

bull Contains p16 p14 and p15 all suppressor genes

bull Presumably all lost together in cases of homozygous 9p21 loss

bull Appears to have special significance in Spitzoid lesions

5212018

15

Xiong Rabkin Piepkorn Barnhill et al JAAD 2014

ldquoGiven that measuring diameter tends to be more objective than grading dysplasia these results could provide increased consistency when assessing risk of melanoma among patients with dysplastic nevirdquo

Rabkin Piepkorn Barnhill et al JAAD

Mild Dysplasia

bull Poorly reproducible diagnosis (vs nevus)bull Not associated with melanoma riskbull Not a high risk precursorbull Not a strong simulant of melanomabull UNCERTAINTY vs Moderate dysplasia No dysplasia

bull Should be considered in the spectrum of banal nevi (junctional or compound nevus eg lentiginous junctional nevus)

bull Complete excision is not necessary even when margins are positive

bull TERM ldquoMILD DYSPLASIArdquo SHOULD NO LONGER BE USED

bull (Lentiginous) Junctional Nevus

lt 4 mm diameter

minimal cytologic atypia

5212018

16

Moderate Dysplasia

bull Controversialbull Poorly reproducible diagnosis (vs mild severe)bull UNCERTAINTY vs Mild dysplasia MISbull Associated with melanoma riskbull Probably not a high risk precursorbull A weak simulant of melanoma (at least

histologically)

bull Complete excision is a consideration observation is an option

Severe Dysplasia

bull Reasonably reproducible diagnosis

bull UNCERTAINTY vs MIS

bull Associated with melanoma risk

bull Probably a high risk precursor

bull A strong simulant of melanoma (at least histologically)

bull Should be managed by complete excision and consideration of follow-up similar to MIS

Proposal for Grading Dysplasia

bull Junctionalcompound nevus

ndash Includes former mild dysplasia and ldquoClarkrsquos nevusrdquo

bull Low Grade Dysplasia (LGD)

ndash Former moderate dysplasia

bull High Grade Dysplasia (HGD)

ndash Former severe dysplasia

5212018

17

Case 4

Part 2-2 5475Clinical Information

Please find enclosed slides on a 36-year-old male with multiple dysplastic nevi removed Reason for Consultation

I have also enclosed a prior pathology report of other lesions removed My diagnosis is compound melanocytic nevus with architectural disorder and moderate cytologic atypia However

I am concerned that this lesion may be severely dysplastic Would you recommend a reexcision procedure

bull Broadbull Symmetricbull Moderately cellular bull Poorly circumscribed

5212018

18

bull Broadbull Symmetricbull Moderately

cellular bull Poorly

circumscribedbull Slight low

level pagetoid scatter

bull Moderate random atypia

bull Nuclear size 1-15x

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

19

Your Diagnosis

Low Grade

High Grade

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription cannot assess less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis (Part 2 Case 3)

Skin back (M36) Compound nevus with moderate dysplasia completely excised see description and comment

OR Compound dysplastic nevus low grade

Comment bull Patient presents with multiple lesions some of which are

dysplastic nevi with moderate dysplasia bull Benign lesions with little or no potential for recurrence and no

potential for metastasis bull Periodic follow-up may be appropriate for this patient

especially if there are other clinically atypical nevi andor a family or personal history of melanoma

bull Although the lesion extends close to the specimen margin there is no essential indication for reexcision especially if the patient is to be followed

This is an MPATH DX Category 1 or perhaps Category 2 lesion depending on clinical correlation and preference

5212018

20

Case 5

Part 2-3Clinical Information

A lesion from the back of a 54 year old manReason for consultation

The clinician was concerned about a melanoma but I favor a dysplastic nevus

Description

Very broad

Moderately cellular

Reasonably symmetrical

Uniformly elongated rete

Patchy infiltrate in dermis

5212018

21

5212018

22

bull Descriptionbull Very broad Moderate pagetoid scatter low

levelbull Moderately cellular Mild to moderate cytologic atypiabull Reasonably symmetrical Mild to moderate solar elastosisbull Uniformly elongated retebull Patchy infiltrate in dermis

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

23

Your Diagnosis

Low Grade

High Grade

Compound nevus with severe dysplasia(Severe architectural disorder moderate cytological atypia)

Feature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Cellularity high intermediate lower

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription common less common uncommon

Nested variable predominant predominant

Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate (1-15X) mild

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells Absent uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 5

bull Junctional nevus with severe melanocytic dysplasia completely excised see note

bull vs Junctional dysplastic nevus high grade

bull vs Intraepidermal atypical melanocytic proliferation (IAMPUS) cannot ro MISndash Diagnosis is based on ldquosevererdquo architectural features

(single cell predominance low level pagetoid scatter) with mild to moderate cytologic atypia

ndash MPATH-Dx Category III (consider excision with up to 5 mm margins if present at the margin)

5212018

24

Next Case

Part 2-5 35728Clinical Information

An irregular pigmented lesion on the back of a 59 year old manReason for Consultation

Is this a nevoid melanoma

Broad focally highly cellular asymmetric diffuse fibroplasia and variably sized nests in dermis

5212018

25

bull Only minimal pagetoid scatter

bull Moderate cytologic atypia

bull No mitosesbull Cells in dermal

nests are small nevoid

bull No confluent sheetlike growth

HMB46 staining is ldquotop-heavyrdquo(stratified)

bull Ki-67 proliferation is minimal in dermis

5212018

26

bull p16 staining is positive in a checkerboard pattern with nuclear and cytoplasmic positivity

Helpful Markers in Nevus vs Melanoma

bull HM45 stratificationndash J Invest Dermatol 1993 Mar100(3)313S-317S Immunophenotyping of compound and spitz nevi and vertical growth-phase

melanomas using a panel of monoclonal antibodies reactive in paraffin sectionsLazzaro B1 Elder DE Rebers A Power L Herlyn M Menrad A Johnson B

bull Low Ki-67 proliferation ratendash A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions

Li LX Crotty KA McCarthy SW Palmer AA Kril JJAm J Dermatopathol 2000 Dec22(6)489-95

bull Preservation of p16 protein expressionndash More problematical presence in an atypical tumor at

least precludes homozygous loss of 9p21 and is therefore reassuring but does not preclude diagnosis of melanoma

9p21 Locus

bull Contains p16 p14 and p15 all suppressor genes

bull Presumably all lost together in cases of homozygous 9p21 loss

bull Appears to have special significance in Spitzoid lesions

5212018

16

Moderate Dysplasia

bull Controversialbull Poorly reproducible diagnosis (vs mild severe)bull UNCERTAINTY vs Mild dysplasia MISbull Associated with melanoma riskbull Probably not a high risk precursorbull A weak simulant of melanoma (at least

histologically)

bull Complete excision is a consideration observation is an option

Severe Dysplasia

bull Reasonably reproducible diagnosis

bull UNCERTAINTY vs MIS

bull Associated with melanoma risk

bull Probably a high risk precursor

bull A strong simulant of melanoma (at least histologically)

bull Should be managed by complete excision and consideration of follow-up similar to MIS

Proposal for Grading Dysplasia

bull Junctionalcompound nevus

ndash Includes former mild dysplasia and ldquoClarkrsquos nevusrdquo

bull Low Grade Dysplasia (LGD)

ndash Former moderate dysplasia

bull High Grade Dysplasia (HGD)

ndash Former severe dysplasia

5212018

17

Case 4

Part 2-2 5475Clinical Information

Please find enclosed slides on a 36-year-old male with multiple dysplastic nevi removed Reason for Consultation

I have also enclosed a prior pathology report of other lesions removed My diagnosis is compound melanocytic nevus with architectural disorder and moderate cytologic atypia However

I am concerned that this lesion may be severely dysplastic Would you recommend a reexcision procedure

bull Broadbull Symmetricbull Moderately cellular bull Poorly circumscribed

5212018

18

bull Broadbull Symmetricbull Moderately

cellular bull Poorly

circumscribedbull Slight low

level pagetoid scatter

bull Moderate random atypia

bull Nuclear size 1-15x

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

19

Your Diagnosis

Low Grade

High Grade

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription cannot assess less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis (Part 2 Case 3)

Skin back (M36) Compound nevus with moderate dysplasia completely excised see description and comment

OR Compound dysplastic nevus low grade

Comment bull Patient presents with multiple lesions some of which are

dysplastic nevi with moderate dysplasia bull Benign lesions with little or no potential for recurrence and no

potential for metastasis bull Periodic follow-up may be appropriate for this patient

especially if there are other clinically atypical nevi andor a family or personal history of melanoma

bull Although the lesion extends close to the specimen margin there is no essential indication for reexcision especially if the patient is to be followed

This is an MPATH DX Category 1 or perhaps Category 2 lesion depending on clinical correlation and preference

5212018

20

Case 5

Part 2-3Clinical Information

A lesion from the back of a 54 year old manReason for consultation

The clinician was concerned about a melanoma but I favor a dysplastic nevus

Description

Very broad

Moderately cellular

Reasonably symmetrical

Uniformly elongated rete

Patchy infiltrate in dermis

5212018

21

5212018

22

bull Descriptionbull Very broad Moderate pagetoid scatter low

levelbull Moderately cellular Mild to moderate cytologic atypiabull Reasonably symmetrical Mild to moderate solar elastosisbull Uniformly elongated retebull Patchy infiltrate in dermis

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

23

Your Diagnosis

Low Grade

High Grade

Compound nevus with severe dysplasia(Severe architectural disorder moderate cytological atypia)

Feature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Cellularity high intermediate lower

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription common less common uncommon

Nested variable predominant predominant

Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate (1-15X) mild

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells Absent uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 5

bull Junctional nevus with severe melanocytic dysplasia completely excised see note

bull vs Junctional dysplastic nevus high grade

bull vs Intraepidermal atypical melanocytic proliferation (IAMPUS) cannot ro MISndash Diagnosis is based on ldquosevererdquo architectural features

(single cell predominance low level pagetoid scatter) with mild to moderate cytologic atypia

ndash MPATH-Dx Category III (consider excision with up to 5 mm margins if present at the margin)

5212018

24

Next Case

Part 2-5 35728Clinical Information

An irregular pigmented lesion on the back of a 59 year old manReason for Consultation

Is this a nevoid melanoma

Broad focally highly cellular asymmetric diffuse fibroplasia and variably sized nests in dermis

5212018

25

bull Only minimal pagetoid scatter

bull Moderate cytologic atypia

bull No mitosesbull Cells in dermal

nests are small nevoid

bull No confluent sheetlike growth

HMB46 staining is ldquotop-heavyrdquo(stratified)

bull Ki-67 proliferation is minimal in dermis

5212018

26

bull p16 staining is positive in a checkerboard pattern with nuclear and cytoplasmic positivity

Helpful Markers in Nevus vs Melanoma

bull HM45 stratificationndash J Invest Dermatol 1993 Mar100(3)313S-317S Immunophenotyping of compound and spitz nevi and vertical growth-phase

melanomas using a panel of monoclonal antibodies reactive in paraffin sectionsLazzaro B1 Elder DE Rebers A Power L Herlyn M Menrad A Johnson B

bull Low Ki-67 proliferation ratendash A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions

Li LX Crotty KA McCarthy SW Palmer AA Kril JJAm J Dermatopathol 2000 Dec22(6)489-95

bull Preservation of p16 protein expressionndash More problematical presence in an atypical tumor at

least precludes homozygous loss of 9p21 and is therefore reassuring but does not preclude diagnosis of melanoma

9p21 Locus

bull Contains p16 p14 and p15 all suppressor genes

bull Presumably all lost together in cases of homozygous 9p21 loss

bull Appears to have special significance in Spitzoid lesions

5212018

17

Case 4

Part 2-2 5475Clinical Information

Please find enclosed slides on a 36-year-old male with multiple dysplastic nevi removed Reason for Consultation

I have also enclosed a prior pathology report of other lesions removed My diagnosis is compound melanocytic nevus with architectural disorder and moderate cytologic atypia However

I am concerned that this lesion may be severely dysplastic Would you recommend a reexcision procedure

bull Broadbull Symmetricbull Moderately cellular bull Poorly circumscribed

5212018

18

bull Broadbull Symmetricbull Moderately

cellular bull Poorly

circumscribedbull Slight low

level pagetoid scatter

bull Moderate random atypia

bull Nuclear size 1-15x

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

19

Your Diagnosis

Low Grade

High Grade

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription cannot assess less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis (Part 2 Case 3)

Skin back (M36) Compound nevus with moderate dysplasia completely excised see description and comment

OR Compound dysplastic nevus low grade

Comment bull Patient presents with multiple lesions some of which are

dysplastic nevi with moderate dysplasia bull Benign lesions with little or no potential for recurrence and no

potential for metastasis bull Periodic follow-up may be appropriate for this patient

especially if there are other clinically atypical nevi andor a family or personal history of melanoma

bull Although the lesion extends close to the specimen margin there is no essential indication for reexcision especially if the patient is to be followed

This is an MPATH DX Category 1 or perhaps Category 2 lesion depending on clinical correlation and preference

5212018

20

Case 5

Part 2-3Clinical Information

A lesion from the back of a 54 year old manReason for consultation

The clinician was concerned about a melanoma but I favor a dysplastic nevus

Description

Very broad

Moderately cellular

Reasonably symmetrical

Uniformly elongated rete

Patchy infiltrate in dermis

5212018

21

5212018

22

bull Descriptionbull Very broad Moderate pagetoid scatter low

levelbull Moderately cellular Mild to moderate cytologic atypiabull Reasonably symmetrical Mild to moderate solar elastosisbull Uniformly elongated retebull Patchy infiltrate in dermis

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

23

Your Diagnosis

Low Grade

High Grade

Compound nevus with severe dysplasia(Severe architectural disorder moderate cytological atypia)

Feature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Cellularity high intermediate lower

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription common less common uncommon

Nested variable predominant predominant

Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate (1-15X) mild

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells Absent uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 5

bull Junctional nevus with severe melanocytic dysplasia completely excised see note

bull vs Junctional dysplastic nevus high grade

bull vs Intraepidermal atypical melanocytic proliferation (IAMPUS) cannot ro MISndash Diagnosis is based on ldquosevererdquo architectural features

(single cell predominance low level pagetoid scatter) with mild to moderate cytologic atypia

ndash MPATH-Dx Category III (consider excision with up to 5 mm margins if present at the margin)

5212018

24

Next Case

Part 2-5 35728Clinical Information

An irregular pigmented lesion on the back of a 59 year old manReason for Consultation

Is this a nevoid melanoma

Broad focally highly cellular asymmetric diffuse fibroplasia and variably sized nests in dermis

5212018

25

bull Only minimal pagetoid scatter

bull Moderate cytologic atypia

bull No mitosesbull Cells in dermal

nests are small nevoid

bull No confluent sheetlike growth

HMB46 staining is ldquotop-heavyrdquo(stratified)

bull Ki-67 proliferation is minimal in dermis

5212018

26

bull p16 staining is positive in a checkerboard pattern with nuclear and cytoplasmic positivity

Helpful Markers in Nevus vs Melanoma

bull HM45 stratificationndash J Invest Dermatol 1993 Mar100(3)313S-317S Immunophenotyping of compound and spitz nevi and vertical growth-phase

melanomas using a panel of monoclonal antibodies reactive in paraffin sectionsLazzaro B1 Elder DE Rebers A Power L Herlyn M Menrad A Johnson B

bull Low Ki-67 proliferation ratendash A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions

Li LX Crotty KA McCarthy SW Palmer AA Kril JJAm J Dermatopathol 2000 Dec22(6)489-95

bull Preservation of p16 protein expressionndash More problematical presence in an atypical tumor at

least precludes homozygous loss of 9p21 and is therefore reassuring but does not preclude diagnosis of melanoma

9p21 Locus

bull Contains p16 p14 and p15 all suppressor genes

bull Presumably all lost together in cases of homozygous 9p21 loss

bull Appears to have special significance in Spitzoid lesions

5212018

18

bull Broadbull Symmetricbull Moderately

cellular bull Poorly

circumscribedbull Slight low

level pagetoid scatter

bull Moderate random atypia

bull Nuclear size 1-15x

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

19

Your Diagnosis

Low Grade

High Grade

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription cannot assess less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis (Part 2 Case 3)

Skin back (M36) Compound nevus with moderate dysplasia completely excised see description and comment

OR Compound dysplastic nevus low grade

Comment bull Patient presents with multiple lesions some of which are

dysplastic nevi with moderate dysplasia bull Benign lesions with little or no potential for recurrence and no

potential for metastasis bull Periodic follow-up may be appropriate for this patient

especially if there are other clinically atypical nevi andor a family or personal history of melanoma

bull Although the lesion extends close to the specimen margin there is no essential indication for reexcision especially if the patient is to be followed

This is an MPATH DX Category 1 or perhaps Category 2 lesion depending on clinical correlation and preference

5212018

20

Case 5

Part 2-3Clinical Information

A lesion from the back of a 54 year old manReason for consultation

The clinician was concerned about a melanoma but I favor a dysplastic nevus

Description

Very broad

Moderately cellular

Reasonably symmetrical

Uniformly elongated rete

Patchy infiltrate in dermis

5212018

21

5212018

22

bull Descriptionbull Very broad Moderate pagetoid scatter low

levelbull Moderately cellular Mild to moderate cytologic atypiabull Reasonably symmetrical Mild to moderate solar elastosisbull Uniformly elongated retebull Patchy infiltrate in dermis

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

23

Your Diagnosis

Low Grade

High Grade

Compound nevus with severe dysplasia(Severe architectural disorder moderate cytological atypia)

Feature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Cellularity high intermediate lower

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription common less common uncommon

Nested variable predominant predominant

Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate (1-15X) mild

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells Absent uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 5

bull Junctional nevus with severe melanocytic dysplasia completely excised see note

bull vs Junctional dysplastic nevus high grade

bull vs Intraepidermal atypical melanocytic proliferation (IAMPUS) cannot ro MISndash Diagnosis is based on ldquosevererdquo architectural features

(single cell predominance low level pagetoid scatter) with mild to moderate cytologic atypia

ndash MPATH-Dx Category III (consider excision with up to 5 mm margins if present at the margin)

5212018

24

Next Case

Part 2-5 35728Clinical Information

An irregular pigmented lesion on the back of a 59 year old manReason for Consultation

Is this a nevoid melanoma

Broad focally highly cellular asymmetric diffuse fibroplasia and variably sized nests in dermis

5212018

25

bull Only minimal pagetoid scatter

bull Moderate cytologic atypia

bull No mitosesbull Cells in dermal

nests are small nevoid

bull No confluent sheetlike growth

HMB46 staining is ldquotop-heavyrdquo(stratified)

bull Ki-67 proliferation is minimal in dermis

5212018

26

bull p16 staining is positive in a checkerboard pattern with nuclear and cytoplasmic positivity

Helpful Markers in Nevus vs Melanoma

bull HM45 stratificationndash J Invest Dermatol 1993 Mar100(3)313S-317S Immunophenotyping of compound and spitz nevi and vertical growth-phase

melanomas using a panel of monoclonal antibodies reactive in paraffin sectionsLazzaro B1 Elder DE Rebers A Power L Herlyn M Menrad A Johnson B

bull Low Ki-67 proliferation ratendash A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions

Li LX Crotty KA McCarthy SW Palmer AA Kril JJAm J Dermatopathol 2000 Dec22(6)489-95

bull Preservation of p16 protein expressionndash More problematical presence in an atypical tumor at

least precludes homozygous loss of 9p21 and is therefore reassuring but does not preclude diagnosis of melanoma

9p21 Locus

bull Contains p16 p14 and p15 all suppressor genes

bull Presumably all lost together in cases of homozygous 9p21 loss

bull Appears to have special significance in Spitzoid lesions

5212018

19

Your Diagnosis

Low Grade

High Grade

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription cannot assess less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous (single cells) continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform moderate- random mild- minimal

severe (size gt 15x) moderate (1-15x) (1x)

Mitoses ndash junctionaldermal about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis (Part 2 Case 3)

Skin back (M36) Compound nevus with moderate dysplasia completely excised see description and comment

OR Compound dysplastic nevus low grade

Comment bull Patient presents with multiple lesions some of which are

dysplastic nevi with moderate dysplasia bull Benign lesions with little or no potential for recurrence and no

potential for metastasis bull Periodic follow-up may be appropriate for this patient

especially if there are other clinically atypical nevi andor a family or personal history of melanoma

bull Although the lesion extends close to the specimen margin there is no essential indication for reexcision especially if the patient is to be followed

This is an MPATH DX Category 1 or perhaps Category 2 lesion depending on clinical correlation and preference

5212018

20

Case 5

Part 2-3Clinical Information

A lesion from the back of a 54 year old manReason for consultation

The clinician was concerned about a melanoma but I favor a dysplastic nevus

Description

Very broad

Moderately cellular

Reasonably symmetrical

Uniformly elongated rete

Patchy infiltrate in dermis

5212018

21

5212018

22

bull Descriptionbull Very broad Moderate pagetoid scatter low

levelbull Moderately cellular Mild to moderate cytologic atypiabull Reasonably symmetrical Mild to moderate solar elastosisbull Uniformly elongated retebull Patchy infiltrate in dermis

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

23

Your Diagnosis

Low Grade

High Grade

Compound nevus with severe dysplasia(Severe architectural disorder moderate cytological atypia)

Feature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Cellularity high intermediate lower

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription common less common uncommon

Nested variable predominant predominant

Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate (1-15X) mild

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells Absent uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 5

bull Junctional nevus with severe melanocytic dysplasia completely excised see note

bull vs Junctional dysplastic nevus high grade

bull vs Intraepidermal atypical melanocytic proliferation (IAMPUS) cannot ro MISndash Diagnosis is based on ldquosevererdquo architectural features

(single cell predominance low level pagetoid scatter) with mild to moderate cytologic atypia

ndash MPATH-Dx Category III (consider excision with up to 5 mm margins if present at the margin)

5212018

24

Next Case

Part 2-5 35728Clinical Information

An irregular pigmented lesion on the back of a 59 year old manReason for Consultation

Is this a nevoid melanoma

Broad focally highly cellular asymmetric diffuse fibroplasia and variably sized nests in dermis

5212018

25

bull Only minimal pagetoid scatter

bull Moderate cytologic atypia

bull No mitosesbull Cells in dermal

nests are small nevoid

bull No confluent sheetlike growth

HMB46 staining is ldquotop-heavyrdquo(stratified)

bull Ki-67 proliferation is minimal in dermis

5212018

26

bull p16 staining is positive in a checkerboard pattern with nuclear and cytoplasmic positivity

Helpful Markers in Nevus vs Melanoma

bull HM45 stratificationndash J Invest Dermatol 1993 Mar100(3)313S-317S Immunophenotyping of compound and spitz nevi and vertical growth-phase

melanomas using a panel of monoclonal antibodies reactive in paraffin sectionsLazzaro B1 Elder DE Rebers A Power L Herlyn M Menrad A Johnson B

bull Low Ki-67 proliferation ratendash A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions

Li LX Crotty KA McCarthy SW Palmer AA Kril JJAm J Dermatopathol 2000 Dec22(6)489-95

bull Preservation of p16 protein expressionndash More problematical presence in an atypical tumor at

least precludes homozygous loss of 9p21 and is therefore reassuring but does not preclude diagnosis of melanoma

9p21 Locus

bull Contains p16 p14 and p15 all suppressor genes

bull Presumably all lost together in cases of homozygous 9p21 loss

bull Appears to have special significance in Spitzoid lesions

5212018

20

Case 5

Part 2-3Clinical Information

A lesion from the back of a 54 year old manReason for consultation

The clinician was concerned about a melanoma but I favor a dysplastic nevus

Description

Very broad

Moderately cellular

Reasonably symmetrical

Uniformly elongated rete

Patchy infiltrate in dermis

5212018

21

5212018

22

bull Descriptionbull Very broad Moderate pagetoid scatter low

levelbull Moderately cellular Mild to moderate cytologic atypiabull Reasonably symmetrical Mild to moderate solar elastosisbull Uniformly elongated retebull Patchy infiltrate in dermis

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

23

Your Diagnosis

Low Grade

High Grade

Compound nevus with severe dysplasia(Severe architectural disorder moderate cytological atypia)

Feature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Cellularity high intermediate lower

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription common less common uncommon

Nested variable predominant predominant

Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate (1-15X) mild

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells Absent uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 5

bull Junctional nevus with severe melanocytic dysplasia completely excised see note

bull vs Junctional dysplastic nevus high grade

bull vs Intraepidermal atypical melanocytic proliferation (IAMPUS) cannot ro MISndash Diagnosis is based on ldquosevererdquo architectural features

(single cell predominance low level pagetoid scatter) with mild to moderate cytologic atypia

ndash MPATH-Dx Category III (consider excision with up to 5 mm margins if present at the margin)

5212018

24

Next Case

Part 2-5 35728Clinical Information

An irregular pigmented lesion on the back of a 59 year old manReason for Consultation

Is this a nevoid melanoma

Broad focally highly cellular asymmetric diffuse fibroplasia and variably sized nests in dermis

5212018

25

bull Only minimal pagetoid scatter

bull Moderate cytologic atypia

bull No mitosesbull Cells in dermal

nests are small nevoid

bull No confluent sheetlike growth

HMB46 staining is ldquotop-heavyrdquo(stratified)

bull Ki-67 proliferation is minimal in dermis

5212018

26

bull p16 staining is positive in a checkerboard pattern with nuclear and cytoplasmic positivity

Helpful Markers in Nevus vs Melanoma

bull HM45 stratificationndash J Invest Dermatol 1993 Mar100(3)313S-317S Immunophenotyping of compound and spitz nevi and vertical growth-phase

melanomas using a panel of monoclonal antibodies reactive in paraffin sectionsLazzaro B1 Elder DE Rebers A Power L Herlyn M Menrad A Johnson B

bull Low Ki-67 proliferation ratendash A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions

Li LX Crotty KA McCarthy SW Palmer AA Kril JJAm J Dermatopathol 2000 Dec22(6)489-95

bull Preservation of p16 protein expressionndash More problematical presence in an atypical tumor at

least precludes homozygous loss of 9p21 and is therefore reassuring but does not preclude diagnosis of melanoma

9p21 Locus

bull Contains p16 p14 and p15 all suppressor genes

bull Presumably all lost together in cases of homozygous 9p21 loss

bull Appears to have special significance in Spitzoid lesions

5212018

21

5212018

22

bull Descriptionbull Very broad Moderate pagetoid scatter low

levelbull Moderately cellular Mild to moderate cytologic atypiabull Reasonably symmetrical Mild to moderate solar elastosisbull Uniformly elongated retebull Patchy infiltrate in dermis

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

23

Your Diagnosis

Low Grade

High Grade

Compound nevus with severe dysplasia(Severe architectural disorder moderate cytological atypia)

Feature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Cellularity high intermediate lower

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription common less common uncommon

Nested variable predominant predominant

Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate (1-15X) mild

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells Absent uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 5

bull Junctional nevus with severe melanocytic dysplasia completely excised see note

bull vs Junctional dysplastic nevus high grade

bull vs Intraepidermal atypical melanocytic proliferation (IAMPUS) cannot ro MISndash Diagnosis is based on ldquosevererdquo architectural features

(single cell predominance low level pagetoid scatter) with mild to moderate cytologic atypia

ndash MPATH-Dx Category III (consider excision with up to 5 mm margins if present at the margin)

5212018

24

Next Case

Part 2-5 35728Clinical Information

An irregular pigmented lesion on the back of a 59 year old manReason for Consultation

Is this a nevoid melanoma

Broad focally highly cellular asymmetric diffuse fibroplasia and variably sized nests in dermis

5212018

25

bull Only minimal pagetoid scatter

bull Moderate cytologic atypia

bull No mitosesbull Cells in dermal

nests are small nevoid

bull No confluent sheetlike growth

HMB46 staining is ldquotop-heavyrdquo(stratified)

bull Ki-67 proliferation is minimal in dermis

5212018

26

bull p16 staining is positive in a checkerboard pattern with nuclear and cytoplasmic positivity

Helpful Markers in Nevus vs Melanoma

bull HM45 stratificationndash J Invest Dermatol 1993 Mar100(3)313S-317S Immunophenotyping of compound and spitz nevi and vertical growth-phase

melanomas using a panel of monoclonal antibodies reactive in paraffin sectionsLazzaro B1 Elder DE Rebers A Power L Herlyn M Menrad A Johnson B

bull Low Ki-67 proliferation ratendash A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions

Li LX Crotty KA McCarthy SW Palmer AA Kril JJAm J Dermatopathol 2000 Dec22(6)489-95

bull Preservation of p16 protein expressionndash More problematical presence in an atypical tumor at

least precludes homozygous loss of 9p21 and is therefore reassuring but does not preclude diagnosis of melanoma

9p21 Locus

bull Contains p16 p14 and p15 all suppressor genes

bull Presumably all lost together in cases of homozygous 9p21 loss

bull Appears to have special significance in Spitzoid lesions

5212018

22

bull Descriptionbull Very broad Moderate pagetoid scatter low

levelbull Moderately cellular Mild to moderate cytologic atypiabull Reasonably symmetrical Mild to moderate solar elastosisbull Uniformly elongated retebull Patchy infiltrate in dermis

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

23

Your Diagnosis

Low Grade

High Grade

Compound nevus with severe dysplasia(Severe architectural disorder moderate cytological atypia)

Feature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Cellularity high intermediate lower

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription common less common uncommon

Nested variable predominant predominant

Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate (1-15X) mild

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells Absent uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 5

bull Junctional nevus with severe melanocytic dysplasia completely excised see note

bull vs Junctional dysplastic nevus high grade

bull vs Intraepidermal atypical melanocytic proliferation (IAMPUS) cannot ro MISndash Diagnosis is based on ldquosevererdquo architectural features

(single cell predominance low level pagetoid scatter) with mild to moderate cytologic atypia

ndash MPATH-Dx Category III (consider excision with up to 5 mm margins if present at the margin)

5212018

24

Next Case

Part 2-5 35728Clinical Information

An irregular pigmented lesion on the back of a 59 year old manReason for Consultation

Is this a nevoid melanoma

Broad focally highly cellular asymmetric diffuse fibroplasia and variably sized nests in dermis

5212018

25

bull Only minimal pagetoid scatter

bull Moderate cytologic atypia

bull No mitosesbull Cells in dermal

nests are small nevoid

bull No confluent sheetlike growth

HMB46 staining is ldquotop-heavyrdquo(stratified)

bull Ki-67 proliferation is minimal in dermis

5212018

26

bull p16 staining is positive in a checkerboard pattern with nuclear and cytoplasmic positivity

Helpful Markers in Nevus vs Melanoma

bull HM45 stratificationndash J Invest Dermatol 1993 Mar100(3)313S-317S Immunophenotyping of compound and spitz nevi and vertical growth-phase

melanomas using a panel of monoclonal antibodies reactive in paraffin sectionsLazzaro B1 Elder DE Rebers A Power L Herlyn M Menrad A Johnson B

bull Low Ki-67 proliferation ratendash A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions

Li LX Crotty KA McCarthy SW Palmer AA Kril JJAm J Dermatopathol 2000 Dec22(6)489-95

bull Preservation of p16 protein expressionndash More problematical presence in an atypical tumor at

least precludes homozygous loss of 9p21 and is therefore reassuring but does not preclude diagnosis of melanoma

9p21 Locus

bull Contains p16 p14 and p15 all suppressor genes

bull Presumably all lost together in cases of homozygous 9p21 loss

bull Appears to have special significance in Spitzoid lesions

5212018

23

Your Diagnosis

Low Grade

High Grade

Compound nevus with severe dysplasia(Severe architectural disorder moderate cytological atypia)

Feature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Cellularity high intermediate lower

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription common less common uncommon

Nested variable predominant predominant

Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate (1-15X) mild

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells Absent uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 5

bull Junctional nevus with severe melanocytic dysplasia completely excised see note

bull vs Junctional dysplastic nevus high grade

bull vs Intraepidermal atypical melanocytic proliferation (IAMPUS) cannot ro MISndash Diagnosis is based on ldquosevererdquo architectural features

(single cell predominance low level pagetoid scatter) with mild to moderate cytologic atypia

ndash MPATH-Dx Category III (consider excision with up to 5 mm margins if present at the margin)

5212018

24

Next Case

Part 2-5 35728Clinical Information

An irregular pigmented lesion on the back of a 59 year old manReason for Consultation

Is this a nevoid melanoma

Broad focally highly cellular asymmetric diffuse fibroplasia and variably sized nests in dermis

5212018

25

bull Only minimal pagetoid scatter

bull Moderate cytologic atypia

bull No mitosesbull Cells in dermal

nests are small nevoid

bull No confluent sheetlike growth

HMB46 staining is ldquotop-heavyrdquo(stratified)

bull Ki-67 proliferation is minimal in dermis

5212018

26

bull p16 staining is positive in a checkerboard pattern with nuclear and cytoplasmic positivity

Helpful Markers in Nevus vs Melanoma

bull HM45 stratificationndash J Invest Dermatol 1993 Mar100(3)313S-317S Immunophenotyping of compound and spitz nevi and vertical growth-phase

melanomas using a panel of monoclonal antibodies reactive in paraffin sectionsLazzaro B1 Elder DE Rebers A Power L Herlyn M Menrad A Johnson B

bull Low Ki-67 proliferation ratendash A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions

Li LX Crotty KA McCarthy SW Palmer AA Kril JJAm J Dermatopathol 2000 Dec22(6)489-95

bull Preservation of p16 protein expressionndash More problematical presence in an atypical tumor at

least precludes homozygous loss of 9p21 and is therefore reassuring but does not preclude diagnosis of melanoma

9p21 Locus

bull Contains p16 p14 and p15 all suppressor genes

bull Presumably all lost together in cases of homozygous 9p21 loss

bull Appears to have special significance in Spitzoid lesions

5212018

24

Next Case

Part 2-5 35728Clinical Information

An irregular pigmented lesion on the back of a 59 year old manReason for Consultation

Is this a nevoid melanoma

Broad focally highly cellular asymmetric diffuse fibroplasia and variably sized nests in dermis

5212018

25

bull Only minimal pagetoid scatter

bull Moderate cytologic atypia

bull No mitosesbull Cells in dermal

nests are small nevoid

bull No confluent sheetlike growth

HMB46 staining is ldquotop-heavyrdquo(stratified)

bull Ki-67 proliferation is minimal in dermis

5212018

26

bull p16 staining is positive in a checkerboard pattern with nuclear and cytoplasmic positivity

Helpful Markers in Nevus vs Melanoma

bull HM45 stratificationndash J Invest Dermatol 1993 Mar100(3)313S-317S Immunophenotyping of compound and spitz nevi and vertical growth-phase

melanomas using a panel of monoclonal antibodies reactive in paraffin sectionsLazzaro B1 Elder DE Rebers A Power L Herlyn M Menrad A Johnson B

bull Low Ki-67 proliferation ratendash A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions

Li LX Crotty KA McCarthy SW Palmer AA Kril JJAm J Dermatopathol 2000 Dec22(6)489-95

bull Preservation of p16 protein expressionndash More problematical presence in an atypical tumor at

least precludes homozygous loss of 9p21 and is therefore reassuring but does not preclude diagnosis of melanoma

9p21 Locus

bull Contains p16 p14 and p15 all suppressor genes

bull Presumably all lost together in cases of homozygous 9p21 loss

bull Appears to have special significance in Spitzoid lesions

5212018

25

bull Only minimal pagetoid scatter

bull Moderate cytologic atypia

bull No mitosesbull Cells in dermal

nests are small nevoid

bull No confluent sheetlike growth

HMB46 staining is ldquotop-heavyrdquo(stratified)

bull Ki-67 proliferation is minimal in dermis

5212018

26

bull p16 staining is positive in a checkerboard pattern with nuclear and cytoplasmic positivity

Helpful Markers in Nevus vs Melanoma

bull HM45 stratificationndash J Invest Dermatol 1993 Mar100(3)313S-317S Immunophenotyping of compound and spitz nevi and vertical growth-phase

melanomas using a panel of monoclonal antibodies reactive in paraffin sectionsLazzaro B1 Elder DE Rebers A Power L Herlyn M Menrad A Johnson B

bull Low Ki-67 proliferation ratendash A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions

Li LX Crotty KA McCarthy SW Palmer AA Kril JJAm J Dermatopathol 2000 Dec22(6)489-95

bull Preservation of p16 protein expressionndash More problematical presence in an atypical tumor at

least precludes homozygous loss of 9p21 and is therefore reassuring but does not preclude diagnosis of melanoma

9p21 Locus

bull Contains p16 p14 and p15 all suppressor genes

bull Presumably all lost together in cases of homozygous 9p21 loss

bull Appears to have special significance in Spitzoid lesions

5212018

26

bull p16 staining is positive in a checkerboard pattern with nuclear and cytoplasmic positivity

Helpful Markers in Nevus vs Melanoma

bull HM45 stratificationndash J Invest Dermatol 1993 Mar100(3)313S-317S Immunophenotyping of compound and spitz nevi and vertical growth-phase

melanomas using a panel of monoclonal antibodies reactive in paraffin sectionsLazzaro B1 Elder DE Rebers A Power L Herlyn M Menrad A Johnson B

bull Low Ki-67 proliferation ratendash A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions

Li LX Crotty KA McCarthy SW Palmer AA Kril JJAm J Dermatopathol 2000 Dec22(6)489-95

bull Preservation of p16 protein expressionndash More problematical presence in an atypical tumor at

least precludes homozygous loss of 9p21 and is therefore reassuring but does not preclude diagnosis of melanoma

9p21 Locus

bull Contains p16 p14 and p15 all suppressor genes

bull Presumably all lost together in cases of homozygous 9p21 loss

bull Appears to have special significance in Spitzoid lesions

5212018

27

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

Your Diagnosis

High Grade

Low Grade

5212018

28

Case 5 M59 backFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Cellularity high intermediate lower

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription common less common uncommon

Nested variable predominantpredominant

Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuousdiscontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate (1-15X) mild

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive or focal rare minimal absent

Dermal Cells Absent uniform atypia random atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 6 M59

bull Skin right mid back Compound nevus with severe dermal and epidermal dysplasia and dermal fibrosis (ldquosclerosing atypical nevusrdquo ldquofibrosing dysplastic nevus) extending close or to specimen base and margins see description and final comment

bull OR - Dysplastic nevus high grade with a sclerosing dermal component

bull Overall Comment

bull The presence of p16 staining rules out the possibility of 9P21 loss which has been associated with aggressive behavior in a recent fluorescence in situ hybridization (FISH) study of atypical lesions most of which were variants of Spitz tumors

bull Despite reassuring findings from special stains (and lack of mitoses) this is objectively an atypical lesion and complete excision would be recommended or perhaps alternatively careful follow-up of the lesional site (MPATH DX Category 2 or 3)

bull Especially if this patient should have other clinically atypical nevi andor a family or personal history of melanoma consideration of periodic surveillance of his skin would also be appropriate

19 Lesions with no recurrence (all completely excised)

5212018

29

Papillomatous naevoid melanomabull Papillomatous epithelial strands dense proliferation lack of

maturation atypia mitoses

bull In-transit or lymph node metastases occurred in 33 of patients

Maturing naevoid melanomabull ldquoChange from epithelioid pleomorphic melanocytes in the

junctional component to hellip smaller but still atypical cells arranged in nests surrounded by dense collagenrdquo

bull ldquohellipno disease progression was seen in those with maturing naevoid melanomas (including two with measured thicknesses of 30 and 35 mm respectively)rdquo

Significance of Nevi

bull Nevi are important mainly in relation to melanoma

ndash Precursors ndash but risk for individual lesions is low

ndash Risk markers ndash important mainly in high risk situations

ndash Simulants ndash important in everyday clinical decision-making

Case 7

Clinical InformationPigmented lesion on the back of a 40 year old

womanReason for Consultation

Rule out melanoma

5212018

30

A Lesion of the Back in a 40 Year Old Woman

bull ldquoshave biopsy under the left arm hellip has caused consternation hellip two of us believing that we are dealing with a hellip melanomahellip two others believing that although worrisome hellip not yet melanomardquo

5212018

31

5212018

32

5212018

33

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

34

Your Diagnosis

High Grade

Low Grade

Clarkrsquos Dysplastic Nevus vs Melanoma in Situ vs Nevus

Feature Melanoma Dysplastic Nevus Nevus

Size tend to be larger intermediate smaller

Symmetry poor good good

Keratinocytes irregular uniform elongated rete uniform

Melanocytes epithelioid mixed nevoid

Nested variable predominant predominant

Nests coalescent bridging discrete

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe (gt 15x) mild-moderate

Mitoses about 13 of cases almost always absent absent

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Diagnosis Rendered

bull ldquomalignant melanoma probably lentigo maligna type showing Clark level III invasion with early tumorigenic but nonmitogenic vertical growth phase at a greatest Breslow thickness of 030 mm hellip associated nevus with congenital pattern featuresrdquo

5212018

35

New Information

ldquoI received a call from the primary care physician of this patient asking me to review a biopsy from June of 2004 which I had signed out as a compound congenital melanocytic nevus She told me that the lesion had developed re-pigmentation in the previous biopsy site hellip rdquo

bull ldquoI think it is almost certain that the subsequent biopsy is a pseudomelanoma based on the fact that there was no atypia in the original shave biopsy specimen the interval between biopsy and re-pigmentation is only three months and the re-pigmentation is in the previous biopsy site The lack of this additional information at the time you received the biopsy was a handicaprdquo

5212018

36

5212018

37

New Report

ldquosuperficial atypical melanocytic proliferation cw recurrent nevus phenomenon extending to specimen marginsrdquo hellip ldquoI would make only one reservation and that is that this lesion should be re-excised again with a margin of normal skin around the scar and any residual lesion helliprdquo

5212018

38

RECURRENT MELANOCYTIC NEVUS

Pseudomelanoma (Ackerman)

ndash pigmented patch at site of prior shave biopsy of a benign compound or dermal nevus

ndash repigmentation occurs quickly (6 weeks)

ndash pigment does not extend beyond scars borders

RECURRENT MELANOCYTIC NEVUS

Histology

bull variably sized and shaped sometimes confluent nests

bull single cells amp nests above DEJ usually not beyond mid-spinous layer

bull occasional lesional cells or nests in dermis

bull slight cytologic atypia (ldquoreactiverdquo) rare mitoses

bull proliferation does not extend beyond scar

bull original nevus should be reviewed

5212018

39

Lessons

bull Atypia in recurrent nevi can be severe yet is ldquoreactiverdquo

ndash Mitoses can be present

ndash Dermal atypia can be present

bull A superficial scar can mimic diffuse fibroplasia seen in many melanomas

bull Keep a high index of suspicion

ndash Consider a full differential diagnosis

ndash Call for history if necessary

5212018

40

Significance of Nevi

bull Nevi are important mainly in relation to melanoma

ndash Precursors ndash but risk for individual lesions is low

ndash Risk markers ndash important mainly in high risk situations

ndash Simulants ndash important in everyday clinical decision-making

Conclusions

bull Former mild dysplasia is a benign lentiginous nevus (the commonest type of nevus)

bull Low grade dysplasia (former moderate dysplasia) can be observed clinically or by patients looking for evidence of changing lesions

bull High grade dysplasia is difficult to distinguish from melanoma in situ (UNCERTAINTY) may have competence for local persistence recurrence and progression and should be completely excised

bull All of these are ldquomelanocytic neoplasms of low (or no) malignant potentialrdquo which have little or no competence for metastasis

Lake Wakatipu and Queenstown New Zealand from the Top of ldquoThe Remarkablesrdquo(Mountains of Mordor in the distance)

5212018

41

Session II High CSD Melanomas and Simulants

Lentigo maligna melanoma

Atypical lentiginous neviproliferations

High CSD Lentiginous Nevi and Lentigo Maligna

Melanoma and Simulant(s)

bull Lentiginous Melanoma of Sun-Damaged Skin

ndash LMM in situ

ndash LMM invasive

ndash Distinction from Dysplastic Nevi (Dysplastic Nevus-like MelanomaNevoid Lentigo Maligna

bull Lentiginous Nevi of the ldquoElderlyrdquo (ie CSD Skin)

bull Solar (actinic) lentigo pigmented AK SK hellip

High UV

Pathway II Pathway III

High-CSD Melanoma (LMM)

Desmoplastic Melanoma

IMP IMP

IAMP IAMP

Lentigo maligna melanoma in situ

Melanoma in situ

Lentigo Maligna Melanoma

Desmoplastic Melanoma

NRAS BRAFnon-V600E KIT NF1

NF1 ERBB2 MAP2K1 MAP3K1 BRAF EGFR MET

TERT CDKN2A TP53 PTEN RAC1

TERT NFKBIE NRAS PIK3CA PTPN11

5212018

42

Case 1

12438

F64 Lesion of back

5212018

43

5212018

44

Your Diagnosis

Dysplastic Nevus - IAMP

Melanoma

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe ( gt 15x) mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Our Diagnosis

Case 1 12438

Lentigo maligna melanoma in situ

5212018

45

Case 2

Part 2-2 7419Clinical Information

A large pigmented lesion of the back in a 74-year-old manReason for Consultation

I called this lesion a dysplastic nevus The clinician then calls back to inform us that this is a 22 cm irregular pigmented lesion Now looking at the deepers we think this

might be a ldquolentiginous melanomardquo

Description

bull Shave biopsy of a broad lesion with a dermal component and a moderately cellular junctional component

bull Lesion is ill-defined (poorly circumscribed) at each periphery with features overlapping with those of actinic lentigo

bull Subtle increase of melanocytes along the dermal-epidermal junction with mild to moderate but relatively uniform cytologic atypia

bull Pagetoid scatter is minimal

bull Focally there are elongated rete ridges overlapping with features of dysplastic nevus however these changes are focal within the lesion rather than being symmetrically distributed at shoulders adjacent to a dermal component

Lentiginous nevus versus lentiginous melanoma

bull Poorly circumscribed at each periphery

5212018

46

bull JunctionaIIAMP

bull Patchy lymphocytic infiltrate

bull Solar elastosis

Bridging rete

5212018

47

Your Diagnosis

Melanoma

Nevus

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Lentiginous nevus versus lentiginous melanomaDiagnosis Case 2 M74

Skin mid back Superficial atypical melanocytic proliferation of uncertain significance most consistent with melanoma in situ lentiginous type (nevoid lentigo maligna) versus atypical lentiginous nevus of the elderly see comment

(ie ldquoSAMPUSrdquo)

5212018

48

Diagnosis Case 2 M74

bull Overall Commentbull There are overlapping features among atypical actinic

lentigines lentiginous junctional nevi with and without atypia and lentiginous or ldquonevoidrdquo lentigo maligna

bull Lesions in a high CSD environment must be interpreted with circumspection

bull Overdiagnosis should be avoided as even atypical lentiginous junctional nevi of the elderly seem to be biologically low grade (non-metastasizing but perhaps locally recurring potential)

bull It is judicious to completely excise these lesions in order to be sure that they have been completely examined histologically and also to minimize any possibility of local persistence recurrence or future progression

Nevoid Lentigo MalignaLentiginous Melanoma(Lentiginous Nevus)

bull Kossard 1997 Aust J Dermatol Nevoid lentigo malignaKing Page Googe amp Mihm Modern Pathology 2005 Lentiginous melanomaFerrahi Egbert amp Swetter J Cutan Pathol 2005 Dysplastic nevus-like LMM

bull Clinical diagnosis may varyndash eg lentigo maligna atypical nevus pigmented basal cell carcinoma seborrheic keratosis and

lentigo

bull Biopsies may mimic junctional nevus or dysplastic nevus at least focallyndash Lentiginous proliferation of melanocytes at the dermo-epidermal junction both as single cells

and as small nests with areas of confluent growth extending to the edges of the biopsy ndash Rete ridges maintainedndash Pagetoid spread of melanocytes was not prominent in HampE - stained sections

bull Diagnosis of melanoma more easily recognized in the complete excision specimens similar atypical melanocytic proliferation occurring over a broad area flanking the prior biopsy sites

bull Stains for MITF and Mart-1 highlight continuous basal melanocytic proliferation as well as foci of pagetoid scatter

Lentiginous MelanomaKing Page Googe Mihm Mod Pathol 2005

bull Initial biopsies mimicked lentiginous nevus or dysplastic nevus

bull Lentiginous proliferation of melanocytes at DEJ both as single cells and as small nests with areas of confluent growth extending to the edges of the biopsy

bull Retiform epidermis was maintained and pagetoid spread of melanocytes was not prominent in HampE sections

bull Immunohistochemical stains for MITF and Mart-1 highlighted the extent of the basalar melanocytic proliferation as well as foci of pagetoid spread by melanocytes

bull UNCERTAINTY IS COMMONbull PROGNOSIS IS GOOD IF LESION IS SUPERFICIALbull IMPORTANT TO COMPLETELY EXCISE

bull FOR FULL EXAMINATION AND TO MINIMIZE ANY POTENTIAL FOR LOCAL PERSISTENCE RECURRENCE AND PROGRESSION

Mart 1

MITF

5212018

49

Case 3

Part 2-3 14474

Clinical InformationLeft posterior shoulder F81

Reason for ConsultationFavor a junctional Clarkrsquos nevus (see enclosed report)

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Some bridging few nests that hang down in a droplet-like pattern bull Cytologic atypia mild but relatively uniform

5212018

50

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 3 F81

bull ldquoDifficult to interpretrdquo bull Cytologic atypia is mild to moderate rather than

severe with somewhat concerning architectural changes

bull ldquoOne is somewhat more concerned about a lesion in chronically sun-damaged skin of older subjectsrdquo

bull Skin left posterior shoulder shave biopsy Intraepidermal atypical melanocytic proliferation of uncertain significance (IAMPUS) most consistent with atypical lentiginous junctional nevus (of the elderlyCSD skin) cannot ro evolving or early established melanoma in situ

bull Complete excision recommended (MPATH-Dx 2 or 3)

Case 4

Part 2-3 14474

Clinical InformationLeft posterior shoulder F84

Reason for ConsultationFavor a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus (see

enclosed report) There is mild melanocytic atypia and that the peripheral and deep margins of the specimen were negative in the

plane of sectioning

5212018

51

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 4 F81

bull Recurrence of Case 8

bull Shave biopsy of similar sun-damaged skinbull Somewhat more cellular proliferation of nevoid and

nevoid to epithelioid melanocytes focally exhibiting severe and uniform cytologic atypia

bull Some of these cells are confined to the epidermis above the scar while others appear to extend some distance beyond the periphery of the scar

bull This latter feature raises some concern for evolving melanoma in situ extending beyond the scar

5212018

52

bull Skin left posterior shoulder shave biopsy (recurrence) Intraepidermal atypical melanocytic proliferation of uncertain significance extending to specimen margins see description and comment

ndash Comment Cannot rule out an evolving more significant lesion suggest complete excision

Case 5

Part 2-3 14474

Clinical InformationBiopsy from posterior shoulder of an 85 year old female

Reason for ConsultationThis specimen in my opinion has histologic features concerning for

melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis I do not see

definitive features of a scar consistent with a prior biopsy site

5212018

53

bull Broadbull Moderately

cellularbull Moderate to

severe CSDbull Poorly

circumscribedbull Few bridging

nestsbull Diffuse

fibroplasiabull Cells in dermis

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Nests in dermis

bull No maturation

5212018

54

Melan-A Stain

bull Moderately cellular

bull Continuous basal proliferation

bull Nests hanging down

bull Low level pagetoid scatter

bull Nests in dermis

bull No maturation

Your Diagnosis

Melanoma

Nevus

Our Diagnosis

Malignant melanoma lentigo maligna type (ldquolentiginous melanomardquo Clark level II Breslow thickness 085 mm

5212018

55

Updated History Cases 3-5

bull Clinical Information

bull Three separate biopsies from left posterior shoulder of an 85-year-old female over a period of three years The biopsies were performed 4 years and 1 year ago and recently

bull The original biopsy was called a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus might have been better interpreted as a lentiginous nevus of the elderlysundamaged skin with mild to moderate atypia ndash The peripheral and deep margins of the specimen were said to be negative in the plane

of sectioning

bull The next biopsy at presumably the same anatomic location was signed out as an atypical melanocytic proliferation consistent with a persistentrecurrent Clarkrsquos (dysplastic) nevus involving the peripheral edge of the biopsy ndash It was mentioned that the differential diagnosis included early melanoma in situ

evolving within a pre-existing nevus and a reexcision was recommended

bull The most recent specimen was concerning for melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis

bull Additional procedure warranted to ensure that the lesion has been completely removed`

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Cytologic atypia mild but relatively uniform bull POTENTIAL PRECURSOR (low risk) VS ACTUAL PRECURSOR (hindsight bias)bull Manage by excision or follow-up

bull Case 5

bull Second recurrence of a lesion that originally had only ldquomildrdquo atypia (but moderate to severe architectural disorder)

bull Diagnosis of dysplastic nevus should be made with caution in elderlyCSD skin

bull Complete excision is appropriate for ldquoatypical lentiginous nevus of elderlysundamaged skinrdquo

5212018

56

Last Case

Part 2-7 12150

Clinical InformationLesion of right shoulder ro melanoma versus nevus in a 76 yo man

Reason for ConsultationIs this anything other than a moderately atypical neurotized compound nevus

bull A relatively broad lesion with irregular thickening and thinning of rete ridges and a sparsely cellular infiltrate in the dermis

bull Generally sparsely cellularbull Moderate to severe CSD

Poorly circumscribed

5212018

57

bull Pigmented melanophages in the dermis

bull Increased number of melanocytes in the epidermis many of them suprabasal

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

5212018

58

S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

bull Melan-A stain highlights the junctional component but the dermal spindle cells are negative

Case 6

bull Skin right superior shoulder Malignant melanoma lentigo maligna type nonulcerated with pure desmoplastic vertical growth phase Clark level IV Breslow thickness not lt 064 mm extending close to the specimen base see Comment 3

bull Commentbull Changes extend close to the base and to a peripheral margin of the

specimenbull It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution Sbull Should be excised locally in order to prevent any possibility of persistence

recurrence or future progression of it bull Based on its microstaging attributes the prognosis for this lesion should

be excellent The prognosis for ldquopurerdquo desmoplastic melanoma is if anything better than that for melanomas of similar thickness

bull This lesion could be managed with a relatively generous wide local excision ndash MPATH DX Category 4 (or 5)

5212018

59

Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

5212018

60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

5212018

28

Case 5 M59 backFeature Melanoma Dysplastic Nevus Nevus

Size larger intermediate smaller

Cellularity high intermediate lower

Symmetry poor good good

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid to epithelioid) nevoid

Poor circumscription common less common uncommon

Nested variable predominantpredominant

Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuousdiscontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate (1-15X) mild

Mitoses - junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon uncommon

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive or focal rare minimal absent

Dermal Cells Absent uniform atypia random atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Diagnosis Case 6 M59

bull Skin right mid back Compound nevus with severe dermal and epidermal dysplasia and dermal fibrosis (ldquosclerosing atypical nevusrdquo ldquofibrosing dysplastic nevus) extending close or to specimen base and margins see description and final comment

bull OR - Dysplastic nevus high grade with a sclerosing dermal component

bull Overall Comment

bull The presence of p16 staining rules out the possibility of 9P21 loss which has been associated with aggressive behavior in a recent fluorescence in situ hybridization (FISH) study of atypical lesions most of which were variants of Spitz tumors

bull Despite reassuring findings from special stains (and lack of mitoses) this is objectively an atypical lesion and complete excision would be recommended or perhaps alternatively careful follow-up of the lesional site (MPATH DX Category 2 or 3)

bull Especially if this patient should have other clinically atypical nevi andor a family or personal history of melanoma consideration of periodic surveillance of his skin would also be appropriate

19 Lesions with no recurrence (all completely excised)

5212018

29

Papillomatous naevoid melanomabull Papillomatous epithelial strands dense proliferation lack of

maturation atypia mitoses

bull In-transit or lymph node metastases occurred in 33 of patients

Maturing naevoid melanomabull ldquoChange from epithelioid pleomorphic melanocytes in the

junctional component to hellip smaller but still atypical cells arranged in nests surrounded by dense collagenrdquo

bull ldquohellipno disease progression was seen in those with maturing naevoid melanomas (including two with measured thicknesses of 30 and 35 mm respectively)rdquo

Significance of Nevi

bull Nevi are important mainly in relation to melanoma

ndash Precursors ndash but risk for individual lesions is low

ndash Risk markers ndash important mainly in high risk situations

ndash Simulants ndash important in everyday clinical decision-making

Case 7

Clinical InformationPigmented lesion on the back of a 40 year old

womanReason for Consultation

Rule out melanoma

5212018

30

A Lesion of the Back in a 40 Year Old Woman

bull ldquoshave biopsy under the left arm hellip has caused consternation hellip two of us believing that we are dealing with a hellip melanomahellip two others believing that although worrisome hellip not yet melanomardquo

5212018

31

5212018

32

5212018

33

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

34

Your Diagnosis

High Grade

Low Grade

Clarkrsquos Dysplastic Nevus vs Melanoma in Situ vs Nevus

Feature Melanoma Dysplastic Nevus Nevus

Size tend to be larger intermediate smaller

Symmetry poor good good

Keratinocytes irregular uniform elongated rete uniform

Melanocytes epithelioid mixed nevoid

Nested variable predominant predominant

Nests coalescent bridging discrete

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe (gt 15x) mild-moderate

Mitoses about 13 of cases almost always absent absent

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Diagnosis Rendered

bull ldquomalignant melanoma probably lentigo maligna type showing Clark level III invasion with early tumorigenic but nonmitogenic vertical growth phase at a greatest Breslow thickness of 030 mm hellip associated nevus with congenital pattern featuresrdquo

5212018

35

New Information

ldquoI received a call from the primary care physician of this patient asking me to review a biopsy from June of 2004 which I had signed out as a compound congenital melanocytic nevus She told me that the lesion had developed re-pigmentation in the previous biopsy site hellip rdquo

bull ldquoI think it is almost certain that the subsequent biopsy is a pseudomelanoma based on the fact that there was no atypia in the original shave biopsy specimen the interval between biopsy and re-pigmentation is only three months and the re-pigmentation is in the previous biopsy site The lack of this additional information at the time you received the biopsy was a handicaprdquo

5212018

36

5212018

37

New Report

ldquosuperficial atypical melanocytic proliferation cw recurrent nevus phenomenon extending to specimen marginsrdquo hellip ldquoI would make only one reservation and that is that this lesion should be re-excised again with a margin of normal skin around the scar and any residual lesion helliprdquo

5212018

38

RECURRENT MELANOCYTIC NEVUS

Pseudomelanoma (Ackerman)

ndash pigmented patch at site of prior shave biopsy of a benign compound or dermal nevus

ndash repigmentation occurs quickly (6 weeks)

ndash pigment does not extend beyond scars borders

RECURRENT MELANOCYTIC NEVUS

Histology

bull variably sized and shaped sometimes confluent nests

bull single cells amp nests above DEJ usually not beyond mid-spinous layer

bull occasional lesional cells or nests in dermis

bull slight cytologic atypia (ldquoreactiverdquo) rare mitoses

bull proliferation does not extend beyond scar

bull original nevus should be reviewed

5212018

39

Lessons

bull Atypia in recurrent nevi can be severe yet is ldquoreactiverdquo

ndash Mitoses can be present

ndash Dermal atypia can be present

bull A superficial scar can mimic diffuse fibroplasia seen in many melanomas

bull Keep a high index of suspicion

ndash Consider a full differential diagnosis

ndash Call for history if necessary

5212018

40

Significance of Nevi

bull Nevi are important mainly in relation to melanoma

ndash Precursors ndash but risk for individual lesions is low

ndash Risk markers ndash important mainly in high risk situations

ndash Simulants ndash important in everyday clinical decision-making

Conclusions

bull Former mild dysplasia is a benign lentiginous nevus (the commonest type of nevus)

bull Low grade dysplasia (former moderate dysplasia) can be observed clinically or by patients looking for evidence of changing lesions

bull High grade dysplasia is difficult to distinguish from melanoma in situ (UNCERTAINTY) may have competence for local persistence recurrence and progression and should be completely excised

bull All of these are ldquomelanocytic neoplasms of low (or no) malignant potentialrdquo which have little or no competence for metastasis

Lake Wakatipu and Queenstown New Zealand from the Top of ldquoThe Remarkablesrdquo(Mountains of Mordor in the distance)

5212018

41

Session II High CSD Melanomas and Simulants

Lentigo maligna melanoma

Atypical lentiginous neviproliferations

High CSD Lentiginous Nevi and Lentigo Maligna

Melanoma and Simulant(s)

bull Lentiginous Melanoma of Sun-Damaged Skin

ndash LMM in situ

ndash LMM invasive

ndash Distinction from Dysplastic Nevi (Dysplastic Nevus-like MelanomaNevoid Lentigo Maligna

bull Lentiginous Nevi of the ldquoElderlyrdquo (ie CSD Skin)

bull Solar (actinic) lentigo pigmented AK SK hellip

High UV

Pathway II Pathway III

High-CSD Melanoma (LMM)

Desmoplastic Melanoma

IMP IMP

IAMP IAMP

Lentigo maligna melanoma in situ

Melanoma in situ

Lentigo Maligna Melanoma

Desmoplastic Melanoma

NRAS BRAFnon-V600E KIT NF1

NF1 ERBB2 MAP2K1 MAP3K1 BRAF EGFR MET

TERT CDKN2A TP53 PTEN RAC1

TERT NFKBIE NRAS PIK3CA PTPN11

5212018

42

Case 1

12438

F64 Lesion of back

5212018

43

5212018

44

Your Diagnosis

Dysplastic Nevus - IAMP

Melanoma

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe ( gt 15x) mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Our Diagnosis

Case 1 12438

Lentigo maligna melanoma in situ

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45

Case 2

Part 2-2 7419Clinical Information

A large pigmented lesion of the back in a 74-year-old manReason for Consultation

I called this lesion a dysplastic nevus The clinician then calls back to inform us that this is a 22 cm irregular pigmented lesion Now looking at the deepers we think this

might be a ldquolentiginous melanomardquo

Description

bull Shave biopsy of a broad lesion with a dermal component and a moderately cellular junctional component

bull Lesion is ill-defined (poorly circumscribed) at each periphery with features overlapping with those of actinic lentigo

bull Subtle increase of melanocytes along the dermal-epidermal junction with mild to moderate but relatively uniform cytologic atypia

bull Pagetoid scatter is minimal

bull Focally there are elongated rete ridges overlapping with features of dysplastic nevus however these changes are focal within the lesion rather than being symmetrically distributed at shoulders adjacent to a dermal component

Lentiginous nevus versus lentiginous melanoma

bull Poorly circumscribed at each periphery

5212018

46

bull JunctionaIIAMP

bull Patchy lymphocytic infiltrate

bull Solar elastosis

Bridging rete

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47

Your Diagnosis

Melanoma

Nevus

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Lentiginous nevus versus lentiginous melanomaDiagnosis Case 2 M74

Skin mid back Superficial atypical melanocytic proliferation of uncertain significance most consistent with melanoma in situ lentiginous type (nevoid lentigo maligna) versus atypical lentiginous nevus of the elderly see comment

(ie ldquoSAMPUSrdquo)

5212018

48

Diagnosis Case 2 M74

bull Overall Commentbull There are overlapping features among atypical actinic

lentigines lentiginous junctional nevi with and without atypia and lentiginous or ldquonevoidrdquo lentigo maligna

bull Lesions in a high CSD environment must be interpreted with circumspection

bull Overdiagnosis should be avoided as even atypical lentiginous junctional nevi of the elderly seem to be biologically low grade (non-metastasizing but perhaps locally recurring potential)

bull It is judicious to completely excise these lesions in order to be sure that they have been completely examined histologically and also to minimize any possibility of local persistence recurrence or future progression

Nevoid Lentigo MalignaLentiginous Melanoma(Lentiginous Nevus)

bull Kossard 1997 Aust J Dermatol Nevoid lentigo malignaKing Page Googe amp Mihm Modern Pathology 2005 Lentiginous melanomaFerrahi Egbert amp Swetter J Cutan Pathol 2005 Dysplastic nevus-like LMM

bull Clinical diagnosis may varyndash eg lentigo maligna atypical nevus pigmented basal cell carcinoma seborrheic keratosis and

lentigo

bull Biopsies may mimic junctional nevus or dysplastic nevus at least focallyndash Lentiginous proliferation of melanocytes at the dermo-epidermal junction both as single cells

and as small nests with areas of confluent growth extending to the edges of the biopsy ndash Rete ridges maintainedndash Pagetoid spread of melanocytes was not prominent in HampE - stained sections

bull Diagnosis of melanoma more easily recognized in the complete excision specimens similar atypical melanocytic proliferation occurring over a broad area flanking the prior biopsy sites

bull Stains for MITF and Mart-1 highlight continuous basal melanocytic proliferation as well as foci of pagetoid scatter

Lentiginous MelanomaKing Page Googe Mihm Mod Pathol 2005

bull Initial biopsies mimicked lentiginous nevus or dysplastic nevus

bull Lentiginous proliferation of melanocytes at DEJ both as single cells and as small nests with areas of confluent growth extending to the edges of the biopsy

bull Retiform epidermis was maintained and pagetoid spread of melanocytes was not prominent in HampE sections

bull Immunohistochemical stains for MITF and Mart-1 highlighted the extent of the basalar melanocytic proliferation as well as foci of pagetoid spread by melanocytes

bull UNCERTAINTY IS COMMONbull PROGNOSIS IS GOOD IF LESION IS SUPERFICIALbull IMPORTANT TO COMPLETELY EXCISE

bull FOR FULL EXAMINATION AND TO MINIMIZE ANY POTENTIAL FOR LOCAL PERSISTENCE RECURRENCE AND PROGRESSION

Mart 1

MITF

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49

Case 3

Part 2-3 14474

Clinical InformationLeft posterior shoulder F81

Reason for ConsultationFavor a junctional Clarkrsquos nevus (see enclosed report)

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Some bridging few nests that hang down in a droplet-like pattern bull Cytologic atypia mild but relatively uniform

5212018

50

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 3 F81

bull ldquoDifficult to interpretrdquo bull Cytologic atypia is mild to moderate rather than

severe with somewhat concerning architectural changes

bull ldquoOne is somewhat more concerned about a lesion in chronically sun-damaged skin of older subjectsrdquo

bull Skin left posterior shoulder shave biopsy Intraepidermal atypical melanocytic proliferation of uncertain significance (IAMPUS) most consistent with atypical lentiginous junctional nevus (of the elderlyCSD skin) cannot ro evolving or early established melanoma in situ

bull Complete excision recommended (MPATH-Dx 2 or 3)

Case 4

Part 2-3 14474

Clinical InformationLeft posterior shoulder F84

Reason for ConsultationFavor a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus (see

enclosed report) There is mild melanocytic atypia and that the peripheral and deep margins of the specimen were negative in the

plane of sectioning

5212018

51

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 4 F81

bull Recurrence of Case 8

bull Shave biopsy of similar sun-damaged skinbull Somewhat more cellular proliferation of nevoid and

nevoid to epithelioid melanocytes focally exhibiting severe and uniform cytologic atypia

bull Some of these cells are confined to the epidermis above the scar while others appear to extend some distance beyond the periphery of the scar

bull This latter feature raises some concern for evolving melanoma in situ extending beyond the scar

5212018

52

bull Skin left posterior shoulder shave biopsy (recurrence) Intraepidermal atypical melanocytic proliferation of uncertain significance extending to specimen margins see description and comment

ndash Comment Cannot rule out an evolving more significant lesion suggest complete excision

Case 5

Part 2-3 14474

Clinical InformationBiopsy from posterior shoulder of an 85 year old female

Reason for ConsultationThis specimen in my opinion has histologic features concerning for

melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis I do not see

definitive features of a scar consistent with a prior biopsy site

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53

bull Broadbull Moderately

cellularbull Moderate to

severe CSDbull Poorly

circumscribedbull Few bridging

nestsbull Diffuse

fibroplasiabull Cells in dermis

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Nests in dermis

bull No maturation

5212018

54

Melan-A Stain

bull Moderately cellular

bull Continuous basal proliferation

bull Nests hanging down

bull Low level pagetoid scatter

bull Nests in dermis

bull No maturation

Your Diagnosis

Melanoma

Nevus

Our Diagnosis

Malignant melanoma lentigo maligna type (ldquolentiginous melanomardquo Clark level II Breslow thickness 085 mm

5212018

55

Updated History Cases 3-5

bull Clinical Information

bull Three separate biopsies from left posterior shoulder of an 85-year-old female over a period of three years The biopsies were performed 4 years and 1 year ago and recently

bull The original biopsy was called a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus might have been better interpreted as a lentiginous nevus of the elderlysundamaged skin with mild to moderate atypia ndash The peripheral and deep margins of the specimen were said to be negative in the plane

of sectioning

bull The next biopsy at presumably the same anatomic location was signed out as an atypical melanocytic proliferation consistent with a persistentrecurrent Clarkrsquos (dysplastic) nevus involving the peripheral edge of the biopsy ndash It was mentioned that the differential diagnosis included early melanoma in situ

evolving within a pre-existing nevus and a reexcision was recommended

bull The most recent specimen was concerning for melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis

bull Additional procedure warranted to ensure that the lesion has been completely removed`

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Cytologic atypia mild but relatively uniform bull POTENTIAL PRECURSOR (low risk) VS ACTUAL PRECURSOR (hindsight bias)bull Manage by excision or follow-up

bull Case 5

bull Second recurrence of a lesion that originally had only ldquomildrdquo atypia (but moderate to severe architectural disorder)

bull Diagnosis of dysplastic nevus should be made with caution in elderlyCSD skin

bull Complete excision is appropriate for ldquoatypical lentiginous nevus of elderlysundamaged skinrdquo

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56

Last Case

Part 2-7 12150

Clinical InformationLesion of right shoulder ro melanoma versus nevus in a 76 yo man

Reason for ConsultationIs this anything other than a moderately atypical neurotized compound nevus

bull A relatively broad lesion with irregular thickening and thinning of rete ridges and a sparsely cellular infiltrate in the dermis

bull Generally sparsely cellularbull Moderate to severe CSD

Poorly circumscribed

5212018

57

bull Pigmented melanophages in the dermis

bull Increased number of melanocytes in the epidermis many of them suprabasal

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

5212018

58

S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

bull Melan-A stain highlights the junctional component but the dermal spindle cells are negative

Case 6

bull Skin right superior shoulder Malignant melanoma lentigo maligna type nonulcerated with pure desmoplastic vertical growth phase Clark level IV Breslow thickness not lt 064 mm extending close to the specimen base see Comment 3

bull Commentbull Changes extend close to the base and to a peripheral margin of the

specimenbull It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution Sbull Should be excised locally in order to prevent any possibility of persistence

recurrence or future progression of it bull Based on its microstaging attributes the prognosis for this lesion should

be excellent The prognosis for ldquopurerdquo desmoplastic melanoma is if anything better than that for melanomas of similar thickness

bull This lesion could be managed with a relatively generous wide local excision ndash MPATH DX Category 4 (or 5)

5212018

59

Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

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60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

5212018

29

Papillomatous naevoid melanomabull Papillomatous epithelial strands dense proliferation lack of

maturation atypia mitoses

bull In-transit or lymph node metastases occurred in 33 of patients

Maturing naevoid melanomabull ldquoChange from epithelioid pleomorphic melanocytes in the

junctional component to hellip smaller but still atypical cells arranged in nests surrounded by dense collagenrdquo

bull ldquohellipno disease progression was seen in those with maturing naevoid melanomas (including two with measured thicknesses of 30 and 35 mm respectively)rdquo

Significance of Nevi

bull Nevi are important mainly in relation to melanoma

ndash Precursors ndash but risk for individual lesions is low

ndash Risk markers ndash important mainly in high risk situations

ndash Simulants ndash important in everyday clinical decision-making

Case 7

Clinical InformationPigmented lesion on the back of a 40 year old

womanReason for Consultation

Rule out melanoma

5212018

30

A Lesion of the Back in a 40 Year Old Woman

bull ldquoshave biopsy under the left arm hellip has caused consternation hellip two of us believing that we are dealing with a hellip melanomahellip two others believing that although worrisome hellip not yet melanomardquo

5212018

31

5212018

32

5212018

33

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

34

Your Diagnosis

High Grade

Low Grade

Clarkrsquos Dysplastic Nevus vs Melanoma in Situ vs Nevus

Feature Melanoma Dysplastic Nevus Nevus

Size tend to be larger intermediate smaller

Symmetry poor good good

Keratinocytes irregular uniform elongated rete uniform

Melanocytes epithelioid mixed nevoid

Nested variable predominant predominant

Nests coalescent bridging discrete

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe (gt 15x) mild-moderate

Mitoses about 13 of cases almost always absent absent

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Diagnosis Rendered

bull ldquomalignant melanoma probably lentigo maligna type showing Clark level III invasion with early tumorigenic but nonmitogenic vertical growth phase at a greatest Breslow thickness of 030 mm hellip associated nevus with congenital pattern featuresrdquo

5212018

35

New Information

ldquoI received a call from the primary care physician of this patient asking me to review a biopsy from June of 2004 which I had signed out as a compound congenital melanocytic nevus She told me that the lesion had developed re-pigmentation in the previous biopsy site hellip rdquo

bull ldquoI think it is almost certain that the subsequent biopsy is a pseudomelanoma based on the fact that there was no atypia in the original shave biopsy specimen the interval between biopsy and re-pigmentation is only three months and the re-pigmentation is in the previous biopsy site The lack of this additional information at the time you received the biopsy was a handicaprdquo

5212018

36

5212018

37

New Report

ldquosuperficial atypical melanocytic proliferation cw recurrent nevus phenomenon extending to specimen marginsrdquo hellip ldquoI would make only one reservation and that is that this lesion should be re-excised again with a margin of normal skin around the scar and any residual lesion helliprdquo

5212018

38

RECURRENT MELANOCYTIC NEVUS

Pseudomelanoma (Ackerman)

ndash pigmented patch at site of prior shave biopsy of a benign compound or dermal nevus

ndash repigmentation occurs quickly (6 weeks)

ndash pigment does not extend beyond scars borders

RECURRENT MELANOCYTIC NEVUS

Histology

bull variably sized and shaped sometimes confluent nests

bull single cells amp nests above DEJ usually not beyond mid-spinous layer

bull occasional lesional cells or nests in dermis

bull slight cytologic atypia (ldquoreactiverdquo) rare mitoses

bull proliferation does not extend beyond scar

bull original nevus should be reviewed

5212018

39

Lessons

bull Atypia in recurrent nevi can be severe yet is ldquoreactiverdquo

ndash Mitoses can be present

ndash Dermal atypia can be present

bull A superficial scar can mimic diffuse fibroplasia seen in many melanomas

bull Keep a high index of suspicion

ndash Consider a full differential diagnosis

ndash Call for history if necessary

5212018

40

Significance of Nevi

bull Nevi are important mainly in relation to melanoma

ndash Precursors ndash but risk for individual lesions is low

ndash Risk markers ndash important mainly in high risk situations

ndash Simulants ndash important in everyday clinical decision-making

Conclusions

bull Former mild dysplasia is a benign lentiginous nevus (the commonest type of nevus)

bull Low grade dysplasia (former moderate dysplasia) can be observed clinically or by patients looking for evidence of changing lesions

bull High grade dysplasia is difficult to distinguish from melanoma in situ (UNCERTAINTY) may have competence for local persistence recurrence and progression and should be completely excised

bull All of these are ldquomelanocytic neoplasms of low (or no) malignant potentialrdquo which have little or no competence for metastasis

Lake Wakatipu and Queenstown New Zealand from the Top of ldquoThe Remarkablesrdquo(Mountains of Mordor in the distance)

5212018

41

Session II High CSD Melanomas and Simulants

Lentigo maligna melanoma

Atypical lentiginous neviproliferations

High CSD Lentiginous Nevi and Lentigo Maligna

Melanoma and Simulant(s)

bull Lentiginous Melanoma of Sun-Damaged Skin

ndash LMM in situ

ndash LMM invasive

ndash Distinction from Dysplastic Nevi (Dysplastic Nevus-like MelanomaNevoid Lentigo Maligna

bull Lentiginous Nevi of the ldquoElderlyrdquo (ie CSD Skin)

bull Solar (actinic) lentigo pigmented AK SK hellip

High UV

Pathway II Pathway III

High-CSD Melanoma (LMM)

Desmoplastic Melanoma

IMP IMP

IAMP IAMP

Lentigo maligna melanoma in situ

Melanoma in situ

Lentigo Maligna Melanoma

Desmoplastic Melanoma

NRAS BRAFnon-V600E KIT NF1

NF1 ERBB2 MAP2K1 MAP3K1 BRAF EGFR MET

TERT CDKN2A TP53 PTEN RAC1

TERT NFKBIE NRAS PIK3CA PTPN11

5212018

42

Case 1

12438

F64 Lesion of back

5212018

43

5212018

44

Your Diagnosis

Dysplastic Nevus - IAMP

Melanoma

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe ( gt 15x) mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Our Diagnosis

Case 1 12438

Lentigo maligna melanoma in situ

5212018

45

Case 2

Part 2-2 7419Clinical Information

A large pigmented lesion of the back in a 74-year-old manReason for Consultation

I called this lesion a dysplastic nevus The clinician then calls back to inform us that this is a 22 cm irregular pigmented lesion Now looking at the deepers we think this

might be a ldquolentiginous melanomardquo

Description

bull Shave biopsy of a broad lesion with a dermal component and a moderately cellular junctional component

bull Lesion is ill-defined (poorly circumscribed) at each periphery with features overlapping with those of actinic lentigo

bull Subtle increase of melanocytes along the dermal-epidermal junction with mild to moderate but relatively uniform cytologic atypia

bull Pagetoid scatter is minimal

bull Focally there are elongated rete ridges overlapping with features of dysplastic nevus however these changes are focal within the lesion rather than being symmetrically distributed at shoulders adjacent to a dermal component

Lentiginous nevus versus lentiginous melanoma

bull Poorly circumscribed at each periphery

5212018

46

bull JunctionaIIAMP

bull Patchy lymphocytic infiltrate

bull Solar elastosis

Bridging rete

5212018

47

Your Diagnosis

Melanoma

Nevus

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Lentiginous nevus versus lentiginous melanomaDiagnosis Case 2 M74

Skin mid back Superficial atypical melanocytic proliferation of uncertain significance most consistent with melanoma in situ lentiginous type (nevoid lentigo maligna) versus atypical lentiginous nevus of the elderly see comment

(ie ldquoSAMPUSrdquo)

5212018

48

Diagnosis Case 2 M74

bull Overall Commentbull There are overlapping features among atypical actinic

lentigines lentiginous junctional nevi with and without atypia and lentiginous or ldquonevoidrdquo lentigo maligna

bull Lesions in a high CSD environment must be interpreted with circumspection

bull Overdiagnosis should be avoided as even atypical lentiginous junctional nevi of the elderly seem to be biologically low grade (non-metastasizing but perhaps locally recurring potential)

bull It is judicious to completely excise these lesions in order to be sure that they have been completely examined histologically and also to minimize any possibility of local persistence recurrence or future progression

Nevoid Lentigo MalignaLentiginous Melanoma(Lentiginous Nevus)

bull Kossard 1997 Aust J Dermatol Nevoid lentigo malignaKing Page Googe amp Mihm Modern Pathology 2005 Lentiginous melanomaFerrahi Egbert amp Swetter J Cutan Pathol 2005 Dysplastic nevus-like LMM

bull Clinical diagnosis may varyndash eg lentigo maligna atypical nevus pigmented basal cell carcinoma seborrheic keratosis and

lentigo

bull Biopsies may mimic junctional nevus or dysplastic nevus at least focallyndash Lentiginous proliferation of melanocytes at the dermo-epidermal junction both as single cells

and as small nests with areas of confluent growth extending to the edges of the biopsy ndash Rete ridges maintainedndash Pagetoid spread of melanocytes was not prominent in HampE - stained sections

bull Diagnosis of melanoma more easily recognized in the complete excision specimens similar atypical melanocytic proliferation occurring over a broad area flanking the prior biopsy sites

bull Stains for MITF and Mart-1 highlight continuous basal melanocytic proliferation as well as foci of pagetoid scatter

Lentiginous MelanomaKing Page Googe Mihm Mod Pathol 2005

bull Initial biopsies mimicked lentiginous nevus or dysplastic nevus

bull Lentiginous proliferation of melanocytes at DEJ both as single cells and as small nests with areas of confluent growth extending to the edges of the biopsy

bull Retiform epidermis was maintained and pagetoid spread of melanocytes was not prominent in HampE sections

bull Immunohistochemical stains for MITF and Mart-1 highlighted the extent of the basalar melanocytic proliferation as well as foci of pagetoid spread by melanocytes

bull UNCERTAINTY IS COMMONbull PROGNOSIS IS GOOD IF LESION IS SUPERFICIALbull IMPORTANT TO COMPLETELY EXCISE

bull FOR FULL EXAMINATION AND TO MINIMIZE ANY POTENTIAL FOR LOCAL PERSISTENCE RECURRENCE AND PROGRESSION

Mart 1

MITF

5212018

49

Case 3

Part 2-3 14474

Clinical InformationLeft posterior shoulder F81

Reason for ConsultationFavor a junctional Clarkrsquos nevus (see enclosed report)

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Some bridging few nests that hang down in a droplet-like pattern bull Cytologic atypia mild but relatively uniform

5212018

50

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 3 F81

bull ldquoDifficult to interpretrdquo bull Cytologic atypia is mild to moderate rather than

severe with somewhat concerning architectural changes

bull ldquoOne is somewhat more concerned about a lesion in chronically sun-damaged skin of older subjectsrdquo

bull Skin left posterior shoulder shave biopsy Intraepidermal atypical melanocytic proliferation of uncertain significance (IAMPUS) most consistent with atypical lentiginous junctional nevus (of the elderlyCSD skin) cannot ro evolving or early established melanoma in situ

bull Complete excision recommended (MPATH-Dx 2 or 3)

Case 4

Part 2-3 14474

Clinical InformationLeft posterior shoulder F84

Reason for ConsultationFavor a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus (see

enclosed report) There is mild melanocytic atypia and that the peripheral and deep margins of the specimen were negative in the

plane of sectioning

5212018

51

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 4 F81

bull Recurrence of Case 8

bull Shave biopsy of similar sun-damaged skinbull Somewhat more cellular proliferation of nevoid and

nevoid to epithelioid melanocytes focally exhibiting severe and uniform cytologic atypia

bull Some of these cells are confined to the epidermis above the scar while others appear to extend some distance beyond the periphery of the scar

bull This latter feature raises some concern for evolving melanoma in situ extending beyond the scar

5212018

52

bull Skin left posterior shoulder shave biopsy (recurrence) Intraepidermal atypical melanocytic proliferation of uncertain significance extending to specimen margins see description and comment

ndash Comment Cannot rule out an evolving more significant lesion suggest complete excision

Case 5

Part 2-3 14474

Clinical InformationBiopsy from posterior shoulder of an 85 year old female

Reason for ConsultationThis specimen in my opinion has histologic features concerning for

melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis I do not see

definitive features of a scar consistent with a prior biopsy site

5212018

53

bull Broadbull Moderately

cellularbull Moderate to

severe CSDbull Poorly

circumscribedbull Few bridging

nestsbull Diffuse

fibroplasiabull Cells in dermis

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Nests in dermis

bull No maturation

5212018

54

Melan-A Stain

bull Moderately cellular

bull Continuous basal proliferation

bull Nests hanging down

bull Low level pagetoid scatter

bull Nests in dermis

bull No maturation

Your Diagnosis

Melanoma

Nevus

Our Diagnosis

Malignant melanoma lentigo maligna type (ldquolentiginous melanomardquo Clark level II Breslow thickness 085 mm

5212018

55

Updated History Cases 3-5

bull Clinical Information

bull Three separate biopsies from left posterior shoulder of an 85-year-old female over a period of three years The biopsies were performed 4 years and 1 year ago and recently

bull The original biopsy was called a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus might have been better interpreted as a lentiginous nevus of the elderlysundamaged skin with mild to moderate atypia ndash The peripheral and deep margins of the specimen were said to be negative in the plane

of sectioning

bull The next biopsy at presumably the same anatomic location was signed out as an atypical melanocytic proliferation consistent with a persistentrecurrent Clarkrsquos (dysplastic) nevus involving the peripheral edge of the biopsy ndash It was mentioned that the differential diagnosis included early melanoma in situ

evolving within a pre-existing nevus and a reexcision was recommended

bull The most recent specimen was concerning for melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis

bull Additional procedure warranted to ensure that the lesion has been completely removed`

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Cytologic atypia mild but relatively uniform bull POTENTIAL PRECURSOR (low risk) VS ACTUAL PRECURSOR (hindsight bias)bull Manage by excision or follow-up

bull Case 5

bull Second recurrence of a lesion that originally had only ldquomildrdquo atypia (but moderate to severe architectural disorder)

bull Diagnosis of dysplastic nevus should be made with caution in elderlyCSD skin

bull Complete excision is appropriate for ldquoatypical lentiginous nevus of elderlysundamaged skinrdquo

5212018

56

Last Case

Part 2-7 12150

Clinical InformationLesion of right shoulder ro melanoma versus nevus in a 76 yo man

Reason for ConsultationIs this anything other than a moderately atypical neurotized compound nevus

bull A relatively broad lesion with irregular thickening and thinning of rete ridges and a sparsely cellular infiltrate in the dermis

bull Generally sparsely cellularbull Moderate to severe CSD

Poorly circumscribed

5212018

57

bull Pigmented melanophages in the dermis

bull Increased number of melanocytes in the epidermis many of them suprabasal

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

5212018

58

S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

bull Melan-A stain highlights the junctional component but the dermal spindle cells are negative

Case 6

bull Skin right superior shoulder Malignant melanoma lentigo maligna type nonulcerated with pure desmoplastic vertical growth phase Clark level IV Breslow thickness not lt 064 mm extending close to the specimen base see Comment 3

bull Commentbull Changes extend close to the base and to a peripheral margin of the

specimenbull It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution Sbull Should be excised locally in order to prevent any possibility of persistence

recurrence or future progression of it bull Based on its microstaging attributes the prognosis for this lesion should

be excellent The prognosis for ldquopurerdquo desmoplastic melanoma is if anything better than that for melanomas of similar thickness

bull This lesion could be managed with a relatively generous wide local excision ndash MPATH DX Category 4 (or 5)

5212018

59

Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

5212018

60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

5212018

30

A Lesion of the Back in a 40 Year Old Woman

bull ldquoshave biopsy under the left arm hellip has caused consternation hellip two of us believing that we are dealing with a hellip melanomahellip two others believing that although worrisome hellip not yet melanomardquo

5212018

31

5212018

32

5212018

33

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

34

Your Diagnosis

High Grade

Low Grade

Clarkrsquos Dysplastic Nevus vs Melanoma in Situ vs Nevus

Feature Melanoma Dysplastic Nevus Nevus

Size tend to be larger intermediate smaller

Symmetry poor good good

Keratinocytes irregular uniform elongated rete uniform

Melanocytes epithelioid mixed nevoid

Nested variable predominant predominant

Nests coalescent bridging discrete

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe (gt 15x) mild-moderate

Mitoses about 13 of cases almost always absent absent

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Diagnosis Rendered

bull ldquomalignant melanoma probably lentigo maligna type showing Clark level III invasion with early tumorigenic but nonmitogenic vertical growth phase at a greatest Breslow thickness of 030 mm hellip associated nevus with congenital pattern featuresrdquo

5212018

35

New Information

ldquoI received a call from the primary care physician of this patient asking me to review a biopsy from June of 2004 which I had signed out as a compound congenital melanocytic nevus She told me that the lesion had developed re-pigmentation in the previous biopsy site hellip rdquo

bull ldquoI think it is almost certain that the subsequent biopsy is a pseudomelanoma based on the fact that there was no atypia in the original shave biopsy specimen the interval between biopsy and re-pigmentation is only three months and the re-pigmentation is in the previous biopsy site The lack of this additional information at the time you received the biopsy was a handicaprdquo

5212018

36

5212018

37

New Report

ldquosuperficial atypical melanocytic proliferation cw recurrent nevus phenomenon extending to specimen marginsrdquo hellip ldquoI would make only one reservation and that is that this lesion should be re-excised again with a margin of normal skin around the scar and any residual lesion helliprdquo

5212018

38

RECURRENT MELANOCYTIC NEVUS

Pseudomelanoma (Ackerman)

ndash pigmented patch at site of prior shave biopsy of a benign compound or dermal nevus

ndash repigmentation occurs quickly (6 weeks)

ndash pigment does not extend beyond scars borders

RECURRENT MELANOCYTIC NEVUS

Histology

bull variably sized and shaped sometimes confluent nests

bull single cells amp nests above DEJ usually not beyond mid-spinous layer

bull occasional lesional cells or nests in dermis

bull slight cytologic atypia (ldquoreactiverdquo) rare mitoses

bull proliferation does not extend beyond scar

bull original nevus should be reviewed

5212018

39

Lessons

bull Atypia in recurrent nevi can be severe yet is ldquoreactiverdquo

ndash Mitoses can be present

ndash Dermal atypia can be present

bull A superficial scar can mimic diffuse fibroplasia seen in many melanomas

bull Keep a high index of suspicion

ndash Consider a full differential diagnosis

ndash Call for history if necessary

5212018

40

Significance of Nevi

bull Nevi are important mainly in relation to melanoma

ndash Precursors ndash but risk for individual lesions is low

ndash Risk markers ndash important mainly in high risk situations

ndash Simulants ndash important in everyday clinical decision-making

Conclusions

bull Former mild dysplasia is a benign lentiginous nevus (the commonest type of nevus)

bull Low grade dysplasia (former moderate dysplasia) can be observed clinically or by patients looking for evidence of changing lesions

bull High grade dysplasia is difficult to distinguish from melanoma in situ (UNCERTAINTY) may have competence for local persistence recurrence and progression and should be completely excised

bull All of these are ldquomelanocytic neoplasms of low (or no) malignant potentialrdquo which have little or no competence for metastasis

Lake Wakatipu and Queenstown New Zealand from the Top of ldquoThe Remarkablesrdquo(Mountains of Mordor in the distance)

5212018

41

Session II High CSD Melanomas and Simulants

Lentigo maligna melanoma

Atypical lentiginous neviproliferations

High CSD Lentiginous Nevi and Lentigo Maligna

Melanoma and Simulant(s)

bull Lentiginous Melanoma of Sun-Damaged Skin

ndash LMM in situ

ndash LMM invasive

ndash Distinction from Dysplastic Nevi (Dysplastic Nevus-like MelanomaNevoid Lentigo Maligna

bull Lentiginous Nevi of the ldquoElderlyrdquo (ie CSD Skin)

bull Solar (actinic) lentigo pigmented AK SK hellip

High UV

Pathway II Pathway III

High-CSD Melanoma (LMM)

Desmoplastic Melanoma

IMP IMP

IAMP IAMP

Lentigo maligna melanoma in situ

Melanoma in situ

Lentigo Maligna Melanoma

Desmoplastic Melanoma

NRAS BRAFnon-V600E KIT NF1

NF1 ERBB2 MAP2K1 MAP3K1 BRAF EGFR MET

TERT CDKN2A TP53 PTEN RAC1

TERT NFKBIE NRAS PIK3CA PTPN11

5212018

42

Case 1

12438

F64 Lesion of back

5212018

43

5212018

44

Your Diagnosis

Dysplastic Nevus - IAMP

Melanoma

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe ( gt 15x) mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Our Diagnosis

Case 1 12438

Lentigo maligna melanoma in situ

5212018

45

Case 2

Part 2-2 7419Clinical Information

A large pigmented lesion of the back in a 74-year-old manReason for Consultation

I called this lesion a dysplastic nevus The clinician then calls back to inform us that this is a 22 cm irregular pigmented lesion Now looking at the deepers we think this

might be a ldquolentiginous melanomardquo

Description

bull Shave biopsy of a broad lesion with a dermal component and a moderately cellular junctional component

bull Lesion is ill-defined (poorly circumscribed) at each periphery with features overlapping with those of actinic lentigo

bull Subtle increase of melanocytes along the dermal-epidermal junction with mild to moderate but relatively uniform cytologic atypia

bull Pagetoid scatter is minimal

bull Focally there are elongated rete ridges overlapping with features of dysplastic nevus however these changes are focal within the lesion rather than being symmetrically distributed at shoulders adjacent to a dermal component

Lentiginous nevus versus lentiginous melanoma

bull Poorly circumscribed at each periphery

5212018

46

bull JunctionaIIAMP

bull Patchy lymphocytic infiltrate

bull Solar elastosis

Bridging rete

5212018

47

Your Diagnosis

Melanoma

Nevus

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Lentiginous nevus versus lentiginous melanomaDiagnosis Case 2 M74

Skin mid back Superficial atypical melanocytic proliferation of uncertain significance most consistent with melanoma in situ lentiginous type (nevoid lentigo maligna) versus atypical lentiginous nevus of the elderly see comment

(ie ldquoSAMPUSrdquo)

5212018

48

Diagnosis Case 2 M74

bull Overall Commentbull There are overlapping features among atypical actinic

lentigines lentiginous junctional nevi with and without atypia and lentiginous or ldquonevoidrdquo lentigo maligna

bull Lesions in a high CSD environment must be interpreted with circumspection

bull Overdiagnosis should be avoided as even atypical lentiginous junctional nevi of the elderly seem to be biologically low grade (non-metastasizing but perhaps locally recurring potential)

bull It is judicious to completely excise these lesions in order to be sure that they have been completely examined histologically and also to minimize any possibility of local persistence recurrence or future progression

Nevoid Lentigo MalignaLentiginous Melanoma(Lentiginous Nevus)

bull Kossard 1997 Aust J Dermatol Nevoid lentigo malignaKing Page Googe amp Mihm Modern Pathology 2005 Lentiginous melanomaFerrahi Egbert amp Swetter J Cutan Pathol 2005 Dysplastic nevus-like LMM

bull Clinical diagnosis may varyndash eg lentigo maligna atypical nevus pigmented basal cell carcinoma seborrheic keratosis and

lentigo

bull Biopsies may mimic junctional nevus or dysplastic nevus at least focallyndash Lentiginous proliferation of melanocytes at the dermo-epidermal junction both as single cells

and as small nests with areas of confluent growth extending to the edges of the biopsy ndash Rete ridges maintainedndash Pagetoid spread of melanocytes was not prominent in HampE - stained sections

bull Diagnosis of melanoma more easily recognized in the complete excision specimens similar atypical melanocytic proliferation occurring over a broad area flanking the prior biopsy sites

bull Stains for MITF and Mart-1 highlight continuous basal melanocytic proliferation as well as foci of pagetoid scatter

Lentiginous MelanomaKing Page Googe Mihm Mod Pathol 2005

bull Initial biopsies mimicked lentiginous nevus or dysplastic nevus

bull Lentiginous proliferation of melanocytes at DEJ both as single cells and as small nests with areas of confluent growth extending to the edges of the biopsy

bull Retiform epidermis was maintained and pagetoid spread of melanocytes was not prominent in HampE sections

bull Immunohistochemical stains for MITF and Mart-1 highlighted the extent of the basalar melanocytic proliferation as well as foci of pagetoid spread by melanocytes

bull UNCERTAINTY IS COMMONbull PROGNOSIS IS GOOD IF LESION IS SUPERFICIALbull IMPORTANT TO COMPLETELY EXCISE

bull FOR FULL EXAMINATION AND TO MINIMIZE ANY POTENTIAL FOR LOCAL PERSISTENCE RECURRENCE AND PROGRESSION

Mart 1

MITF

5212018

49

Case 3

Part 2-3 14474

Clinical InformationLeft posterior shoulder F81

Reason for ConsultationFavor a junctional Clarkrsquos nevus (see enclosed report)

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Some bridging few nests that hang down in a droplet-like pattern bull Cytologic atypia mild but relatively uniform

5212018

50

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 3 F81

bull ldquoDifficult to interpretrdquo bull Cytologic atypia is mild to moderate rather than

severe with somewhat concerning architectural changes

bull ldquoOne is somewhat more concerned about a lesion in chronically sun-damaged skin of older subjectsrdquo

bull Skin left posterior shoulder shave biopsy Intraepidermal atypical melanocytic proliferation of uncertain significance (IAMPUS) most consistent with atypical lentiginous junctional nevus (of the elderlyCSD skin) cannot ro evolving or early established melanoma in situ

bull Complete excision recommended (MPATH-Dx 2 or 3)

Case 4

Part 2-3 14474

Clinical InformationLeft posterior shoulder F84

Reason for ConsultationFavor a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus (see

enclosed report) There is mild melanocytic atypia and that the peripheral and deep margins of the specimen were negative in the

plane of sectioning

5212018

51

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 4 F81

bull Recurrence of Case 8

bull Shave biopsy of similar sun-damaged skinbull Somewhat more cellular proliferation of nevoid and

nevoid to epithelioid melanocytes focally exhibiting severe and uniform cytologic atypia

bull Some of these cells are confined to the epidermis above the scar while others appear to extend some distance beyond the periphery of the scar

bull This latter feature raises some concern for evolving melanoma in situ extending beyond the scar

5212018

52

bull Skin left posterior shoulder shave biopsy (recurrence) Intraepidermal atypical melanocytic proliferation of uncertain significance extending to specimen margins see description and comment

ndash Comment Cannot rule out an evolving more significant lesion suggest complete excision

Case 5

Part 2-3 14474

Clinical InformationBiopsy from posterior shoulder of an 85 year old female

Reason for ConsultationThis specimen in my opinion has histologic features concerning for

melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis I do not see

definitive features of a scar consistent with a prior biopsy site

5212018

53

bull Broadbull Moderately

cellularbull Moderate to

severe CSDbull Poorly

circumscribedbull Few bridging

nestsbull Diffuse

fibroplasiabull Cells in dermis

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Nests in dermis

bull No maturation

5212018

54

Melan-A Stain

bull Moderately cellular

bull Continuous basal proliferation

bull Nests hanging down

bull Low level pagetoid scatter

bull Nests in dermis

bull No maturation

Your Diagnosis

Melanoma

Nevus

Our Diagnosis

Malignant melanoma lentigo maligna type (ldquolentiginous melanomardquo Clark level II Breslow thickness 085 mm

5212018

55

Updated History Cases 3-5

bull Clinical Information

bull Three separate biopsies from left posterior shoulder of an 85-year-old female over a period of three years The biopsies were performed 4 years and 1 year ago and recently

bull The original biopsy was called a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus might have been better interpreted as a lentiginous nevus of the elderlysundamaged skin with mild to moderate atypia ndash The peripheral and deep margins of the specimen were said to be negative in the plane

of sectioning

bull The next biopsy at presumably the same anatomic location was signed out as an atypical melanocytic proliferation consistent with a persistentrecurrent Clarkrsquos (dysplastic) nevus involving the peripheral edge of the biopsy ndash It was mentioned that the differential diagnosis included early melanoma in situ

evolving within a pre-existing nevus and a reexcision was recommended

bull The most recent specimen was concerning for melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis

bull Additional procedure warranted to ensure that the lesion has been completely removed`

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Cytologic atypia mild but relatively uniform bull POTENTIAL PRECURSOR (low risk) VS ACTUAL PRECURSOR (hindsight bias)bull Manage by excision or follow-up

bull Case 5

bull Second recurrence of a lesion that originally had only ldquomildrdquo atypia (but moderate to severe architectural disorder)

bull Diagnosis of dysplastic nevus should be made with caution in elderlyCSD skin

bull Complete excision is appropriate for ldquoatypical lentiginous nevus of elderlysundamaged skinrdquo

5212018

56

Last Case

Part 2-7 12150

Clinical InformationLesion of right shoulder ro melanoma versus nevus in a 76 yo man

Reason for ConsultationIs this anything other than a moderately atypical neurotized compound nevus

bull A relatively broad lesion with irregular thickening and thinning of rete ridges and a sparsely cellular infiltrate in the dermis

bull Generally sparsely cellularbull Moderate to severe CSD

Poorly circumscribed

5212018

57

bull Pigmented melanophages in the dermis

bull Increased number of melanocytes in the epidermis many of them suprabasal

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

5212018

58

S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

bull Melan-A stain highlights the junctional component but the dermal spindle cells are negative

Case 6

bull Skin right superior shoulder Malignant melanoma lentigo maligna type nonulcerated with pure desmoplastic vertical growth phase Clark level IV Breslow thickness not lt 064 mm extending close to the specimen base see Comment 3

bull Commentbull Changes extend close to the base and to a peripheral margin of the

specimenbull It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution Sbull Should be excised locally in order to prevent any possibility of persistence

recurrence or future progression of it bull Based on its microstaging attributes the prognosis for this lesion should

be excellent The prognosis for ldquopurerdquo desmoplastic melanoma is if anything better than that for melanomas of similar thickness

bull This lesion could be managed with a relatively generous wide local excision ndash MPATH DX Category 4 (or 5)

5212018

59

Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

5212018

60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

5212018

31

5212018

32

5212018

33

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

34

Your Diagnosis

High Grade

Low Grade

Clarkrsquos Dysplastic Nevus vs Melanoma in Situ vs Nevus

Feature Melanoma Dysplastic Nevus Nevus

Size tend to be larger intermediate smaller

Symmetry poor good good

Keratinocytes irregular uniform elongated rete uniform

Melanocytes epithelioid mixed nevoid

Nested variable predominant predominant

Nests coalescent bridging discrete

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe (gt 15x) mild-moderate

Mitoses about 13 of cases almost always absent absent

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Diagnosis Rendered

bull ldquomalignant melanoma probably lentigo maligna type showing Clark level III invasion with early tumorigenic but nonmitogenic vertical growth phase at a greatest Breslow thickness of 030 mm hellip associated nevus with congenital pattern featuresrdquo

5212018

35

New Information

ldquoI received a call from the primary care physician of this patient asking me to review a biopsy from June of 2004 which I had signed out as a compound congenital melanocytic nevus She told me that the lesion had developed re-pigmentation in the previous biopsy site hellip rdquo

bull ldquoI think it is almost certain that the subsequent biopsy is a pseudomelanoma based on the fact that there was no atypia in the original shave biopsy specimen the interval between biopsy and re-pigmentation is only three months and the re-pigmentation is in the previous biopsy site The lack of this additional information at the time you received the biopsy was a handicaprdquo

5212018

36

5212018

37

New Report

ldquosuperficial atypical melanocytic proliferation cw recurrent nevus phenomenon extending to specimen marginsrdquo hellip ldquoI would make only one reservation and that is that this lesion should be re-excised again with a margin of normal skin around the scar and any residual lesion helliprdquo

5212018

38

RECURRENT MELANOCYTIC NEVUS

Pseudomelanoma (Ackerman)

ndash pigmented patch at site of prior shave biopsy of a benign compound or dermal nevus

ndash repigmentation occurs quickly (6 weeks)

ndash pigment does not extend beyond scars borders

RECURRENT MELANOCYTIC NEVUS

Histology

bull variably sized and shaped sometimes confluent nests

bull single cells amp nests above DEJ usually not beyond mid-spinous layer

bull occasional lesional cells or nests in dermis

bull slight cytologic atypia (ldquoreactiverdquo) rare mitoses

bull proliferation does not extend beyond scar

bull original nevus should be reviewed

5212018

39

Lessons

bull Atypia in recurrent nevi can be severe yet is ldquoreactiverdquo

ndash Mitoses can be present

ndash Dermal atypia can be present

bull A superficial scar can mimic diffuse fibroplasia seen in many melanomas

bull Keep a high index of suspicion

ndash Consider a full differential diagnosis

ndash Call for history if necessary

5212018

40

Significance of Nevi

bull Nevi are important mainly in relation to melanoma

ndash Precursors ndash but risk for individual lesions is low

ndash Risk markers ndash important mainly in high risk situations

ndash Simulants ndash important in everyday clinical decision-making

Conclusions

bull Former mild dysplasia is a benign lentiginous nevus (the commonest type of nevus)

bull Low grade dysplasia (former moderate dysplasia) can be observed clinically or by patients looking for evidence of changing lesions

bull High grade dysplasia is difficult to distinguish from melanoma in situ (UNCERTAINTY) may have competence for local persistence recurrence and progression and should be completely excised

bull All of these are ldquomelanocytic neoplasms of low (or no) malignant potentialrdquo which have little or no competence for metastasis

Lake Wakatipu and Queenstown New Zealand from the Top of ldquoThe Remarkablesrdquo(Mountains of Mordor in the distance)

5212018

41

Session II High CSD Melanomas and Simulants

Lentigo maligna melanoma

Atypical lentiginous neviproliferations

High CSD Lentiginous Nevi and Lentigo Maligna

Melanoma and Simulant(s)

bull Lentiginous Melanoma of Sun-Damaged Skin

ndash LMM in situ

ndash LMM invasive

ndash Distinction from Dysplastic Nevi (Dysplastic Nevus-like MelanomaNevoid Lentigo Maligna

bull Lentiginous Nevi of the ldquoElderlyrdquo (ie CSD Skin)

bull Solar (actinic) lentigo pigmented AK SK hellip

High UV

Pathway II Pathway III

High-CSD Melanoma (LMM)

Desmoplastic Melanoma

IMP IMP

IAMP IAMP

Lentigo maligna melanoma in situ

Melanoma in situ

Lentigo Maligna Melanoma

Desmoplastic Melanoma

NRAS BRAFnon-V600E KIT NF1

NF1 ERBB2 MAP2K1 MAP3K1 BRAF EGFR MET

TERT CDKN2A TP53 PTEN RAC1

TERT NFKBIE NRAS PIK3CA PTPN11

5212018

42

Case 1

12438

F64 Lesion of back

5212018

43

5212018

44

Your Diagnosis

Dysplastic Nevus - IAMP

Melanoma

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe ( gt 15x) mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Our Diagnosis

Case 1 12438

Lentigo maligna melanoma in situ

5212018

45

Case 2

Part 2-2 7419Clinical Information

A large pigmented lesion of the back in a 74-year-old manReason for Consultation

I called this lesion a dysplastic nevus The clinician then calls back to inform us that this is a 22 cm irregular pigmented lesion Now looking at the deepers we think this

might be a ldquolentiginous melanomardquo

Description

bull Shave biopsy of a broad lesion with a dermal component and a moderately cellular junctional component

bull Lesion is ill-defined (poorly circumscribed) at each periphery with features overlapping with those of actinic lentigo

bull Subtle increase of melanocytes along the dermal-epidermal junction with mild to moderate but relatively uniform cytologic atypia

bull Pagetoid scatter is minimal

bull Focally there are elongated rete ridges overlapping with features of dysplastic nevus however these changes are focal within the lesion rather than being symmetrically distributed at shoulders adjacent to a dermal component

Lentiginous nevus versus lentiginous melanoma

bull Poorly circumscribed at each periphery

5212018

46

bull JunctionaIIAMP

bull Patchy lymphocytic infiltrate

bull Solar elastosis

Bridging rete

5212018

47

Your Diagnosis

Melanoma

Nevus

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Lentiginous nevus versus lentiginous melanomaDiagnosis Case 2 M74

Skin mid back Superficial atypical melanocytic proliferation of uncertain significance most consistent with melanoma in situ lentiginous type (nevoid lentigo maligna) versus atypical lentiginous nevus of the elderly see comment

(ie ldquoSAMPUSrdquo)

5212018

48

Diagnosis Case 2 M74

bull Overall Commentbull There are overlapping features among atypical actinic

lentigines lentiginous junctional nevi with and without atypia and lentiginous or ldquonevoidrdquo lentigo maligna

bull Lesions in a high CSD environment must be interpreted with circumspection

bull Overdiagnosis should be avoided as even atypical lentiginous junctional nevi of the elderly seem to be biologically low grade (non-metastasizing but perhaps locally recurring potential)

bull It is judicious to completely excise these lesions in order to be sure that they have been completely examined histologically and also to minimize any possibility of local persistence recurrence or future progression

Nevoid Lentigo MalignaLentiginous Melanoma(Lentiginous Nevus)

bull Kossard 1997 Aust J Dermatol Nevoid lentigo malignaKing Page Googe amp Mihm Modern Pathology 2005 Lentiginous melanomaFerrahi Egbert amp Swetter J Cutan Pathol 2005 Dysplastic nevus-like LMM

bull Clinical diagnosis may varyndash eg lentigo maligna atypical nevus pigmented basal cell carcinoma seborrheic keratosis and

lentigo

bull Biopsies may mimic junctional nevus or dysplastic nevus at least focallyndash Lentiginous proliferation of melanocytes at the dermo-epidermal junction both as single cells

and as small nests with areas of confluent growth extending to the edges of the biopsy ndash Rete ridges maintainedndash Pagetoid spread of melanocytes was not prominent in HampE - stained sections

bull Diagnosis of melanoma more easily recognized in the complete excision specimens similar atypical melanocytic proliferation occurring over a broad area flanking the prior biopsy sites

bull Stains for MITF and Mart-1 highlight continuous basal melanocytic proliferation as well as foci of pagetoid scatter

Lentiginous MelanomaKing Page Googe Mihm Mod Pathol 2005

bull Initial biopsies mimicked lentiginous nevus or dysplastic nevus

bull Lentiginous proliferation of melanocytes at DEJ both as single cells and as small nests with areas of confluent growth extending to the edges of the biopsy

bull Retiform epidermis was maintained and pagetoid spread of melanocytes was not prominent in HampE sections

bull Immunohistochemical stains for MITF and Mart-1 highlighted the extent of the basalar melanocytic proliferation as well as foci of pagetoid spread by melanocytes

bull UNCERTAINTY IS COMMONbull PROGNOSIS IS GOOD IF LESION IS SUPERFICIALbull IMPORTANT TO COMPLETELY EXCISE

bull FOR FULL EXAMINATION AND TO MINIMIZE ANY POTENTIAL FOR LOCAL PERSISTENCE RECURRENCE AND PROGRESSION

Mart 1

MITF

5212018

49

Case 3

Part 2-3 14474

Clinical InformationLeft posterior shoulder F81

Reason for ConsultationFavor a junctional Clarkrsquos nevus (see enclosed report)

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Some bridging few nests that hang down in a droplet-like pattern bull Cytologic atypia mild but relatively uniform

5212018

50

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 3 F81

bull ldquoDifficult to interpretrdquo bull Cytologic atypia is mild to moderate rather than

severe with somewhat concerning architectural changes

bull ldquoOne is somewhat more concerned about a lesion in chronically sun-damaged skin of older subjectsrdquo

bull Skin left posterior shoulder shave biopsy Intraepidermal atypical melanocytic proliferation of uncertain significance (IAMPUS) most consistent with atypical lentiginous junctional nevus (of the elderlyCSD skin) cannot ro evolving or early established melanoma in situ

bull Complete excision recommended (MPATH-Dx 2 or 3)

Case 4

Part 2-3 14474

Clinical InformationLeft posterior shoulder F84

Reason for ConsultationFavor a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus (see

enclosed report) There is mild melanocytic atypia and that the peripheral and deep margins of the specimen were negative in the

plane of sectioning

5212018

51

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 4 F81

bull Recurrence of Case 8

bull Shave biopsy of similar sun-damaged skinbull Somewhat more cellular proliferation of nevoid and

nevoid to epithelioid melanocytes focally exhibiting severe and uniform cytologic atypia

bull Some of these cells are confined to the epidermis above the scar while others appear to extend some distance beyond the periphery of the scar

bull This latter feature raises some concern for evolving melanoma in situ extending beyond the scar

5212018

52

bull Skin left posterior shoulder shave biopsy (recurrence) Intraepidermal atypical melanocytic proliferation of uncertain significance extending to specimen margins see description and comment

ndash Comment Cannot rule out an evolving more significant lesion suggest complete excision

Case 5

Part 2-3 14474

Clinical InformationBiopsy from posterior shoulder of an 85 year old female

Reason for ConsultationThis specimen in my opinion has histologic features concerning for

melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis I do not see

definitive features of a scar consistent with a prior biopsy site

5212018

53

bull Broadbull Moderately

cellularbull Moderate to

severe CSDbull Poorly

circumscribedbull Few bridging

nestsbull Diffuse

fibroplasiabull Cells in dermis

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Nests in dermis

bull No maturation

5212018

54

Melan-A Stain

bull Moderately cellular

bull Continuous basal proliferation

bull Nests hanging down

bull Low level pagetoid scatter

bull Nests in dermis

bull No maturation

Your Diagnosis

Melanoma

Nevus

Our Diagnosis

Malignant melanoma lentigo maligna type (ldquolentiginous melanomardquo Clark level II Breslow thickness 085 mm

5212018

55

Updated History Cases 3-5

bull Clinical Information

bull Three separate biopsies from left posterior shoulder of an 85-year-old female over a period of three years The biopsies were performed 4 years and 1 year ago and recently

bull The original biopsy was called a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus might have been better interpreted as a lentiginous nevus of the elderlysundamaged skin with mild to moderate atypia ndash The peripheral and deep margins of the specimen were said to be negative in the plane

of sectioning

bull The next biopsy at presumably the same anatomic location was signed out as an atypical melanocytic proliferation consistent with a persistentrecurrent Clarkrsquos (dysplastic) nevus involving the peripheral edge of the biopsy ndash It was mentioned that the differential diagnosis included early melanoma in situ

evolving within a pre-existing nevus and a reexcision was recommended

bull The most recent specimen was concerning for melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis

bull Additional procedure warranted to ensure that the lesion has been completely removed`

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Cytologic atypia mild but relatively uniform bull POTENTIAL PRECURSOR (low risk) VS ACTUAL PRECURSOR (hindsight bias)bull Manage by excision or follow-up

bull Case 5

bull Second recurrence of a lesion that originally had only ldquomildrdquo atypia (but moderate to severe architectural disorder)

bull Diagnosis of dysplastic nevus should be made with caution in elderlyCSD skin

bull Complete excision is appropriate for ldquoatypical lentiginous nevus of elderlysundamaged skinrdquo

5212018

56

Last Case

Part 2-7 12150

Clinical InformationLesion of right shoulder ro melanoma versus nevus in a 76 yo man

Reason for ConsultationIs this anything other than a moderately atypical neurotized compound nevus

bull A relatively broad lesion with irregular thickening and thinning of rete ridges and a sparsely cellular infiltrate in the dermis

bull Generally sparsely cellularbull Moderate to severe CSD

Poorly circumscribed

5212018

57

bull Pigmented melanophages in the dermis

bull Increased number of melanocytes in the epidermis many of them suprabasal

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

5212018

58

S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

bull Melan-A stain highlights the junctional component but the dermal spindle cells are negative

Case 6

bull Skin right superior shoulder Malignant melanoma lentigo maligna type nonulcerated with pure desmoplastic vertical growth phase Clark level IV Breslow thickness not lt 064 mm extending close to the specimen base see Comment 3

bull Commentbull Changes extend close to the base and to a peripheral margin of the

specimenbull It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution Sbull Should be excised locally in order to prevent any possibility of persistence

recurrence or future progression of it bull Based on its microstaging attributes the prognosis for this lesion should

be excellent The prognosis for ldquopurerdquo desmoplastic melanoma is if anything better than that for melanomas of similar thickness

bull This lesion could be managed with a relatively generous wide local excision ndash MPATH DX Category 4 (or 5)

5212018

59

Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

5212018

60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

5212018

32

5212018

33

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

34

Your Diagnosis

High Grade

Low Grade

Clarkrsquos Dysplastic Nevus vs Melanoma in Situ vs Nevus

Feature Melanoma Dysplastic Nevus Nevus

Size tend to be larger intermediate smaller

Symmetry poor good good

Keratinocytes irregular uniform elongated rete uniform

Melanocytes epithelioid mixed nevoid

Nested variable predominant predominant

Nests coalescent bridging discrete

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe (gt 15x) mild-moderate

Mitoses about 13 of cases almost always absent absent

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Diagnosis Rendered

bull ldquomalignant melanoma probably lentigo maligna type showing Clark level III invasion with early tumorigenic but nonmitogenic vertical growth phase at a greatest Breslow thickness of 030 mm hellip associated nevus with congenital pattern featuresrdquo

5212018

35

New Information

ldquoI received a call from the primary care physician of this patient asking me to review a biopsy from June of 2004 which I had signed out as a compound congenital melanocytic nevus She told me that the lesion had developed re-pigmentation in the previous biopsy site hellip rdquo

bull ldquoI think it is almost certain that the subsequent biopsy is a pseudomelanoma based on the fact that there was no atypia in the original shave biopsy specimen the interval between biopsy and re-pigmentation is only three months and the re-pigmentation is in the previous biopsy site The lack of this additional information at the time you received the biopsy was a handicaprdquo

5212018

36

5212018

37

New Report

ldquosuperficial atypical melanocytic proliferation cw recurrent nevus phenomenon extending to specimen marginsrdquo hellip ldquoI would make only one reservation and that is that this lesion should be re-excised again with a margin of normal skin around the scar and any residual lesion helliprdquo

5212018

38

RECURRENT MELANOCYTIC NEVUS

Pseudomelanoma (Ackerman)

ndash pigmented patch at site of prior shave biopsy of a benign compound or dermal nevus

ndash repigmentation occurs quickly (6 weeks)

ndash pigment does not extend beyond scars borders

RECURRENT MELANOCYTIC NEVUS

Histology

bull variably sized and shaped sometimes confluent nests

bull single cells amp nests above DEJ usually not beyond mid-spinous layer

bull occasional lesional cells or nests in dermis

bull slight cytologic atypia (ldquoreactiverdquo) rare mitoses

bull proliferation does not extend beyond scar

bull original nevus should be reviewed

5212018

39

Lessons

bull Atypia in recurrent nevi can be severe yet is ldquoreactiverdquo

ndash Mitoses can be present

ndash Dermal atypia can be present

bull A superficial scar can mimic diffuse fibroplasia seen in many melanomas

bull Keep a high index of suspicion

ndash Consider a full differential diagnosis

ndash Call for history if necessary

5212018

40

Significance of Nevi

bull Nevi are important mainly in relation to melanoma

ndash Precursors ndash but risk for individual lesions is low

ndash Risk markers ndash important mainly in high risk situations

ndash Simulants ndash important in everyday clinical decision-making

Conclusions

bull Former mild dysplasia is a benign lentiginous nevus (the commonest type of nevus)

bull Low grade dysplasia (former moderate dysplasia) can be observed clinically or by patients looking for evidence of changing lesions

bull High grade dysplasia is difficult to distinguish from melanoma in situ (UNCERTAINTY) may have competence for local persistence recurrence and progression and should be completely excised

bull All of these are ldquomelanocytic neoplasms of low (or no) malignant potentialrdquo which have little or no competence for metastasis

Lake Wakatipu and Queenstown New Zealand from the Top of ldquoThe Remarkablesrdquo(Mountains of Mordor in the distance)

5212018

41

Session II High CSD Melanomas and Simulants

Lentigo maligna melanoma

Atypical lentiginous neviproliferations

High CSD Lentiginous Nevi and Lentigo Maligna

Melanoma and Simulant(s)

bull Lentiginous Melanoma of Sun-Damaged Skin

ndash LMM in situ

ndash LMM invasive

ndash Distinction from Dysplastic Nevi (Dysplastic Nevus-like MelanomaNevoid Lentigo Maligna

bull Lentiginous Nevi of the ldquoElderlyrdquo (ie CSD Skin)

bull Solar (actinic) lentigo pigmented AK SK hellip

High UV

Pathway II Pathway III

High-CSD Melanoma (LMM)

Desmoplastic Melanoma

IMP IMP

IAMP IAMP

Lentigo maligna melanoma in situ

Melanoma in situ

Lentigo Maligna Melanoma

Desmoplastic Melanoma

NRAS BRAFnon-V600E KIT NF1

NF1 ERBB2 MAP2K1 MAP3K1 BRAF EGFR MET

TERT CDKN2A TP53 PTEN RAC1

TERT NFKBIE NRAS PIK3CA PTPN11

5212018

42

Case 1

12438

F64 Lesion of back

5212018

43

5212018

44

Your Diagnosis

Dysplastic Nevus - IAMP

Melanoma

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe ( gt 15x) mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Our Diagnosis

Case 1 12438

Lentigo maligna melanoma in situ

5212018

45

Case 2

Part 2-2 7419Clinical Information

A large pigmented lesion of the back in a 74-year-old manReason for Consultation

I called this lesion a dysplastic nevus The clinician then calls back to inform us that this is a 22 cm irregular pigmented lesion Now looking at the deepers we think this

might be a ldquolentiginous melanomardquo

Description

bull Shave biopsy of a broad lesion with a dermal component and a moderately cellular junctional component

bull Lesion is ill-defined (poorly circumscribed) at each periphery with features overlapping with those of actinic lentigo

bull Subtle increase of melanocytes along the dermal-epidermal junction with mild to moderate but relatively uniform cytologic atypia

bull Pagetoid scatter is minimal

bull Focally there are elongated rete ridges overlapping with features of dysplastic nevus however these changes are focal within the lesion rather than being symmetrically distributed at shoulders adjacent to a dermal component

Lentiginous nevus versus lentiginous melanoma

bull Poorly circumscribed at each periphery

5212018

46

bull JunctionaIIAMP

bull Patchy lymphocytic infiltrate

bull Solar elastosis

Bridging rete

5212018

47

Your Diagnosis

Melanoma

Nevus

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Lentiginous nevus versus lentiginous melanomaDiagnosis Case 2 M74

Skin mid back Superficial atypical melanocytic proliferation of uncertain significance most consistent with melanoma in situ lentiginous type (nevoid lentigo maligna) versus atypical lentiginous nevus of the elderly see comment

(ie ldquoSAMPUSrdquo)

5212018

48

Diagnosis Case 2 M74

bull Overall Commentbull There are overlapping features among atypical actinic

lentigines lentiginous junctional nevi with and without atypia and lentiginous or ldquonevoidrdquo lentigo maligna

bull Lesions in a high CSD environment must be interpreted with circumspection

bull Overdiagnosis should be avoided as even atypical lentiginous junctional nevi of the elderly seem to be biologically low grade (non-metastasizing but perhaps locally recurring potential)

bull It is judicious to completely excise these lesions in order to be sure that they have been completely examined histologically and also to minimize any possibility of local persistence recurrence or future progression

Nevoid Lentigo MalignaLentiginous Melanoma(Lentiginous Nevus)

bull Kossard 1997 Aust J Dermatol Nevoid lentigo malignaKing Page Googe amp Mihm Modern Pathology 2005 Lentiginous melanomaFerrahi Egbert amp Swetter J Cutan Pathol 2005 Dysplastic nevus-like LMM

bull Clinical diagnosis may varyndash eg lentigo maligna atypical nevus pigmented basal cell carcinoma seborrheic keratosis and

lentigo

bull Biopsies may mimic junctional nevus or dysplastic nevus at least focallyndash Lentiginous proliferation of melanocytes at the dermo-epidermal junction both as single cells

and as small nests with areas of confluent growth extending to the edges of the biopsy ndash Rete ridges maintainedndash Pagetoid spread of melanocytes was not prominent in HampE - stained sections

bull Diagnosis of melanoma more easily recognized in the complete excision specimens similar atypical melanocytic proliferation occurring over a broad area flanking the prior biopsy sites

bull Stains for MITF and Mart-1 highlight continuous basal melanocytic proliferation as well as foci of pagetoid scatter

Lentiginous MelanomaKing Page Googe Mihm Mod Pathol 2005

bull Initial biopsies mimicked lentiginous nevus or dysplastic nevus

bull Lentiginous proliferation of melanocytes at DEJ both as single cells and as small nests with areas of confluent growth extending to the edges of the biopsy

bull Retiform epidermis was maintained and pagetoid spread of melanocytes was not prominent in HampE sections

bull Immunohistochemical stains for MITF and Mart-1 highlighted the extent of the basalar melanocytic proliferation as well as foci of pagetoid spread by melanocytes

bull UNCERTAINTY IS COMMONbull PROGNOSIS IS GOOD IF LESION IS SUPERFICIALbull IMPORTANT TO COMPLETELY EXCISE

bull FOR FULL EXAMINATION AND TO MINIMIZE ANY POTENTIAL FOR LOCAL PERSISTENCE RECURRENCE AND PROGRESSION

Mart 1

MITF

5212018

49

Case 3

Part 2-3 14474

Clinical InformationLeft posterior shoulder F81

Reason for ConsultationFavor a junctional Clarkrsquos nevus (see enclosed report)

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Some bridging few nests that hang down in a droplet-like pattern bull Cytologic atypia mild but relatively uniform

5212018

50

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 3 F81

bull ldquoDifficult to interpretrdquo bull Cytologic atypia is mild to moderate rather than

severe with somewhat concerning architectural changes

bull ldquoOne is somewhat more concerned about a lesion in chronically sun-damaged skin of older subjectsrdquo

bull Skin left posterior shoulder shave biopsy Intraepidermal atypical melanocytic proliferation of uncertain significance (IAMPUS) most consistent with atypical lentiginous junctional nevus (of the elderlyCSD skin) cannot ro evolving or early established melanoma in situ

bull Complete excision recommended (MPATH-Dx 2 or 3)

Case 4

Part 2-3 14474

Clinical InformationLeft posterior shoulder F84

Reason for ConsultationFavor a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus (see

enclosed report) There is mild melanocytic atypia and that the peripheral and deep margins of the specimen were negative in the

plane of sectioning

5212018

51

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 4 F81

bull Recurrence of Case 8

bull Shave biopsy of similar sun-damaged skinbull Somewhat more cellular proliferation of nevoid and

nevoid to epithelioid melanocytes focally exhibiting severe and uniform cytologic atypia

bull Some of these cells are confined to the epidermis above the scar while others appear to extend some distance beyond the periphery of the scar

bull This latter feature raises some concern for evolving melanoma in situ extending beyond the scar

5212018

52

bull Skin left posterior shoulder shave biopsy (recurrence) Intraepidermal atypical melanocytic proliferation of uncertain significance extending to specimen margins see description and comment

ndash Comment Cannot rule out an evolving more significant lesion suggest complete excision

Case 5

Part 2-3 14474

Clinical InformationBiopsy from posterior shoulder of an 85 year old female

Reason for ConsultationThis specimen in my opinion has histologic features concerning for

melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis I do not see

definitive features of a scar consistent with a prior biopsy site

5212018

53

bull Broadbull Moderately

cellularbull Moderate to

severe CSDbull Poorly

circumscribedbull Few bridging

nestsbull Diffuse

fibroplasiabull Cells in dermis

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Nests in dermis

bull No maturation

5212018

54

Melan-A Stain

bull Moderately cellular

bull Continuous basal proliferation

bull Nests hanging down

bull Low level pagetoid scatter

bull Nests in dermis

bull No maturation

Your Diagnosis

Melanoma

Nevus

Our Diagnosis

Malignant melanoma lentigo maligna type (ldquolentiginous melanomardquo Clark level II Breslow thickness 085 mm

5212018

55

Updated History Cases 3-5

bull Clinical Information

bull Three separate biopsies from left posterior shoulder of an 85-year-old female over a period of three years The biopsies were performed 4 years and 1 year ago and recently

bull The original biopsy was called a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus might have been better interpreted as a lentiginous nevus of the elderlysundamaged skin with mild to moderate atypia ndash The peripheral and deep margins of the specimen were said to be negative in the plane

of sectioning

bull The next biopsy at presumably the same anatomic location was signed out as an atypical melanocytic proliferation consistent with a persistentrecurrent Clarkrsquos (dysplastic) nevus involving the peripheral edge of the biopsy ndash It was mentioned that the differential diagnosis included early melanoma in situ

evolving within a pre-existing nevus and a reexcision was recommended

bull The most recent specimen was concerning for melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis

bull Additional procedure warranted to ensure that the lesion has been completely removed`

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Cytologic atypia mild but relatively uniform bull POTENTIAL PRECURSOR (low risk) VS ACTUAL PRECURSOR (hindsight bias)bull Manage by excision or follow-up

bull Case 5

bull Second recurrence of a lesion that originally had only ldquomildrdquo atypia (but moderate to severe architectural disorder)

bull Diagnosis of dysplastic nevus should be made with caution in elderlyCSD skin

bull Complete excision is appropriate for ldquoatypical lentiginous nevus of elderlysundamaged skinrdquo

5212018

56

Last Case

Part 2-7 12150

Clinical InformationLesion of right shoulder ro melanoma versus nevus in a 76 yo man

Reason for ConsultationIs this anything other than a moderately atypical neurotized compound nevus

bull A relatively broad lesion with irregular thickening and thinning of rete ridges and a sparsely cellular infiltrate in the dermis

bull Generally sparsely cellularbull Moderate to severe CSD

Poorly circumscribed

5212018

57

bull Pigmented melanophages in the dermis

bull Increased number of melanocytes in the epidermis many of them suprabasal

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

5212018

58

S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

bull Melan-A stain highlights the junctional component but the dermal spindle cells are negative

Case 6

bull Skin right superior shoulder Malignant melanoma lentigo maligna type nonulcerated with pure desmoplastic vertical growth phase Clark level IV Breslow thickness not lt 064 mm extending close to the specimen base see Comment 3

bull Commentbull Changes extend close to the base and to a peripheral margin of the

specimenbull It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution Sbull Should be excised locally in order to prevent any possibility of persistence

recurrence or future progression of it bull Based on its microstaging attributes the prognosis for this lesion should

be excellent The prognosis for ldquopurerdquo desmoplastic melanoma is if anything better than that for melanomas of similar thickness

bull This lesion could be managed with a relatively generous wide local excision ndash MPATH DX Category 4 (or 5)

5212018

59

Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

5212018

60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

5212018

33

Your Diagnosis

Melanoma

Nevus

Your Diagnosis

Dysplastic

Nondysplastic

5212018

34

Your Diagnosis

High Grade

Low Grade

Clarkrsquos Dysplastic Nevus vs Melanoma in Situ vs Nevus

Feature Melanoma Dysplastic Nevus Nevus

Size tend to be larger intermediate smaller

Symmetry poor good good

Keratinocytes irregular uniform elongated rete uniform

Melanocytes epithelioid mixed nevoid

Nested variable predominant predominant

Nests coalescent bridging discrete

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe (gt 15x) mild-moderate

Mitoses about 13 of cases almost always absent absent

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Diagnosis Rendered

bull ldquomalignant melanoma probably lentigo maligna type showing Clark level III invasion with early tumorigenic but nonmitogenic vertical growth phase at a greatest Breslow thickness of 030 mm hellip associated nevus with congenital pattern featuresrdquo

5212018

35

New Information

ldquoI received a call from the primary care physician of this patient asking me to review a biopsy from June of 2004 which I had signed out as a compound congenital melanocytic nevus She told me that the lesion had developed re-pigmentation in the previous biopsy site hellip rdquo

bull ldquoI think it is almost certain that the subsequent biopsy is a pseudomelanoma based on the fact that there was no atypia in the original shave biopsy specimen the interval between biopsy and re-pigmentation is only three months and the re-pigmentation is in the previous biopsy site The lack of this additional information at the time you received the biopsy was a handicaprdquo

5212018

36

5212018

37

New Report

ldquosuperficial atypical melanocytic proliferation cw recurrent nevus phenomenon extending to specimen marginsrdquo hellip ldquoI would make only one reservation and that is that this lesion should be re-excised again with a margin of normal skin around the scar and any residual lesion helliprdquo

5212018

38

RECURRENT MELANOCYTIC NEVUS

Pseudomelanoma (Ackerman)

ndash pigmented patch at site of prior shave biopsy of a benign compound or dermal nevus

ndash repigmentation occurs quickly (6 weeks)

ndash pigment does not extend beyond scars borders

RECURRENT MELANOCYTIC NEVUS

Histology

bull variably sized and shaped sometimes confluent nests

bull single cells amp nests above DEJ usually not beyond mid-spinous layer

bull occasional lesional cells or nests in dermis

bull slight cytologic atypia (ldquoreactiverdquo) rare mitoses

bull proliferation does not extend beyond scar

bull original nevus should be reviewed

5212018

39

Lessons

bull Atypia in recurrent nevi can be severe yet is ldquoreactiverdquo

ndash Mitoses can be present

ndash Dermal atypia can be present

bull A superficial scar can mimic diffuse fibroplasia seen in many melanomas

bull Keep a high index of suspicion

ndash Consider a full differential diagnosis

ndash Call for history if necessary

5212018

40

Significance of Nevi

bull Nevi are important mainly in relation to melanoma

ndash Precursors ndash but risk for individual lesions is low

ndash Risk markers ndash important mainly in high risk situations

ndash Simulants ndash important in everyday clinical decision-making

Conclusions

bull Former mild dysplasia is a benign lentiginous nevus (the commonest type of nevus)

bull Low grade dysplasia (former moderate dysplasia) can be observed clinically or by patients looking for evidence of changing lesions

bull High grade dysplasia is difficult to distinguish from melanoma in situ (UNCERTAINTY) may have competence for local persistence recurrence and progression and should be completely excised

bull All of these are ldquomelanocytic neoplasms of low (or no) malignant potentialrdquo which have little or no competence for metastasis

Lake Wakatipu and Queenstown New Zealand from the Top of ldquoThe Remarkablesrdquo(Mountains of Mordor in the distance)

5212018

41

Session II High CSD Melanomas and Simulants

Lentigo maligna melanoma

Atypical lentiginous neviproliferations

High CSD Lentiginous Nevi and Lentigo Maligna

Melanoma and Simulant(s)

bull Lentiginous Melanoma of Sun-Damaged Skin

ndash LMM in situ

ndash LMM invasive

ndash Distinction from Dysplastic Nevi (Dysplastic Nevus-like MelanomaNevoid Lentigo Maligna

bull Lentiginous Nevi of the ldquoElderlyrdquo (ie CSD Skin)

bull Solar (actinic) lentigo pigmented AK SK hellip

High UV

Pathway II Pathway III

High-CSD Melanoma (LMM)

Desmoplastic Melanoma

IMP IMP

IAMP IAMP

Lentigo maligna melanoma in situ

Melanoma in situ

Lentigo Maligna Melanoma

Desmoplastic Melanoma

NRAS BRAFnon-V600E KIT NF1

NF1 ERBB2 MAP2K1 MAP3K1 BRAF EGFR MET

TERT CDKN2A TP53 PTEN RAC1

TERT NFKBIE NRAS PIK3CA PTPN11

5212018

42

Case 1

12438

F64 Lesion of back

5212018

43

5212018

44

Your Diagnosis

Dysplastic Nevus - IAMP

Melanoma

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe ( gt 15x) mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Our Diagnosis

Case 1 12438

Lentigo maligna melanoma in situ

5212018

45

Case 2

Part 2-2 7419Clinical Information

A large pigmented lesion of the back in a 74-year-old manReason for Consultation

I called this lesion a dysplastic nevus The clinician then calls back to inform us that this is a 22 cm irregular pigmented lesion Now looking at the deepers we think this

might be a ldquolentiginous melanomardquo

Description

bull Shave biopsy of a broad lesion with a dermal component and a moderately cellular junctional component

bull Lesion is ill-defined (poorly circumscribed) at each periphery with features overlapping with those of actinic lentigo

bull Subtle increase of melanocytes along the dermal-epidermal junction with mild to moderate but relatively uniform cytologic atypia

bull Pagetoid scatter is minimal

bull Focally there are elongated rete ridges overlapping with features of dysplastic nevus however these changes are focal within the lesion rather than being symmetrically distributed at shoulders adjacent to a dermal component

Lentiginous nevus versus lentiginous melanoma

bull Poorly circumscribed at each periphery

5212018

46

bull JunctionaIIAMP

bull Patchy lymphocytic infiltrate

bull Solar elastosis

Bridging rete

5212018

47

Your Diagnosis

Melanoma

Nevus

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Lentiginous nevus versus lentiginous melanomaDiagnosis Case 2 M74

Skin mid back Superficial atypical melanocytic proliferation of uncertain significance most consistent with melanoma in situ lentiginous type (nevoid lentigo maligna) versus atypical lentiginous nevus of the elderly see comment

(ie ldquoSAMPUSrdquo)

5212018

48

Diagnosis Case 2 M74

bull Overall Commentbull There are overlapping features among atypical actinic

lentigines lentiginous junctional nevi with and without atypia and lentiginous or ldquonevoidrdquo lentigo maligna

bull Lesions in a high CSD environment must be interpreted with circumspection

bull Overdiagnosis should be avoided as even atypical lentiginous junctional nevi of the elderly seem to be biologically low grade (non-metastasizing but perhaps locally recurring potential)

bull It is judicious to completely excise these lesions in order to be sure that they have been completely examined histologically and also to minimize any possibility of local persistence recurrence or future progression

Nevoid Lentigo MalignaLentiginous Melanoma(Lentiginous Nevus)

bull Kossard 1997 Aust J Dermatol Nevoid lentigo malignaKing Page Googe amp Mihm Modern Pathology 2005 Lentiginous melanomaFerrahi Egbert amp Swetter J Cutan Pathol 2005 Dysplastic nevus-like LMM

bull Clinical diagnosis may varyndash eg lentigo maligna atypical nevus pigmented basal cell carcinoma seborrheic keratosis and

lentigo

bull Biopsies may mimic junctional nevus or dysplastic nevus at least focallyndash Lentiginous proliferation of melanocytes at the dermo-epidermal junction both as single cells

and as small nests with areas of confluent growth extending to the edges of the biopsy ndash Rete ridges maintainedndash Pagetoid spread of melanocytes was not prominent in HampE - stained sections

bull Diagnosis of melanoma more easily recognized in the complete excision specimens similar atypical melanocytic proliferation occurring over a broad area flanking the prior biopsy sites

bull Stains for MITF and Mart-1 highlight continuous basal melanocytic proliferation as well as foci of pagetoid scatter

Lentiginous MelanomaKing Page Googe Mihm Mod Pathol 2005

bull Initial biopsies mimicked lentiginous nevus or dysplastic nevus

bull Lentiginous proliferation of melanocytes at DEJ both as single cells and as small nests with areas of confluent growth extending to the edges of the biopsy

bull Retiform epidermis was maintained and pagetoid spread of melanocytes was not prominent in HampE sections

bull Immunohistochemical stains for MITF and Mart-1 highlighted the extent of the basalar melanocytic proliferation as well as foci of pagetoid spread by melanocytes

bull UNCERTAINTY IS COMMONbull PROGNOSIS IS GOOD IF LESION IS SUPERFICIALbull IMPORTANT TO COMPLETELY EXCISE

bull FOR FULL EXAMINATION AND TO MINIMIZE ANY POTENTIAL FOR LOCAL PERSISTENCE RECURRENCE AND PROGRESSION

Mart 1

MITF

5212018

49

Case 3

Part 2-3 14474

Clinical InformationLeft posterior shoulder F81

Reason for ConsultationFavor a junctional Clarkrsquos nevus (see enclosed report)

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Some bridging few nests that hang down in a droplet-like pattern bull Cytologic atypia mild but relatively uniform

5212018

50

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 3 F81

bull ldquoDifficult to interpretrdquo bull Cytologic atypia is mild to moderate rather than

severe with somewhat concerning architectural changes

bull ldquoOne is somewhat more concerned about a lesion in chronically sun-damaged skin of older subjectsrdquo

bull Skin left posterior shoulder shave biopsy Intraepidermal atypical melanocytic proliferation of uncertain significance (IAMPUS) most consistent with atypical lentiginous junctional nevus (of the elderlyCSD skin) cannot ro evolving or early established melanoma in situ

bull Complete excision recommended (MPATH-Dx 2 or 3)

Case 4

Part 2-3 14474

Clinical InformationLeft posterior shoulder F84

Reason for ConsultationFavor a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus (see

enclosed report) There is mild melanocytic atypia and that the peripheral and deep margins of the specimen were negative in the

plane of sectioning

5212018

51

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 4 F81

bull Recurrence of Case 8

bull Shave biopsy of similar sun-damaged skinbull Somewhat more cellular proliferation of nevoid and

nevoid to epithelioid melanocytes focally exhibiting severe and uniform cytologic atypia

bull Some of these cells are confined to the epidermis above the scar while others appear to extend some distance beyond the periphery of the scar

bull This latter feature raises some concern for evolving melanoma in situ extending beyond the scar

5212018

52

bull Skin left posterior shoulder shave biopsy (recurrence) Intraepidermal atypical melanocytic proliferation of uncertain significance extending to specimen margins see description and comment

ndash Comment Cannot rule out an evolving more significant lesion suggest complete excision

Case 5

Part 2-3 14474

Clinical InformationBiopsy from posterior shoulder of an 85 year old female

Reason for ConsultationThis specimen in my opinion has histologic features concerning for

melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis I do not see

definitive features of a scar consistent with a prior biopsy site

5212018

53

bull Broadbull Moderately

cellularbull Moderate to

severe CSDbull Poorly

circumscribedbull Few bridging

nestsbull Diffuse

fibroplasiabull Cells in dermis

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Nests in dermis

bull No maturation

5212018

54

Melan-A Stain

bull Moderately cellular

bull Continuous basal proliferation

bull Nests hanging down

bull Low level pagetoid scatter

bull Nests in dermis

bull No maturation

Your Diagnosis

Melanoma

Nevus

Our Diagnosis

Malignant melanoma lentigo maligna type (ldquolentiginous melanomardquo Clark level II Breslow thickness 085 mm

5212018

55

Updated History Cases 3-5

bull Clinical Information

bull Three separate biopsies from left posterior shoulder of an 85-year-old female over a period of three years The biopsies were performed 4 years and 1 year ago and recently

bull The original biopsy was called a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus might have been better interpreted as a lentiginous nevus of the elderlysundamaged skin with mild to moderate atypia ndash The peripheral and deep margins of the specimen were said to be negative in the plane

of sectioning

bull The next biopsy at presumably the same anatomic location was signed out as an atypical melanocytic proliferation consistent with a persistentrecurrent Clarkrsquos (dysplastic) nevus involving the peripheral edge of the biopsy ndash It was mentioned that the differential diagnosis included early melanoma in situ

evolving within a pre-existing nevus and a reexcision was recommended

bull The most recent specimen was concerning for melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis

bull Additional procedure warranted to ensure that the lesion has been completely removed`

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Cytologic atypia mild but relatively uniform bull POTENTIAL PRECURSOR (low risk) VS ACTUAL PRECURSOR (hindsight bias)bull Manage by excision or follow-up

bull Case 5

bull Second recurrence of a lesion that originally had only ldquomildrdquo atypia (but moderate to severe architectural disorder)

bull Diagnosis of dysplastic nevus should be made with caution in elderlyCSD skin

bull Complete excision is appropriate for ldquoatypical lentiginous nevus of elderlysundamaged skinrdquo

5212018

56

Last Case

Part 2-7 12150

Clinical InformationLesion of right shoulder ro melanoma versus nevus in a 76 yo man

Reason for ConsultationIs this anything other than a moderately atypical neurotized compound nevus

bull A relatively broad lesion with irregular thickening and thinning of rete ridges and a sparsely cellular infiltrate in the dermis

bull Generally sparsely cellularbull Moderate to severe CSD

Poorly circumscribed

5212018

57

bull Pigmented melanophages in the dermis

bull Increased number of melanocytes in the epidermis many of them suprabasal

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

5212018

58

S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

bull Melan-A stain highlights the junctional component but the dermal spindle cells are negative

Case 6

bull Skin right superior shoulder Malignant melanoma lentigo maligna type nonulcerated with pure desmoplastic vertical growth phase Clark level IV Breslow thickness not lt 064 mm extending close to the specimen base see Comment 3

bull Commentbull Changes extend close to the base and to a peripheral margin of the

specimenbull It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution Sbull Should be excised locally in order to prevent any possibility of persistence

recurrence or future progression of it bull Based on its microstaging attributes the prognosis for this lesion should

be excellent The prognosis for ldquopurerdquo desmoplastic melanoma is if anything better than that for melanomas of similar thickness

bull This lesion could be managed with a relatively generous wide local excision ndash MPATH DX Category 4 (or 5)

5212018

59

Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

5212018

60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

5212018

34

Your Diagnosis

High Grade

Low Grade

Clarkrsquos Dysplastic Nevus vs Melanoma in Situ vs Nevus

Feature Melanoma Dysplastic Nevus Nevus

Size tend to be larger intermediate smaller

Symmetry poor good good

Keratinocytes irregular uniform elongated rete uniform

Melanocytes epithelioid mixed nevoid

Nested variable predominant predominant

Nests coalescent bridging discrete

Lentiginous continuous discontinuous discontinuous

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe (gt 15x) mild-moderate

Mitoses about 13 of cases almost always absent absent

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Diagnosis Rendered

bull ldquomalignant melanoma probably lentigo maligna type showing Clark level III invasion with early tumorigenic but nonmitogenic vertical growth phase at a greatest Breslow thickness of 030 mm hellip associated nevus with congenital pattern featuresrdquo

5212018

35

New Information

ldquoI received a call from the primary care physician of this patient asking me to review a biopsy from June of 2004 which I had signed out as a compound congenital melanocytic nevus She told me that the lesion had developed re-pigmentation in the previous biopsy site hellip rdquo

bull ldquoI think it is almost certain that the subsequent biopsy is a pseudomelanoma based on the fact that there was no atypia in the original shave biopsy specimen the interval between biopsy and re-pigmentation is only three months and the re-pigmentation is in the previous biopsy site The lack of this additional information at the time you received the biopsy was a handicaprdquo

5212018

36

5212018

37

New Report

ldquosuperficial atypical melanocytic proliferation cw recurrent nevus phenomenon extending to specimen marginsrdquo hellip ldquoI would make only one reservation and that is that this lesion should be re-excised again with a margin of normal skin around the scar and any residual lesion helliprdquo

5212018

38

RECURRENT MELANOCYTIC NEVUS

Pseudomelanoma (Ackerman)

ndash pigmented patch at site of prior shave biopsy of a benign compound or dermal nevus

ndash repigmentation occurs quickly (6 weeks)

ndash pigment does not extend beyond scars borders

RECURRENT MELANOCYTIC NEVUS

Histology

bull variably sized and shaped sometimes confluent nests

bull single cells amp nests above DEJ usually not beyond mid-spinous layer

bull occasional lesional cells or nests in dermis

bull slight cytologic atypia (ldquoreactiverdquo) rare mitoses

bull proliferation does not extend beyond scar

bull original nevus should be reviewed

5212018

39

Lessons

bull Atypia in recurrent nevi can be severe yet is ldquoreactiverdquo

ndash Mitoses can be present

ndash Dermal atypia can be present

bull A superficial scar can mimic diffuse fibroplasia seen in many melanomas

bull Keep a high index of suspicion

ndash Consider a full differential diagnosis

ndash Call for history if necessary

5212018

40

Significance of Nevi

bull Nevi are important mainly in relation to melanoma

ndash Precursors ndash but risk for individual lesions is low

ndash Risk markers ndash important mainly in high risk situations

ndash Simulants ndash important in everyday clinical decision-making

Conclusions

bull Former mild dysplasia is a benign lentiginous nevus (the commonest type of nevus)

bull Low grade dysplasia (former moderate dysplasia) can be observed clinically or by patients looking for evidence of changing lesions

bull High grade dysplasia is difficult to distinguish from melanoma in situ (UNCERTAINTY) may have competence for local persistence recurrence and progression and should be completely excised

bull All of these are ldquomelanocytic neoplasms of low (or no) malignant potentialrdquo which have little or no competence for metastasis

Lake Wakatipu and Queenstown New Zealand from the Top of ldquoThe Remarkablesrdquo(Mountains of Mordor in the distance)

5212018

41

Session II High CSD Melanomas and Simulants

Lentigo maligna melanoma

Atypical lentiginous neviproliferations

High CSD Lentiginous Nevi and Lentigo Maligna

Melanoma and Simulant(s)

bull Lentiginous Melanoma of Sun-Damaged Skin

ndash LMM in situ

ndash LMM invasive

ndash Distinction from Dysplastic Nevi (Dysplastic Nevus-like MelanomaNevoid Lentigo Maligna

bull Lentiginous Nevi of the ldquoElderlyrdquo (ie CSD Skin)

bull Solar (actinic) lentigo pigmented AK SK hellip

High UV

Pathway II Pathway III

High-CSD Melanoma (LMM)

Desmoplastic Melanoma

IMP IMP

IAMP IAMP

Lentigo maligna melanoma in situ

Melanoma in situ

Lentigo Maligna Melanoma

Desmoplastic Melanoma

NRAS BRAFnon-V600E KIT NF1

NF1 ERBB2 MAP2K1 MAP3K1 BRAF EGFR MET

TERT CDKN2A TP53 PTEN RAC1

TERT NFKBIE NRAS PIK3CA PTPN11

5212018

42

Case 1

12438

F64 Lesion of back

5212018

43

5212018

44

Your Diagnosis

Dysplastic Nevus - IAMP

Melanoma

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe ( gt 15x) mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Our Diagnosis

Case 1 12438

Lentigo maligna melanoma in situ

5212018

45

Case 2

Part 2-2 7419Clinical Information

A large pigmented lesion of the back in a 74-year-old manReason for Consultation

I called this lesion a dysplastic nevus The clinician then calls back to inform us that this is a 22 cm irregular pigmented lesion Now looking at the deepers we think this

might be a ldquolentiginous melanomardquo

Description

bull Shave biopsy of a broad lesion with a dermal component and a moderately cellular junctional component

bull Lesion is ill-defined (poorly circumscribed) at each periphery with features overlapping with those of actinic lentigo

bull Subtle increase of melanocytes along the dermal-epidermal junction with mild to moderate but relatively uniform cytologic atypia

bull Pagetoid scatter is minimal

bull Focally there are elongated rete ridges overlapping with features of dysplastic nevus however these changes are focal within the lesion rather than being symmetrically distributed at shoulders adjacent to a dermal component

Lentiginous nevus versus lentiginous melanoma

bull Poorly circumscribed at each periphery

5212018

46

bull JunctionaIIAMP

bull Patchy lymphocytic infiltrate

bull Solar elastosis

Bridging rete

5212018

47

Your Diagnosis

Melanoma

Nevus

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Lentiginous nevus versus lentiginous melanomaDiagnosis Case 2 M74

Skin mid back Superficial atypical melanocytic proliferation of uncertain significance most consistent with melanoma in situ lentiginous type (nevoid lentigo maligna) versus atypical lentiginous nevus of the elderly see comment

(ie ldquoSAMPUSrdquo)

5212018

48

Diagnosis Case 2 M74

bull Overall Commentbull There are overlapping features among atypical actinic

lentigines lentiginous junctional nevi with and without atypia and lentiginous or ldquonevoidrdquo lentigo maligna

bull Lesions in a high CSD environment must be interpreted with circumspection

bull Overdiagnosis should be avoided as even atypical lentiginous junctional nevi of the elderly seem to be biologically low grade (non-metastasizing but perhaps locally recurring potential)

bull It is judicious to completely excise these lesions in order to be sure that they have been completely examined histologically and also to minimize any possibility of local persistence recurrence or future progression

Nevoid Lentigo MalignaLentiginous Melanoma(Lentiginous Nevus)

bull Kossard 1997 Aust J Dermatol Nevoid lentigo malignaKing Page Googe amp Mihm Modern Pathology 2005 Lentiginous melanomaFerrahi Egbert amp Swetter J Cutan Pathol 2005 Dysplastic nevus-like LMM

bull Clinical diagnosis may varyndash eg lentigo maligna atypical nevus pigmented basal cell carcinoma seborrheic keratosis and

lentigo

bull Biopsies may mimic junctional nevus or dysplastic nevus at least focallyndash Lentiginous proliferation of melanocytes at the dermo-epidermal junction both as single cells

and as small nests with areas of confluent growth extending to the edges of the biopsy ndash Rete ridges maintainedndash Pagetoid spread of melanocytes was not prominent in HampE - stained sections

bull Diagnosis of melanoma more easily recognized in the complete excision specimens similar atypical melanocytic proliferation occurring over a broad area flanking the prior biopsy sites

bull Stains for MITF and Mart-1 highlight continuous basal melanocytic proliferation as well as foci of pagetoid scatter

Lentiginous MelanomaKing Page Googe Mihm Mod Pathol 2005

bull Initial biopsies mimicked lentiginous nevus or dysplastic nevus

bull Lentiginous proliferation of melanocytes at DEJ both as single cells and as small nests with areas of confluent growth extending to the edges of the biopsy

bull Retiform epidermis was maintained and pagetoid spread of melanocytes was not prominent in HampE sections

bull Immunohistochemical stains for MITF and Mart-1 highlighted the extent of the basalar melanocytic proliferation as well as foci of pagetoid spread by melanocytes

bull UNCERTAINTY IS COMMONbull PROGNOSIS IS GOOD IF LESION IS SUPERFICIALbull IMPORTANT TO COMPLETELY EXCISE

bull FOR FULL EXAMINATION AND TO MINIMIZE ANY POTENTIAL FOR LOCAL PERSISTENCE RECURRENCE AND PROGRESSION

Mart 1

MITF

5212018

49

Case 3

Part 2-3 14474

Clinical InformationLeft posterior shoulder F81

Reason for ConsultationFavor a junctional Clarkrsquos nevus (see enclosed report)

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Some bridging few nests that hang down in a droplet-like pattern bull Cytologic atypia mild but relatively uniform

5212018

50

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 3 F81

bull ldquoDifficult to interpretrdquo bull Cytologic atypia is mild to moderate rather than

severe with somewhat concerning architectural changes

bull ldquoOne is somewhat more concerned about a lesion in chronically sun-damaged skin of older subjectsrdquo

bull Skin left posterior shoulder shave biopsy Intraepidermal atypical melanocytic proliferation of uncertain significance (IAMPUS) most consistent with atypical lentiginous junctional nevus (of the elderlyCSD skin) cannot ro evolving or early established melanoma in situ

bull Complete excision recommended (MPATH-Dx 2 or 3)

Case 4

Part 2-3 14474

Clinical InformationLeft posterior shoulder F84

Reason for ConsultationFavor a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus (see

enclosed report) There is mild melanocytic atypia and that the peripheral and deep margins of the specimen were negative in the

plane of sectioning

5212018

51

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 4 F81

bull Recurrence of Case 8

bull Shave biopsy of similar sun-damaged skinbull Somewhat more cellular proliferation of nevoid and

nevoid to epithelioid melanocytes focally exhibiting severe and uniform cytologic atypia

bull Some of these cells are confined to the epidermis above the scar while others appear to extend some distance beyond the periphery of the scar

bull This latter feature raises some concern for evolving melanoma in situ extending beyond the scar

5212018

52

bull Skin left posterior shoulder shave biopsy (recurrence) Intraepidermal atypical melanocytic proliferation of uncertain significance extending to specimen margins see description and comment

ndash Comment Cannot rule out an evolving more significant lesion suggest complete excision

Case 5

Part 2-3 14474

Clinical InformationBiopsy from posterior shoulder of an 85 year old female

Reason for ConsultationThis specimen in my opinion has histologic features concerning for

melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis I do not see

definitive features of a scar consistent with a prior biopsy site

5212018

53

bull Broadbull Moderately

cellularbull Moderate to

severe CSDbull Poorly

circumscribedbull Few bridging

nestsbull Diffuse

fibroplasiabull Cells in dermis

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Nests in dermis

bull No maturation

5212018

54

Melan-A Stain

bull Moderately cellular

bull Continuous basal proliferation

bull Nests hanging down

bull Low level pagetoid scatter

bull Nests in dermis

bull No maturation

Your Diagnosis

Melanoma

Nevus

Our Diagnosis

Malignant melanoma lentigo maligna type (ldquolentiginous melanomardquo Clark level II Breslow thickness 085 mm

5212018

55

Updated History Cases 3-5

bull Clinical Information

bull Three separate biopsies from left posterior shoulder of an 85-year-old female over a period of three years The biopsies were performed 4 years and 1 year ago and recently

bull The original biopsy was called a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus might have been better interpreted as a lentiginous nevus of the elderlysundamaged skin with mild to moderate atypia ndash The peripheral and deep margins of the specimen were said to be negative in the plane

of sectioning

bull The next biopsy at presumably the same anatomic location was signed out as an atypical melanocytic proliferation consistent with a persistentrecurrent Clarkrsquos (dysplastic) nevus involving the peripheral edge of the biopsy ndash It was mentioned that the differential diagnosis included early melanoma in situ

evolving within a pre-existing nevus and a reexcision was recommended

bull The most recent specimen was concerning for melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis

bull Additional procedure warranted to ensure that the lesion has been completely removed`

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Cytologic atypia mild but relatively uniform bull POTENTIAL PRECURSOR (low risk) VS ACTUAL PRECURSOR (hindsight bias)bull Manage by excision or follow-up

bull Case 5

bull Second recurrence of a lesion that originally had only ldquomildrdquo atypia (but moderate to severe architectural disorder)

bull Diagnosis of dysplastic nevus should be made with caution in elderlyCSD skin

bull Complete excision is appropriate for ldquoatypical lentiginous nevus of elderlysundamaged skinrdquo

5212018

56

Last Case

Part 2-7 12150

Clinical InformationLesion of right shoulder ro melanoma versus nevus in a 76 yo man

Reason for ConsultationIs this anything other than a moderately atypical neurotized compound nevus

bull A relatively broad lesion with irregular thickening and thinning of rete ridges and a sparsely cellular infiltrate in the dermis

bull Generally sparsely cellularbull Moderate to severe CSD

Poorly circumscribed

5212018

57

bull Pigmented melanophages in the dermis

bull Increased number of melanocytes in the epidermis many of them suprabasal

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

5212018

58

S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

bull Melan-A stain highlights the junctional component but the dermal spindle cells are negative

Case 6

bull Skin right superior shoulder Malignant melanoma lentigo maligna type nonulcerated with pure desmoplastic vertical growth phase Clark level IV Breslow thickness not lt 064 mm extending close to the specimen base see Comment 3

bull Commentbull Changes extend close to the base and to a peripheral margin of the

specimenbull It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution Sbull Should be excised locally in order to prevent any possibility of persistence

recurrence or future progression of it bull Based on its microstaging attributes the prognosis for this lesion should

be excellent The prognosis for ldquopurerdquo desmoplastic melanoma is if anything better than that for melanomas of similar thickness

bull This lesion could be managed with a relatively generous wide local excision ndash MPATH DX Category 4 (or 5)

5212018

59

Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

5212018

60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

5212018

35

New Information

ldquoI received a call from the primary care physician of this patient asking me to review a biopsy from June of 2004 which I had signed out as a compound congenital melanocytic nevus She told me that the lesion had developed re-pigmentation in the previous biopsy site hellip rdquo

bull ldquoI think it is almost certain that the subsequent biopsy is a pseudomelanoma based on the fact that there was no atypia in the original shave biopsy specimen the interval between biopsy and re-pigmentation is only three months and the re-pigmentation is in the previous biopsy site The lack of this additional information at the time you received the biopsy was a handicaprdquo

5212018

36

5212018

37

New Report

ldquosuperficial atypical melanocytic proliferation cw recurrent nevus phenomenon extending to specimen marginsrdquo hellip ldquoI would make only one reservation and that is that this lesion should be re-excised again with a margin of normal skin around the scar and any residual lesion helliprdquo

5212018

38

RECURRENT MELANOCYTIC NEVUS

Pseudomelanoma (Ackerman)

ndash pigmented patch at site of prior shave biopsy of a benign compound or dermal nevus

ndash repigmentation occurs quickly (6 weeks)

ndash pigment does not extend beyond scars borders

RECURRENT MELANOCYTIC NEVUS

Histology

bull variably sized and shaped sometimes confluent nests

bull single cells amp nests above DEJ usually not beyond mid-spinous layer

bull occasional lesional cells or nests in dermis

bull slight cytologic atypia (ldquoreactiverdquo) rare mitoses

bull proliferation does not extend beyond scar

bull original nevus should be reviewed

5212018

39

Lessons

bull Atypia in recurrent nevi can be severe yet is ldquoreactiverdquo

ndash Mitoses can be present

ndash Dermal atypia can be present

bull A superficial scar can mimic diffuse fibroplasia seen in many melanomas

bull Keep a high index of suspicion

ndash Consider a full differential diagnosis

ndash Call for history if necessary

5212018

40

Significance of Nevi

bull Nevi are important mainly in relation to melanoma

ndash Precursors ndash but risk for individual lesions is low

ndash Risk markers ndash important mainly in high risk situations

ndash Simulants ndash important in everyday clinical decision-making

Conclusions

bull Former mild dysplasia is a benign lentiginous nevus (the commonest type of nevus)

bull Low grade dysplasia (former moderate dysplasia) can be observed clinically or by patients looking for evidence of changing lesions

bull High grade dysplasia is difficult to distinguish from melanoma in situ (UNCERTAINTY) may have competence for local persistence recurrence and progression and should be completely excised

bull All of these are ldquomelanocytic neoplasms of low (or no) malignant potentialrdquo which have little or no competence for metastasis

Lake Wakatipu and Queenstown New Zealand from the Top of ldquoThe Remarkablesrdquo(Mountains of Mordor in the distance)

5212018

41

Session II High CSD Melanomas and Simulants

Lentigo maligna melanoma

Atypical lentiginous neviproliferations

High CSD Lentiginous Nevi and Lentigo Maligna

Melanoma and Simulant(s)

bull Lentiginous Melanoma of Sun-Damaged Skin

ndash LMM in situ

ndash LMM invasive

ndash Distinction from Dysplastic Nevi (Dysplastic Nevus-like MelanomaNevoid Lentigo Maligna

bull Lentiginous Nevi of the ldquoElderlyrdquo (ie CSD Skin)

bull Solar (actinic) lentigo pigmented AK SK hellip

High UV

Pathway II Pathway III

High-CSD Melanoma (LMM)

Desmoplastic Melanoma

IMP IMP

IAMP IAMP

Lentigo maligna melanoma in situ

Melanoma in situ

Lentigo Maligna Melanoma

Desmoplastic Melanoma

NRAS BRAFnon-V600E KIT NF1

NF1 ERBB2 MAP2K1 MAP3K1 BRAF EGFR MET

TERT CDKN2A TP53 PTEN RAC1

TERT NFKBIE NRAS PIK3CA PTPN11

5212018

42

Case 1

12438

F64 Lesion of back

5212018

43

5212018

44

Your Diagnosis

Dysplastic Nevus - IAMP

Melanoma

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe ( gt 15x) mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Our Diagnosis

Case 1 12438

Lentigo maligna melanoma in situ

5212018

45

Case 2

Part 2-2 7419Clinical Information

A large pigmented lesion of the back in a 74-year-old manReason for Consultation

I called this lesion a dysplastic nevus The clinician then calls back to inform us that this is a 22 cm irregular pigmented lesion Now looking at the deepers we think this

might be a ldquolentiginous melanomardquo

Description

bull Shave biopsy of a broad lesion with a dermal component and a moderately cellular junctional component

bull Lesion is ill-defined (poorly circumscribed) at each periphery with features overlapping with those of actinic lentigo

bull Subtle increase of melanocytes along the dermal-epidermal junction with mild to moderate but relatively uniform cytologic atypia

bull Pagetoid scatter is minimal

bull Focally there are elongated rete ridges overlapping with features of dysplastic nevus however these changes are focal within the lesion rather than being symmetrically distributed at shoulders adjacent to a dermal component

Lentiginous nevus versus lentiginous melanoma

bull Poorly circumscribed at each periphery

5212018

46

bull JunctionaIIAMP

bull Patchy lymphocytic infiltrate

bull Solar elastosis

Bridging rete

5212018

47

Your Diagnosis

Melanoma

Nevus

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Lentiginous nevus versus lentiginous melanomaDiagnosis Case 2 M74

Skin mid back Superficial atypical melanocytic proliferation of uncertain significance most consistent with melanoma in situ lentiginous type (nevoid lentigo maligna) versus atypical lentiginous nevus of the elderly see comment

(ie ldquoSAMPUSrdquo)

5212018

48

Diagnosis Case 2 M74

bull Overall Commentbull There are overlapping features among atypical actinic

lentigines lentiginous junctional nevi with and without atypia and lentiginous or ldquonevoidrdquo lentigo maligna

bull Lesions in a high CSD environment must be interpreted with circumspection

bull Overdiagnosis should be avoided as even atypical lentiginous junctional nevi of the elderly seem to be biologically low grade (non-metastasizing but perhaps locally recurring potential)

bull It is judicious to completely excise these lesions in order to be sure that they have been completely examined histologically and also to minimize any possibility of local persistence recurrence or future progression

Nevoid Lentigo MalignaLentiginous Melanoma(Lentiginous Nevus)

bull Kossard 1997 Aust J Dermatol Nevoid lentigo malignaKing Page Googe amp Mihm Modern Pathology 2005 Lentiginous melanomaFerrahi Egbert amp Swetter J Cutan Pathol 2005 Dysplastic nevus-like LMM

bull Clinical diagnosis may varyndash eg lentigo maligna atypical nevus pigmented basal cell carcinoma seborrheic keratosis and

lentigo

bull Biopsies may mimic junctional nevus or dysplastic nevus at least focallyndash Lentiginous proliferation of melanocytes at the dermo-epidermal junction both as single cells

and as small nests with areas of confluent growth extending to the edges of the biopsy ndash Rete ridges maintainedndash Pagetoid spread of melanocytes was not prominent in HampE - stained sections

bull Diagnosis of melanoma more easily recognized in the complete excision specimens similar atypical melanocytic proliferation occurring over a broad area flanking the prior biopsy sites

bull Stains for MITF and Mart-1 highlight continuous basal melanocytic proliferation as well as foci of pagetoid scatter

Lentiginous MelanomaKing Page Googe Mihm Mod Pathol 2005

bull Initial biopsies mimicked lentiginous nevus or dysplastic nevus

bull Lentiginous proliferation of melanocytes at DEJ both as single cells and as small nests with areas of confluent growth extending to the edges of the biopsy

bull Retiform epidermis was maintained and pagetoid spread of melanocytes was not prominent in HampE sections

bull Immunohistochemical stains for MITF and Mart-1 highlighted the extent of the basalar melanocytic proliferation as well as foci of pagetoid spread by melanocytes

bull UNCERTAINTY IS COMMONbull PROGNOSIS IS GOOD IF LESION IS SUPERFICIALbull IMPORTANT TO COMPLETELY EXCISE

bull FOR FULL EXAMINATION AND TO MINIMIZE ANY POTENTIAL FOR LOCAL PERSISTENCE RECURRENCE AND PROGRESSION

Mart 1

MITF

5212018

49

Case 3

Part 2-3 14474

Clinical InformationLeft posterior shoulder F81

Reason for ConsultationFavor a junctional Clarkrsquos nevus (see enclosed report)

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Some bridging few nests that hang down in a droplet-like pattern bull Cytologic atypia mild but relatively uniform

5212018

50

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 3 F81

bull ldquoDifficult to interpretrdquo bull Cytologic atypia is mild to moderate rather than

severe with somewhat concerning architectural changes

bull ldquoOne is somewhat more concerned about a lesion in chronically sun-damaged skin of older subjectsrdquo

bull Skin left posterior shoulder shave biopsy Intraepidermal atypical melanocytic proliferation of uncertain significance (IAMPUS) most consistent with atypical lentiginous junctional nevus (of the elderlyCSD skin) cannot ro evolving or early established melanoma in situ

bull Complete excision recommended (MPATH-Dx 2 or 3)

Case 4

Part 2-3 14474

Clinical InformationLeft posterior shoulder F84

Reason for ConsultationFavor a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus (see

enclosed report) There is mild melanocytic atypia and that the peripheral and deep margins of the specimen were negative in the

plane of sectioning

5212018

51

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 4 F81

bull Recurrence of Case 8

bull Shave biopsy of similar sun-damaged skinbull Somewhat more cellular proliferation of nevoid and

nevoid to epithelioid melanocytes focally exhibiting severe and uniform cytologic atypia

bull Some of these cells are confined to the epidermis above the scar while others appear to extend some distance beyond the periphery of the scar

bull This latter feature raises some concern for evolving melanoma in situ extending beyond the scar

5212018

52

bull Skin left posterior shoulder shave biopsy (recurrence) Intraepidermal atypical melanocytic proliferation of uncertain significance extending to specimen margins see description and comment

ndash Comment Cannot rule out an evolving more significant lesion suggest complete excision

Case 5

Part 2-3 14474

Clinical InformationBiopsy from posterior shoulder of an 85 year old female

Reason for ConsultationThis specimen in my opinion has histologic features concerning for

melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis I do not see

definitive features of a scar consistent with a prior biopsy site

5212018

53

bull Broadbull Moderately

cellularbull Moderate to

severe CSDbull Poorly

circumscribedbull Few bridging

nestsbull Diffuse

fibroplasiabull Cells in dermis

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Nests in dermis

bull No maturation

5212018

54

Melan-A Stain

bull Moderately cellular

bull Continuous basal proliferation

bull Nests hanging down

bull Low level pagetoid scatter

bull Nests in dermis

bull No maturation

Your Diagnosis

Melanoma

Nevus

Our Diagnosis

Malignant melanoma lentigo maligna type (ldquolentiginous melanomardquo Clark level II Breslow thickness 085 mm

5212018

55

Updated History Cases 3-5

bull Clinical Information

bull Three separate biopsies from left posterior shoulder of an 85-year-old female over a period of three years The biopsies were performed 4 years and 1 year ago and recently

bull The original biopsy was called a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus might have been better interpreted as a lentiginous nevus of the elderlysundamaged skin with mild to moderate atypia ndash The peripheral and deep margins of the specimen were said to be negative in the plane

of sectioning

bull The next biopsy at presumably the same anatomic location was signed out as an atypical melanocytic proliferation consistent with a persistentrecurrent Clarkrsquos (dysplastic) nevus involving the peripheral edge of the biopsy ndash It was mentioned that the differential diagnosis included early melanoma in situ

evolving within a pre-existing nevus and a reexcision was recommended

bull The most recent specimen was concerning for melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis

bull Additional procedure warranted to ensure that the lesion has been completely removed`

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Cytologic atypia mild but relatively uniform bull POTENTIAL PRECURSOR (low risk) VS ACTUAL PRECURSOR (hindsight bias)bull Manage by excision or follow-up

bull Case 5

bull Second recurrence of a lesion that originally had only ldquomildrdquo atypia (but moderate to severe architectural disorder)

bull Diagnosis of dysplastic nevus should be made with caution in elderlyCSD skin

bull Complete excision is appropriate for ldquoatypical lentiginous nevus of elderlysundamaged skinrdquo

5212018

56

Last Case

Part 2-7 12150

Clinical InformationLesion of right shoulder ro melanoma versus nevus in a 76 yo man

Reason for ConsultationIs this anything other than a moderately atypical neurotized compound nevus

bull A relatively broad lesion with irregular thickening and thinning of rete ridges and a sparsely cellular infiltrate in the dermis

bull Generally sparsely cellularbull Moderate to severe CSD

Poorly circumscribed

5212018

57

bull Pigmented melanophages in the dermis

bull Increased number of melanocytes in the epidermis many of them suprabasal

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

5212018

58

S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

bull Melan-A stain highlights the junctional component but the dermal spindle cells are negative

Case 6

bull Skin right superior shoulder Malignant melanoma lentigo maligna type nonulcerated with pure desmoplastic vertical growth phase Clark level IV Breslow thickness not lt 064 mm extending close to the specimen base see Comment 3

bull Commentbull Changes extend close to the base and to a peripheral margin of the

specimenbull It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution Sbull Should be excised locally in order to prevent any possibility of persistence

recurrence or future progression of it bull Based on its microstaging attributes the prognosis for this lesion should

be excellent The prognosis for ldquopurerdquo desmoplastic melanoma is if anything better than that for melanomas of similar thickness

bull This lesion could be managed with a relatively generous wide local excision ndash MPATH DX Category 4 (or 5)

5212018

59

Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

5212018

60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

5212018

36

5212018

37

New Report

ldquosuperficial atypical melanocytic proliferation cw recurrent nevus phenomenon extending to specimen marginsrdquo hellip ldquoI would make only one reservation and that is that this lesion should be re-excised again with a margin of normal skin around the scar and any residual lesion helliprdquo

5212018

38

RECURRENT MELANOCYTIC NEVUS

Pseudomelanoma (Ackerman)

ndash pigmented patch at site of prior shave biopsy of a benign compound or dermal nevus

ndash repigmentation occurs quickly (6 weeks)

ndash pigment does not extend beyond scars borders

RECURRENT MELANOCYTIC NEVUS

Histology

bull variably sized and shaped sometimes confluent nests

bull single cells amp nests above DEJ usually not beyond mid-spinous layer

bull occasional lesional cells or nests in dermis

bull slight cytologic atypia (ldquoreactiverdquo) rare mitoses

bull proliferation does not extend beyond scar

bull original nevus should be reviewed

5212018

39

Lessons

bull Atypia in recurrent nevi can be severe yet is ldquoreactiverdquo

ndash Mitoses can be present

ndash Dermal atypia can be present

bull A superficial scar can mimic diffuse fibroplasia seen in many melanomas

bull Keep a high index of suspicion

ndash Consider a full differential diagnosis

ndash Call for history if necessary

5212018

40

Significance of Nevi

bull Nevi are important mainly in relation to melanoma

ndash Precursors ndash but risk for individual lesions is low

ndash Risk markers ndash important mainly in high risk situations

ndash Simulants ndash important in everyday clinical decision-making

Conclusions

bull Former mild dysplasia is a benign lentiginous nevus (the commonest type of nevus)

bull Low grade dysplasia (former moderate dysplasia) can be observed clinically or by patients looking for evidence of changing lesions

bull High grade dysplasia is difficult to distinguish from melanoma in situ (UNCERTAINTY) may have competence for local persistence recurrence and progression and should be completely excised

bull All of these are ldquomelanocytic neoplasms of low (or no) malignant potentialrdquo which have little or no competence for metastasis

Lake Wakatipu and Queenstown New Zealand from the Top of ldquoThe Remarkablesrdquo(Mountains of Mordor in the distance)

5212018

41

Session II High CSD Melanomas and Simulants

Lentigo maligna melanoma

Atypical lentiginous neviproliferations

High CSD Lentiginous Nevi and Lentigo Maligna

Melanoma and Simulant(s)

bull Lentiginous Melanoma of Sun-Damaged Skin

ndash LMM in situ

ndash LMM invasive

ndash Distinction from Dysplastic Nevi (Dysplastic Nevus-like MelanomaNevoid Lentigo Maligna

bull Lentiginous Nevi of the ldquoElderlyrdquo (ie CSD Skin)

bull Solar (actinic) lentigo pigmented AK SK hellip

High UV

Pathway II Pathway III

High-CSD Melanoma (LMM)

Desmoplastic Melanoma

IMP IMP

IAMP IAMP

Lentigo maligna melanoma in situ

Melanoma in situ

Lentigo Maligna Melanoma

Desmoplastic Melanoma

NRAS BRAFnon-V600E KIT NF1

NF1 ERBB2 MAP2K1 MAP3K1 BRAF EGFR MET

TERT CDKN2A TP53 PTEN RAC1

TERT NFKBIE NRAS PIK3CA PTPN11

5212018

42

Case 1

12438

F64 Lesion of back

5212018

43

5212018

44

Your Diagnosis

Dysplastic Nevus - IAMP

Melanoma

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe ( gt 15x) mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Our Diagnosis

Case 1 12438

Lentigo maligna melanoma in situ

5212018

45

Case 2

Part 2-2 7419Clinical Information

A large pigmented lesion of the back in a 74-year-old manReason for Consultation

I called this lesion a dysplastic nevus The clinician then calls back to inform us that this is a 22 cm irregular pigmented lesion Now looking at the deepers we think this

might be a ldquolentiginous melanomardquo

Description

bull Shave biopsy of a broad lesion with a dermal component and a moderately cellular junctional component

bull Lesion is ill-defined (poorly circumscribed) at each periphery with features overlapping with those of actinic lentigo

bull Subtle increase of melanocytes along the dermal-epidermal junction with mild to moderate but relatively uniform cytologic atypia

bull Pagetoid scatter is minimal

bull Focally there are elongated rete ridges overlapping with features of dysplastic nevus however these changes are focal within the lesion rather than being symmetrically distributed at shoulders adjacent to a dermal component

Lentiginous nevus versus lentiginous melanoma

bull Poorly circumscribed at each periphery

5212018

46

bull JunctionaIIAMP

bull Patchy lymphocytic infiltrate

bull Solar elastosis

Bridging rete

5212018

47

Your Diagnosis

Melanoma

Nevus

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Lentiginous nevus versus lentiginous melanomaDiagnosis Case 2 M74

Skin mid back Superficial atypical melanocytic proliferation of uncertain significance most consistent with melanoma in situ lentiginous type (nevoid lentigo maligna) versus atypical lentiginous nevus of the elderly see comment

(ie ldquoSAMPUSrdquo)

5212018

48

Diagnosis Case 2 M74

bull Overall Commentbull There are overlapping features among atypical actinic

lentigines lentiginous junctional nevi with and without atypia and lentiginous or ldquonevoidrdquo lentigo maligna

bull Lesions in a high CSD environment must be interpreted with circumspection

bull Overdiagnosis should be avoided as even atypical lentiginous junctional nevi of the elderly seem to be biologically low grade (non-metastasizing but perhaps locally recurring potential)

bull It is judicious to completely excise these lesions in order to be sure that they have been completely examined histologically and also to minimize any possibility of local persistence recurrence or future progression

Nevoid Lentigo MalignaLentiginous Melanoma(Lentiginous Nevus)

bull Kossard 1997 Aust J Dermatol Nevoid lentigo malignaKing Page Googe amp Mihm Modern Pathology 2005 Lentiginous melanomaFerrahi Egbert amp Swetter J Cutan Pathol 2005 Dysplastic nevus-like LMM

bull Clinical diagnosis may varyndash eg lentigo maligna atypical nevus pigmented basal cell carcinoma seborrheic keratosis and

lentigo

bull Biopsies may mimic junctional nevus or dysplastic nevus at least focallyndash Lentiginous proliferation of melanocytes at the dermo-epidermal junction both as single cells

and as small nests with areas of confluent growth extending to the edges of the biopsy ndash Rete ridges maintainedndash Pagetoid spread of melanocytes was not prominent in HampE - stained sections

bull Diagnosis of melanoma more easily recognized in the complete excision specimens similar atypical melanocytic proliferation occurring over a broad area flanking the prior biopsy sites

bull Stains for MITF and Mart-1 highlight continuous basal melanocytic proliferation as well as foci of pagetoid scatter

Lentiginous MelanomaKing Page Googe Mihm Mod Pathol 2005

bull Initial biopsies mimicked lentiginous nevus or dysplastic nevus

bull Lentiginous proliferation of melanocytes at DEJ both as single cells and as small nests with areas of confluent growth extending to the edges of the biopsy

bull Retiform epidermis was maintained and pagetoid spread of melanocytes was not prominent in HampE sections

bull Immunohistochemical stains for MITF and Mart-1 highlighted the extent of the basalar melanocytic proliferation as well as foci of pagetoid spread by melanocytes

bull UNCERTAINTY IS COMMONbull PROGNOSIS IS GOOD IF LESION IS SUPERFICIALbull IMPORTANT TO COMPLETELY EXCISE

bull FOR FULL EXAMINATION AND TO MINIMIZE ANY POTENTIAL FOR LOCAL PERSISTENCE RECURRENCE AND PROGRESSION

Mart 1

MITF

5212018

49

Case 3

Part 2-3 14474

Clinical InformationLeft posterior shoulder F81

Reason for ConsultationFavor a junctional Clarkrsquos nevus (see enclosed report)

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Some bridging few nests that hang down in a droplet-like pattern bull Cytologic atypia mild but relatively uniform

5212018

50

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 3 F81

bull ldquoDifficult to interpretrdquo bull Cytologic atypia is mild to moderate rather than

severe with somewhat concerning architectural changes

bull ldquoOne is somewhat more concerned about a lesion in chronically sun-damaged skin of older subjectsrdquo

bull Skin left posterior shoulder shave biopsy Intraepidermal atypical melanocytic proliferation of uncertain significance (IAMPUS) most consistent with atypical lentiginous junctional nevus (of the elderlyCSD skin) cannot ro evolving or early established melanoma in situ

bull Complete excision recommended (MPATH-Dx 2 or 3)

Case 4

Part 2-3 14474

Clinical InformationLeft posterior shoulder F84

Reason for ConsultationFavor a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus (see

enclosed report) There is mild melanocytic atypia and that the peripheral and deep margins of the specimen were negative in the

plane of sectioning

5212018

51

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 4 F81

bull Recurrence of Case 8

bull Shave biopsy of similar sun-damaged skinbull Somewhat more cellular proliferation of nevoid and

nevoid to epithelioid melanocytes focally exhibiting severe and uniform cytologic atypia

bull Some of these cells are confined to the epidermis above the scar while others appear to extend some distance beyond the periphery of the scar

bull This latter feature raises some concern for evolving melanoma in situ extending beyond the scar

5212018

52

bull Skin left posterior shoulder shave biopsy (recurrence) Intraepidermal atypical melanocytic proliferation of uncertain significance extending to specimen margins see description and comment

ndash Comment Cannot rule out an evolving more significant lesion suggest complete excision

Case 5

Part 2-3 14474

Clinical InformationBiopsy from posterior shoulder of an 85 year old female

Reason for ConsultationThis specimen in my opinion has histologic features concerning for

melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis I do not see

definitive features of a scar consistent with a prior biopsy site

5212018

53

bull Broadbull Moderately

cellularbull Moderate to

severe CSDbull Poorly

circumscribedbull Few bridging

nestsbull Diffuse

fibroplasiabull Cells in dermis

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Nests in dermis

bull No maturation

5212018

54

Melan-A Stain

bull Moderately cellular

bull Continuous basal proliferation

bull Nests hanging down

bull Low level pagetoid scatter

bull Nests in dermis

bull No maturation

Your Diagnosis

Melanoma

Nevus

Our Diagnosis

Malignant melanoma lentigo maligna type (ldquolentiginous melanomardquo Clark level II Breslow thickness 085 mm

5212018

55

Updated History Cases 3-5

bull Clinical Information

bull Three separate biopsies from left posterior shoulder of an 85-year-old female over a period of three years The biopsies were performed 4 years and 1 year ago and recently

bull The original biopsy was called a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus might have been better interpreted as a lentiginous nevus of the elderlysundamaged skin with mild to moderate atypia ndash The peripheral and deep margins of the specimen were said to be negative in the plane

of sectioning

bull The next biopsy at presumably the same anatomic location was signed out as an atypical melanocytic proliferation consistent with a persistentrecurrent Clarkrsquos (dysplastic) nevus involving the peripheral edge of the biopsy ndash It was mentioned that the differential diagnosis included early melanoma in situ

evolving within a pre-existing nevus and a reexcision was recommended

bull The most recent specimen was concerning for melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis

bull Additional procedure warranted to ensure that the lesion has been completely removed`

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Cytologic atypia mild but relatively uniform bull POTENTIAL PRECURSOR (low risk) VS ACTUAL PRECURSOR (hindsight bias)bull Manage by excision or follow-up

bull Case 5

bull Second recurrence of a lesion that originally had only ldquomildrdquo atypia (but moderate to severe architectural disorder)

bull Diagnosis of dysplastic nevus should be made with caution in elderlyCSD skin

bull Complete excision is appropriate for ldquoatypical lentiginous nevus of elderlysundamaged skinrdquo

5212018

56

Last Case

Part 2-7 12150

Clinical InformationLesion of right shoulder ro melanoma versus nevus in a 76 yo man

Reason for ConsultationIs this anything other than a moderately atypical neurotized compound nevus

bull A relatively broad lesion with irregular thickening and thinning of rete ridges and a sparsely cellular infiltrate in the dermis

bull Generally sparsely cellularbull Moderate to severe CSD

Poorly circumscribed

5212018

57

bull Pigmented melanophages in the dermis

bull Increased number of melanocytes in the epidermis many of them suprabasal

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

5212018

58

S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

bull Melan-A stain highlights the junctional component but the dermal spindle cells are negative

Case 6

bull Skin right superior shoulder Malignant melanoma lentigo maligna type nonulcerated with pure desmoplastic vertical growth phase Clark level IV Breslow thickness not lt 064 mm extending close to the specimen base see Comment 3

bull Commentbull Changes extend close to the base and to a peripheral margin of the

specimenbull It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution Sbull Should be excised locally in order to prevent any possibility of persistence

recurrence or future progression of it bull Based on its microstaging attributes the prognosis for this lesion should

be excellent The prognosis for ldquopurerdquo desmoplastic melanoma is if anything better than that for melanomas of similar thickness

bull This lesion could be managed with a relatively generous wide local excision ndash MPATH DX Category 4 (or 5)

5212018

59

Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

5212018

60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

5212018

37

New Report

ldquosuperficial atypical melanocytic proliferation cw recurrent nevus phenomenon extending to specimen marginsrdquo hellip ldquoI would make only one reservation and that is that this lesion should be re-excised again with a margin of normal skin around the scar and any residual lesion helliprdquo

5212018

38

RECURRENT MELANOCYTIC NEVUS

Pseudomelanoma (Ackerman)

ndash pigmented patch at site of prior shave biopsy of a benign compound or dermal nevus

ndash repigmentation occurs quickly (6 weeks)

ndash pigment does not extend beyond scars borders

RECURRENT MELANOCYTIC NEVUS

Histology

bull variably sized and shaped sometimes confluent nests

bull single cells amp nests above DEJ usually not beyond mid-spinous layer

bull occasional lesional cells or nests in dermis

bull slight cytologic atypia (ldquoreactiverdquo) rare mitoses

bull proliferation does not extend beyond scar

bull original nevus should be reviewed

5212018

39

Lessons

bull Atypia in recurrent nevi can be severe yet is ldquoreactiverdquo

ndash Mitoses can be present

ndash Dermal atypia can be present

bull A superficial scar can mimic diffuse fibroplasia seen in many melanomas

bull Keep a high index of suspicion

ndash Consider a full differential diagnosis

ndash Call for history if necessary

5212018

40

Significance of Nevi

bull Nevi are important mainly in relation to melanoma

ndash Precursors ndash but risk for individual lesions is low

ndash Risk markers ndash important mainly in high risk situations

ndash Simulants ndash important in everyday clinical decision-making

Conclusions

bull Former mild dysplasia is a benign lentiginous nevus (the commonest type of nevus)

bull Low grade dysplasia (former moderate dysplasia) can be observed clinically or by patients looking for evidence of changing lesions

bull High grade dysplasia is difficult to distinguish from melanoma in situ (UNCERTAINTY) may have competence for local persistence recurrence and progression and should be completely excised

bull All of these are ldquomelanocytic neoplasms of low (or no) malignant potentialrdquo which have little or no competence for metastasis

Lake Wakatipu and Queenstown New Zealand from the Top of ldquoThe Remarkablesrdquo(Mountains of Mordor in the distance)

5212018

41

Session II High CSD Melanomas and Simulants

Lentigo maligna melanoma

Atypical lentiginous neviproliferations

High CSD Lentiginous Nevi and Lentigo Maligna

Melanoma and Simulant(s)

bull Lentiginous Melanoma of Sun-Damaged Skin

ndash LMM in situ

ndash LMM invasive

ndash Distinction from Dysplastic Nevi (Dysplastic Nevus-like MelanomaNevoid Lentigo Maligna

bull Lentiginous Nevi of the ldquoElderlyrdquo (ie CSD Skin)

bull Solar (actinic) lentigo pigmented AK SK hellip

High UV

Pathway II Pathway III

High-CSD Melanoma (LMM)

Desmoplastic Melanoma

IMP IMP

IAMP IAMP

Lentigo maligna melanoma in situ

Melanoma in situ

Lentigo Maligna Melanoma

Desmoplastic Melanoma

NRAS BRAFnon-V600E KIT NF1

NF1 ERBB2 MAP2K1 MAP3K1 BRAF EGFR MET

TERT CDKN2A TP53 PTEN RAC1

TERT NFKBIE NRAS PIK3CA PTPN11

5212018

42

Case 1

12438

F64 Lesion of back

5212018

43

5212018

44

Your Diagnosis

Dysplastic Nevus - IAMP

Melanoma

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe ( gt 15x) mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Our Diagnosis

Case 1 12438

Lentigo maligna melanoma in situ

5212018

45

Case 2

Part 2-2 7419Clinical Information

A large pigmented lesion of the back in a 74-year-old manReason for Consultation

I called this lesion a dysplastic nevus The clinician then calls back to inform us that this is a 22 cm irregular pigmented lesion Now looking at the deepers we think this

might be a ldquolentiginous melanomardquo

Description

bull Shave biopsy of a broad lesion with a dermal component and a moderately cellular junctional component

bull Lesion is ill-defined (poorly circumscribed) at each periphery with features overlapping with those of actinic lentigo

bull Subtle increase of melanocytes along the dermal-epidermal junction with mild to moderate but relatively uniform cytologic atypia

bull Pagetoid scatter is minimal

bull Focally there are elongated rete ridges overlapping with features of dysplastic nevus however these changes are focal within the lesion rather than being symmetrically distributed at shoulders adjacent to a dermal component

Lentiginous nevus versus lentiginous melanoma

bull Poorly circumscribed at each periphery

5212018

46

bull JunctionaIIAMP

bull Patchy lymphocytic infiltrate

bull Solar elastosis

Bridging rete

5212018

47

Your Diagnosis

Melanoma

Nevus

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Lentiginous nevus versus lentiginous melanomaDiagnosis Case 2 M74

Skin mid back Superficial atypical melanocytic proliferation of uncertain significance most consistent with melanoma in situ lentiginous type (nevoid lentigo maligna) versus atypical lentiginous nevus of the elderly see comment

(ie ldquoSAMPUSrdquo)

5212018

48

Diagnosis Case 2 M74

bull Overall Commentbull There are overlapping features among atypical actinic

lentigines lentiginous junctional nevi with and without atypia and lentiginous or ldquonevoidrdquo lentigo maligna

bull Lesions in a high CSD environment must be interpreted with circumspection

bull Overdiagnosis should be avoided as even atypical lentiginous junctional nevi of the elderly seem to be biologically low grade (non-metastasizing but perhaps locally recurring potential)

bull It is judicious to completely excise these lesions in order to be sure that they have been completely examined histologically and also to minimize any possibility of local persistence recurrence or future progression

Nevoid Lentigo MalignaLentiginous Melanoma(Lentiginous Nevus)

bull Kossard 1997 Aust J Dermatol Nevoid lentigo malignaKing Page Googe amp Mihm Modern Pathology 2005 Lentiginous melanomaFerrahi Egbert amp Swetter J Cutan Pathol 2005 Dysplastic nevus-like LMM

bull Clinical diagnosis may varyndash eg lentigo maligna atypical nevus pigmented basal cell carcinoma seborrheic keratosis and

lentigo

bull Biopsies may mimic junctional nevus or dysplastic nevus at least focallyndash Lentiginous proliferation of melanocytes at the dermo-epidermal junction both as single cells

and as small nests with areas of confluent growth extending to the edges of the biopsy ndash Rete ridges maintainedndash Pagetoid spread of melanocytes was not prominent in HampE - stained sections

bull Diagnosis of melanoma more easily recognized in the complete excision specimens similar atypical melanocytic proliferation occurring over a broad area flanking the prior biopsy sites

bull Stains for MITF and Mart-1 highlight continuous basal melanocytic proliferation as well as foci of pagetoid scatter

Lentiginous MelanomaKing Page Googe Mihm Mod Pathol 2005

bull Initial biopsies mimicked lentiginous nevus or dysplastic nevus

bull Lentiginous proliferation of melanocytes at DEJ both as single cells and as small nests with areas of confluent growth extending to the edges of the biopsy

bull Retiform epidermis was maintained and pagetoid spread of melanocytes was not prominent in HampE sections

bull Immunohistochemical stains for MITF and Mart-1 highlighted the extent of the basalar melanocytic proliferation as well as foci of pagetoid spread by melanocytes

bull UNCERTAINTY IS COMMONbull PROGNOSIS IS GOOD IF LESION IS SUPERFICIALbull IMPORTANT TO COMPLETELY EXCISE

bull FOR FULL EXAMINATION AND TO MINIMIZE ANY POTENTIAL FOR LOCAL PERSISTENCE RECURRENCE AND PROGRESSION

Mart 1

MITF

5212018

49

Case 3

Part 2-3 14474

Clinical InformationLeft posterior shoulder F81

Reason for ConsultationFavor a junctional Clarkrsquos nevus (see enclosed report)

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Some bridging few nests that hang down in a droplet-like pattern bull Cytologic atypia mild but relatively uniform

5212018

50

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 3 F81

bull ldquoDifficult to interpretrdquo bull Cytologic atypia is mild to moderate rather than

severe with somewhat concerning architectural changes

bull ldquoOne is somewhat more concerned about a lesion in chronically sun-damaged skin of older subjectsrdquo

bull Skin left posterior shoulder shave biopsy Intraepidermal atypical melanocytic proliferation of uncertain significance (IAMPUS) most consistent with atypical lentiginous junctional nevus (of the elderlyCSD skin) cannot ro evolving or early established melanoma in situ

bull Complete excision recommended (MPATH-Dx 2 or 3)

Case 4

Part 2-3 14474

Clinical InformationLeft posterior shoulder F84

Reason for ConsultationFavor a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus (see

enclosed report) There is mild melanocytic atypia and that the peripheral and deep margins of the specimen were negative in the

plane of sectioning

5212018

51

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 4 F81

bull Recurrence of Case 8

bull Shave biopsy of similar sun-damaged skinbull Somewhat more cellular proliferation of nevoid and

nevoid to epithelioid melanocytes focally exhibiting severe and uniform cytologic atypia

bull Some of these cells are confined to the epidermis above the scar while others appear to extend some distance beyond the periphery of the scar

bull This latter feature raises some concern for evolving melanoma in situ extending beyond the scar

5212018

52

bull Skin left posterior shoulder shave biopsy (recurrence) Intraepidermal atypical melanocytic proliferation of uncertain significance extending to specimen margins see description and comment

ndash Comment Cannot rule out an evolving more significant lesion suggest complete excision

Case 5

Part 2-3 14474

Clinical InformationBiopsy from posterior shoulder of an 85 year old female

Reason for ConsultationThis specimen in my opinion has histologic features concerning for

melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis I do not see

definitive features of a scar consistent with a prior biopsy site

5212018

53

bull Broadbull Moderately

cellularbull Moderate to

severe CSDbull Poorly

circumscribedbull Few bridging

nestsbull Diffuse

fibroplasiabull Cells in dermis

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Nests in dermis

bull No maturation

5212018

54

Melan-A Stain

bull Moderately cellular

bull Continuous basal proliferation

bull Nests hanging down

bull Low level pagetoid scatter

bull Nests in dermis

bull No maturation

Your Diagnosis

Melanoma

Nevus

Our Diagnosis

Malignant melanoma lentigo maligna type (ldquolentiginous melanomardquo Clark level II Breslow thickness 085 mm

5212018

55

Updated History Cases 3-5

bull Clinical Information

bull Three separate biopsies from left posterior shoulder of an 85-year-old female over a period of three years The biopsies were performed 4 years and 1 year ago and recently

bull The original biopsy was called a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus might have been better interpreted as a lentiginous nevus of the elderlysundamaged skin with mild to moderate atypia ndash The peripheral and deep margins of the specimen were said to be negative in the plane

of sectioning

bull The next biopsy at presumably the same anatomic location was signed out as an atypical melanocytic proliferation consistent with a persistentrecurrent Clarkrsquos (dysplastic) nevus involving the peripheral edge of the biopsy ndash It was mentioned that the differential diagnosis included early melanoma in situ

evolving within a pre-existing nevus and a reexcision was recommended

bull The most recent specimen was concerning for melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis

bull Additional procedure warranted to ensure that the lesion has been completely removed`

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Cytologic atypia mild but relatively uniform bull POTENTIAL PRECURSOR (low risk) VS ACTUAL PRECURSOR (hindsight bias)bull Manage by excision or follow-up

bull Case 5

bull Second recurrence of a lesion that originally had only ldquomildrdquo atypia (but moderate to severe architectural disorder)

bull Diagnosis of dysplastic nevus should be made with caution in elderlyCSD skin

bull Complete excision is appropriate for ldquoatypical lentiginous nevus of elderlysundamaged skinrdquo

5212018

56

Last Case

Part 2-7 12150

Clinical InformationLesion of right shoulder ro melanoma versus nevus in a 76 yo man

Reason for ConsultationIs this anything other than a moderately atypical neurotized compound nevus

bull A relatively broad lesion with irregular thickening and thinning of rete ridges and a sparsely cellular infiltrate in the dermis

bull Generally sparsely cellularbull Moderate to severe CSD

Poorly circumscribed

5212018

57

bull Pigmented melanophages in the dermis

bull Increased number of melanocytes in the epidermis many of them suprabasal

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

5212018

58

S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

bull Melan-A stain highlights the junctional component but the dermal spindle cells are negative

Case 6

bull Skin right superior shoulder Malignant melanoma lentigo maligna type nonulcerated with pure desmoplastic vertical growth phase Clark level IV Breslow thickness not lt 064 mm extending close to the specimen base see Comment 3

bull Commentbull Changes extend close to the base and to a peripheral margin of the

specimenbull It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution Sbull Should be excised locally in order to prevent any possibility of persistence

recurrence or future progression of it bull Based on its microstaging attributes the prognosis for this lesion should

be excellent The prognosis for ldquopurerdquo desmoplastic melanoma is if anything better than that for melanomas of similar thickness

bull This lesion could be managed with a relatively generous wide local excision ndash MPATH DX Category 4 (or 5)

5212018

59

Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

5212018

60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

5212018

38

RECURRENT MELANOCYTIC NEVUS

Pseudomelanoma (Ackerman)

ndash pigmented patch at site of prior shave biopsy of a benign compound or dermal nevus

ndash repigmentation occurs quickly (6 weeks)

ndash pigment does not extend beyond scars borders

RECURRENT MELANOCYTIC NEVUS

Histology

bull variably sized and shaped sometimes confluent nests

bull single cells amp nests above DEJ usually not beyond mid-spinous layer

bull occasional lesional cells or nests in dermis

bull slight cytologic atypia (ldquoreactiverdquo) rare mitoses

bull proliferation does not extend beyond scar

bull original nevus should be reviewed

5212018

39

Lessons

bull Atypia in recurrent nevi can be severe yet is ldquoreactiverdquo

ndash Mitoses can be present

ndash Dermal atypia can be present

bull A superficial scar can mimic diffuse fibroplasia seen in many melanomas

bull Keep a high index of suspicion

ndash Consider a full differential diagnosis

ndash Call for history if necessary

5212018

40

Significance of Nevi

bull Nevi are important mainly in relation to melanoma

ndash Precursors ndash but risk for individual lesions is low

ndash Risk markers ndash important mainly in high risk situations

ndash Simulants ndash important in everyday clinical decision-making

Conclusions

bull Former mild dysplasia is a benign lentiginous nevus (the commonest type of nevus)

bull Low grade dysplasia (former moderate dysplasia) can be observed clinically or by patients looking for evidence of changing lesions

bull High grade dysplasia is difficult to distinguish from melanoma in situ (UNCERTAINTY) may have competence for local persistence recurrence and progression and should be completely excised

bull All of these are ldquomelanocytic neoplasms of low (or no) malignant potentialrdquo which have little or no competence for metastasis

Lake Wakatipu and Queenstown New Zealand from the Top of ldquoThe Remarkablesrdquo(Mountains of Mordor in the distance)

5212018

41

Session II High CSD Melanomas and Simulants

Lentigo maligna melanoma

Atypical lentiginous neviproliferations

High CSD Lentiginous Nevi and Lentigo Maligna

Melanoma and Simulant(s)

bull Lentiginous Melanoma of Sun-Damaged Skin

ndash LMM in situ

ndash LMM invasive

ndash Distinction from Dysplastic Nevi (Dysplastic Nevus-like MelanomaNevoid Lentigo Maligna

bull Lentiginous Nevi of the ldquoElderlyrdquo (ie CSD Skin)

bull Solar (actinic) lentigo pigmented AK SK hellip

High UV

Pathway II Pathway III

High-CSD Melanoma (LMM)

Desmoplastic Melanoma

IMP IMP

IAMP IAMP

Lentigo maligna melanoma in situ

Melanoma in situ

Lentigo Maligna Melanoma

Desmoplastic Melanoma

NRAS BRAFnon-V600E KIT NF1

NF1 ERBB2 MAP2K1 MAP3K1 BRAF EGFR MET

TERT CDKN2A TP53 PTEN RAC1

TERT NFKBIE NRAS PIK3CA PTPN11

5212018

42

Case 1

12438

F64 Lesion of back

5212018

43

5212018

44

Your Diagnosis

Dysplastic Nevus - IAMP

Melanoma

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe ( gt 15x) mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Our Diagnosis

Case 1 12438

Lentigo maligna melanoma in situ

5212018

45

Case 2

Part 2-2 7419Clinical Information

A large pigmented lesion of the back in a 74-year-old manReason for Consultation

I called this lesion a dysplastic nevus The clinician then calls back to inform us that this is a 22 cm irregular pigmented lesion Now looking at the deepers we think this

might be a ldquolentiginous melanomardquo

Description

bull Shave biopsy of a broad lesion with a dermal component and a moderately cellular junctional component

bull Lesion is ill-defined (poorly circumscribed) at each periphery with features overlapping with those of actinic lentigo

bull Subtle increase of melanocytes along the dermal-epidermal junction with mild to moderate but relatively uniform cytologic atypia

bull Pagetoid scatter is minimal

bull Focally there are elongated rete ridges overlapping with features of dysplastic nevus however these changes are focal within the lesion rather than being symmetrically distributed at shoulders adjacent to a dermal component

Lentiginous nevus versus lentiginous melanoma

bull Poorly circumscribed at each periphery

5212018

46

bull JunctionaIIAMP

bull Patchy lymphocytic infiltrate

bull Solar elastosis

Bridging rete

5212018

47

Your Diagnosis

Melanoma

Nevus

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Lentiginous nevus versus lentiginous melanomaDiagnosis Case 2 M74

Skin mid back Superficial atypical melanocytic proliferation of uncertain significance most consistent with melanoma in situ lentiginous type (nevoid lentigo maligna) versus atypical lentiginous nevus of the elderly see comment

(ie ldquoSAMPUSrdquo)

5212018

48

Diagnosis Case 2 M74

bull Overall Commentbull There are overlapping features among atypical actinic

lentigines lentiginous junctional nevi with and without atypia and lentiginous or ldquonevoidrdquo lentigo maligna

bull Lesions in a high CSD environment must be interpreted with circumspection

bull Overdiagnosis should be avoided as even atypical lentiginous junctional nevi of the elderly seem to be biologically low grade (non-metastasizing but perhaps locally recurring potential)

bull It is judicious to completely excise these lesions in order to be sure that they have been completely examined histologically and also to minimize any possibility of local persistence recurrence or future progression

Nevoid Lentigo MalignaLentiginous Melanoma(Lentiginous Nevus)

bull Kossard 1997 Aust J Dermatol Nevoid lentigo malignaKing Page Googe amp Mihm Modern Pathology 2005 Lentiginous melanomaFerrahi Egbert amp Swetter J Cutan Pathol 2005 Dysplastic nevus-like LMM

bull Clinical diagnosis may varyndash eg lentigo maligna atypical nevus pigmented basal cell carcinoma seborrheic keratosis and

lentigo

bull Biopsies may mimic junctional nevus or dysplastic nevus at least focallyndash Lentiginous proliferation of melanocytes at the dermo-epidermal junction both as single cells

and as small nests with areas of confluent growth extending to the edges of the biopsy ndash Rete ridges maintainedndash Pagetoid spread of melanocytes was not prominent in HampE - stained sections

bull Diagnosis of melanoma more easily recognized in the complete excision specimens similar atypical melanocytic proliferation occurring over a broad area flanking the prior biopsy sites

bull Stains for MITF and Mart-1 highlight continuous basal melanocytic proliferation as well as foci of pagetoid scatter

Lentiginous MelanomaKing Page Googe Mihm Mod Pathol 2005

bull Initial biopsies mimicked lentiginous nevus or dysplastic nevus

bull Lentiginous proliferation of melanocytes at DEJ both as single cells and as small nests with areas of confluent growth extending to the edges of the biopsy

bull Retiform epidermis was maintained and pagetoid spread of melanocytes was not prominent in HampE sections

bull Immunohistochemical stains for MITF and Mart-1 highlighted the extent of the basalar melanocytic proliferation as well as foci of pagetoid spread by melanocytes

bull UNCERTAINTY IS COMMONbull PROGNOSIS IS GOOD IF LESION IS SUPERFICIALbull IMPORTANT TO COMPLETELY EXCISE

bull FOR FULL EXAMINATION AND TO MINIMIZE ANY POTENTIAL FOR LOCAL PERSISTENCE RECURRENCE AND PROGRESSION

Mart 1

MITF

5212018

49

Case 3

Part 2-3 14474

Clinical InformationLeft posterior shoulder F81

Reason for ConsultationFavor a junctional Clarkrsquos nevus (see enclosed report)

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Some bridging few nests that hang down in a droplet-like pattern bull Cytologic atypia mild but relatively uniform

5212018

50

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 3 F81

bull ldquoDifficult to interpretrdquo bull Cytologic atypia is mild to moderate rather than

severe with somewhat concerning architectural changes

bull ldquoOne is somewhat more concerned about a lesion in chronically sun-damaged skin of older subjectsrdquo

bull Skin left posterior shoulder shave biopsy Intraepidermal atypical melanocytic proliferation of uncertain significance (IAMPUS) most consistent with atypical lentiginous junctional nevus (of the elderlyCSD skin) cannot ro evolving or early established melanoma in situ

bull Complete excision recommended (MPATH-Dx 2 or 3)

Case 4

Part 2-3 14474

Clinical InformationLeft posterior shoulder F84

Reason for ConsultationFavor a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus (see

enclosed report) There is mild melanocytic atypia and that the peripheral and deep margins of the specimen were negative in the

plane of sectioning

5212018

51

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 4 F81

bull Recurrence of Case 8

bull Shave biopsy of similar sun-damaged skinbull Somewhat more cellular proliferation of nevoid and

nevoid to epithelioid melanocytes focally exhibiting severe and uniform cytologic atypia

bull Some of these cells are confined to the epidermis above the scar while others appear to extend some distance beyond the periphery of the scar

bull This latter feature raises some concern for evolving melanoma in situ extending beyond the scar

5212018

52

bull Skin left posterior shoulder shave biopsy (recurrence) Intraepidermal atypical melanocytic proliferation of uncertain significance extending to specimen margins see description and comment

ndash Comment Cannot rule out an evolving more significant lesion suggest complete excision

Case 5

Part 2-3 14474

Clinical InformationBiopsy from posterior shoulder of an 85 year old female

Reason for ConsultationThis specimen in my opinion has histologic features concerning for

melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis I do not see

definitive features of a scar consistent with a prior biopsy site

5212018

53

bull Broadbull Moderately

cellularbull Moderate to

severe CSDbull Poorly

circumscribedbull Few bridging

nestsbull Diffuse

fibroplasiabull Cells in dermis

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Nests in dermis

bull No maturation

5212018

54

Melan-A Stain

bull Moderately cellular

bull Continuous basal proliferation

bull Nests hanging down

bull Low level pagetoid scatter

bull Nests in dermis

bull No maturation

Your Diagnosis

Melanoma

Nevus

Our Diagnosis

Malignant melanoma lentigo maligna type (ldquolentiginous melanomardquo Clark level II Breslow thickness 085 mm

5212018

55

Updated History Cases 3-5

bull Clinical Information

bull Three separate biopsies from left posterior shoulder of an 85-year-old female over a period of three years The biopsies were performed 4 years and 1 year ago and recently

bull The original biopsy was called a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus might have been better interpreted as a lentiginous nevus of the elderlysundamaged skin with mild to moderate atypia ndash The peripheral and deep margins of the specimen were said to be negative in the plane

of sectioning

bull The next biopsy at presumably the same anatomic location was signed out as an atypical melanocytic proliferation consistent with a persistentrecurrent Clarkrsquos (dysplastic) nevus involving the peripheral edge of the biopsy ndash It was mentioned that the differential diagnosis included early melanoma in situ

evolving within a pre-existing nevus and a reexcision was recommended

bull The most recent specimen was concerning for melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis

bull Additional procedure warranted to ensure that the lesion has been completely removed`

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Cytologic atypia mild but relatively uniform bull POTENTIAL PRECURSOR (low risk) VS ACTUAL PRECURSOR (hindsight bias)bull Manage by excision or follow-up

bull Case 5

bull Second recurrence of a lesion that originally had only ldquomildrdquo atypia (but moderate to severe architectural disorder)

bull Diagnosis of dysplastic nevus should be made with caution in elderlyCSD skin

bull Complete excision is appropriate for ldquoatypical lentiginous nevus of elderlysundamaged skinrdquo

5212018

56

Last Case

Part 2-7 12150

Clinical InformationLesion of right shoulder ro melanoma versus nevus in a 76 yo man

Reason for ConsultationIs this anything other than a moderately atypical neurotized compound nevus

bull A relatively broad lesion with irregular thickening and thinning of rete ridges and a sparsely cellular infiltrate in the dermis

bull Generally sparsely cellularbull Moderate to severe CSD

Poorly circumscribed

5212018

57

bull Pigmented melanophages in the dermis

bull Increased number of melanocytes in the epidermis many of them suprabasal

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

5212018

58

S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

bull Melan-A stain highlights the junctional component but the dermal spindle cells are negative

Case 6

bull Skin right superior shoulder Malignant melanoma lentigo maligna type nonulcerated with pure desmoplastic vertical growth phase Clark level IV Breslow thickness not lt 064 mm extending close to the specimen base see Comment 3

bull Commentbull Changes extend close to the base and to a peripheral margin of the

specimenbull It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution Sbull Should be excised locally in order to prevent any possibility of persistence

recurrence or future progression of it bull Based on its microstaging attributes the prognosis for this lesion should

be excellent The prognosis for ldquopurerdquo desmoplastic melanoma is if anything better than that for melanomas of similar thickness

bull This lesion could be managed with a relatively generous wide local excision ndash MPATH DX Category 4 (or 5)

5212018

59

Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

5212018

60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

5212018

39

Lessons

bull Atypia in recurrent nevi can be severe yet is ldquoreactiverdquo

ndash Mitoses can be present

ndash Dermal atypia can be present

bull A superficial scar can mimic diffuse fibroplasia seen in many melanomas

bull Keep a high index of suspicion

ndash Consider a full differential diagnosis

ndash Call for history if necessary

5212018

40

Significance of Nevi

bull Nevi are important mainly in relation to melanoma

ndash Precursors ndash but risk for individual lesions is low

ndash Risk markers ndash important mainly in high risk situations

ndash Simulants ndash important in everyday clinical decision-making

Conclusions

bull Former mild dysplasia is a benign lentiginous nevus (the commonest type of nevus)

bull Low grade dysplasia (former moderate dysplasia) can be observed clinically or by patients looking for evidence of changing lesions

bull High grade dysplasia is difficult to distinguish from melanoma in situ (UNCERTAINTY) may have competence for local persistence recurrence and progression and should be completely excised

bull All of these are ldquomelanocytic neoplasms of low (or no) malignant potentialrdquo which have little or no competence for metastasis

Lake Wakatipu and Queenstown New Zealand from the Top of ldquoThe Remarkablesrdquo(Mountains of Mordor in the distance)

5212018

41

Session II High CSD Melanomas and Simulants

Lentigo maligna melanoma

Atypical lentiginous neviproliferations

High CSD Lentiginous Nevi and Lentigo Maligna

Melanoma and Simulant(s)

bull Lentiginous Melanoma of Sun-Damaged Skin

ndash LMM in situ

ndash LMM invasive

ndash Distinction from Dysplastic Nevi (Dysplastic Nevus-like MelanomaNevoid Lentigo Maligna

bull Lentiginous Nevi of the ldquoElderlyrdquo (ie CSD Skin)

bull Solar (actinic) lentigo pigmented AK SK hellip

High UV

Pathway II Pathway III

High-CSD Melanoma (LMM)

Desmoplastic Melanoma

IMP IMP

IAMP IAMP

Lentigo maligna melanoma in situ

Melanoma in situ

Lentigo Maligna Melanoma

Desmoplastic Melanoma

NRAS BRAFnon-V600E KIT NF1

NF1 ERBB2 MAP2K1 MAP3K1 BRAF EGFR MET

TERT CDKN2A TP53 PTEN RAC1

TERT NFKBIE NRAS PIK3CA PTPN11

5212018

42

Case 1

12438

F64 Lesion of back

5212018

43

5212018

44

Your Diagnosis

Dysplastic Nevus - IAMP

Melanoma

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe ( gt 15x) mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Our Diagnosis

Case 1 12438

Lentigo maligna melanoma in situ

5212018

45

Case 2

Part 2-2 7419Clinical Information

A large pigmented lesion of the back in a 74-year-old manReason for Consultation

I called this lesion a dysplastic nevus The clinician then calls back to inform us that this is a 22 cm irregular pigmented lesion Now looking at the deepers we think this

might be a ldquolentiginous melanomardquo

Description

bull Shave biopsy of a broad lesion with a dermal component and a moderately cellular junctional component

bull Lesion is ill-defined (poorly circumscribed) at each periphery with features overlapping with those of actinic lentigo

bull Subtle increase of melanocytes along the dermal-epidermal junction with mild to moderate but relatively uniform cytologic atypia

bull Pagetoid scatter is minimal

bull Focally there are elongated rete ridges overlapping with features of dysplastic nevus however these changes are focal within the lesion rather than being symmetrically distributed at shoulders adjacent to a dermal component

Lentiginous nevus versus lentiginous melanoma

bull Poorly circumscribed at each periphery

5212018

46

bull JunctionaIIAMP

bull Patchy lymphocytic infiltrate

bull Solar elastosis

Bridging rete

5212018

47

Your Diagnosis

Melanoma

Nevus

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Lentiginous nevus versus lentiginous melanomaDiagnosis Case 2 M74

Skin mid back Superficial atypical melanocytic proliferation of uncertain significance most consistent with melanoma in situ lentiginous type (nevoid lentigo maligna) versus atypical lentiginous nevus of the elderly see comment

(ie ldquoSAMPUSrdquo)

5212018

48

Diagnosis Case 2 M74

bull Overall Commentbull There are overlapping features among atypical actinic

lentigines lentiginous junctional nevi with and without atypia and lentiginous or ldquonevoidrdquo lentigo maligna

bull Lesions in a high CSD environment must be interpreted with circumspection

bull Overdiagnosis should be avoided as even atypical lentiginous junctional nevi of the elderly seem to be biologically low grade (non-metastasizing but perhaps locally recurring potential)

bull It is judicious to completely excise these lesions in order to be sure that they have been completely examined histologically and also to minimize any possibility of local persistence recurrence or future progression

Nevoid Lentigo MalignaLentiginous Melanoma(Lentiginous Nevus)

bull Kossard 1997 Aust J Dermatol Nevoid lentigo malignaKing Page Googe amp Mihm Modern Pathology 2005 Lentiginous melanomaFerrahi Egbert amp Swetter J Cutan Pathol 2005 Dysplastic nevus-like LMM

bull Clinical diagnosis may varyndash eg lentigo maligna atypical nevus pigmented basal cell carcinoma seborrheic keratosis and

lentigo

bull Biopsies may mimic junctional nevus or dysplastic nevus at least focallyndash Lentiginous proliferation of melanocytes at the dermo-epidermal junction both as single cells

and as small nests with areas of confluent growth extending to the edges of the biopsy ndash Rete ridges maintainedndash Pagetoid spread of melanocytes was not prominent in HampE - stained sections

bull Diagnosis of melanoma more easily recognized in the complete excision specimens similar atypical melanocytic proliferation occurring over a broad area flanking the prior biopsy sites

bull Stains for MITF and Mart-1 highlight continuous basal melanocytic proliferation as well as foci of pagetoid scatter

Lentiginous MelanomaKing Page Googe Mihm Mod Pathol 2005

bull Initial biopsies mimicked lentiginous nevus or dysplastic nevus

bull Lentiginous proliferation of melanocytes at DEJ both as single cells and as small nests with areas of confluent growth extending to the edges of the biopsy

bull Retiform epidermis was maintained and pagetoid spread of melanocytes was not prominent in HampE sections

bull Immunohistochemical stains for MITF and Mart-1 highlighted the extent of the basalar melanocytic proliferation as well as foci of pagetoid spread by melanocytes

bull UNCERTAINTY IS COMMONbull PROGNOSIS IS GOOD IF LESION IS SUPERFICIALbull IMPORTANT TO COMPLETELY EXCISE

bull FOR FULL EXAMINATION AND TO MINIMIZE ANY POTENTIAL FOR LOCAL PERSISTENCE RECURRENCE AND PROGRESSION

Mart 1

MITF

5212018

49

Case 3

Part 2-3 14474

Clinical InformationLeft posterior shoulder F81

Reason for ConsultationFavor a junctional Clarkrsquos nevus (see enclosed report)

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Some bridging few nests that hang down in a droplet-like pattern bull Cytologic atypia mild but relatively uniform

5212018

50

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 3 F81

bull ldquoDifficult to interpretrdquo bull Cytologic atypia is mild to moderate rather than

severe with somewhat concerning architectural changes

bull ldquoOne is somewhat more concerned about a lesion in chronically sun-damaged skin of older subjectsrdquo

bull Skin left posterior shoulder shave biopsy Intraepidermal atypical melanocytic proliferation of uncertain significance (IAMPUS) most consistent with atypical lentiginous junctional nevus (of the elderlyCSD skin) cannot ro evolving or early established melanoma in situ

bull Complete excision recommended (MPATH-Dx 2 or 3)

Case 4

Part 2-3 14474

Clinical InformationLeft posterior shoulder F84

Reason for ConsultationFavor a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus (see

enclosed report) There is mild melanocytic atypia and that the peripheral and deep margins of the specimen were negative in the

plane of sectioning

5212018

51

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 4 F81

bull Recurrence of Case 8

bull Shave biopsy of similar sun-damaged skinbull Somewhat more cellular proliferation of nevoid and

nevoid to epithelioid melanocytes focally exhibiting severe and uniform cytologic atypia

bull Some of these cells are confined to the epidermis above the scar while others appear to extend some distance beyond the periphery of the scar

bull This latter feature raises some concern for evolving melanoma in situ extending beyond the scar

5212018

52

bull Skin left posterior shoulder shave biopsy (recurrence) Intraepidermal atypical melanocytic proliferation of uncertain significance extending to specimen margins see description and comment

ndash Comment Cannot rule out an evolving more significant lesion suggest complete excision

Case 5

Part 2-3 14474

Clinical InformationBiopsy from posterior shoulder of an 85 year old female

Reason for ConsultationThis specimen in my opinion has histologic features concerning for

melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis I do not see

definitive features of a scar consistent with a prior biopsy site

5212018

53

bull Broadbull Moderately

cellularbull Moderate to

severe CSDbull Poorly

circumscribedbull Few bridging

nestsbull Diffuse

fibroplasiabull Cells in dermis

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Nests in dermis

bull No maturation

5212018

54

Melan-A Stain

bull Moderately cellular

bull Continuous basal proliferation

bull Nests hanging down

bull Low level pagetoid scatter

bull Nests in dermis

bull No maturation

Your Diagnosis

Melanoma

Nevus

Our Diagnosis

Malignant melanoma lentigo maligna type (ldquolentiginous melanomardquo Clark level II Breslow thickness 085 mm

5212018

55

Updated History Cases 3-5

bull Clinical Information

bull Three separate biopsies from left posterior shoulder of an 85-year-old female over a period of three years The biopsies were performed 4 years and 1 year ago and recently

bull The original biopsy was called a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus might have been better interpreted as a lentiginous nevus of the elderlysundamaged skin with mild to moderate atypia ndash The peripheral and deep margins of the specimen were said to be negative in the plane

of sectioning

bull The next biopsy at presumably the same anatomic location was signed out as an atypical melanocytic proliferation consistent with a persistentrecurrent Clarkrsquos (dysplastic) nevus involving the peripheral edge of the biopsy ndash It was mentioned that the differential diagnosis included early melanoma in situ

evolving within a pre-existing nevus and a reexcision was recommended

bull The most recent specimen was concerning for melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis

bull Additional procedure warranted to ensure that the lesion has been completely removed`

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Cytologic atypia mild but relatively uniform bull POTENTIAL PRECURSOR (low risk) VS ACTUAL PRECURSOR (hindsight bias)bull Manage by excision or follow-up

bull Case 5

bull Second recurrence of a lesion that originally had only ldquomildrdquo atypia (but moderate to severe architectural disorder)

bull Diagnosis of dysplastic nevus should be made with caution in elderlyCSD skin

bull Complete excision is appropriate for ldquoatypical lentiginous nevus of elderlysundamaged skinrdquo

5212018

56

Last Case

Part 2-7 12150

Clinical InformationLesion of right shoulder ro melanoma versus nevus in a 76 yo man

Reason for ConsultationIs this anything other than a moderately atypical neurotized compound nevus

bull A relatively broad lesion with irregular thickening and thinning of rete ridges and a sparsely cellular infiltrate in the dermis

bull Generally sparsely cellularbull Moderate to severe CSD

Poorly circumscribed

5212018

57

bull Pigmented melanophages in the dermis

bull Increased number of melanocytes in the epidermis many of them suprabasal

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

5212018

58

S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

bull Melan-A stain highlights the junctional component but the dermal spindle cells are negative

Case 6

bull Skin right superior shoulder Malignant melanoma lentigo maligna type nonulcerated with pure desmoplastic vertical growth phase Clark level IV Breslow thickness not lt 064 mm extending close to the specimen base see Comment 3

bull Commentbull Changes extend close to the base and to a peripheral margin of the

specimenbull It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution Sbull Should be excised locally in order to prevent any possibility of persistence

recurrence or future progression of it bull Based on its microstaging attributes the prognosis for this lesion should

be excellent The prognosis for ldquopurerdquo desmoplastic melanoma is if anything better than that for melanomas of similar thickness

bull This lesion could be managed with a relatively generous wide local excision ndash MPATH DX Category 4 (or 5)

5212018

59

Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

5212018

60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

5212018

40

Significance of Nevi

bull Nevi are important mainly in relation to melanoma

ndash Precursors ndash but risk for individual lesions is low

ndash Risk markers ndash important mainly in high risk situations

ndash Simulants ndash important in everyday clinical decision-making

Conclusions

bull Former mild dysplasia is a benign lentiginous nevus (the commonest type of nevus)

bull Low grade dysplasia (former moderate dysplasia) can be observed clinically or by patients looking for evidence of changing lesions

bull High grade dysplasia is difficult to distinguish from melanoma in situ (UNCERTAINTY) may have competence for local persistence recurrence and progression and should be completely excised

bull All of these are ldquomelanocytic neoplasms of low (or no) malignant potentialrdquo which have little or no competence for metastasis

Lake Wakatipu and Queenstown New Zealand from the Top of ldquoThe Remarkablesrdquo(Mountains of Mordor in the distance)

5212018

41

Session II High CSD Melanomas and Simulants

Lentigo maligna melanoma

Atypical lentiginous neviproliferations

High CSD Lentiginous Nevi and Lentigo Maligna

Melanoma and Simulant(s)

bull Lentiginous Melanoma of Sun-Damaged Skin

ndash LMM in situ

ndash LMM invasive

ndash Distinction from Dysplastic Nevi (Dysplastic Nevus-like MelanomaNevoid Lentigo Maligna

bull Lentiginous Nevi of the ldquoElderlyrdquo (ie CSD Skin)

bull Solar (actinic) lentigo pigmented AK SK hellip

High UV

Pathway II Pathway III

High-CSD Melanoma (LMM)

Desmoplastic Melanoma

IMP IMP

IAMP IAMP

Lentigo maligna melanoma in situ

Melanoma in situ

Lentigo Maligna Melanoma

Desmoplastic Melanoma

NRAS BRAFnon-V600E KIT NF1

NF1 ERBB2 MAP2K1 MAP3K1 BRAF EGFR MET

TERT CDKN2A TP53 PTEN RAC1

TERT NFKBIE NRAS PIK3CA PTPN11

5212018

42

Case 1

12438

F64 Lesion of back

5212018

43

5212018

44

Your Diagnosis

Dysplastic Nevus - IAMP

Melanoma

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe ( gt 15x) mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Our Diagnosis

Case 1 12438

Lentigo maligna melanoma in situ

5212018

45

Case 2

Part 2-2 7419Clinical Information

A large pigmented lesion of the back in a 74-year-old manReason for Consultation

I called this lesion a dysplastic nevus The clinician then calls back to inform us that this is a 22 cm irregular pigmented lesion Now looking at the deepers we think this

might be a ldquolentiginous melanomardquo

Description

bull Shave biopsy of a broad lesion with a dermal component and a moderately cellular junctional component

bull Lesion is ill-defined (poorly circumscribed) at each periphery with features overlapping with those of actinic lentigo

bull Subtle increase of melanocytes along the dermal-epidermal junction with mild to moderate but relatively uniform cytologic atypia

bull Pagetoid scatter is minimal

bull Focally there are elongated rete ridges overlapping with features of dysplastic nevus however these changes are focal within the lesion rather than being symmetrically distributed at shoulders adjacent to a dermal component

Lentiginous nevus versus lentiginous melanoma

bull Poorly circumscribed at each periphery

5212018

46

bull JunctionaIIAMP

bull Patchy lymphocytic infiltrate

bull Solar elastosis

Bridging rete

5212018

47

Your Diagnosis

Melanoma

Nevus

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Lentiginous nevus versus lentiginous melanomaDiagnosis Case 2 M74

Skin mid back Superficial atypical melanocytic proliferation of uncertain significance most consistent with melanoma in situ lentiginous type (nevoid lentigo maligna) versus atypical lentiginous nevus of the elderly see comment

(ie ldquoSAMPUSrdquo)

5212018

48

Diagnosis Case 2 M74

bull Overall Commentbull There are overlapping features among atypical actinic

lentigines lentiginous junctional nevi with and without atypia and lentiginous or ldquonevoidrdquo lentigo maligna

bull Lesions in a high CSD environment must be interpreted with circumspection

bull Overdiagnosis should be avoided as even atypical lentiginous junctional nevi of the elderly seem to be biologically low grade (non-metastasizing but perhaps locally recurring potential)

bull It is judicious to completely excise these lesions in order to be sure that they have been completely examined histologically and also to minimize any possibility of local persistence recurrence or future progression

Nevoid Lentigo MalignaLentiginous Melanoma(Lentiginous Nevus)

bull Kossard 1997 Aust J Dermatol Nevoid lentigo malignaKing Page Googe amp Mihm Modern Pathology 2005 Lentiginous melanomaFerrahi Egbert amp Swetter J Cutan Pathol 2005 Dysplastic nevus-like LMM

bull Clinical diagnosis may varyndash eg lentigo maligna atypical nevus pigmented basal cell carcinoma seborrheic keratosis and

lentigo

bull Biopsies may mimic junctional nevus or dysplastic nevus at least focallyndash Lentiginous proliferation of melanocytes at the dermo-epidermal junction both as single cells

and as small nests with areas of confluent growth extending to the edges of the biopsy ndash Rete ridges maintainedndash Pagetoid spread of melanocytes was not prominent in HampE - stained sections

bull Diagnosis of melanoma more easily recognized in the complete excision specimens similar atypical melanocytic proliferation occurring over a broad area flanking the prior biopsy sites

bull Stains for MITF and Mart-1 highlight continuous basal melanocytic proliferation as well as foci of pagetoid scatter

Lentiginous MelanomaKing Page Googe Mihm Mod Pathol 2005

bull Initial biopsies mimicked lentiginous nevus or dysplastic nevus

bull Lentiginous proliferation of melanocytes at DEJ both as single cells and as small nests with areas of confluent growth extending to the edges of the biopsy

bull Retiform epidermis was maintained and pagetoid spread of melanocytes was not prominent in HampE sections

bull Immunohistochemical stains for MITF and Mart-1 highlighted the extent of the basalar melanocytic proliferation as well as foci of pagetoid spread by melanocytes

bull UNCERTAINTY IS COMMONbull PROGNOSIS IS GOOD IF LESION IS SUPERFICIALbull IMPORTANT TO COMPLETELY EXCISE

bull FOR FULL EXAMINATION AND TO MINIMIZE ANY POTENTIAL FOR LOCAL PERSISTENCE RECURRENCE AND PROGRESSION

Mart 1

MITF

5212018

49

Case 3

Part 2-3 14474

Clinical InformationLeft posterior shoulder F81

Reason for ConsultationFavor a junctional Clarkrsquos nevus (see enclosed report)

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Some bridging few nests that hang down in a droplet-like pattern bull Cytologic atypia mild but relatively uniform

5212018

50

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 3 F81

bull ldquoDifficult to interpretrdquo bull Cytologic atypia is mild to moderate rather than

severe with somewhat concerning architectural changes

bull ldquoOne is somewhat more concerned about a lesion in chronically sun-damaged skin of older subjectsrdquo

bull Skin left posterior shoulder shave biopsy Intraepidermal atypical melanocytic proliferation of uncertain significance (IAMPUS) most consistent with atypical lentiginous junctional nevus (of the elderlyCSD skin) cannot ro evolving or early established melanoma in situ

bull Complete excision recommended (MPATH-Dx 2 or 3)

Case 4

Part 2-3 14474

Clinical InformationLeft posterior shoulder F84

Reason for ConsultationFavor a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus (see

enclosed report) There is mild melanocytic atypia and that the peripheral and deep margins of the specimen were negative in the

plane of sectioning

5212018

51

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 4 F81

bull Recurrence of Case 8

bull Shave biopsy of similar sun-damaged skinbull Somewhat more cellular proliferation of nevoid and

nevoid to epithelioid melanocytes focally exhibiting severe and uniform cytologic atypia

bull Some of these cells are confined to the epidermis above the scar while others appear to extend some distance beyond the periphery of the scar

bull This latter feature raises some concern for evolving melanoma in situ extending beyond the scar

5212018

52

bull Skin left posterior shoulder shave biopsy (recurrence) Intraepidermal atypical melanocytic proliferation of uncertain significance extending to specimen margins see description and comment

ndash Comment Cannot rule out an evolving more significant lesion suggest complete excision

Case 5

Part 2-3 14474

Clinical InformationBiopsy from posterior shoulder of an 85 year old female

Reason for ConsultationThis specimen in my opinion has histologic features concerning for

melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis I do not see

definitive features of a scar consistent with a prior biopsy site

5212018

53

bull Broadbull Moderately

cellularbull Moderate to

severe CSDbull Poorly

circumscribedbull Few bridging

nestsbull Diffuse

fibroplasiabull Cells in dermis

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Nests in dermis

bull No maturation

5212018

54

Melan-A Stain

bull Moderately cellular

bull Continuous basal proliferation

bull Nests hanging down

bull Low level pagetoid scatter

bull Nests in dermis

bull No maturation

Your Diagnosis

Melanoma

Nevus

Our Diagnosis

Malignant melanoma lentigo maligna type (ldquolentiginous melanomardquo Clark level II Breslow thickness 085 mm

5212018

55

Updated History Cases 3-5

bull Clinical Information

bull Three separate biopsies from left posterior shoulder of an 85-year-old female over a period of three years The biopsies were performed 4 years and 1 year ago and recently

bull The original biopsy was called a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus might have been better interpreted as a lentiginous nevus of the elderlysundamaged skin with mild to moderate atypia ndash The peripheral and deep margins of the specimen were said to be negative in the plane

of sectioning

bull The next biopsy at presumably the same anatomic location was signed out as an atypical melanocytic proliferation consistent with a persistentrecurrent Clarkrsquos (dysplastic) nevus involving the peripheral edge of the biopsy ndash It was mentioned that the differential diagnosis included early melanoma in situ

evolving within a pre-existing nevus and a reexcision was recommended

bull The most recent specimen was concerning for melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis

bull Additional procedure warranted to ensure that the lesion has been completely removed`

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Cytologic atypia mild but relatively uniform bull POTENTIAL PRECURSOR (low risk) VS ACTUAL PRECURSOR (hindsight bias)bull Manage by excision or follow-up

bull Case 5

bull Second recurrence of a lesion that originally had only ldquomildrdquo atypia (but moderate to severe architectural disorder)

bull Diagnosis of dysplastic nevus should be made with caution in elderlyCSD skin

bull Complete excision is appropriate for ldquoatypical lentiginous nevus of elderlysundamaged skinrdquo

5212018

56

Last Case

Part 2-7 12150

Clinical InformationLesion of right shoulder ro melanoma versus nevus in a 76 yo man

Reason for ConsultationIs this anything other than a moderately atypical neurotized compound nevus

bull A relatively broad lesion with irregular thickening and thinning of rete ridges and a sparsely cellular infiltrate in the dermis

bull Generally sparsely cellularbull Moderate to severe CSD

Poorly circumscribed

5212018

57

bull Pigmented melanophages in the dermis

bull Increased number of melanocytes in the epidermis many of them suprabasal

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

5212018

58

S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

bull Melan-A stain highlights the junctional component but the dermal spindle cells are negative

Case 6

bull Skin right superior shoulder Malignant melanoma lentigo maligna type nonulcerated with pure desmoplastic vertical growth phase Clark level IV Breslow thickness not lt 064 mm extending close to the specimen base see Comment 3

bull Commentbull Changes extend close to the base and to a peripheral margin of the

specimenbull It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution Sbull Should be excised locally in order to prevent any possibility of persistence

recurrence or future progression of it bull Based on its microstaging attributes the prognosis for this lesion should

be excellent The prognosis for ldquopurerdquo desmoplastic melanoma is if anything better than that for melanomas of similar thickness

bull This lesion could be managed with a relatively generous wide local excision ndash MPATH DX Category 4 (or 5)

5212018

59

Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

5212018

60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

5212018

41

Session II High CSD Melanomas and Simulants

Lentigo maligna melanoma

Atypical lentiginous neviproliferations

High CSD Lentiginous Nevi and Lentigo Maligna

Melanoma and Simulant(s)

bull Lentiginous Melanoma of Sun-Damaged Skin

ndash LMM in situ

ndash LMM invasive

ndash Distinction from Dysplastic Nevi (Dysplastic Nevus-like MelanomaNevoid Lentigo Maligna

bull Lentiginous Nevi of the ldquoElderlyrdquo (ie CSD Skin)

bull Solar (actinic) lentigo pigmented AK SK hellip

High UV

Pathway II Pathway III

High-CSD Melanoma (LMM)

Desmoplastic Melanoma

IMP IMP

IAMP IAMP

Lentigo maligna melanoma in situ

Melanoma in situ

Lentigo Maligna Melanoma

Desmoplastic Melanoma

NRAS BRAFnon-V600E KIT NF1

NF1 ERBB2 MAP2K1 MAP3K1 BRAF EGFR MET

TERT CDKN2A TP53 PTEN RAC1

TERT NFKBIE NRAS PIK3CA PTPN11

5212018

42

Case 1

12438

F64 Lesion of back

5212018

43

5212018

44

Your Diagnosis

Dysplastic Nevus - IAMP

Melanoma

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe ( gt 15x) mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Our Diagnosis

Case 1 12438

Lentigo maligna melanoma in situ

5212018

45

Case 2

Part 2-2 7419Clinical Information

A large pigmented lesion of the back in a 74-year-old manReason for Consultation

I called this lesion a dysplastic nevus The clinician then calls back to inform us that this is a 22 cm irregular pigmented lesion Now looking at the deepers we think this

might be a ldquolentiginous melanomardquo

Description

bull Shave biopsy of a broad lesion with a dermal component and a moderately cellular junctional component

bull Lesion is ill-defined (poorly circumscribed) at each periphery with features overlapping with those of actinic lentigo

bull Subtle increase of melanocytes along the dermal-epidermal junction with mild to moderate but relatively uniform cytologic atypia

bull Pagetoid scatter is minimal

bull Focally there are elongated rete ridges overlapping with features of dysplastic nevus however these changes are focal within the lesion rather than being symmetrically distributed at shoulders adjacent to a dermal component

Lentiginous nevus versus lentiginous melanoma

bull Poorly circumscribed at each periphery

5212018

46

bull JunctionaIIAMP

bull Patchy lymphocytic infiltrate

bull Solar elastosis

Bridging rete

5212018

47

Your Diagnosis

Melanoma

Nevus

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Lentiginous nevus versus lentiginous melanomaDiagnosis Case 2 M74

Skin mid back Superficial atypical melanocytic proliferation of uncertain significance most consistent with melanoma in situ lentiginous type (nevoid lentigo maligna) versus atypical lentiginous nevus of the elderly see comment

(ie ldquoSAMPUSrdquo)

5212018

48

Diagnosis Case 2 M74

bull Overall Commentbull There are overlapping features among atypical actinic

lentigines lentiginous junctional nevi with and without atypia and lentiginous or ldquonevoidrdquo lentigo maligna

bull Lesions in a high CSD environment must be interpreted with circumspection

bull Overdiagnosis should be avoided as even atypical lentiginous junctional nevi of the elderly seem to be biologically low grade (non-metastasizing but perhaps locally recurring potential)

bull It is judicious to completely excise these lesions in order to be sure that they have been completely examined histologically and also to minimize any possibility of local persistence recurrence or future progression

Nevoid Lentigo MalignaLentiginous Melanoma(Lentiginous Nevus)

bull Kossard 1997 Aust J Dermatol Nevoid lentigo malignaKing Page Googe amp Mihm Modern Pathology 2005 Lentiginous melanomaFerrahi Egbert amp Swetter J Cutan Pathol 2005 Dysplastic nevus-like LMM

bull Clinical diagnosis may varyndash eg lentigo maligna atypical nevus pigmented basal cell carcinoma seborrheic keratosis and

lentigo

bull Biopsies may mimic junctional nevus or dysplastic nevus at least focallyndash Lentiginous proliferation of melanocytes at the dermo-epidermal junction both as single cells

and as small nests with areas of confluent growth extending to the edges of the biopsy ndash Rete ridges maintainedndash Pagetoid spread of melanocytes was not prominent in HampE - stained sections

bull Diagnosis of melanoma more easily recognized in the complete excision specimens similar atypical melanocytic proliferation occurring over a broad area flanking the prior biopsy sites

bull Stains for MITF and Mart-1 highlight continuous basal melanocytic proliferation as well as foci of pagetoid scatter

Lentiginous MelanomaKing Page Googe Mihm Mod Pathol 2005

bull Initial biopsies mimicked lentiginous nevus or dysplastic nevus

bull Lentiginous proliferation of melanocytes at DEJ both as single cells and as small nests with areas of confluent growth extending to the edges of the biopsy

bull Retiform epidermis was maintained and pagetoid spread of melanocytes was not prominent in HampE sections

bull Immunohistochemical stains for MITF and Mart-1 highlighted the extent of the basalar melanocytic proliferation as well as foci of pagetoid spread by melanocytes

bull UNCERTAINTY IS COMMONbull PROGNOSIS IS GOOD IF LESION IS SUPERFICIALbull IMPORTANT TO COMPLETELY EXCISE

bull FOR FULL EXAMINATION AND TO MINIMIZE ANY POTENTIAL FOR LOCAL PERSISTENCE RECURRENCE AND PROGRESSION

Mart 1

MITF

5212018

49

Case 3

Part 2-3 14474

Clinical InformationLeft posterior shoulder F81

Reason for ConsultationFavor a junctional Clarkrsquos nevus (see enclosed report)

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Some bridging few nests that hang down in a droplet-like pattern bull Cytologic atypia mild but relatively uniform

5212018

50

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 3 F81

bull ldquoDifficult to interpretrdquo bull Cytologic atypia is mild to moderate rather than

severe with somewhat concerning architectural changes

bull ldquoOne is somewhat more concerned about a lesion in chronically sun-damaged skin of older subjectsrdquo

bull Skin left posterior shoulder shave biopsy Intraepidermal atypical melanocytic proliferation of uncertain significance (IAMPUS) most consistent with atypical lentiginous junctional nevus (of the elderlyCSD skin) cannot ro evolving or early established melanoma in situ

bull Complete excision recommended (MPATH-Dx 2 or 3)

Case 4

Part 2-3 14474

Clinical InformationLeft posterior shoulder F84

Reason for ConsultationFavor a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus (see

enclosed report) There is mild melanocytic atypia and that the peripheral and deep margins of the specimen were negative in the

plane of sectioning

5212018

51

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 4 F81

bull Recurrence of Case 8

bull Shave biopsy of similar sun-damaged skinbull Somewhat more cellular proliferation of nevoid and

nevoid to epithelioid melanocytes focally exhibiting severe and uniform cytologic atypia

bull Some of these cells are confined to the epidermis above the scar while others appear to extend some distance beyond the periphery of the scar

bull This latter feature raises some concern for evolving melanoma in situ extending beyond the scar

5212018

52

bull Skin left posterior shoulder shave biopsy (recurrence) Intraepidermal atypical melanocytic proliferation of uncertain significance extending to specimen margins see description and comment

ndash Comment Cannot rule out an evolving more significant lesion suggest complete excision

Case 5

Part 2-3 14474

Clinical InformationBiopsy from posterior shoulder of an 85 year old female

Reason for ConsultationThis specimen in my opinion has histologic features concerning for

melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis I do not see

definitive features of a scar consistent with a prior biopsy site

5212018

53

bull Broadbull Moderately

cellularbull Moderate to

severe CSDbull Poorly

circumscribedbull Few bridging

nestsbull Diffuse

fibroplasiabull Cells in dermis

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Nests in dermis

bull No maturation

5212018

54

Melan-A Stain

bull Moderately cellular

bull Continuous basal proliferation

bull Nests hanging down

bull Low level pagetoid scatter

bull Nests in dermis

bull No maturation

Your Diagnosis

Melanoma

Nevus

Our Diagnosis

Malignant melanoma lentigo maligna type (ldquolentiginous melanomardquo Clark level II Breslow thickness 085 mm

5212018

55

Updated History Cases 3-5

bull Clinical Information

bull Three separate biopsies from left posterior shoulder of an 85-year-old female over a period of three years The biopsies were performed 4 years and 1 year ago and recently

bull The original biopsy was called a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus might have been better interpreted as a lentiginous nevus of the elderlysundamaged skin with mild to moderate atypia ndash The peripheral and deep margins of the specimen were said to be negative in the plane

of sectioning

bull The next biopsy at presumably the same anatomic location was signed out as an atypical melanocytic proliferation consistent with a persistentrecurrent Clarkrsquos (dysplastic) nevus involving the peripheral edge of the biopsy ndash It was mentioned that the differential diagnosis included early melanoma in situ

evolving within a pre-existing nevus and a reexcision was recommended

bull The most recent specimen was concerning for melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis

bull Additional procedure warranted to ensure that the lesion has been completely removed`

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Cytologic atypia mild but relatively uniform bull POTENTIAL PRECURSOR (low risk) VS ACTUAL PRECURSOR (hindsight bias)bull Manage by excision or follow-up

bull Case 5

bull Second recurrence of a lesion that originally had only ldquomildrdquo atypia (but moderate to severe architectural disorder)

bull Diagnosis of dysplastic nevus should be made with caution in elderlyCSD skin

bull Complete excision is appropriate for ldquoatypical lentiginous nevus of elderlysundamaged skinrdquo

5212018

56

Last Case

Part 2-7 12150

Clinical InformationLesion of right shoulder ro melanoma versus nevus in a 76 yo man

Reason for ConsultationIs this anything other than a moderately atypical neurotized compound nevus

bull A relatively broad lesion with irregular thickening and thinning of rete ridges and a sparsely cellular infiltrate in the dermis

bull Generally sparsely cellularbull Moderate to severe CSD

Poorly circumscribed

5212018

57

bull Pigmented melanophages in the dermis

bull Increased number of melanocytes in the epidermis many of them suprabasal

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

5212018

58

S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

bull Melan-A stain highlights the junctional component but the dermal spindle cells are negative

Case 6

bull Skin right superior shoulder Malignant melanoma lentigo maligna type nonulcerated with pure desmoplastic vertical growth phase Clark level IV Breslow thickness not lt 064 mm extending close to the specimen base see Comment 3

bull Commentbull Changes extend close to the base and to a peripheral margin of the

specimenbull It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution Sbull Should be excised locally in order to prevent any possibility of persistence

recurrence or future progression of it bull Based on its microstaging attributes the prognosis for this lesion should

be excellent The prognosis for ldquopurerdquo desmoplastic melanoma is if anything better than that for melanomas of similar thickness

bull This lesion could be managed with a relatively generous wide local excision ndash MPATH DX Category 4 (or 5)

5212018

59

Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

5212018

60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

5212018

42

Case 1

12438

F64 Lesion of back

5212018

43

5212018

44

Your Diagnosis

Dysplastic Nevus - IAMP

Melanoma

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe ( gt 15x) mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Our Diagnosis

Case 1 12438

Lentigo maligna melanoma in situ

5212018

45

Case 2

Part 2-2 7419Clinical Information

A large pigmented lesion of the back in a 74-year-old manReason for Consultation

I called this lesion a dysplastic nevus The clinician then calls back to inform us that this is a 22 cm irregular pigmented lesion Now looking at the deepers we think this

might be a ldquolentiginous melanomardquo

Description

bull Shave biopsy of a broad lesion with a dermal component and a moderately cellular junctional component

bull Lesion is ill-defined (poorly circumscribed) at each periphery with features overlapping with those of actinic lentigo

bull Subtle increase of melanocytes along the dermal-epidermal junction with mild to moderate but relatively uniform cytologic atypia

bull Pagetoid scatter is minimal

bull Focally there are elongated rete ridges overlapping with features of dysplastic nevus however these changes are focal within the lesion rather than being symmetrically distributed at shoulders adjacent to a dermal component

Lentiginous nevus versus lentiginous melanoma

bull Poorly circumscribed at each periphery

5212018

46

bull JunctionaIIAMP

bull Patchy lymphocytic infiltrate

bull Solar elastosis

Bridging rete

5212018

47

Your Diagnosis

Melanoma

Nevus

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Lentiginous nevus versus lentiginous melanomaDiagnosis Case 2 M74

Skin mid back Superficial atypical melanocytic proliferation of uncertain significance most consistent with melanoma in situ lentiginous type (nevoid lentigo maligna) versus atypical lentiginous nevus of the elderly see comment

(ie ldquoSAMPUSrdquo)

5212018

48

Diagnosis Case 2 M74

bull Overall Commentbull There are overlapping features among atypical actinic

lentigines lentiginous junctional nevi with and without atypia and lentiginous or ldquonevoidrdquo lentigo maligna

bull Lesions in a high CSD environment must be interpreted with circumspection

bull Overdiagnosis should be avoided as even atypical lentiginous junctional nevi of the elderly seem to be biologically low grade (non-metastasizing but perhaps locally recurring potential)

bull It is judicious to completely excise these lesions in order to be sure that they have been completely examined histologically and also to minimize any possibility of local persistence recurrence or future progression

Nevoid Lentigo MalignaLentiginous Melanoma(Lentiginous Nevus)

bull Kossard 1997 Aust J Dermatol Nevoid lentigo malignaKing Page Googe amp Mihm Modern Pathology 2005 Lentiginous melanomaFerrahi Egbert amp Swetter J Cutan Pathol 2005 Dysplastic nevus-like LMM

bull Clinical diagnosis may varyndash eg lentigo maligna atypical nevus pigmented basal cell carcinoma seborrheic keratosis and

lentigo

bull Biopsies may mimic junctional nevus or dysplastic nevus at least focallyndash Lentiginous proliferation of melanocytes at the dermo-epidermal junction both as single cells

and as small nests with areas of confluent growth extending to the edges of the biopsy ndash Rete ridges maintainedndash Pagetoid spread of melanocytes was not prominent in HampE - stained sections

bull Diagnosis of melanoma more easily recognized in the complete excision specimens similar atypical melanocytic proliferation occurring over a broad area flanking the prior biopsy sites

bull Stains for MITF and Mart-1 highlight continuous basal melanocytic proliferation as well as foci of pagetoid scatter

Lentiginous MelanomaKing Page Googe Mihm Mod Pathol 2005

bull Initial biopsies mimicked lentiginous nevus or dysplastic nevus

bull Lentiginous proliferation of melanocytes at DEJ both as single cells and as small nests with areas of confluent growth extending to the edges of the biopsy

bull Retiform epidermis was maintained and pagetoid spread of melanocytes was not prominent in HampE sections

bull Immunohistochemical stains for MITF and Mart-1 highlighted the extent of the basalar melanocytic proliferation as well as foci of pagetoid spread by melanocytes

bull UNCERTAINTY IS COMMONbull PROGNOSIS IS GOOD IF LESION IS SUPERFICIALbull IMPORTANT TO COMPLETELY EXCISE

bull FOR FULL EXAMINATION AND TO MINIMIZE ANY POTENTIAL FOR LOCAL PERSISTENCE RECURRENCE AND PROGRESSION

Mart 1

MITF

5212018

49

Case 3

Part 2-3 14474

Clinical InformationLeft posterior shoulder F81

Reason for ConsultationFavor a junctional Clarkrsquos nevus (see enclosed report)

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Some bridging few nests that hang down in a droplet-like pattern bull Cytologic atypia mild but relatively uniform

5212018

50

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 3 F81

bull ldquoDifficult to interpretrdquo bull Cytologic atypia is mild to moderate rather than

severe with somewhat concerning architectural changes

bull ldquoOne is somewhat more concerned about a lesion in chronically sun-damaged skin of older subjectsrdquo

bull Skin left posterior shoulder shave biopsy Intraepidermal atypical melanocytic proliferation of uncertain significance (IAMPUS) most consistent with atypical lentiginous junctional nevus (of the elderlyCSD skin) cannot ro evolving or early established melanoma in situ

bull Complete excision recommended (MPATH-Dx 2 or 3)

Case 4

Part 2-3 14474

Clinical InformationLeft posterior shoulder F84

Reason for ConsultationFavor a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus (see

enclosed report) There is mild melanocytic atypia and that the peripheral and deep margins of the specimen were negative in the

plane of sectioning

5212018

51

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 4 F81

bull Recurrence of Case 8

bull Shave biopsy of similar sun-damaged skinbull Somewhat more cellular proliferation of nevoid and

nevoid to epithelioid melanocytes focally exhibiting severe and uniform cytologic atypia

bull Some of these cells are confined to the epidermis above the scar while others appear to extend some distance beyond the periphery of the scar

bull This latter feature raises some concern for evolving melanoma in situ extending beyond the scar

5212018

52

bull Skin left posterior shoulder shave biopsy (recurrence) Intraepidermal atypical melanocytic proliferation of uncertain significance extending to specimen margins see description and comment

ndash Comment Cannot rule out an evolving more significant lesion suggest complete excision

Case 5

Part 2-3 14474

Clinical InformationBiopsy from posterior shoulder of an 85 year old female

Reason for ConsultationThis specimen in my opinion has histologic features concerning for

melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis I do not see

definitive features of a scar consistent with a prior biopsy site

5212018

53

bull Broadbull Moderately

cellularbull Moderate to

severe CSDbull Poorly

circumscribedbull Few bridging

nestsbull Diffuse

fibroplasiabull Cells in dermis

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Nests in dermis

bull No maturation

5212018

54

Melan-A Stain

bull Moderately cellular

bull Continuous basal proliferation

bull Nests hanging down

bull Low level pagetoid scatter

bull Nests in dermis

bull No maturation

Your Diagnosis

Melanoma

Nevus

Our Diagnosis

Malignant melanoma lentigo maligna type (ldquolentiginous melanomardquo Clark level II Breslow thickness 085 mm

5212018

55

Updated History Cases 3-5

bull Clinical Information

bull Three separate biopsies from left posterior shoulder of an 85-year-old female over a period of three years The biopsies were performed 4 years and 1 year ago and recently

bull The original biopsy was called a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus might have been better interpreted as a lentiginous nevus of the elderlysundamaged skin with mild to moderate atypia ndash The peripheral and deep margins of the specimen were said to be negative in the plane

of sectioning

bull The next biopsy at presumably the same anatomic location was signed out as an atypical melanocytic proliferation consistent with a persistentrecurrent Clarkrsquos (dysplastic) nevus involving the peripheral edge of the biopsy ndash It was mentioned that the differential diagnosis included early melanoma in situ

evolving within a pre-existing nevus and a reexcision was recommended

bull The most recent specimen was concerning for melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis

bull Additional procedure warranted to ensure that the lesion has been completely removed`

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Cytologic atypia mild but relatively uniform bull POTENTIAL PRECURSOR (low risk) VS ACTUAL PRECURSOR (hindsight bias)bull Manage by excision or follow-up

bull Case 5

bull Second recurrence of a lesion that originally had only ldquomildrdquo atypia (but moderate to severe architectural disorder)

bull Diagnosis of dysplastic nevus should be made with caution in elderlyCSD skin

bull Complete excision is appropriate for ldquoatypical lentiginous nevus of elderlysundamaged skinrdquo

5212018

56

Last Case

Part 2-7 12150

Clinical InformationLesion of right shoulder ro melanoma versus nevus in a 76 yo man

Reason for ConsultationIs this anything other than a moderately atypical neurotized compound nevus

bull A relatively broad lesion with irregular thickening and thinning of rete ridges and a sparsely cellular infiltrate in the dermis

bull Generally sparsely cellularbull Moderate to severe CSD

Poorly circumscribed

5212018

57

bull Pigmented melanophages in the dermis

bull Increased number of melanocytes in the epidermis many of them suprabasal

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

5212018

58

S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

bull Melan-A stain highlights the junctional component but the dermal spindle cells are negative

Case 6

bull Skin right superior shoulder Malignant melanoma lentigo maligna type nonulcerated with pure desmoplastic vertical growth phase Clark level IV Breslow thickness not lt 064 mm extending close to the specimen base see Comment 3

bull Commentbull Changes extend close to the base and to a peripheral margin of the

specimenbull It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution Sbull Should be excised locally in order to prevent any possibility of persistence

recurrence or future progression of it bull Based on its microstaging attributes the prognosis for this lesion should

be excellent The prognosis for ldquopurerdquo desmoplastic melanoma is if anything better than that for melanomas of similar thickness

bull This lesion could be managed with a relatively generous wide local excision ndash MPATH DX Category 4 (or 5)

5212018

59

Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

5212018

60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

5212018

43

5212018

44

Your Diagnosis

Dysplastic Nevus - IAMP

Melanoma

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe ( gt 15x) mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Our Diagnosis

Case 1 12438

Lentigo maligna melanoma in situ

5212018

45

Case 2

Part 2-2 7419Clinical Information

A large pigmented lesion of the back in a 74-year-old manReason for Consultation

I called this lesion a dysplastic nevus The clinician then calls back to inform us that this is a 22 cm irregular pigmented lesion Now looking at the deepers we think this

might be a ldquolentiginous melanomardquo

Description

bull Shave biopsy of a broad lesion with a dermal component and a moderately cellular junctional component

bull Lesion is ill-defined (poorly circumscribed) at each periphery with features overlapping with those of actinic lentigo

bull Subtle increase of melanocytes along the dermal-epidermal junction with mild to moderate but relatively uniform cytologic atypia

bull Pagetoid scatter is minimal

bull Focally there are elongated rete ridges overlapping with features of dysplastic nevus however these changes are focal within the lesion rather than being symmetrically distributed at shoulders adjacent to a dermal component

Lentiginous nevus versus lentiginous melanoma

bull Poorly circumscribed at each periphery

5212018

46

bull JunctionaIIAMP

bull Patchy lymphocytic infiltrate

bull Solar elastosis

Bridging rete

5212018

47

Your Diagnosis

Melanoma

Nevus

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Lentiginous nevus versus lentiginous melanomaDiagnosis Case 2 M74

Skin mid back Superficial atypical melanocytic proliferation of uncertain significance most consistent with melanoma in situ lentiginous type (nevoid lentigo maligna) versus atypical lentiginous nevus of the elderly see comment

(ie ldquoSAMPUSrdquo)

5212018

48

Diagnosis Case 2 M74

bull Overall Commentbull There are overlapping features among atypical actinic

lentigines lentiginous junctional nevi with and without atypia and lentiginous or ldquonevoidrdquo lentigo maligna

bull Lesions in a high CSD environment must be interpreted with circumspection

bull Overdiagnosis should be avoided as even atypical lentiginous junctional nevi of the elderly seem to be biologically low grade (non-metastasizing but perhaps locally recurring potential)

bull It is judicious to completely excise these lesions in order to be sure that they have been completely examined histologically and also to minimize any possibility of local persistence recurrence or future progression

Nevoid Lentigo MalignaLentiginous Melanoma(Lentiginous Nevus)

bull Kossard 1997 Aust J Dermatol Nevoid lentigo malignaKing Page Googe amp Mihm Modern Pathology 2005 Lentiginous melanomaFerrahi Egbert amp Swetter J Cutan Pathol 2005 Dysplastic nevus-like LMM

bull Clinical diagnosis may varyndash eg lentigo maligna atypical nevus pigmented basal cell carcinoma seborrheic keratosis and

lentigo

bull Biopsies may mimic junctional nevus or dysplastic nevus at least focallyndash Lentiginous proliferation of melanocytes at the dermo-epidermal junction both as single cells

and as small nests with areas of confluent growth extending to the edges of the biopsy ndash Rete ridges maintainedndash Pagetoid spread of melanocytes was not prominent in HampE - stained sections

bull Diagnosis of melanoma more easily recognized in the complete excision specimens similar atypical melanocytic proliferation occurring over a broad area flanking the prior biopsy sites

bull Stains for MITF and Mart-1 highlight continuous basal melanocytic proliferation as well as foci of pagetoid scatter

Lentiginous MelanomaKing Page Googe Mihm Mod Pathol 2005

bull Initial biopsies mimicked lentiginous nevus or dysplastic nevus

bull Lentiginous proliferation of melanocytes at DEJ both as single cells and as small nests with areas of confluent growth extending to the edges of the biopsy

bull Retiform epidermis was maintained and pagetoid spread of melanocytes was not prominent in HampE sections

bull Immunohistochemical stains for MITF and Mart-1 highlighted the extent of the basalar melanocytic proliferation as well as foci of pagetoid spread by melanocytes

bull UNCERTAINTY IS COMMONbull PROGNOSIS IS GOOD IF LESION IS SUPERFICIALbull IMPORTANT TO COMPLETELY EXCISE

bull FOR FULL EXAMINATION AND TO MINIMIZE ANY POTENTIAL FOR LOCAL PERSISTENCE RECURRENCE AND PROGRESSION

Mart 1

MITF

5212018

49

Case 3

Part 2-3 14474

Clinical InformationLeft posterior shoulder F81

Reason for ConsultationFavor a junctional Clarkrsquos nevus (see enclosed report)

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Some bridging few nests that hang down in a droplet-like pattern bull Cytologic atypia mild but relatively uniform

5212018

50

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 3 F81

bull ldquoDifficult to interpretrdquo bull Cytologic atypia is mild to moderate rather than

severe with somewhat concerning architectural changes

bull ldquoOne is somewhat more concerned about a lesion in chronically sun-damaged skin of older subjectsrdquo

bull Skin left posterior shoulder shave biopsy Intraepidermal atypical melanocytic proliferation of uncertain significance (IAMPUS) most consistent with atypical lentiginous junctional nevus (of the elderlyCSD skin) cannot ro evolving or early established melanoma in situ

bull Complete excision recommended (MPATH-Dx 2 or 3)

Case 4

Part 2-3 14474

Clinical InformationLeft posterior shoulder F84

Reason for ConsultationFavor a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus (see

enclosed report) There is mild melanocytic atypia and that the peripheral and deep margins of the specimen were negative in the

plane of sectioning

5212018

51

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 4 F81

bull Recurrence of Case 8

bull Shave biopsy of similar sun-damaged skinbull Somewhat more cellular proliferation of nevoid and

nevoid to epithelioid melanocytes focally exhibiting severe and uniform cytologic atypia

bull Some of these cells are confined to the epidermis above the scar while others appear to extend some distance beyond the periphery of the scar

bull This latter feature raises some concern for evolving melanoma in situ extending beyond the scar

5212018

52

bull Skin left posterior shoulder shave biopsy (recurrence) Intraepidermal atypical melanocytic proliferation of uncertain significance extending to specimen margins see description and comment

ndash Comment Cannot rule out an evolving more significant lesion suggest complete excision

Case 5

Part 2-3 14474

Clinical InformationBiopsy from posterior shoulder of an 85 year old female

Reason for ConsultationThis specimen in my opinion has histologic features concerning for

melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis I do not see

definitive features of a scar consistent with a prior biopsy site

5212018

53

bull Broadbull Moderately

cellularbull Moderate to

severe CSDbull Poorly

circumscribedbull Few bridging

nestsbull Diffuse

fibroplasiabull Cells in dermis

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Nests in dermis

bull No maturation

5212018

54

Melan-A Stain

bull Moderately cellular

bull Continuous basal proliferation

bull Nests hanging down

bull Low level pagetoid scatter

bull Nests in dermis

bull No maturation

Your Diagnosis

Melanoma

Nevus

Our Diagnosis

Malignant melanoma lentigo maligna type (ldquolentiginous melanomardquo Clark level II Breslow thickness 085 mm

5212018

55

Updated History Cases 3-5

bull Clinical Information

bull Three separate biopsies from left posterior shoulder of an 85-year-old female over a period of three years The biopsies were performed 4 years and 1 year ago and recently

bull The original biopsy was called a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus might have been better interpreted as a lentiginous nevus of the elderlysundamaged skin with mild to moderate atypia ndash The peripheral and deep margins of the specimen were said to be negative in the plane

of sectioning

bull The next biopsy at presumably the same anatomic location was signed out as an atypical melanocytic proliferation consistent with a persistentrecurrent Clarkrsquos (dysplastic) nevus involving the peripheral edge of the biopsy ndash It was mentioned that the differential diagnosis included early melanoma in situ

evolving within a pre-existing nevus and a reexcision was recommended

bull The most recent specimen was concerning for melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis

bull Additional procedure warranted to ensure that the lesion has been completely removed`

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Cytologic atypia mild but relatively uniform bull POTENTIAL PRECURSOR (low risk) VS ACTUAL PRECURSOR (hindsight bias)bull Manage by excision or follow-up

bull Case 5

bull Second recurrence of a lesion that originally had only ldquomildrdquo atypia (but moderate to severe architectural disorder)

bull Diagnosis of dysplastic nevus should be made with caution in elderlyCSD skin

bull Complete excision is appropriate for ldquoatypical lentiginous nevus of elderlysundamaged skinrdquo

5212018

56

Last Case

Part 2-7 12150

Clinical InformationLesion of right shoulder ro melanoma versus nevus in a 76 yo man

Reason for ConsultationIs this anything other than a moderately atypical neurotized compound nevus

bull A relatively broad lesion with irregular thickening and thinning of rete ridges and a sparsely cellular infiltrate in the dermis

bull Generally sparsely cellularbull Moderate to severe CSD

Poorly circumscribed

5212018

57

bull Pigmented melanophages in the dermis

bull Increased number of melanocytes in the epidermis many of them suprabasal

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

5212018

58

S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

bull Melan-A stain highlights the junctional component but the dermal spindle cells are negative

Case 6

bull Skin right superior shoulder Malignant melanoma lentigo maligna type nonulcerated with pure desmoplastic vertical growth phase Clark level IV Breslow thickness not lt 064 mm extending close to the specimen base see Comment 3

bull Commentbull Changes extend close to the base and to a peripheral margin of the

specimenbull It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution Sbull Should be excised locally in order to prevent any possibility of persistence

recurrence or future progression of it bull Based on its microstaging attributes the prognosis for this lesion should

be excellent The prognosis for ldquopurerdquo desmoplastic melanoma is if anything better than that for melanomas of similar thickness

bull This lesion could be managed with a relatively generous wide local excision ndash MPATH DX Category 4 (or 5)

5212018

59

Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

5212018

60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

5212018

44

Your Diagnosis

Dysplastic Nevus - IAMP

Melanoma

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

severe ( gt 15x) mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Our Diagnosis

Case 1 12438

Lentigo maligna melanoma in situ

5212018

45

Case 2

Part 2-2 7419Clinical Information

A large pigmented lesion of the back in a 74-year-old manReason for Consultation

I called this lesion a dysplastic nevus The clinician then calls back to inform us that this is a 22 cm irregular pigmented lesion Now looking at the deepers we think this

might be a ldquolentiginous melanomardquo

Description

bull Shave biopsy of a broad lesion with a dermal component and a moderately cellular junctional component

bull Lesion is ill-defined (poorly circumscribed) at each periphery with features overlapping with those of actinic lentigo

bull Subtle increase of melanocytes along the dermal-epidermal junction with mild to moderate but relatively uniform cytologic atypia

bull Pagetoid scatter is minimal

bull Focally there are elongated rete ridges overlapping with features of dysplastic nevus however these changes are focal within the lesion rather than being symmetrically distributed at shoulders adjacent to a dermal component

Lentiginous nevus versus lentiginous melanoma

bull Poorly circumscribed at each periphery

5212018

46

bull JunctionaIIAMP

bull Patchy lymphocytic infiltrate

bull Solar elastosis

Bridging rete

5212018

47

Your Diagnosis

Melanoma

Nevus

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Lentiginous nevus versus lentiginous melanomaDiagnosis Case 2 M74

Skin mid back Superficial atypical melanocytic proliferation of uncertain significance most consistent with melanoma in situ lentiginous type (nevoid lentigo maligna) versus atypical lentiginous nevus of the elderly see comment

(ie ldquoSAMPUSrdquo)

5212018

48

Diagnosis Case 2 M74

bull Overall Commentbull There are overlapping features among atypical actinic

lentigines lentiginous junctional nevi with and without atypia and lentiginous or ldquonevoidrdquo lentigo maligna

bull Lesions in a high CSD environment must be interpreted with circumspection

bull Overdiagnosis should be avoided as even atypical lentiginous junctional nevi of the elderly seem to be biologically low grade (non-metastasizing but perhaps locally recurring potential)

bull It is judicious to completely excise these lesions in order to be sure that they have been completely examined histologically and also to minimize any possibility of local persistence recurrence or future progression

Nevoid Lentigo MalignaLentiginous Melanoma(Lentiginous Nevus)

bull Kossard 1997 Aust J Dermatol Nevoid lentigo malignaKing Page Googe amp Mihm Modern Pathology 2005 Lentiginous melanomaFerrahi Egbert amp Swetter J Cutan Pathol 2005 Dysplastic nevus-like LMM

bull Clinical diagnosis may varyndash eg lentigo maligna atypical nevus pigmented basal cell carcinoma seborrheic keratosis and

lentigo

bull Biopsies may mimic junctional nevus or dysplastic nevus at least focallyndash Lentiginous proliferation of melanocytes at the dermo-epidermal junction both as single cells

and as small nests with areas of confluent growth extending to the edges of the biopsy ndash Rete ridges maintainedndash Pagetoid spread of melanocytes was not prominent in HampE - stained sections

bull Diagnosis of melanoma more easily recognized in the complete excision specimens similar atypical melanocytic proliferation occurring over a broad area flanking the prior biopsy sites

bull Stains for MITF and Mart-1 highlight continuous basal melanocytic proliferation as well as foci of pagetoid scatter

Lentiginous MelanomaKing Page Googe Mihm Mod Pathol 2005

bull Initial biopsies mimicked lentiginous nevus or dysplastic nevus

bull Lentiginous proliferation of melanocytes at DEJ both as single cells and as small nests with areas of confluent growth extending to the edges of the biopsy

bull Retiform epidermis was maintained and pagetoid spread of melanocytes was not prominent in HampE sections

bull Immunohistochemical stains for MITF and Mart-1 highlighted the extent of the basalar melanocytic proliferation as well as foci of pagetoid spread by melanocytes

bull UNCERTAINTY IS COMMONbull PROGNOSIS IS GOOD IF LESION IS SUPERFICIALbull IMPORTANT TO COMPLETELY EXCISE

bull FOR FULL EXAMINATION AND TO MINIMIZE ANY POTENTIAL FOR LOCAL PERSISTENCE RECURRENCE AND PROGRESSION

Mart 1

MITF

5212018

49

Case 3

Part 2-3 14474

Clinical InformationLeft posterior shoulder F81

Reason for ConsultationFavor a junctional Clarkrsquos nevus (see enclosed report)

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Some bridging few nests that hang down in a droplet-like pattern bull Cytologic atypia mild but relatively uniform

5212018

50

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 3 F81

bull ldquoDifficult to interpretrdquo bull Cytologic atypia is mild to moderate rather than

severe with somewhat concerning architectural changes

bull ldquoOne is somewhat more concerned about a lesion in chronically sun-damaged skin of older subjectsrdquo

bull Skin left posterior shoulder shave biopsy Intraepidermal atypical melanocytic proliferation of uncertain significance (IAMPUS) most consistent with atypical lentiginous junctional nevus (of the elderlyCSD skin) cannot ro evolving or early established melanoma in situ

bull Complete excision recommended (MPATH-Dx 2 or 3)

Case 4

Part 2-3 14474

Clinical InformationLeft posterior shoulder F84

Reason for ConsultationFavor a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus (see

enclosed report) There is mild melanocytic atypia and that the peripheral and deep margins of the specimen were negative in the

plane of sectioning

5212018

51

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 4 F81

bull Recurrence of Case 8

bull Shave biopsy of similar sun-damaged skinbull Somewhat more cellular proliferation of nevoid and

nevoid to epithelioid melanocytes focally exhibiting severe and uniform cytologic atypia

bull Some of these cells are confined to the epidermis above the scar while others appear to extend some distance beyond the periphery of the scar

bull This latter feature raises some concern for evolving melanoma in situ extending beyond the scar

5212018

52

bull Skin left posterior shoulder shave biopsy (recurrence) Intraepidermal atypical melanocytic proliferation of uncertain significance extending to specimen margins see description and comment

ndash Comment Cannot rule out an evolving more significant lesion suggest complete excision

Case 5

Part 2-3 14474

Clinical InformationBiopsy from posterior shoulder of an 85 year old female

Reason for ConsultationThis specimen in my opinion has histologic features concerning for

melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis I do not see

definitive features of a scar consistent with a prior biopsy site

5212018

53

bull Broadbull Moderately

cellularbull Moderate to

severe CSDbull Poorly

circumscribedbull Few bridging

nestsbull Diffuse

fibroplasiabull Cells in dermis

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Nests in dermis

bull No maturation

5212018

54

Melan-A Stain

bull Moderately cellular

bull Continuous basal proliferation

bull Nests hanging down

bull Low level pagetoid scatter

bull Nests in dermis

bull No maturation

Your Diagnosis

Melanoma

Nevus

Our Diagnosis

Malignant melanoma lentigo maligna type (ldquolentiginous melanomardquo Clark level II Breslow thickness 085 mm

5212018

55

Updated History Cases 3-5

bull Clinical Information

bull Three separate biopsies from left posterior shoulder of an 85-year-old female over a period of three years The biopsies were performed 4 years and 1 year ago and recently

bull The original biopsy was called a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus might have been better interpreted as a lentiginous nevus of the elderlysundamaged skin with mild to moderate atypia ndash The peripheral and deep margins of the specimen were said to be negative in the plane

of sectioning

bull The next biopsy at presumably the same anatomic location was signed out as an atypical melanocytic proliferation consistent with a persistentrecurrent Clarkrsquos (dysplastic) nevus involving the peripheral edge of the biopsy ndash It was mentioned that the differential diagnosis included early melanoma in situ

evolving within a pre-existing nevus and a reexcision was recommended

bull The most recent specimen was concerning for melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis

bull Additional procedure warranted to ensure that the lesion has been completely removed`

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Cytologic atypia mild but relatively uniform bull POTENTIAL PRECURSOR (low risk) VS ACTUAL PRECURSOR (hindsight bias)bull Manage by excision or follow-up

bull Case 5

bull Second recurrence of a lesion that originally had only ldquomildrdquo atypia (but moderate to severe architectural disorder)

bull Diagnosis of dysplastic nevus should be made with caution in elderlyCSD skin

bull Complete excision is appropriate for ldquoatypical lentiginous nevus of elderlysundamaged skinrdquo

5212018

56

Last Case

Part 2-7 12150

Clinical InformationLesion of right shoulder ro melanoma versus nevus in a 76 yo man

Reason for ConsultationIs this anything other than a moderately atypical neurotized compound nevus

bull A relatively broad lesion with irregular thickening and thinning of rete ridges and a sparsely cellular infiltrate in the dermis

bull Generally sparsely cellularbull Moderate to severe CSD

Poorly circumscribed

5212018

57

bull Pigmented melanophages in the dermis

bull Increased number of melanocytes in the epidermis many of them suprabasal

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

5212018

58

S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

bull Melan-A stain highlights the junctional component but the dermal spindle cells are negative

Case 6

bull Skin right superior shoulder Malignant melanoma lentigo maligna type nonulcerated with pure desmoplastic vertical growth phase Clark level IV Breslow thickness not lt 064 mm extending close to the specimen base see Comment 3

bull Commentbull Changes extend close to the base and to a peripheral margin of the

specimenbull It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution Sbull Should be excised locally in order to prevent any possibility of persistence

recurrence or future progression of it bull Based on its microstaging attributes the prognosis for this lesion should

be excellent The prognosis for ldquopurerdquo desmoplastic melanoma is if anything better than that for melanomas of similar thickness

bull This lesion could be managed with a relatively generous wide local excision ndash MPATH DX Category 4 (or 5)

5212018

59

Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

5212018

60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

5212018

45

Case 2

Part 2-2 7419Clinical Information

A large pigmented lesion of the back in a 74-year-old manReason for Consultation

I called this lesion a dysplastic nevus The clinician then calls back to inform us that this is a 22 cm irregular pigmented lesion Now looking at the deepers we think this

might be a ldquolentiginous melanomardquo

Description

bull Shave biopsy of a broad lesion with a dermal component and a moderately cellular junctional component

bull Lesion is ill-defined (poorly circumscribed) at each periphery with features overlapping with those of actinic lentigo

bull Subtle increase of melanocytes along the dermal-epidermal junction with mild to moderate but relatively uniform cytologic atypia

bull Pagetoid scatter is minimal

bull Focally there are elongated rete ridges overlapping with features of dysplastic nevus however these changes are focal within the lesion rather than being symmetrically distributed at shoulders adjacent to a dermal component

Lentiginous nevus versus lentiginous melanoma

bull Poorly circumscribed at each periphery

5212018

46

bull JunctionaIIAMP

bull Patchy lymphocytic infiltrate

bull Solar elastosis

Bridging rete

5212018

47

Your Diagnosis

Melanoma

Nevus

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Lentiginous nevus versus lentiginous melanomaDiagnosis Case 2 M74

Skin mid back Superficial atypical melanocytic proliferation of uncertain significance most consistent with melanoma in situ lentiginous type (nevoid lentigo maligna) versus atypical lentiginous nevus of the elderly see comment

(ie ldquoSAMPUSrdquo)

5212018

48

Diagnosis Case 2 M74

bull Overall Commentbull There are overlapping features among atypical actinic

lentigines lentiginous junctional nevi with and without atypia and lentiginous or ldquonevoidrdquo lentigo maligna

bull Lesions in a high CSD environment must be interpreted with circumspection

bull Overdiagnosis should be avoided as even atypical lentiginous junctional nevi of the elderly seem to be biologically low grade (non-metastasizing but perhaps locally recurring potential)

bull It is judicious to completely excise these lesions in order to be sure that they have been completely examined histologically and also to minimize any possibility of local persistence recurrence or future progression

Nevoid Lentigo MalignaLentiginous Melanoma(Lentiginous Nevus)

bull Kossard 1997 Aust J Dermatol Nevoid lentigo malignaKing Page Googe amp Mihm Modern Pathology 2005 Lentiginous melanomaFerrahi Egbert amp Swetter J Cutan Pathol 2005 Dysplastic nevus-like LMM

bull Clinical diagnosis may varyndash eg lentigo maligna atypical nevus pigmented basal cell carcinoma seborrheic keratosis and

lentigo

bull Biopsies may mimic junctional nevus or dysplastic nevus at least focallyndash Lentiginous proliferation of melanocytes at the dermo-epidermal junction both as single cells

and as small nests with areas of confluent growth extending to the edges of the biopsy ndash Rete ridges maintainedndash Pagetoid spread of melanocytes was not prominent in HampE - stained sections

bull Diagnosis of melanoma more easily recognized in the complete excision specimens similar atypical melanocytic proliferation occurring over a broad area flanking the prior biopsy sites

bull Stains for MITF and Mart-1 highlight continuous basal melanocytic proliferation as well as foci of pagetoid scatter

Lentiginous MelanomaKing Page Googe Mihm Mod Pathol 2005

bull Initial biopsies mimicked lentiginous nevus or dysplastic nevus

bull Lentiginous proliferation of melanocytes at DEJ both as single cells and as small nests with areas of confluent growth extending to the edges of the biopsy

bull Retiform epidermis was maintained and pagetoid spread of melanocytes was not prominent in HampE sections

bull Immunohistochemical stains for MITF and Mart-1 highlighted the extent of the basalar melanocytic proliferation as well as foci of pagetoid spread by melanocytes

bull UNCERTAINTY IS COMMONbull PROGNOSIS IS GOOD IF LESION IS SUPERFICIALbull IMPORTANT TO COMPLETELY EXCISE

bull FOR FULL EXAMINATION AND TO MINIMIZE ANY POTENTIAL FOR LOCAL PERSISTENCE RECURRENCE AND PROGRESSION

Mart 1

MITF

5212018

49

Case 3

Part 2-3 14474

Clinical InformationLeft posterior shoulder F81

Reason for ConsultationFavor a junctional Clarkrsquos nevus (see enclosed report)

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Some bridging few nests that hang down in a droplet-like pattern bull Cytologic atypia mild but relatively uniform

5212018

50

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 3 F81

bull ldquoDifficult to interpretrdquo bull Cytologic atypia is mild to moderate rather than

severe with somewhat concerning architectural changes

bull ldquoOne is somewhat more concerned about a lesion in chronically sun-damaged skin of older subjectsrdquo

bull Skin left posterior shoulder shave biopsy Intraepidermal atypical melanocytic proliferation of uncertain significance (IAMPUS) most consistent with atypical lentiginous junctional nevus (of the elderlyCSD skin) cannot ro evolving or early established melanoma in situ

bull Complete excision recommended (MPATH-Dx 2 or 3)

Case 4

Part 2-3 14474

Clinical InformationLeft posterior shoulder F84

Reason for ConsultationFavor a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus (see

enclosed report) There is mild melanocytic atypia and that the peripheral and deep margins of the specimen were negative in the

plane of sectioning

5212018

51

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 4 F81

bull Recurrence of Case 8

bull Shave biopsy of similar sun-damaged skinbull Somewhat more cellular proliferation of nevoid and

nevoid to epithelioid melanocytes focally exhibiting severe and uniform cytologic atypia

bull Some of these cells are confined to the epidermis above the scar while others appear to extend some distance beyond the periphery of the scar

bull This latter feature raises some concern for evolving melanoma in situ extending beyond the scar

5212018

52

bull Skin left posterior shoulder shave biopsy (recurrence) Intraepidermal atypical melanocytic proliferation of uncertain significance extending to specimen margins see description and comment

ndash Comment Cannot rule out an evolving more significant lesion suggest complete excision

Case 5

Part 2-3 14474

Clinical InformationBiopsy from posterior shoulder of an 85 year old female

Reason for ConsultationThis specimen in my opinion has histologic features concerning for

melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis I do not see

definitive features of a scar consistent with a prior biopsy site

5212018

53

bull Broadbull Moderately

cellularbull Moderate to

severe CSDbull Poorly

circumscribedbull Few bridging

nestsbull Diffuse

fibroplasiabull Cells in dermis

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Nests in dermis

bull No maturation

5212018

54

Melan-A Stain

bull Moderately cellular

bull Continuous basal proliferation

bull Nests hanging down

bull Low level pagetoid scatter

bull Nests in dermis

bull No maturation

Your Diagnosis

Melanoma

Nevus

Our Diagnosis

Malignant melanoma lentigo maligna type (ldquolentiginous melanomardquo Clark level II Breslow thickness 085 mm

5212018

55

Updated History Cases 3-5

bull Clinical Information

bull Three separate biopsies from left posterior shoulder of an 85-year-old female over a period of three years The biopsies were performed 4 years and 1 year ago and recently

bull The original biopsy was called a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus might have been better interpreted as a lentiginous nevus of the elderlysundamaged skin with mild to moderate atypia ndash The peripheral and deep margins of the specimen were said to be negative in the plane

of sectioning

bull The next biopsy at presumably the same anatomic location was signed out as an atypical melanocytic proliferation consistent with a persistentrecurrent Clarkrsquos (dysplastic) nevus involving the peripheral edge of the biopsy ndash It was mentioned that the differential diagnosis included early melanoma in situ

evolving within a pre-existing nevus and a reexcision was recommended

bull The most recent specimen was concerning for melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis

bull Additional procedure warranted to ensure that the lesion has been completely removed`

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Cytologic atypia mild but relatively uniform bull POTENTIAL PRECURSOR (low risk) VS ACTUAL PRECURSOR (hindsight bias)bull Manage by excision or follow-up

bull Case 5

bull Second recurrence of a lesion that originally had only ldquomildrdquo atypia (but moderate to severe architectural disorder)

bull Diagnosis of dysplastic nevus should be made with caution in elderlyCSD skin

bull Complete excision is appropriate for ldquoatypical lentiginous nevus of elderlysundamaged skinrdquo

5212018

56

Last Case

Part 2-7 12150

Clinical InformationLesion of right shoulder ro melanoma versus nevus in a 76 yo man

Reason for ConsultationIs this anything other than a moderately atypical neurotized compound nevus

bull A relatively broad lesion with irregular thickening and thinning of rete ridges and a sparsely cellular infiltrate in the dermis

bull Generally sparsely cellularbull Moderate to severe CSD

Poorly circumscribed

5212018

57

bull Pigmented melanophages in the dermis

bull Increased number of melanocytes in the epidermis many of them suprabasal

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

5212018

58

S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

bull Melan-A stain highlights the junctional component but the dermal spindle cells are negative

Case 6

bull Skin right superior shoulder Malignant melanoma lentigo maligna type nonulcerated with pure desmoplastic vertical growth phase Clark level IV Breslow thickness not lt 064 mm extending close to the specimen base see Comment 3

bull Commentbull Changes extend close to the base and to a peripheral margin of the

specimenbull It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution Sbull Should be excised locally in order to prevent any possibility of persistence

recurrence or future progression of it bull Based on its microstaging attributes the prognosis for this lesion should

be excellent The prognosis for ldquopurerdquo desmoplastic melanoma is if anything better than that for melanomas of similar thickness

bull This lesion could be managed with a relatively generous wide local excision ndash MPATH DX Category 4 (or 5)

5212018

59

Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

5212018

60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

5212018

46

bull JunctionaIIAMP

bull Patchy lymphocytic infiltrate

bull Solar elastosis

Bridging rete

5212018

47

Your Diagnosis

Melanoma

Nevus

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Lentiginous nevus versus lentiginous melanomaDiagnosis Case 2 M74

Skin mid back Superficial atypical melanocytic proliferation of uncertain significance most consistent with melanoma in situ lentiginous type (nevoid lentigo maligna) versus atypical lentiginous nevus of the elderly see comment

(ie ldquoSAMPUSrdquo)

5212018

48

Diagnosis Case 2 M74

bull Overall Commentbull There are overlapping features among atypical actinic

lentigines lentiginous junctional nevi with and without atypia and lentiginous or ldquonevoidrdquo lentigo maligna

bull Lesions in a high CSD environment must be interpreted with circumspection

bull Overdiagnosis should be avoided as even atypical lentiginous junctional nevi of the elderly seem to be biologically low grade (non-metastasizing but perhaps locally recurring potential)

bull It is judicious to completely excise these lesions in order to be sure that they have been completely examined histologically and also to minimize any possibility of local persistence recurrence or future progression

Nevoid Lentigo MalignaLentiginous Melanoma(Lentiginous Nevus)

bull Kossard 1997 Aust J Dermatol Nevoid lentigo malignaKing Page Googe amp Mihm Modern Pathology 2005 Lentiginous melanomaFerrahi Egbert amp Swetter J Cutan Pathol 2005 Dysplastic nevus-like LMM

bull Clinical diagnosis may varyndash eg lentigo maligna atypical nevus pigmented basal cell carcinoma seborrheic keratosis and

lentigo

bull Biopsies may mimic junctional nevus or dysplastic nevus at least focallyndash Lentiginous proliferation of melanocytes at the dermo-epidermal junction both as single cells

and as small nests with areas of confluent growth extending to the edges of the biopsy ndash Rete ridges maintainedndash Pagetoid spread of melanocytes was not prominent in HampE - stained sections

bull Diagnosis of melanoma more easily recognized in the complete excision specimens similar atypical melanocytic proliferation occurring over a broad area flanking the prior biopsy sites

bull Stains for MITF and Mart-1 highlight continuous basal melanocytic proliferation as well as foci of pagetoid scatter

Lentiginous MelanomaKing Page Googe Mihm Mod Pathol 2005

bull Initial biopsies mimicked lentiginous nevus or dysplastic nevus

bull Lentiginous proliferation of melanocytes at DEJ both as single cells and as small nests with areas of confluent growth extending to the edges of the biopsy

bull Retiform epidermis was maintained and pagetoid spread of melanocytes was not prominent in HampE sections

bull Immunohistochemical stains for MITF and Mart-1 highlighted the extent of the basalar melanocytic proliferation as well as foci of pagetoid spread by melanocytes

bull UNCERTAINTY IS COMMONbull PROGNOSIS IS GOOD IF LESION IS SUPERFICIALbull IMPORTANT TO COMPLETELY EXCISE

bull FOR FULL EXAMINATION AND TO MINIMIZE ANY POTENTIAL FOR LOCAL PERSISTENCE RECURRENCE AND PROGRESSION

Mart 1

MITF

5212018

49

Case 3

Part 2-3 14474

Clinical InformationLeft posterior shoulder F81

Reason for ConsultationFavor a junctional Clarkrsquos nevus (see enclosed report)

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Some bridging few nests that hang down in a droplet-like pattern bull Cytologic atypia mild but relatively uniform

5212018

50

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 3 F81

bull ldquoDifficult to interpretrdquo bull Cytologic atypia is mild to moderate rather than

severe with somewhat concerning architectural changes

bull ldquoOne is somewhat more concerned about a lesion in chronically sun-damaged skin of older subjectsrdquo

bull Skin left posterior shoulder shave biopsy Intraepidermal atypical melanocytic proliferation of uncertain significance (IAMPUS) most consistent with atypical lentiginous junctional nevus (of the elderlyCSD skin) cannot ro evolving or early established melanoma in situ

bull Complete excision recommended (MPATH-Dx 2 or 3)

Case 4

Part 2-3 14474

Clinical InformationLeft posterior shoulder F84

Reason for ConsultationFavor a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus (see

enclosed report) There is mild melanocytic atypia and that the peripheral and deep margins of the specimen were negative in the

plane of sectioning

5212018

51

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 4 F81

bull Recurrence of Case 8

bull Shave biopsy of similar sun-damaged skinbull Somewhat more cellular proliferation of nevoid and

nevoid to epithelioid melanocytes focally exhibiting severe and uniform cytologic atypia

bull Some of these cells are confined to the epidermis above the scar while others appear to extend some distance beyond the periphery of the scar

bull This latter feature raises some concern for evolving melanoma in situ extending beyond the scar

5212018

52

bull Skin left posterior shoulder shave biopsy (recurrence) Intraepidermal atypical melanocytic proliferation of uncertain significance extending to specimen margins see description and comment

ndash Comment Cannot rule out an evolving more significant lesion suggest complete excision

Case 5

Part 2-3 14474

Clinical InformationBiopsy from posterior shoulder of an 85 year old female

Reason for ConsultationThis specimen in my opinion has histologic features concerning for

melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis I do not see

definitive features of a scar consistent with a prior biopsy site

5212018

53

bull Broadbull Moderately

cellularbull Moderate to

severe CSDbull Poorly

circumscribedbull Few bridging

nestsbull Diffuse

fibroplasiabull Cells in dermis

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Nests in dermis

bull No maturation

5212018

54

Melan-A Stain

bull Moderately cellular

bull Continuous basal proliferation

bull Nests hanging down

bull Low level pagetoid scatter

bull Nests in dermis

bull No maturation

Your Diagnosis

Melanoma

Nevus

Our Diagnosis

Malignant melanoma lentigo maligna type (ldquolentiginous melanomardquo Clark level II Breslow thickness 085 mm

5212018

55

Updated History Cases 3-5

bull Clinical Information

bull Three separate biopsies from left posterior shoulder of an 85-year-old female over a period of three years The biopsies were performed 4 years and 1 year ago and recently

bull The original biopsy was called a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus might have been better interpreted as a lentiginous nevus of the elderlysundamaged skin with mild to moderate atypia ndash The peripheral and deep margins of the specimen were said to be negative in the plane

of sectioning

bull The next biopsy at presumably the same anatomic location was signed out as an atypical melanocytic proliferation consistent with a persistentrecurrent Clarkrsquos (dysplastic) nevus involving the peripheral edge of the biopsy ndash It was mentioned that the differential diagnosis included early melanoma in situ

evolving within a pre-existing nevus and a reexcision was recommended

bull The most recent specimen was concerning for melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis

bull Additional procedure warranted to ensure that the lesion has been completely removed`

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Cytologic atypia mild but relatively uniform bull POTENTIAL PRECURSOR (low risk) VS ACTUAL PRECURSOR (hindsight bias)bull Manage by excision or follow-up

bull Case 5

bull Second recurrence of a lesion that originally had only ldquomildrdquo atypia (but moderate to severe architectural disorder)

bull Diagnosis of dysplastic nevus should be made with caution in elderlyCSD skin

bull Complete excision is appropriate for ldquoatypical lentiginous nevus of elderlysundamaged skinrdquo

5212018

56

Last Case

Part 2-7 12150

Clinical InformationLesion of right shoulder ro melanoma versus nevus in a 76 yo man

Reason for ConsultationIs this anything other than a moderately atypical neurotized compound nevus

bull A relatively broad lesion with irregular thickening and thinning of rete ridges and a sparsely cellular infiltrate in the dermis

bull Generally sparsely cellularbull Moderate to severe CSD

Poorly circumscribed

5212018

57

bull Pigmented melanophages in the dermis

bull Increased number of melanocytes in the epidermis many of them suprabasal

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

5212018

58

S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

bull Melan-A stain highlights the junctional component but the dermal spindle cells are negative

Case 6

bull Skin right superior shoulder Malignant melanoma lentigo maligna type nonulcerated with pure desmoplastic vertical growth phase Clark level IV Breslow thickness not lt 064 mm extending close to the specimen base see Comment 3

bull Commentbull Changes extend close to the base and to a peripheral margin of the

specimenbull It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution Sbull Should be excised locally in order to prevent any possibility of persistence

recurrence or future progression of it bull Based on its microstaging attributes the prognosis for this lesion should

be excellent The prognosis for ldquopurerdquo desmoplastic melanoma is if anything better than that for melanomas of similar thickness

bull This lesion could be managed with a relatively generous wide local excision ndash MPATH DX Category 4 (or 5)

5212018

59

Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

5212018

60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

5212018

47

Your Diagnosis

Melanoma

Nevus

Criteria for Melanoma vs NeviFeature Melanoma Dysplastic Nevus Superficial Nevus

Size larger intermediate smaller

Symmetry poor good good

Elastosis moderate-severe mild-moderate minimal- mild

Rete ridges irregular uniformly elongated uniform

Junctional Melanocytes epithelioid mixed (nevoid epithelioid) nevoid

Poor circumscription often less common uncommon

Distribution of Nests variable irregular predominant regular predominant regular

Distribution of Nests coalescent (confluent) bridging discrete

Size of Nests variable uniform uniform

Lentiginous continuous discontinuous minimal

Pagetoid high extensive low focal minimal minimal

Nuclear atypia uniform atypia random atypia minimal

moderate-severe mild-moderate

Mitoses ndash junctional about 13 of cases almost always absent absent

Pyknosisnecrosis common uncommon none

Fibroplasia diffuse concentric minimal

Lymphocytes bandlike lichenoid patchy perivascular minimal

Regression frequent extensive rare minimal absent

Dermal Cells uniform atypia random or no atypia no atypia

limited maturation maturation maturation

mitoses no mitoses no mitoses

Lentiginous nevus versus lentiginous melanomaDiagnosis Case 2 M74

Skin mid back Superficial atypical melanocytic proliferation of uncertain significance most consistent with melanoma in situ lentiginous type (nevoid lentigo maligna) versus atypical lentiginous nevus of the elderly see comment

(ie ldquoSAMPUSrdquo)

5212018

48

Diagnosis Case 2 M74

bull Overall Commentbull There are overlapping features among atypical actinic

lentigines lentiginous junctional nevi with and without atypia and lentiginous or ldquonevoidrdquo lentigo maligna

bull Lesions in a high CSD environment must be interpreted with circumspection

bull Overdiagnosis should be avoided as even atypical lentiginous junctional nevi of the elderly seem to be biologically low grade (non-metastasizing but perhaps locally recurring potential)

bull It is judicious to completely excise these lesions in order to be sure that they have been completely examined histologically and also to minimize any possibility of local persistence recurrence or future progression

Nevoid Lentigo MalignaLentiginous Melanoma(Lentiginous Nevus)

bull Kossard 1997 Aust J Dermatol Nevoid lentigo malignaKing Page Googe amp Mihm Modern Pathology 2005 Lentiginous melanomaFerrahi Egbert amp Swetter J Cutan Pathol 2005 Dysplastic nevus-like LMM

bull Clinical diagnosis may varyndash eg lentigo maligna atypical nevus pigmented basal cell carcinoma seborrheic keratosis and

lentigo

bull Biopsies may mimic junctional nevus or dysplastic nevus at least focallyndash Lentiginous proliferation of melanocytes at the dermo-epidermal junction both as single cells

and as small nests with areas of confluent growth extending to the edges of the biopsy ndash Rete ridges maintainedndash Pagetoid spread of melanocytes was not prominent in HampE - stained sections

bull Diagnosis of melanoma more easily recognized in the complete excision specimens similar atypical melanocytic proliferation occurring over a broad area flanking the prior biopsy sites

bull Stains for MITF and Mart-1 highlight continuous basal melanocytic proliferation as well as foci of pagetoid scatter

Lentiginous MelanomaKing Page Googe Mihm Mod Pathol 2005

bull Initial biopsies mimicked lentiginous nevus or dysplastic nevus

bull Lentiginous proliferation of melanocytes at DEJ both as single cells and as small nests with areas of confluent growth extending to the edges of the biopsy

bull Retiform epidermis was maintained and pagetoid spread of melanocytes was not prominent in HampE sections

bull Immunohistochemical stains for MITF and Mart-1 highlighted the extent of the basalar melanocytic proliferation as well as foci of pagetoid spread by melanocytes

bull UNCERTAINTY IS COMMONbull PROGNOSIS IS GOOD IF LESION IS SUPERFICIALbull IMPORTANT TO COMPLETELY EXCISE

bull FOR FULL EXAMINATION AND TO MINIMIZE ANY POTENTIAL FOR LOCAL PERSISTENCE RECURRENCE AND PROGRESSION

Mart 1

MITF

5212018

49

Case 3

Part 2-3 14474

Clinical InformationLeft posterior shoulder F81

Reason for ConsultationFavor a junctional Clarkrsquos nevus (see enclosed report)

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Some bridging few nests that hang down in a droplet-like pattern bull Cytologic atypia mild but relatively uniform

5212018

50

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 3 F81

bull ldquoDifficult to interpretrdquo bull Cytologic atypia is mild to moderate rather than

severe with somewhat concerning architectural changes

bull ldquoOne is somewhat more concerned about a lesion in chronically sun-damaged skin of older subjectsrdquo

bull Skin left posterior shoulder shave biopsy Intraepidermal atypical melanocytic proliferation of uncertain significance (IAMPUS) most consistent with atypical lentiginous junctional nevus (of the elderlyCSD skin) cannot ro evolving or early established melanoma in situ

bull Complete excision recommended (MPATH-Dx 2 or 3)

Case 4

Part 2-3 14474

Clinical InformationLeft posterior shoulder F84

Reason for ConsultationFavor a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus (see

enclosed report) There is mild melanocytic atypia and that the peripheral and deep margins of the specimen were negative in the

plane of sectioning

5212018

51

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 4 F81

bull Recurrence of Case 8

bull Shave biopsy of similar sun-damaged skinbull Somewhat more cellular proliferation of nevoid and

nevoid to epithelioid melanocytes focally exhibiting severe and uniform cytologic atypia

bull Some of these cells are confined to the epidermis above the scar while others appear to extend some distance beyond the periphery of the scar

bull This latter feature raises some concern for evolving melanoma in situ extending beyond the scar

5212018

52

bull Skin left posterior shoulder shave biopsy (recurrence) Intraepidermal atypical melanocytic proliferation of uncertain significance extending to specimen margins see description and comment

ndash Comment Cannot rule out an evolving more significant lesion suggest complete excision

Case 5

Part 2-3 14474

Clinical InformationBiopsy from posterior shoulder of an 85 year old female

Reason for ConsultationThis specimen in my opinion has histologic features concerning for

melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis I do not see

definitive features of a scar consistent with a prior biopsy site

5212018

53

bull Broadbull Moderately

cellularbull Moderate to

severe CSDbull Poorly

circumscribedbull Few bridging

nestsbull Diffuse

fibroplasiabull Cells in dermis

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Nests in dermis

bull No maturation

5212018

54

Melan-A Stain

bull Moderately cellular

bull Continuous basal proliferation

bull Nests hanging down

bull Low level pagetoid scatter

bull Nests in dermis

bull No maturation

Your Diagnosis

Melanoma

Nevus

Our Diagnosis

Malignant melanoma lentigo maligna type (ldquolentiginous melanomardquo Clark level II Breslow thickness 085 mm

5212018

55

Updated History Cases 3-5

bull Clinical Information

bull Three separate biopsies from left posterior shoulder of an 85-year-old female over a period of three years The biopsies were performed 4 years and 1 year ago and recently

bull The original biopsy was called a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus might have been better interpreted as a lentiginous nevus of the elderlysundamaged skin with mild to moderate atypia ndash The peripheral and deep margins of the specimen were said to be negative in the plane

of sectioning

bull The next biopsy at presumably the same anatomic location was signed out as an atypical melanocytic proliferation consistent with a persistentrecurrent Clarkrsquos (dysplastic) nevus involving the peripheral edge of the biopsy ndash It was mentioned that the differential diagnosis included early melanoma in situ

evolving within a pre-existing nevus and a reexcision was recommended

bull The most recent specimen was concerning for melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis

bull Additional procedure warranted to ensure that the lesion has been completely removed`

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Cytologic atypia mild but relatively uniform bull POTENTIAL PRECURSOR (low risk) VS ACTUAL PRECURSOR (hindsight bias)bull Manage by excision or follow-up

bull Case 5

bull Second recurrence of a lesion that originally had only ldquomildrdquo atypia (but moderate to severe architectural disorder)

bull Diagnosis of dysplastic nevus should be made with caution in elderlyCSD skin

bull Complete excision is appropriate for ldquoatypical lentiginous nevus of elderlysundamaged skinrdquo

5212018

56

Last Case

Part 2-7 12150

Clinical InformationLesion of right shoulder ro melanoma versus nevus in a 76 yo man

Reason for ConsultationIs this anything other than a moderately atypical neurotized compound nevus

bull A relatively broad lesion with irregular thickening and thinning of rete ridges and a sparsely cellular infiltrate in the dermis

bull Generally sparsely cellularbull Moderate to severe CSD

Poorly circumscribed

5212018

57

bull Pigmented melanophages in the dermis

bull Increased number of melanocytes in the epidermis many of them suprabasal

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

5212018

58

S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

bull Melan-A stain highlights the junctional component but the dermal spindle cells are negative

Case 6

bull Skin right superior shoulder Malignant melanoma lentigo maligna type nonulcerated with pure desmoplastic vertical growth phase Clark level IV Breslow thickness not lt 064 mm extending close to the specimen base see Comment 3

bull Commentbull Changes extend close to the base and to a peripheral margin of the

specimenbull It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution Sbull Should be excised locally in order to prevent any possibility of persistence

recurrence or future progression of it bull Based on its microstaging attributes the prognosis for this lesion should

be excellent The prognosis for ldquopurerdquo desmoplastic melanoma is if anything better than that for melanomas of similar thickness

bull This lesion could be managed with a relatively generous wide local excision ndash MPATH DX Category 4 (or 5)

5212018

59

Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

5212018

60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

5212018

48

Diagnosis Case 2 M74

bull Overall Commentbull There are overlapping features among atypical actinic

lentigines lentiginous junctional nevi with and without atypia and lentiginous or ldquonevoidrdquo lentigo maligna

bull Lesions in a high CSD environment must be interpreted with circumspection

bull Overdiagnosis should be avoided as even atypical lentiginous junctional nevi of the elderly seem to be biologically low grade (non-metastasizing but perhaps locally recurring potential)

bull It is judicious to completely excise these lesions in order to be sure that they have been completely examined histologically and also to minimize any possibility of local persistence recurrence or future progression

Nevoid Lentigo MalignaLentiginous Melanoma(Lentiginous Nevus)

bull Kossard 1997 Aust J Dermatol Nevoid lentigo malignaKing Page Googe amp Mihm Modern Pathology 2005 Lentiginous melanomaFerrahi Egbert amp Swetter J Cutan Pathol 2005 Dysplastic nevus-like LMM

bull Clinical diagnosis may varyndash eg lentigo maligna atypical nevus pigmented basal cell carcinoma seborrheic keratosis and

lentigo

bull Biopsies may mimic junctional nevus or dysplastic nevus at least focallyndash Lentiginous proliferation of melanocytes at the dermo-epidermal junction both as single cells

and as small nests with areas of confluent growth extending to the edges of the biopsy ndash Rete ridges maintainedndash Pagetoid spread of melanocytes was not prominent in HampE - stained sections

bull Diagnosis of melanoma more easily recognized in the complete excision specimens similar atypical melanocytic proliferation occurring over a broad area flanking the prior biopsy sites

bull Stains for MITF and Mart-1 highlight continuous basal melanocytic proliferation as well as foci of pagetoid scatter

Lentiginous MelanomaKing Page Googe Mihm Mod Pathol 2005

bull Initial biopsies mimicked lentiginous nevus or dysplastic nevus

bull Lentiginous proliferation of melanocytes at DEJ both as single cells and as small nests with areas of confluent growth extending to the edges of the biopsy

bull Retiform epidermis was maintained and pagetoid spread of melanocytes was not prominent in HampE sections

bull Immunohistochemical stains for MITF and Mart-1 highlighted the extent of the basalar melanocytic proliferation as well as foci of pagetoid spread by melanocytes

bull UNCERTAINTY IS COMMONbull PROGNOSIS IS GOOD IF LESION IS SUPERFICIALbull IMPORTANT TO COMPLETELY EXCISE

bull FOR FULL EXAMINATION AND TO MINIMIZE ANY POTENTIAL FOR LOCAL PERSISTENCE RECURRENCE AND PROGRESSION

Mart 1

MITF

5212018

49

Case 3

Part 2-3 14474

Clinical InformationLeft posterior shoulder F81

Reason for ConsultationFavor a junctional Clarkrsquos nevus (see enclosed report)

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Some bridging few nests that hang down in a droplet-like pattern bull Cytologic atypia mild but relatively uniform

5212018

50

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 3 F81

bull ldquoDifficult to interpretrdquo bull Cytologic atypia is mild to moderate rather than

severe with somewhat concerning architectural changes

bull ldquoOne is somewhat more concerned about a lesion in chronically sun-damaged skin of older subjectsrdquo

bull Skin left posterior shoulder shave biopsy Intraepidermal atypical melanocytic proliferation of uncertain significance (IAMPUS) most consistent with atypical lentiginous junctional nevus (of the elderlyCSD skin) cannot ro evolving or early established melanoma in situ

bull Complete excision recommended (MPATH-Dx 2 or 3)

Case 4

Part 2-3 14474

Clinical InformationLeft posterior shoulder F84

Reason for ConsultationFavor a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus (see

enclosed report) There is mild melanocytic atypia and that the peripheral and deep margins of the specimen were negative in the

plane of sectioning

5212018

51

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 4 F81

bull Recurrence of Case 8

bull Shave biopsy of similar sun-damaged skinbull Somewhat more cellular proliferation of nevoid and

nevoid to epithelioid melanocytes focally exhibiting severe and uniform cytologic atypia

bull Some of these cells are confined to the epidermis above the scar while others appear to extend some distance beyond the periphery of the scar

bull This latter feature raises some concern for evolving melanoma in situ extending beyond the scar

5212018

52

bull Skin left posterior shoulder shave biopsy (recurrence) Intraepidermal atypical melanocytic proliferation of uncertain significance extending to specimen margins see description and comment

ndash Comment Cannot rule out an evolving more significant lesion suggest complete excision

Case 5

Part 2-3 14474

Clinical InformationBiopsy from posterior shoulder of an 85 year old female

Reason for ConsultationThis specimen in my opinion has histologic features concerning for

melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis I do not see

definitive features of a scar consistent with a prior biopsy site

5212018

53

bull Broadbull Moderately

cellularbull Moderate to

severe CSDbull Poorly

circumscribedbull Few bridging

nestsbull Diffuse

fibroplasiabull Cells in dermis

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Nests in dermis

bull No maturation

5212018

54

Melan-A Stain

bull Moderately cellular

bull Continuous basal proliferation

bull Nests hanging down

bull Low level pagetoid scatter

bull Nests in dermis

bull No maturation

Your Diagnosis

Melanoma

Nevus

Our Diagnosis

Malignant melanoma lentigo maligna type (ldquolentiginous melanomardquo Clark level II Breslow thickness 085 mm

5212018

55

Updated History Cases 3-5

bull Clinical Information

bull Three separate biopsies from left posterior shoulder of an 85-year-old female over a period of three years The biopsies were performed 4 years and 1 year ago and recently

bull The original biopsy was called a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus might have been better interpreted as a lentiginous nevus of the elderlysundamaged skin with mild to moderate atypia ndash The peripheral and deep margins of the specimen were said to be negative in the plane

of sectioning

bull The next biopsy at presumably the same anatomic location was signed out as an atypical melanocytic proliferation consistent with a persistentrecurrent Clarkrsquos (dysplastic) nevus involving the peripheral edge of the biopsy ndash It was mentioned that the differential diagnosis included early melanoma in situ

evolving within a pre-existing nevus and a reexcision was recommended

bull The most recent specimen was concerning for melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis

bull Additional procedure warranted to ensure that the lesion has been completely removed`

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Cytologic atypia mild but relatively uniform bull POTENTIAL PRECURSOR (low risk) VS ACTUAL PRECURSOR (hindsight bias)bull Manage by excision or follow-up

bull Case 5

bull Second recurrence of a lesion that originally had only ldquomildrdquo atypia (but moderate to severe architectural disorder)

bull Diagnosis of dysplastic nevus should be made with caution in elderlyCSD skin

bull Complete excision is appropriate for ldquoatypical lentiginous nevus of elderlysundamaged skinrdquo

5212018

56

Last Case

Part 2-7 12150

Clinical InformationLesion of right shoulder ro melanoma versus nevus in a 76 yo man

Reason for ConsultationIs this anything other than a moderately atypical neurotized compound nevus

bull A relatively broad lesion with irregular thickening and thinning of rete ridges and a sparsely cellular infiltrate in the dermis

bull Generally sparsely cellularbull Moderate to severe CSD

Poorly circumscribed

5212018

57

bull Pigmented melanophages in the dermis

bull Increased number of melanocytes in the epidermis many of them suprabasal

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

5212018

58

S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

bull Melan-A stain highlights the junctional component but the dermal spindle cells are negative

Case 6

bull Skin right superior shoulder Malignant melanoma lentigo maligna type nonulcerated with pure desmoplastic vertical growth phase Clark level IV Breslow thickness not lt 064 mm extending close to the specimen base see Comment 3

bull Commentbull Changes extend close to the base and to a peripheral margin of the

specimenbull It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution Sbull Should be excised locally in order to prevent any possibility of persistence

recurrence or future progression of it bull Based on its microstaging attributes the prognosis for this lesion should

be excellent The prognosis for ldquopurerdquo desmoplastic melanoma is if anything better than that for melanomas of similar thickness

bull This lesion could be managed with a relatively generous wide local excision ndash MPATH DX Category 4 (or 5)

5212018

59

Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

5212018

60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

5212018

49

Case 3

Part 2-3 14474

Clinical InformationLeft posterior shoulder F81

Reason for ConsultationFavor a junctional Clarkrsquos nevus (see enclosed report)

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Some bridging few nests that hang down in a droplet-like pattern bull Cytologic atypia mild but relatively uniform

5212018

50

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 3 F81

bull ldquoDifficult to interpretrdquo bull Cytologic atypia is mild to moderate rather than

severe with somewhat concerning architectural changes

bull ldquoOne is somewhat more concerned about a lesion in chronically sun-damaged skin of older subjectsrdquo

bull Skin left posterior shoulder shave biopsy Intraepidermal atypical melanocytic proliferation of uncertain significance (IAMPUS) most consistent with atypical lentiginous junctional nevus (of the elderlyCSD skin) cannot ro evolving or early established melanoma in situ

bull Complete excision recommended (MPATH-Dx 2 or 3)

Case 4

Part 2-3 14474

Clinical InformationLeft posterior shoulder F84

Reason for ConsultationFavor a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus (see

enclosed report) There is mild melanocytic atypia and that the peripheral and deep margins of the specimen were negative in the

plane of sectioning

5212018

51

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 4 F81

bull Recurrence of Case 8

bull Shave biopsy of similar sun-damaged skinbull Somewhat more cellular proliferation of nevoid and

nevoid to epithelioid melanocytes focally exhibiting severe and uniform cytologic atypia

bull Some of these cells are confined to the epidermis above the scar while others appear to extend some distance beyond the periphery of the scar

bull This latter feature raises some concern for evolving melanoma in situ extending beyond the scar

5212018

52

bull Skin left posterior shoulder shave biopsy (recurrence) Intraepidermal atypical melanocytic proliferation of uncertain significance extending to specimen margins see description and comment

ndash Comment Cannot rule out an evolving more significant lesion suggest complete excision

Case 5

Part 2-3 14474

Clinical InformationBiopsy from posterior shoulder of an 85 year old female

Reason for ConsultationThis specimen in my opinion has histologic features concerning for

melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis I do not see

definitive features of a scar consistent with a prior biopsy site

5212018

53

bull Broadbull Moderately

cellularbull Moderate to

severe CSDbull Poorly

circumscribedbull Few bridging

nestsbull Diffuse

fibroplasiabull Cells in dermis

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Nests in dermis

bull No maturation

5212018

54

Melan-A Stain

bull Moderately cellular

bull Continuous basal proliferation

bull Nests hanging down

bull Low level pagetoid scatter

bull Nests in dermis

bull No maturation

Your Diagnosis

Melanoma

Nevus

Our Diagnosis

Malignant melanoma lentigo maligna type (ldquolentiginous melanomardquo Clark level II Breslow thickness 085 mm

5212018

55

Updated History Cases 3-5

bull Clinical Information

bull Three separate biopsies from left posterior shoulder of an 85-year-old female over a period of three years The biopsies were performed 4 years and 1 year ago and recently

bull The original biopsy was called a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus might have been better interpreted as a lentiginous nevus of the elderlysundamaged skin with mild to moderate atypia ndash The peripheral and deep margins of the specimen were said to be negative in the plane

of sectioning

bull The next biopsy at presumably the same anatomic location was signed out as an atypical melanocytic proliferation consistent with a persistentrecurrent Clarkrsquos (dysplastic) nevus involving the peripheral edge of the biopsy ndash It was mentioned that the differential diagnosis included early melanoma in situ

evolving within a pre-existing nevus and a reexcision was recommended

bull The most recent specimen was concerning for melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis

bull Additional procedure warranted to ensure that the lesion has been completely removed`

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Cytologic atypia mild but relatively uniform bull POTENTIAL PRECURSOR (low risk) VS ACTUAL PRECURSOR (hindsight bias)bull Manage by excision or follow-up

bull Case 5

bull Second recurrence of a lesion that originally had only ldquomildrdquo atypia (but moderate to severe architectural disorder)

bull Diagnosis of dysplastic nevus should be made with caution in elderlyCSD skin

bull Complete excision is appropriate for ldquoatypical lentiginous nevus of elderlysundamaged skinrdquo

5212018

56

Last Case

Part 2-7 12150

Clinical InformationLesion of right shoulder ro melanoma versus nevus in a 76 yo man

Reason for ConsultationIs this anything other than a moderately atypical neurotized compound nevus

bull A relatively broad lesion with irregular thickening and thinning of rete ridges and a sparsely cellular infiltrate in the dermis

bull Generally sparsely cellularbull Moderate to severe CSD

Poorly circumscribed

5212018

57

bull Pigmented melanophages in the dermis

bull Increased number of melanocytes in the epidermis many of them suprabasal

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

5212018

58

S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

bull Melan-A stain highlights the junctional component but the dermal spindle cells are negative

Case 6

bull Skin right superior shoulder Malignant melanoma lentigo maligna type nonulcerated with pure desmoplastic vertical growth phase Clark level IV Breslow thickness not lt 064 mm extending close to the specimen base see Comment 3

bull Commentbull Changes extend close to the base and to a peripheral margin of the

specimenbull It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution Sbull Should be excised locally in order to prevent any possibility of persistence

recurrence or future progression of it bull Based on its microstaging attributes the prognosis for this lesion should

be excellent The prognosis for ldquopurerdquo desmoplastic melanoma is if anything better than that for melanomas of similar thickness

bull This lesion could be managed with a relatively generous wide local excision ndash MPATH DX Category 4 (or 5)

5212018

59

Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

5212018

60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

5212018

50

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 3 F81

bull ldquoDifficult to interpretrdquo bull Cytologic atypia is mild to moderate rather than

severe with somewhat concerning architectural changes

bull ldquoOne is somewhat more concerned about a lesion in chronically sun-damaged skin of older subjectsrdquo

bull Skin left posterior shoulder shave biopsy Intraepidermal atypical melanocytic proliferation of uncertain significance (IAMPUS) most consistent with atypical lentiginous junctional nevus (of the elderlyCSD skin) cannot ro evolving or early established melanoma in situ

bull Complete excision recommended (MPATH-Dx 2 or 3)

Case 4

Part 2-3 14474

Clinical InformationLeft posterior shoulder F84

Reason for ConsultationFavor a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus (see

enclosed report) There is mild melanocytic atypia and that the peripheral and deep margins of the specimen were negative in the

plane of sectioning

5212018

51

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 4 F81

bull Recurrence of Case 8

bull Shave biopsy of similar sun-damaged skinbull Somewhat more cellular proliferation of nevoid and

nevoid to epithelioid melanocytes focally exhibiting severe and uniform cytologic atypia

bull Some of these cells are confined to the epidermis above the scar while others appear to extend some distance beyond the periphery of the scar

bull This latter feature raises some concern for evolving melanoma in situ extending beyond the scar

5212018

52

bull Skin left posterior shoulder shave biopsy (recurrence) Intraepidermal atypical melanocytic proliferation of uncertain significance extending to specimen margins see description and comment

ndash Comment Cannot rule out an evolving more significant lesion suggest complete excision

Case 5

Part 2-3 14474

Clinical InformationBiopsy from posterior shoulder of an 85 year old female

Reason for ConsultationThis specimen in my opinion has histologic features concerning for

melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis I do not see

definitive features of a scar consistent with a prior biopsy site

5212018

53

bull Broadbull Moderately

cellularbull Moderate to

severe CSDbull Poorly

circumscribedbull Few bridging

nestsbull Diffuse

fibroplasiabull Cells in dermis

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Nests in dermis

bull No maturation

5212018

54

Melan-A Stain

bull Moderately cellular

bull Continuous basal proliferation

bull Nests hanging down

bull Low level pagetoid scatter

bull Nests in dermis

bull No maturation

Your Diagnosis

Melanoma

Nevus

Our Diagnosis

Malignant melanoma lentigo maligna type (ldquolentiginous melanomardquo Clark level II Breslow thickness 085 mm

5212018

55

Updated History Cases 3-5

bull Clinical Information

bull Three separate biopsies from left posterior shoulder of an 85-year-old female over a period of three years The biopsies were performed 4 years and 1 year ago and recently

bull The original biopsy was called a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus might have been better interpreted as a lentiginous nevus of the elderlysundamaged skin with mild to moderate atypia ndash The peripheral and deep margins of the specimen were said to be negative in the plane

of sectioning

bull The next biopsy at presumably the same anatomic location was signed out as an atypical melanocytic proliferation consistent with a persistentrecurrent Clarkrsquos (dysplastic) nevus involving the peripheral edge of the biopsy ndash It was mentioned that the differential diagnosis included early melanoma in situ

evolving within a pre-existing nevus and a reexcision was recommended

bull The most recent specimen was concerning for melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis

bull Additional procedure warranted to ensure that the lesion has been completely removed`

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Cytologic atypia mild but relatively uniform bull POTENTIAL PRECURSOR (low risk) VS ACTUAL PRECURSOR (hindsight bias)bull Manage by excision or follow-up

bull Case 5

bull Second recurrence of a lesion that originally had only ldquomildrdquo atypia (but moderate to severe architectural disorder)

bull Diagnosis of dysplastic nevus should be made with caution in elderlyCSD skin

bull Complete excision is appropriate for ldquoatypical lentiginous nevus of elderlysundamaged skinrdquo

5212018

56

Last Case

Part 2-7 12150

Clinical InformationLesion of right shoulder ro melanoma versus nevus in a 76 yo man

Reason for ConsultationIs this anything other than a moderately atypical neurotized compound nevus

bull A relatively broad lesion with irregular thickening and thinning of rete ridges and a sparsely cellular infiltrate in the dermis

bull Generally sparsely cellularbull Moderate to severe CSD

Poorly circumscribed

5212018

57

bull Pigmented melanophages in the dermis

bull Increased number of melanocytes in the epidermis many of them suprabasal

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

5212018

58

S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

bull Melan-A stain highlights the junctional component but the dermal spindle cells are negative

Case 6

bull Skin right superior shoulder Malignant melanoma lentigo maligna type nonulcerated with pure desmoplastic vertical growth phase Clark level IV Breslow thickness not lt 064 mm extending close to the specimen base see Comment 3

bull Commentbull Changes extend close to the base and to a peripheral margin of the

specimenbull It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution Sbull Should be excised locally in order to prevent any possibility of persistence

recurrence or future progression of it bull Based on its microstaging attributes the prognosis for this lesion should

be excellent The prognosis for ldquopurerdquo desmoplastic melanoma is if anything better than that for melanomas of similar thickness

bull This lesion could be managed with a relatively generous wide local excision ndash MPATH DX Category 4 (or 5)

5212018

59

Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

5212018

60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

5212018

51

Your Diagnosis

Melanoma

Nevus

Diagnosis Case 4 F81

bull Recurrence of Case 8

bull Shave biopsy of similar sun-damaged skinbull Somewhat more cellular proliferation of nevoid and

nevoid to epithelioid melanocytes focally exhibiting severe and uniform cytologic atypia

bull Some of these cells are confined to the epidermis above the scar while others appear to extend some distance beyond the periphery of the scar

bull This latter feature raises some concern for evolving melanoma in situ extending beyond the scar

5212018

52

bull Skin left posterior shoulder shave biopsy (recurrence) Intraepidermal atypical melanocytic proliferation of uncertain significance extending to specimen margins see description and comment

ndash Comment Cannot rule out an evolving more significant lesion suggest complete excision

Case 5

Part 2-3 14474

Clinical InformationBiopsy from posterior shoulder of an 85 year old female

Reason for ConsultationThis specimen in my opinion has histologic features concerning for

melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis I do not see

definitive features of a scar consistent with a prior biopsy site

5212018

53

bull Broadbull Moderately

cellularbull Moderate to

severe CSDbull Poorly

circumscribedbull Few bridging

nestsbull Diffuse

fibroplasiabull Cells in dermis

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Nests in dermis

bull No maturation

5212018

54

Melan-A Stain

bull Moderately cellular

bull Continuous basal proliferation

bull Nests hanging down

bull Low level pagetoid scatter

bull Nests in dermis

bull No maturation

Your Diagnosis

Melanoma

Nevus

Our Diagnosis

Malignant melanoma lentigo maligna type (ldquolentiginous melanomardquo Clark level II Breslow thickness 085 mm

5212018

55

Updated History Cases 3-5

bull Clinical Information

bull Three separate biopsies from left posterior shoulder of an 85-year-old female over a period of three years The biopsies were performed 4 years and 1 year ago and recently

bull The original biopsy was called a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus might have been better interpreted as a lentiginous nevus of the elderlysundamaged skin with mild to moderate atypia ndash The peripheral and deep margins of the specimen were said to be negative in the plane

of sectioning

bull The next biopsy at presumably the same anatomic location was signed out as an atypical melanocytic proliferation consistent with a persistentrecurrent Clarkrsquos (dysplastic) nevus involving the peripheral edge of the biopsy ndash It was mentioned that the differential diagnosis included early melanoma in situ

evolving within a pre-existing nevus and a reexcision was recommended

bull The most recent specimen was concerning for melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis

bull Additional procedure warranted to ensure that the lesion has been completely removed`

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Cytologic atypia mild but relatively uniform bull POTENTIAL PRECURSOR (low risk) VS ACTUAL PRECURSOR (hindsight bias)bull Manage by excision or follow-up

bull Case 5

bull Second recurrence of a lesion that originally had only ldquomildrdquo atypia (but moderate to severe architectural disorder)

bull Diagnosis of dysplastic nevus should be made with caution in elderlyCSD skin

bull Complete excision is appropriate for ldquoatypical lentiginous nevus of elderlysundamaged skinrdquo

5212018

56

Last Case

Part 2-7 12150

Clinical InformationLesion of right shoulder ro melanoma versus nevus in a 76 yo man

Reason for ConsultationIs this anything other than a moderately atypical neurotized compound nevus

bull A relatively broad lesion with irregular thickening and thinning of rete ridges and a sparsely cellular infiltrate in the dermis

bull Generally sparsely cellularbull Moderate to severe CSD

Poorly circumscribed

5212018

57

bull Pigmented melanophages in the dermis

bull Increased number of melanocytes in the epidermis many of them suprabasal

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

5212018

58

S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

bull Melan-A stain highlights the junctional component but the dermal spindle cells are negative

Case 6

bull Skin right superior shoulder Malignant melanoma lentigo maligna type nonulcerated with pure desmoplastic vertical growth phase Clark level IV Breslow thickness not lt 064 mm extending close to the specimen base see Comment 3

bull Commentbull Changes extend close to the base and to a peripheral margin of the

specimenbull It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution Sbull Should be excised locally in order to prevent any possibility of persistence

recurrence or future progression of it bull Based on its microstaging attributes the prognosis for this lesion should

be excellent The prognosis for ldquopurerdquo desmoplastic melanoma is if anything better than that for melanomas of similar thickness

bull This lesion could be managed with a relatively generous wide local excision ndash MPATH DX Category 4 (or 5)

5212018

59

Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

5212018

60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

5212018

52

bull Skin left posterior shoulder shave biopsy (recurrence) Intraepidermal atypical melanocytic proliferation of uncertain significance extending to specimen margins see description and comment

ndash Comment Cannot rule out an evolving more significant lesion suggest complete excision

Case 5

Part 2-3 14474

Clinical InformationBiopsy from posterior shoulder of an 85 year old female

Reason for ConsultationThis specimen in my opinion has histologic features concerning for

melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis I do not see

definitive features of a scar consistent with a prior biopsy site

5212018

53

bull Broadbull Moderately

cellularbull Moderate to

severe CSDbull Poorly

circumscribedbull Few bridging

nestsbull Diffuse

fibroplasiabull Cells in dermis

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Nests in dermis

bull No maturation

5212018

54

Melan-A Stain

bull Moderately cellular

bull Continuous basal proliferation

bull Nests hanging down

bull Low level pagetoid scatter

bull Nests in dermis

bull No maturation

Your Diagnosis

Melanoma

Nevus

Our Diagnosis

Malignant melanoma lentigo maligna type (ldquolentiginous melanomardquo Clark level II Breslow thickness 085 mm

5212018

55

Updated History Cases 3-5

bull Clinical Information

bull Three separate biopsies from left posterior shoulder of an 85-year-old female over a period of three years The biopsies were performed 4 years and 1 year ago and recently

bull The original biopsy was called a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus might have been better interpreted as a lentiginous nevus of the elderlysundamaged skin with mild to moderate atypia ndash The peripheral and deep margins of the specimen were said to be negative in the plane

of sectioning

bull The next biopsy at presumably the same anatomic location was signed out as an atypical melanocytic proliferation consistent with a persistentrecurrent Clarkrsquos (dysplastic) nevus involving the peripheral edge of the biopsy ndash It was mentioned that the differential diagnosis included early melanoma in situ

evolving within a pre-existing nevus and a reexcision was recommended

bull The most recent specimen was concerning for melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis

bull Additional procedure warranted to ensure that the lesion has been completely removed`

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Cytologic atypia mild but relatively uniform bull POTENTIAL PRECURSOR (low risk) VS ACTUAL PRECURSOR (hindsight bias)bull Manage by excision or follow-up

bull Case 5

bull Second recurrence of a lesion that originally had only ldquomildrdquo atypia (but moderate to severe architectural disorder)

bull Diagnosis of dysplastic nevus should be made with caution in elderlyCSD skin

bull Complete excision is appropriate for ldquoatypical lentiginous nevus of elderlysundamaged skinrdquo

5212018

56

Last Case

Part 2-7 12150

Clinical InformationLesion of right shoulder ro melanoma versus nevus in a 76 yo man

Reason for ConsultationIs this anything other than a moderately atypical neurotized compound nevus

bull A relatively broad lesion with irregular thickening and thinning of rete ridges and a sparsely cellular infiltrate in the dermis

bull Generally sparsely cellularbull Moderate to severe CSD

Poorly circumscribed

5212018

57

bull Pigmented melanophages in the dermis

bull Increased number of melanocytes in the epidermis many of them suprabasal

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

5212018

58

S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

bull Melan-A stain highlights the junctional component but the dermal spindle cells are negative

Case 6

bull Skin right superior shoulder Malignant melanoma lentigo maligna type nonulcerated with pure desmoplastic vertical growth phase Clark level IV Breslow thickness not lt 064 mm extending close to the specimen base see Comment 3

bull Commentbull Changes extend close to the base and to a peripheral margin of the

specimenbull It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution Sbull Should be excised locally in order to prevent any possibility of persistence

recurrence or future progression of it bull Based on its microstaging attributes the prognosis for this lesion should

be excellent The prognosis for ldquopurerdquo desmoplastic melanoma is if anything better than that for melanomas of similar thickness

bull This lesion could be managed with a relatively generous wide local excision ndash MPATH DX Category 4 (or 5)

5212018

59

Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

5212018

60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

5212018

53

bull Broadbull Moderately

cellularbull Moderate to

severe CSDbull Poorly

circumscribedbull Few bridging

nestsbull Diffuse

fibroplasiabull Cells in dermis

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Moderately cellular

bull Moderate to severe CSD

bull Nests hanging down

bull Diffuse fibroplasia (not a scar)

bull Nests in dermis

bull No maturation

5212018

54

Melan-A Stain

bull Moderately cellular

bull Continuous basal proliferation

bull Nests hanging down

bull Low level pagetoid scatter

bull Nests in dermis

bull No maturation

Your Diagnosis

Melanoma

Nevus

Our Diagnosis

Malignant melanoma lentigo maligna type (ldquolentiginous melanomardquo Clark level II Breslow thickness 085 mm

5212018

55

Updated History Cases 3-5

bull Clinical Information

bull Three separate biopsies from left posterior shoulder of an 85-year-old female over a period of three years The biopsies were performed 4 years and 1 year ago and recently

bull The original biopsy was called a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus might have been better interpreted as a lentiginous nevus of the elderlysundamaged skin with mild to moderate atypia ndash The peripheral and deep margins of the specimen were said to be negative in the plane

of sectioning

bull The next biopsy at presumably the same anatomic location was signed out as an atypical melanocytic proliferation consistent with a persistentrecurrent Clarkrsquos (dysplastic) nevus involving the peripheral edge of the biopsy ndash It was mentioned that the differential diagnosis included early melanoma in situ

evolving within a pre-existing nevus and a reexcision was recommended

bull The most recent specimen was concerning for melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis

bull Additional procedure warranted to ensure that the lesion has been completely removed`

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Cytologic atypia mild but relatively uniform bull POTENTIAL PRECURSOR (low risk) VS ACTUAL PRECURSOR (hindsight bias)bull Manage by excision or follow-up

bull Case 5

bull Second recurrence of a lesion that originally had only ldquomildrdquo atypia (but moderate to severe architectural disorder)

bull Diagnosis of dysplastic nevus should be made with caution in elderlyCSD skin

bull Complete excision is appropriate for ldquoatypical lentiginous nevus of elderlysundamaged skinrdquo

5212018

56

Last Case

Part 2-7 12150

Clinical InformationLesion of right shoulder ro melanoma versus nevus in a 76 yo man

Reason for ConsultationIs this anything other than a moderately atypical neurotized compound nevus

bull A relatively broad lesion with irregular thickening and thinning of rete ridges and a sparsely cellular infiltrate in the dermis

bull Generally sparsely cellularbull Moderate to severe CSD

Poorly circumscribed

5212018

57

bull Pigmented melanophages in the dermis

bull Increased number of melanocytes in the epidermis many of them suprabasal

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

5212018

58

S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

bull Melan-A stain highlights the junctional component but the dermal spindle cells are negative

Case 6

bull Skin right superior shoulder Malignant melanoma lentigo maligna type nonulcerated with pure desmoplastic vertical growth phase Clark level IV Breslow thickness not lt 064 mm extending close to the specimen base see Comment 3

bull Commentbull Changes extend close to the base and to a peripheral margin of the

specimenbull It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution Sbull Should be excised locally in order to prevent any possibility of persistence

recurrence or future progression of it bull Based on its microstaging attributes the prognosis for this lesion should

be excellent The prognosis for ldquopurerdquo desmoplastic melanoma is if anything better than that for melanomas of similar thickness

bull This lesion could be managed with a relatively generous wide local excision ndash MPATH DX Category 4 (or 5)

5212018

59

Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

5212018

60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

5212018

54

Melan-A Stain

bull Moderately cellular

bull Continuous basal proliferation

bull Nests hanging down

bull Low level pagetoid scatter

bull Nests in dermis

bull No maturation

Your Diagnosis

Melanoma

Nevus

Our Diagnosis

Malignant melanoma lentigo maligna type (ldquolentiginous melanomardquo Clark level II Breslow thickness 085 mm

5212018

55

Updated History Cases 3-5

bull Clinical Information

bull Three separate biopsies from left posterior shoulder of an 85-year-old female over a period of three years The biopsies were performed 4 years and 1 year ago and recently

bull The original biopsy was called a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus might have been better interpreted as a lentiginous nevus of the elderlysundamaged skin with mild to moderate atypia ndash The peripheral and deep margins of the specimen were said to be negative in the plane

of sectioning

bull The next biopsy at presumably the same anatomic location was signed out as an atypical melanocytic proliferation consistent with a persistentrecurrent Clarkrsquos (dysplastic) nevus involving the peripheral edge of the biopsy ndash It was mentioned that the differential diagnosis included early melanoma in situ

evolving within a pre-existing nevus and a reexcision was recommended

bull The most recent specimen was concerning for melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis

bull Additional procedure warranted to ensure that the lesion has been completely removed`

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Cytologic atypia mild but relatively uniform bull POTENTIAL PRECURSOR (low risk) VS ACTUAL PRECURSOR (hindsight bias)bull Manage by excision or follow-up

bull Case 5

bull Second recurrence of a lesion that originally had only ldquomildrdquo atypia (but moderate to severe architectural disorder)

bull Diagnosis of dysplastic nevus should be made with caution in elderlyCSD skin

bull Complete excision is appropriate for ldquoatypical lentiginous nevus of elderlysundamaged skinrdquo

5212018

56

Last Case

Part 2-7 12150

Clinical InformationLesion of right shoulder ro melanoma versus nevus in a 76 yo man

Reason for ConsultationIs this anything other than a moderately atypical neurotized compound nevus

bull A relatively broad lesion with irregular thickening and thinning of rete ridges and a sparsely cellular infiltrate in the dermis

bull Generally sparsely cellularbull Moderate to severe CSD

Poorly circumscribed

5212018

57

bull Pigmented melanophages in the dermis

bull Increased number of melanocytes in the epidermis many of them suprabasal

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

5212018

58

S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

bull Melan-A stain highlights the junctional component but the dermal spindle cells are negative

Case 6

bull Skin right superior shoulder Malignant melanoma lentigo maligna type nonulcerated with pure desmoplastic vertical growth phase Clark level IV Breslow thickness not lt 064 mm extending close to the specimen base see Comment 3

bull Commentbull Changes extend close to the base and to a peripheral margin of the

specimenbull It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution Sbull Should be excised locally in order to prevent any possibility of persistence

recurrence or future progression of it bull Based on its microstaging attributes the prognosis for this lesion should

be excellent The prognosis for ldquopurerdquo desmoplastic melanoma is if anything better than that for melanomas of similar thickness

bull This lesion could be managed with a relatively generous wide local excision ndash MPATH DX Category 4 (or 5)

5212018

59

Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

5212018

60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

5212018

55

Updated History Cases 3-5

bull Clinical Information

bull Three separate biopsies from left posterior shoulder of an 85-year-old female over a period of three years The biopsies were performed 4 years and 1 year ago and recently

bull The original biopsy was called a junctional Clarkrsquos (mildly dysplastic) melanocytic nevus might have been better interpreted as a lentiginous nevus of the elderlysundamaged skin with mild to moderate atypia ndash The peripheral and deep margins of the specimen were said to be negative in the plane

of sectioning

bull The next biopsy at presumably the same anatomic location was signed out as an atypical melanocytic proliferation consistent with a persistentrecurrent Clarkrsquos (dysplastic) nevus involving the peripheral edge of the biopsy ndash It was mentioned that the differential diagnosis included early melanoma in situ

evolving within a pre-existing nevus and a reexcision was recommended

bull The most recent specimen was concerning for melanoma because of the architectural symmetry ill-defined borders contiguous proliferation of atypical solitary melanocytes and some pagetoid spread of melanocytes within the epidermis

bull Additional procedure warranted to ensure that the lesion has been completely removed`

bull Broad lesion poorly circumscribed sparse cellularity single and nested melanocytesbull Mainly near the dermal-epidermal junction focal pagetoid scatterbull Moderate chronic CSD bull Cytologic atypia mild but relatively uniform bull POTENTIAL PRECURSOR (low risk) VS ACTUAL PRECURSOR (hindsight bias)bull Manage by excision or follow-up

bull Case 5

bull Second recurrence of a lesion that originally had only ldquomildrdquo atypia (but moderate to severe architectural disorder)

bull Diagnosis of dysplastic nevus should be made with caution in elderlyCSD skin

bull Complete excision is appropriate for ldquoatypical lentiginous nevus of elderlysundamaged skinrdquo

5212018

56

Last Case

Part 2-7 12150

Clinical InformationLesion of right shoulder ro melanoma versus nevus in a 76 yo man

Reason for ConsultationIs this anything other than a moderately atypical neurotized compound nevus

bull A relatively broad lesion with irregular thickening and thinning of rete ridges and a sparsely cellular infiltrate in the dermis

bull Generally sparsely cellularbull Moderate to severe CSD

Poorly circumscribed

5212018

57

bull Pigmented melanophages in the dermis

bull Increased number of melanocytes in the epidermis many of them suprabasal

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

5212018

58

S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

bull Melan-A stain highlights the junctional component but the dermal spindle cells are negative

Case 6

bull Skin right superior shoulder Malignant melanoma lentigo maligna type nonulcerated with pure desmoplastic vertical growth phase Clark level IV Breslow thickness not lt 064 mm extending close to the specimen base see Comment 3

bull Commentbull Changes extend close to the base and to a peripheral margin of the

specimenbull It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution Sbull Should be excised locally in order to prevent any possibility of persistence

recurrence or future progression of it bull Based on its microstaging attributes the prognosis for this lesion should

be excellent The prognosis for ldquopurerdquo desmoplastic melanoma is if anything better than that for melanomas of similar thickness

bull This lesion could be managed with a relatively generous wide local excision ndash MPATH DX Category 4 (or 5)

5212018

59

Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

5212018

60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

5212018

56

Last Case

Part 2-7 12150

Clinical InformationLesion of right shoulder ro melanoma versus nevus in a 76 yo man

Reason for ConsultationIs this anything other than a moderately atypical neurotized compound nevus

bull A relatively broad lesion with irregular thickening and thinning of rete ridges and a sparsely cellular infiltrate in the dermis

bull Generally sparsely cellularbull Moderate to severe CSD

Poorly circumscribed

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bull Pigmented melanophages in the dermis

bull Increased number of melanocytes in the epidermis many of them suprabasal

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

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S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

bull Melan-A stain highlights the junctional component but the dermal spindle cells are negative

Case 6

bull Skin right superior shoulder Malignant melanoma lentigo maligna type nonulcerated with pure desmoplastic vertical growth phase Clark level IV Breslow thickness not lt 064 mm extending close to the specimen base see Comment 3

bull Commentbull Changes extend close to the base and to a peripheral margin of the

specimenbull It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution Sbull Should be excised locally in order to prevent any possibility of persistence

recurrence or future progression of it bull Based on its microstaging attributes the prognosis for this lesion should

be excellent The prognosis for ldquopurerdquo desmoplastic melanoma is if anything better than that for melanomas of similar thickness

bull This lesion could be managed with a relatively generous wide local excision ndash MPATH DX Category 4 (or 5)

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Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

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2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

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57

bull Pigmented melanophages in the dermis

bull Increased number of melanocytes in the epidermis many of them suprabasal

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

bull Cells in the papillary dermis are delicate spindle cells and there is a sprinkling of lymphocytes

5212018

58

S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

bull Melan-A stain highlights the junctional component but the dermal spindle cells are negative

Case 6

bull Skin right superior shoulder Malignant melanoma lentigo maligna type nonulcerated with pure desmoplastic vertical growth phase Clark level IV Breslow thickness not lt 064 mm extending close to the specimen base see Comment 3

bull Commentbull Changes extend close to the base and to a peripheral margin of the

specimenbull It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution Sbull Should be excised locally in order to prevent any possibility of persistence

recurrence or future progression of it bull Based on its microstaging attributes the prognosis for this lesion should

be excellent The prognosis for ldquopurerdquo desmoplastic melanoma is if anything better than that for melanomas of similar thickness

bull This lesion could be managed with a relatively generous wide local excision ndash MPATH DX Category 4 (or 5)

5212018

59

Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

5212018

60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

5212018

58

S100 stain highlights the increased cellularity in the epidermis and also labels the spindle cells in the papillary dermis

bull Melan-A stain highlights the junctional component but the dermal spindle cells are negative

Case 6

bull Skin right superior shoulder Malignant melanoma lentigo maligna type nonulcerated with pure desmoplastic vertical growth phase Clark level IV Breslow thickness not lt 064 mm extending close to the specimen base see Comment 3

bull Commentbull Changes extend close to the base and to a peripheral margin of the

specimenbull It is unusual to see a small desmoplastic melanoma at this early stage of

its evolution Sbull Should be excised locally in order to prevent any possibility of persistence

recurrence or future progression of it bull Based on its microstaging attributes the prognosis for this lesion should

be excellent The prognosis for ldquopurerdquo desmoplastic melanoma is if anything better than that for melanomas of similar thickness

bull This lesion could be managed with a relatively generous wide local excision ndash MPATH DX Category 4 (or 5)

5212018

59

Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

5212018

60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

5212018

59

Take Home Messages

bull Earlyevolving LMM IS can be subtle

bull Changes at periphery and at margins can be subtlendash Confluence or continuous proliferation of uniformly

atypical cells

ndash Nests in epidermis overlying elastotic dermis (LeBoit)

bull Focal areas in LMM IS can mimic dysplastic nevusndash Diagnosis of dysplastic nevus in sun-damaged skin of

elderly is fraught with hazard

bull Diagnosis is often based more on architectural disorder(including size) than on severe cytologic atypia

High CSD Lesions

bull Cautious approach ndash beware of nests of melanocytes in epidermis above solar elastosis

bull Caution in diagnosis of dysplastic nevus in CSD skin

bull Do not overcall actinic atypia in re-excision specimens (more of a risk marker than a precursor)

bull Beware of subtle spindle cells in dermal component of CSD melanomas

5212018

60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014

5212018

60

2 Melanocytic Tumours2-0 Introduction to melanocytic tumours

2-1A Pathway concept

2-1B Genomic landscape of melanoma

2-1 Nodular nevoid and metastatic melanomas

2-2A Nodular melanoma

2-2B Nevoid melanoma

2-2C Metastatic melanoma

2-2 Melanoma in Intermittently sun-exposed skin and simulantsprecursors

2-3A Superficial spreading melanoma

2-3B Simple lentigo junctional naevus compound naevus dermal naevus

2-3C Speckled lentiginous naevus and naevus spilus

2-3D Dysplastic nevi

2-3E Special site nevi ndash breast axilla scalp ear

2-3F Halo naevus

2-3G Meyerson nevus

2-3H Deep penetrating naevus

2-3I Recurrent naevus

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2-4 Melanoma in acral skin and simulantsprecursors

2-5A Acral melanoma

2-5B Acral naevus

2-5 Melanoma arising from blue naevus and simulantsprecursors

2-6A Melanoma arising from blue naevus

2-6B Blue naevus cellular blue naevus

2-6C Pigmented epithelioid melanocytoma

2-6D Mongolian spot

2-6E Naevus of Ito and Ota

2-6F Combined naevus

2-6 Melanoma arising in congenital naevi and simulantsprecursors

2-7A Melanoma arising in a giant congenital naevus

2-7B Congenital melanocytic naevus junctional naevus compound naevus

2-7C Proliferative nodules in congenital naevi

2-7 Spitz Tumours

2-8A Malignant Spitz tumour

2-8B Spitz naevus tumour

2-8C Pigmented spindle cell naevustumour (Reed)

2-8 Genital and mucosal melanomas and precursorssimulants

2-9A Mucosal melanoma (genital oral sinonasal)

2-9B Genital naevi

2-9 Ocular melanoma

2-10A Uveal melanoma

2-10B Conjunctival melanoma

2018 Proposed Classification of Melanoma Precursors and Simulants

2 Melanocytic Tumours

2-3 Melanoma in chronically sun-exposed skin and simulantsprecursors

2-4A Lentigo maligna melanoma

2-4B Desmoplastic melanoma

2-4C Lentiginous naevus

2018 Proposed Classification of Melanoma Precursors and Simulants

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

CSDDesmopl

melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Non-CSDmelanoma

Spitz nevus

Atypical Spitz tumor

Spitzoid melanoma

NRAS

HRAS

BRAF

KIT

Fusions

Bastian 2014