Melanocytic proliferations in sun- Atypical Spitzoid Tumor...

Department of Cutaneous Oncology#

Melanocytic proliferations in sun-damaged skin

Jane L. Messina, MDInternational Melanoma Pathology

Working Group 4th annual meeting

Tampa, FloridaNovember 14, 2011

Atypical Atypical SpitzoidSpitzoid Tumor: What Does It Tumor: What Does It

Mean And How Should It Be Managed?Mean And How Should It Be Managed?

Jane L. MessinaMelanoma and Other Cutaneous Malignancies, Session 5

March 23, 2013 8:45-9:05 am

Department of Cutaneous Oncology

Disclosures

• Durect Corporation-consultant

• Glaxo Smith Kline-consultant

2


Exhibit 1

• 19 y/o M with lesion on posterior neck

• 3 diagnoses proferred:

� “severely atypical compound melanocytic

lesion with Spitzoidfeatures, favor melanoma”

� “favor peculiar nevus

with Spitzoid and congenital features but cannot r/o melanoma”

� “markedly atypical

compound Spitzoidmelanocytic tumor”

• WLE and SLNbx: both negative

3

Four years after surgery: patient develops multiple brain and lung metastases


Basic conundrum

• Criteria don’t always predict behavior (or even SLN involvement)

• Misdiagnosed melanoma major issue (#1 lawsuit for

dermatopathologists)

4

Underdiagnosis

•Recurrence or death

•Loss of

opportunity for

adjuvant treatment

•Medicolegal

Overdiagnosis

•Surgical morbidity

•SLNB procedure

not proven to increase OS

•Psychological trauma

•Insurability


Goals

•Historical perspective

•Pathologic criteria

•Sentinel node issues

•Molecular advances

•Treatment algorithm


Spitz S. Melanoma of

childhood. Am J

Pathol. 1948;24:591-609

Allen AC. A

reorientation of

the

histogenesis

and clinical

significance of

cutaneous

nevi and

melanomas.

Cancer. 1949; 2:28-56.

Smith KH, Barrett TL, Skelton HG et al. Spindle cell

and epithelioid cell nevi with atypia and metastasis

(malignant Spitz nevus). Am J Surg Pathol. 1989;13:931-939.

Barnhill RL et al. Atypical Spitz

nevi/tumor: lack of consensus

for diagnosis, discrimination

from melanoma, and prediction

of outcome. Hum Pathol. 1999;30:513-520.

??


Atypical Spitz nevus

7

• 1969: “We propose the term

‘atypical Spitz’s nevus’ in the same

fashion as Helwig, who uses atypical

for the pseudomalignant characterof the atypical fibroxanthoma.”

• 1975: Reed et al. first use term

“atypical Spitz nevus” in American literature

• 1976: Helwig reports 23 young

patients with metastatic melanoma

and Spitz-like primary tumor, proposed better prognosis

• 1977: Weedon and Little put forth

histologic characteristics to

distinguish atypical Spitz’s nevusfrom melanoma

Helwig EB.Heath Memorial Award Lecture. Year Book Medical Publishers, Inc; 1975: 11-26.Reed RJ et al. Semin Oncol, 1975;2:119-47.Weedon D, Little JH. Cancer, 1977; 40:217-225.


“Conventional”

Spitz Nevus

Atypical

Spitz Nevus/TumorSpitzoid

melanoma

??


Atypical Spitz TumorDistinct entity or IDK?

• Large size, generally > 1.0cm

• Deeper extension, often involving subcutis

• Asymmetry, ulceration, poor circumscription

• Prominent pagetoid melanocytosis

• High cellular density and/or confluence of melanocytes

• Absence of maturation

• Increased deep/marginal mitoses (>2-6/mm2)

• Spitzoid cytomorphology

Barnhill, RL. Modern Pathol 19: S21-S33;2006.Caraco et al. Eur J Surg Oncol Oct. 2012, 932-935


“Conventional”

Spitz Nevus

Atypical

Spitz Nevus/TumorSpitzoid

melanoma“Conventional”

Spitz Nevus

AtypicalSpitz Nevus/Tumor

Spitzoidmelanoma


Atypical Spitz tumorRelevant questions

• What is the outcome of the reported series of AST?

• What is the incidence and meaning of SLN involvement?

• Does AST have a distinct histologic, immunohistochemical, genetic or molecular profile?

• How do we find the Spitzoid melanomas?


Death in patients with AST

• >300 reported cases of AST, most treated with SLN mapping

• Seven total deaths Ages 12,13,14, 24, 43, 46, and 50

�6 had no SLNB, 1 had +SLN

Raskin L et al. Am J Surg Pathol 2011;35:243-52. Ludgate MW et al. Cancer2009;115:631-41/Cerroni L et al. Am J Surg Pathol 2010;34:314-260/Barnhill RL et al. Hum Pathol 1999;30:513-20./ Gerami et al. Am J Surg Pathol Feb 2013;

Department of Cutaneous Oncology 14

Pts Mean age Mean depth mm

SLN+rate

Pts w/+CLND

Lohmann et al. 2002 10 21 3.9 50% 1/5

Su et al 2003 18 16 3.5 44% 1/8

Gamblin et al 2006 10 21 n/d 33% 1/3

Urso et al. 2006 12 23.2 2.9 33% 1/3

Murali et al 2008 21 31 2.1 25% 0/6

Ludgate et al. 2009 67 23.7 2.4 47% 1/27

Ghazi et al 2010 27 15.5 1.9 22% 0/4

Cerroni et al. 2010 35 21 3.5 71% n/d

Raskin et al. 2011 15 17.5 3.0 53% 0/8

Sepehr et al 2011 6 23.5 n/d 17% 0/1

Mills et al 2012 10 13 2.2 20% 1/2

Caraco et al 2012 40 32 1.5 0% n/a

Hung et al. 2012 23 27 2.0 26% 0/3

Totals 294 -- -- 34% 6/70 (9%)

AST SLN biopsy results


Features of SLN in AST

• Four series describe SLN deposits

�Largest series of 27: 85% had <1% nodal involvement, 62% <0.2 mm

�Remaining 3 series: 50% of patients had

isolated parenchymal/subcapsular disease, all <2 mm

Urso, Murali, Ludgate, Gamblin


Features of involved SLN in AST


Contrast: Capsular nevus cell aggregates


Contrast: Intratrabecular nevus cell aggregates


Melanoma micrometastasis

20


Features predictive of SLN involvement in AST

• Most series, including largest, have found no

significant differences between SLN+ and SLN-tumors

• Significant:

�Deep mitoses, less inflammation plasma cells1

�Mean tumor thickness2

�>6 mitoses/sq mm3

1.Massi et al. J Am Acad Dermatol 2011;64:919-35

2. Murali et al. Annals of Surgical Oncology 15(1):302–309

3. Hung et al Human Pathology (2013) 44, 87–94


Outcome of AST patients with SLNBPatients Mean duration

f/u in moRecurrence beyond SLN

Death with metatasis

Lohmann et al. 2002 10 33.7 0/10 0/10

Su et al 2003 18 9.8 0/18 0/18

Gamblin et al 2006 10 33.7 0/10 0/10

Urso et al. 2006 12 26.3 0/12 0/12

Murali et al 2008 21 25.8 0/21 0/21

Ludgate et al. 2009 57 43.8 0/57 0/57

Ghazi et al. 27 56 0/6 0/6

Cerroni et al. 2010 35 83.5 8/35 1/35

Raskin et al. 2011 15 NR 0/15 0/15

Sepehr et al 2011 6 64.6 0/6 0/6

Caraco et et 2012 40 39 0/40 0/40

Mills et al 2012 10 49 0/10 0/10

Hung et al. 2012 23 55.6 0/23 0/23

Totals 284 9-64 8/263 1/263


Meaning of SLN involvement

• Recurrence and death vanishingly rare in 13 series with followup ranging from 9-64 months

• Comparison with childhood melanoma

�5 year o/s ~75%

�~1/2 of recurrence/death occurs after 5 years

• AST could represent unique, less aggressive

subtype of melanoma potentially cured by SLN removal


Pros and cons of SLN biopsy

Pros

• Guides further therapy/monitoring

• May be saved more extensive surgery later

• Alleviates uncertainty,

about 2/3 get “good news”

• May be therapeutic

Cons• Guides further

therapy/monitoring

• May create unecessary anxiety

Diagnosis? “Metastatic melanocytic tumor of uncertain malignant potential”


Case 2-HH-age 14

• 1997: presented to pediatrician with longstanding mole since birth, biopsied and told benign

• 1999: mother went to MCC presentation and noted similarities to daugher’s mole, prompting rebiopsy: diagnosis of malignant melanoma of back, Clark IV, 3.4 mm in depth

• Underwent WLE and SLNB� No residual tumor

� 0/3 +SLN right neck

� 1/11 +SLN right axilla


14 y/o F

with 3.4 mm

melanoma of back

L axillaSLN 9


Same patient 10 years after CLND and adjuvant interferon


Fluorescence in situ hybridization

• Initial four-probe assay (6p25, Cep6, 6q23, 11q13) tested on unequivocal neoplasms: sensitivity 87%, specificity 95%

• Newer four-probe assay with 6p25, 8q24, 9p21, 11q13: sens. 94%, spec. 98%

• Polyploidy: 10% of typical Spitz have balanced gains in all four probe sets (3-4x)

Isaac et al. Am J Dermatopathol 2010;32:144–148


FISHing for ASTsOriginal assay

• 25 typical and atypical Spitz with known

outcome (4 deaths/advanced logoregionaldisease)

�24% of cases FISH positive (3 had <5 year f/u)

�100% sensitive, 57% specific

• 16 AST with long-term outcome (1 death)

�All negative (0% sensitive, 0% specific)

Massi et al. J Am Acad Dermatol 2011;64:919-35Raskin et al. Am J Surg Pathol 2011;35:243–252


FISHing for ASTsNewer assay

• Recently tested on 75 AST

�64 uneventful 5 year f/u, 11 with advanced locoregional disease, distant metastasis or death

�All 11 patients with advanced disease had abnormality of at least one locus

�9 showed deletions of 9p21-most significant and only feature predictive of death

�However, 24.3% of patients with uneventful follow up had a positive result

�Sensitivity 100%, specificity 74%Gerami et al, Am J Surg Pathol, Feb 2013


Comparative genomic hybridization

• 95% of melanomas harbor numerous chromosomal gains and losses

• Nevi rarely show aberrations

• 15% of Spitz nevi (esp. recurrent) have 11p or 7q gain

• 7/16 AST had abnormalities (esp. 1p, 9 loss or gain, none in chromosomes evaluated by FISH)

Bastian BC et al. J Invest Dermatol. 1999;113:1065–1069.Bastian BC et al. Am J Pathol. 2003;163:1765–1770Raskin et al. Am J Surg Pathol 2011;35:243–252


Molecular characteristics of AST

• BRAF: 0-75% found in 54 lesions tested in four series

�0/7, 12/16, 1/16, 2/15

• HRAS: 15% (4/26) in two series

• NRAS: 6% (2/31) in two series

Raskin et al. Am J Surg Pathol 2011;35:243–252

Massi et al. J Am Acad Dermatol 2011;64:919-35

Takata et al. British Journal of Dermatology 2007 156, pp1287–1294Fullen et al. Mod Pathol 2006;19:1324-32.


Immunohistochemical staining

• Ki-67 for proliferative activity: >10% favors melanoma, <10% does not exclude

• pHH3 for mitoses

• HMB-45 for maturation

• BAP1 if multiple lesions

• P16 loss, BRAFv600E significance unclear

Nasr MR, El-Zammar O. Am J Dermatopathol. Apr 2008;30(2):117-122Ohsie et al. J Cutan Pathol 2008; 35:433-444


Ki-67: the good, the bad, and the ugly


Phosphohistone H3 stains cells in mitosis


p16 and malignant potential

• p16:multiple studies show loss in 50-98% of melanoma

• Loss of p16 in 6/6 childhood Spitzoidmelanoma, but present in 18/18 Spitz nevi and 12/12 melanocytic nevi

• Recently, present in 15/19 (79%) Spitzoidmelanoma and 83% Spitz

Al Dhaybi R et al J Am Acad Dermatol. Aug 2011;65(2):357-363Ohsie et al. J Cutan Pathol 2008; 35:433-444Mason et al. J Cutan Pathol 2012; 39(12): 1062-74.


Loss of p16 in childhood melanoma


p16 stains childhood Spitz nevi


HMB-45

• Diminished staining with dermal depth in most benign nevi including Spitz

• Stains entire dermal component of melanoma

Ohsie et al. J Cutan Pathol 2008; 35:433-444


HMB-45 staining in nevus


Summary

Atypical Spitz tumor: What does it mean and how is it managed?

• Increasingly recognized melanocytic neoplasm

which deviates from typical benign Spitz but

does not seem to have a distinctive molecular or genetic profile

• Most common in children and young adults

• Frequent but low-volume SLN metastasis

• Low recurrence rate with relatively long-term followup

44


Summary

Atypical Spitz tumor: What does it mean and how is it managed?

• Workup should include expert consultation, molecular analysis by FISH and/or CGH

• Recommend wide excision and SLN biopsy until reliable test to exclude melanoma is available

Melanocytic proliferations in sun- Atypical Spitzoid Tumor...

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