L E C T U R E 1M O N D A Y , 2 7 J A N 2 07 : 0 0 A M – 7 : 4 5 A M

THE 2018 WHO CLASSIFICATION OF MELANOMA, ITS PRECURSORS & SIMULANTS

L E C T U R E 2M O N D A Y , 2 7 J A N 2 08 : 3 0 A M – 9 : 1 5 A M

SUPERFICIAL ATYPICAL MELANOCYTIC PROLIFERATIONS (SSM, LMM, & THEIR

SIMULANTS) PART 1 SSM.

L E C T U R E 3M O N D A Y , 2 7 J A N 2 01 0 : 3 0 A M – 1 1 : 1 5 A M

SUPERFICIAL ATYPICAL MELANOCYTIC PROLIFERATIONS (SSM, LMM, & THEIR

SIMULANTS) PART 2 LMM.

University of Pennsylvania, Founded by Ben Franklin in 1740

The 2018 WHO Classification of Cutaneous and Mucosal Melanoma

Classification of Melanoma, Simulants and Precursors, and Pathway Concept Maui, HI 2020

David E ElderHospital of the University of Pennsylvania

WHO Classification of Skin Tumours• Edited by • David E Elder• Daniela Massi• Richard A Scolyer• Rein Willemze

• And > 100 contributors

The “New” Classification builds on previous work …

3rd Edition, 2006

REFERENCES

LeBoit P, Burg G, Weedon D, Sarasin A. Melanocytic Tumors. In: LeBoit PE, Burg G, Weedon D, Sarasin A, editors. Pathology and Genetics of Skin Tumors. World Health Organization Classification of Tumors. Lyon: IARC Press; 2006. p. 49-120.

Clark WH JR. A classification of malignant melanoma in man correlated with histogenesis and biologic behavior. In: Montagna W, Hu F, editors. Advances in the Biology of the Skin Volume VIII. New York: Pergamon Press; 1967. p. 621-47.

McGovern VJ. The classification of melanoma and its relationship with prognosis. Pathology. 1970;2:85-98.

Arrington JH 3d, Reed RJ, Ichinose H, Krementz ET. Plantar lentiginous melanoma: a distinctive variant of human cutaneous malignant melanoma. Am J Surg Pathol. 1977;1:131-43.

Spitz S. Melanomas of childhood. Am J Pathol. 1948;24:591-609.

VJ McGovern WH Clark JR RJ Reed S. Spitz

The “new” Classification was Built on the Work of Mentors, Friends and Pioneers

CSD/Site-Related Classification

• Bastian’s CSD/Site-Related Classification (Taxonomy) of Melanoma

• “The guiding principles for distinguishing taxa are genetic alterations that arise early during progression; clinical or histologic features of the primary tumor; characteristics of the host, such as age of onset, ethnicity, and skin type; and the role of environmental factors such as UV radiation.”

Boris Bastian MD, PhD

Benign

Borderline

Malignant

Site

Epithelium associated

High UV

HighCSD

Desmopl. melanoma

Glabrous Mucosa

Acralmelanoma

Mucosal melanoma

Low UV

Acquired nevus

Dysplastic nevus

Low-CSDmelanoma

Spitz nevus

Atypical Spitz

tumor

Spitzoid melanoma

Point mutations 103

105

Structural Rearrangements

Bastian BC. The molecular pathology of melanoma: an integrated taxonomy of melanocytic neoplasia. AnnuRev Pathol. 2014;9:239-71.

Multidimensional Pathway Classification of Melanocytic Tumors. WHO 4th Edition, 2018.

• Epidemiologic, Clinical, Histologic and Genomic Aspects of Melanoma

David E. Elder, MB ChB, FRCPAUniversity of Pennsylvania, Philadelphia, PA, USA

USCAP March 2019

Fourth Edition WHO “Pathway” Classification

• 4e WHO Classification “Blue Book” (2018), defines 9 “Pathways” to melanoma.

• The “Pathway” concept is based on epidemiologic, clinical, histological, and genomic attributes and includes the mode of evolution of melanomas from precursors.

•

Fourth Edition WHO “Pathway” Classification• Term “Pathway” is attributable to Whiteman and to Bastian, both in 2003:• Whiteman et al (Brisbane), distinguished two pathways for common cutaneous

melanomas by epidemiology:• “Cutaneous melanomas may arise through two pathways, one associated with

melanocyte proliferation and the other with chronic exposure to sunlight”. • Whiteman DC, Watt P, Purdie DM, Hughes MC, Hayward NK, Green AC. Melanocytic nevi, solar keratoses, and divergent pathways to

cutaneous melanoma. J.Natl.Cancer Inst. 2003;95:806-12.

• Bastian’s group (UCSF) described two pathways at the molecular level:• “BRAF mutations are … more common in melanomas occurring on skin subject to

intermittent sun exposure … the uneven distribution of BRAF mutations strongly suggests distinct genetic pathways leading to melanoma”.

• Maldonado JL, Fridlyand J, Patel H, et al. Determinants of BRAF mutations in primary melanomas. J Natl Cancer Inst. 2003;95(24):1878-1890.

New Classification of Melanoma

• Assists in sensitivity, specificity and reproducibility of diagnosis by providing a conceptual morphologic framework

• Provides a context for selection of therapy:• Targeted therapy directed against oncogenes• Immune therapy directed against neoantigens

New (Revised) Classification

• The new classification incorporates benign, intermediate or “borderline” and malignant lesions

• The benign lesions have a single genomic abnormality (e.g. BRAF V600E)

• The intermediate lesions typically have two genomic abnormalities • e.g. hemizygous loss of CDKN2A, TERT promoter mutations, BAP1 loss

• They have architectural and cytological features different from benign lesions (architectural disorder and cytological atypia)• e.g. dysplastic nevi, deep penetrating nevus (DPN), Pigmented Epithelioid Melanocytoma

(PEM), BAP1 deficiency “Melanocytomas”

• More Common in Sun-Susceptible Populations:• Pathway I. Low CSD Melanoma/Superficial Spreading Melanoma (SSM)• Pathway II. High CSD Melanoma/Lentigo Maligna Melanoma (LMM)• Pathway III. Desmoplastic Melanoma

• Incidence about the same world-wide• Pathway IV. Malignant Spitz Tumor (?)• Pathway V. Acral Melanoma• Pathway VI. Mucosal Melanoma• Pathway VII. Melanoma in Congenital Nevus (MCN)• Pathway VIII. Melanoma in Blue Nevus (MBN)• Pathway IX. Uveal Melanoma

• Variable Pathways: Nodular Melanoma

Lv, Jiaojie, Dai, Bo, Kong, Yunyi, Shen, Xuxia, Kong, Jincheng (Shanghai, 2016)

Tumor Progression in Melanoma

• Precursor Nevus• Radial Growth Phase (RGP)/MIS

• Good Prognosis

• Vertical Growth Phase (VGP)• Worse Prognosis

• Characteristics of Precursors:• Not obligate• Steps can be skipped

The Genetic Evolution of Melanoma from Precursor Lesions. Shain AH, Yeh I, Kovalyshyn I, Sriharan A, Talevich E, Gagnon A, et al. The Genetic Evolution of Melanoma from Precursor Lesions. N Engl J Med. 2015;373(20):1926-36.

• Dissected parts of lesions and did next generation sequencing

• Parts (regions) were classified as “Benign”, “Intermediate, Probably Benign”, “Intermediate probably Malignant”, “Melanoma in situ”, and “Invasive Melanoma”

The Genetic Evolution of Melanoma from Precursor Lesions. Shain, NEJM 2015.

• Unequivocally benign precursors had only BRAF V600E mutations

• “Intermediate” lesions (e.g. dysplastic nevi) had NRAS and additional driver mutations.

• TERT promoter mutations were present in intermediate lesions and melanomas in situ.

• Biallelic inactivation of CDKN2A exclusively found in invasive melanomas.

“Intermediate” category has more than one genetic alteration and distinctive histopathologic features.

“Intermediate” category has more than one genetic alteration and distinctive histopathologic features.

Role of UV: Low UV High UV Low to No (or Variable) CSD

Pathway: I II III IV V VI VII VIII IX

Low-CSD MelanomaSuperficial Spreading Melanoma

High-CSD Melanoma (LMM)

Desmoplastic Melanoma

Spitz Melanoma Acral Melanoma Mucosal

MelanomaMelanoma in

Congenital NevusMelanoma

In Blue Nevus Uveal Melanoma

Benign Nevus ? IAMP ? IAMP Spitz Nevus ?IAMP Melanosis Congenital Nevus (CN) Blue Nevus ?

Borderline Low Low Grade Dysplasia Bap-1 Deficiency

Melanocytoma /MELTUMP

DPN Melanocytoma

/MELTUMP

PEM Melanocytoma

/MELTUMP

? IAMP ? IAMP Atypical Spitz nevus

Atypical melanocytic proliferation

Atypical melanosis Nodular proliferation in CN

Cellular Blue Nevus Uveal nevus

Borderline High High Grade Dysplasia Lentigo maligna Melanoma in situ STUMP Melanoma in situ IAMPUS/ SAMPUS ? MIS in CN Atypical CBN ?

MalignantSuperficial Spreading Melanoma

Melanoma in BPDM (rare)

Melanoma in DPN (rare)

Melanoma in PEM (rare)

Lentigo Maligna Melanoma Desmoplastic Melanoma Malignant Spitz

TumorAcral lentiginous melanoma

Mucosal lentiginous melanoma

Melanoma in CN Melanoma ex Blue Nevus Uveal melanoma

Common mutations

BRAF V600E, NRAS(BRAF or NRAS)+BAP1

(BRAF, MEK1, or NRAS) +(CTNNB1 or APC)

(BRAF +PRKAR1A) or PRKCA

NRAS, BRAFnon-V600E, KIT, NF1

NF1, ERBB2, MAP2K1, MAP3K1, BRAF, EGFR, MET,

HRAS, ALK, ROS1, RET, NTRK1, NTRK3, BRAF,MET

KIT, NRAS, BRAF, HRAS, KRAS, NTRK3, ALK, NF1

KIT, NRAS, KRAS, or BRAF

NRAS, BRAF V600E(small lesions), BRAF

GNAQ, GNA11, or CYSLTR2

GNAQ, GNA11, CYSLTR2, or PLCB4

TERT, CDKN2A, TP53, PTEN

TERT, CDKN2A, TP53, PTEN, RAC1

TERT, NFKBIE, NRAS, PIK3CA , PTPN11

CDKN2A CDKN2A, TERT CCND1, GAB2

NF1, CDKN2A SF3B1, CCND1, CDK4, MDM2

BAP1, EIF1AX, SF3B1

BAP1SF3B1, EIF1AX,

Table 1. Classification of Melanocytic Tumors by Epidemiologic, Clinical, Histopathologic & Genomic Attributes

Notes: Progression is not obligate and steps can be skipped

Color Code: Mutations: Red; gain of function; Blue, loss of function; Green, change of function, Black, promoter mutation. Orange, amplifications. Purple: Rearrangements.

CSD Melanomas (Pathways 1-III)

Bastian BC, de la Fouchardiere, A, Elder, DE, Gerami P, Lazar AJ, Massi D, Nagore E, Scolyer RA, Yun SJ. Genomic Landscape of Melanoma.In Elder DE, Massi D, Scolyer RA, Willemze R: WHO Classification of Skin Tumours, Lyon, 2018

Low UVPathway I

Low-CSD MelanomaSuperficial Spreading Melanoma

Precursors:Banal Acquired Nevus (junctional, compound, dermal)

Low Grade DysplasiaBap-1 Deficiency Melanocytoma

Deep penetrating nevus (DPN)/ Melanocytoma

Pigmented Epithelioid Melanocytoma (PEM)

High Grade Dysplasia

Superficial Spreading Melanoma Melanoma in BPDM (rare)Melanoma in DPN (rare) Melanoma in PEM (rare)

BRAF V600E, NRAS (Gain of function, activated oncogenes, mutually exclusive)

(BRAF or NRAS)+BAP1 (BRAF, MEK1, or NRAS) +(CBNN1 or APC)

BRAF + PRKAR1A or PRKCA

TERT (promoter mutation)CDKN2A, TP53, PTEN (loss of function/ suppressor)

Lentiginous junctional nevus

Compound dysplastic nevus

Superficial spreading or “pagetoid” melanoma

Superficial Spreading Melanoma SSM

• Asymmetry

• Border irregularity

• Color variegation

• Diameter > 4 mm

• Discrete border

Viros A, et al. Improving melanoma classification by integrating genetic and morphologic features. Plos Med. 2008;5(6):e120

SSM v LMM• High pigment• High scatter• High nesting• Good circumscription• Thickened epidermis • Larger cell size• Similar nuclear size• Epithelioid > spindle

cells• Lower CSD

High UVPathway II

High-CSD Melanoma (LMM)

Severe CSD (exposed skin, outdoor work)

High Tumor Mutation Burden (TMB)UV signature mutations

Lentigo maligna melanoma in situ before invasive melanoma, may progress to vertical growth phase

Lentigo Maligna Melanoma: Continuous basal “lentiginous” proliferation of uniformly atypical melanocytes.

NRAS, BRAFnon-V600E, KIT, (gain of function, activated oncogenes, mutually exclusive)NF1 (Loss of function)

TERT (promoter mutation), CDKN2A, TP53, PTEN (Loss of function)RAC1

Viros A, et al. Improving melanoma classification by integrating genetic and morphologic features. Plos Med. 2008;5(6):e120

SSM v LMM• Low pigment• Low scatter• Low nesting• Poor circumscription• Thinned epidermis • Smaller cell size• Similar nuclear size• Spindle > epithelioid

cells• HIGH CSD

High UVPathway III

Desmoplastic Melanoma

Skin with Severe CSD

High Tumor Mutation Burden

Melanoma in situ, or may be no in situ lesion

Infiltrative spindle cells separated by “desmoplastic” collagen

NF1 (loss of function)ERBB2, MAP2K1, MAP3K1, BRAF, EGFR, MET (amplifications)

TERT, NFKBIE, NRAS PIK3CA PTPN11

Desmoplastic Melanoma

NF1, ERBB2, MAP2K1, MAP3K1, BRAF, EGFR, MET,

TERT, NFKBIE, NRAS PIK3CA PTPN11

HIGH TUMOR MUTATION BURDEN (Potential checkpoint therapy)

Eroglu Z, Zaretsky JM, Hu-Lieskovan S, Kim DW, Algazi A, Johnson DB, et al. High response rate to PD-1 blockade in desmoplastic melanomas. Nature. 2018;553(7688):347-50.

“ … patients with advanced desmoplastic melanoma derive substantial clinical benefit from PD-1 or PD-L1 immune checkpoint blockade therapy, even though desmoplastic melanoma is defined by its dense desmoplastic fibrous stroma. The benefit is likely to result from the high mutational burden and a frequent pre-existing adaptive immune response limited by PD-L1 expression”

CSD Melanomas (Pathways IV-IX)

Bastian BC, de la Fouchardiere, A, Elder, DE, Gerami P, Lazar AJ, Massi D, Nagore E, Scolyer RA, Yun SJ. Genomic Landscape of Melanoma.In Elder DE, Massi D, Scolyer RA, Willemze R: WHO Classification of Skin Tumours, Lyon, 2018

Pathway IVNo UV

Malignant Spitz TumorSpitz Nevus

Atypical Spitz nevus

STUMPMalignant Spitz Tumor(vs. Malignant Spitzoid Tumor, vs. “Melanoma with Spitzoid Features”)HRAS (GOF), ALK, ROS1, RET, NTRK1, NTRK3, BRAF, MET (Fusions),

CDKN2A (LOF)

Fatal Malignant Spitz tumor (vs Spitzoid melanoma) in a 12 y.o. girl

• Younger patients/ children

• Fusion genes • Closely related

pigmented spindle cell nevus of Reed

Wiesner T, He J, Yelensky R, Esteve-Puig R, Botton T, Yeh I, et al. Kinase fusions are frequent in Spitz tumours and spitzoid melanomas. Nature communications. 2014;5:3116

VandenBoom T, Quan VL, Zhang B, Garfield EM, Kong BY, IsalesMC, et al. Genomic Fusions in Pigmented Spindle Cell Nevus of Reed. The American journal of surgical pathology. 2018;42(8):1042-51

Typical Spitz Nevus

Atypical Spitz Tumor

- 4 y.o. child, large size- Mitotic rate 4 per sq mm- Lack of good maturation

HRAS (GOF, Activated oncogene), ALK, ROS1, RET, NTRK1, NTRK3, BRAF, MET (fusions),

CDKN2A (loss of function, suppressor gene)

Table from: Barnhill R.L. Bahrami A. Bastian B.C. Busam K.J. Cerroni L. de la Fouchardière A., Elder DE, et al. Malignant Spitz tumour (Spitz melanoma). In Elder DE, Massi D, Scolyer RA, Willemze R. WHO Classification of Melanoma, Lyon, IARC, p132, 2018

Pathway VNo UV

Acral Melanoma

Atypical melanocytic proliferation

Melanoma in situ

Acral lentiginous melanoma

KIT, NRAS, BRAF, HRAS, KRAS, NTRK3, ALK, NF1

CDKN2A, TERT CCND1, GAB2

• RELATIVELY COMMON IN ASIA, ALSO AFRICA, POLYNESIA• ABSOLUTE INCIDENCE ABOUT THE SAME IN ALL ETHNICITIES

• Moon KR, Choi YD, Kim JM, Jin S, Shin MH, Shim HJ, et al. Genetic Alterations in Primary Acral Melanoma and Acral Melanocytic Nevus in Korea: Common Mutated Genes Show Distinct Cytomorphological Features. J Invest Dermatol. 2018;138(4):933-45.

• Hayward NK, Wilmott JS, Waddell N, Johansson PA, Field MA, Nones K, et al. Whole-genome landscapes of major melanoma subtypes. Nature. 2017;545(7653):175-80.

ALM:Very poorly circumscribed at periphery

Pathway VINo UV

Mucosal MelanomaMelanosis

Atypical melanosis

IAMPUS/ SAMPUSMucosal lentiginous melanomaKIT, NRAS, KRAS, or BRAF

NF1, CDKN2A SF3B1, CCND1, CDK4, MDM2

Substitutions, insertions, deletions and structural variants

Probably about the same incidence in all ethnicities

Mucosal Melanoma• Anal Mucosa• Elderly woman• Two VGP nodules,

RGP between them

KIT, NRAS, KRAS, or BRAF (activated oncogenes, mutually exclusive)

NF1, CDKN2A SF3B1 (suppressors, loss of function)

CCND1, CDK4, MDM2 (amplifications)

Substitutions, insertions, deletionsand structural variants

Hayward NK, Wilmott JS, Waddell N, Johansson PA, Field MA, Nones K, et al. Whole-genome landscapes of major melanoma subtypes. Nature. 2017;545(7653):175-80.

Pathway VIINo/Variable UV

Melanoma in Congenital Nevus (MCN)

Congenital Nevus (CN)

Nodular proliferation in CN

? MIS in CN

Melanoma in CN

NRAS, BRAF V600E (small nevi)

BRAF fusions

Probably about the same incidence in all ethnicities

“ …increased expression of 22 genes in GHN compared with nearby normal skin. Decreased expression was noted in 73 genes …Dasu MR, Barrow RE, Hawkins HK, McCauley RL. Gene expression profiles of giant hairy naevi. J Clin Pathol. 2004;57(8):849-55.

Nodular intradermal and subcutaneous proliferation of atypical epithelioid melanocytes, of uncertain malignant potential, arising secondarily in a giant congenital melanocytic nevus

Array CGH done in another institution demonstrated gain and chromosomes 1Q, 2, 4, 6, 8, 10, 13, 19, 20 and 21, as well as loss of chromosome 14. With the exception of gain in 1q, the copy number change consists of whole chromosome gain or loss as is common to proliferative nodules.

Bastian BC, Xiong J, Frieden IJ, Williams ML, Chou P, Busam K, et al. Genetic changes in neoplasms arising in congenital melanocytic nevi : differences between nodular proliferations and melanomas. Am J Pathol. 2002;161(4):1163-9.

This young patient died of his disease about 2 years after presenting

Pathway VIIINo/Variable UV

Melanoma in Blue Nevus (MBN)

Blue Nevus

Cellular Blue Nevus

Atypical CBN

Melanoma in Blue Nevus (MBN)

GNAQ, GNA11, CYSLTR2

BAP1 mutation or loss, EIF1AX SF3B1, Change of function

Probably about the same incidence in all ethnicities

Genetic profile of coexistent GNAQ or GNA11 mutations with BAP1 or SF3B1 mutations can aid the histopathological diagnosis and distinguish blue nevus-like melanoma from conventional epidermal-derived melanomas.”

Griewank KG, Muller H, Jackett LA, Emberger M, Moller I, van de NesJA, et al (Scolyer, Schadendorf). SF3B1 and BAP1 mutations in blue nevus-like melanoma. Modern pathology 2017;30:928-39.

Nodular Melanoma - Clinical Features

• Detectable RGP is absent by definition • Tumorigenic melanoma without an adjacent non-tumorigenic component• Short-lived RGP may be obliterated by the developing tumor.• Likely to occur in all pathways

• ABCD criteria may not apply• lesions are often symmetrical

nodules/papules with raised discrete borders, fairly uniform color, diameter not always > 6 mm

• Prognosis is similar to other melanomas of same microstage

• However small diameter lesions can be “thick” dangerous melanomas

Nodular melanoma

Dermal nevus adjacent to nodular melanoma -indicative of tumor progression, renders metastasis unlikely.

New (Revised) Classification of Melanoma

• Integrates Epidemiology, Genomic, Clinical and Histopathologic Features

• Assists in reproducibility of diagnosis by providing a conceptual morphologic framework

• Provides a context for selection of therapy:• Targeted therapy directed against oncogenes

• Driver oncogene• Immune therapy directed against neoantigens

• Mutation burden – high in high CSD, low in mucosal

Acknowledgements

Chapter Authors (Melanoma ClassificationDavid ElderRaymond BarnhillBoris BastianMartin CookArnaud de la FouchardièrePedram GeramiAlexander LazarDaniela MassiMartin MihmEduardo NagoreRichard ScolyerSook Jung YunInternational Melanoma Pathology Study Group> 150 Authors (Blue Book 4e)WHOIan CreeHiroko Ohgawa

References• 1. Bastian BC. The molecular pathology of melanoma: an integrated taxonomy of melanocytic neoplasia. Annu Rev Pathol. 2014;9:239-71.

• 2. Clark WHJ. A classification of malignant melanoma in man correlated with histogenesis and biologic behavior. In: Montagna W, Hu F, editors. Advances in the Biology of the Skin Volume VIII. New York: Pergamon Press; 1967. p. 621-47.

• 3. Clark WHJ, From L, Bernardino EA, Mihm MCJ. The histogenesis and biologic behavior of primary human malignant melanomas of the skin. Cancer Res. 1969;29:705-27.

• 4. Arrington JHd, Reed RJ, Ichinose H, Krementz ET. Plantar lentiginous melanoma: a distinctive variant of human cutaneous malignant melanoma. Am J Surg Pathol. 1977;1:131-43.

• 5. Coleman WPd, Loria PR, Reed RJ, Krementz ET. Acral lentiginous melanoma. Arch Dermatol. 1980;116:773-6.

• 6. Spitz S. Melanomas of childhood. Am J Pathol. 1948;24(3):591-609.

• 7. Allen AC, Spitz S. Malignant melanoma; a clinicopathological analysis of the criteria for diagnosis and prognosis. Cancer. 1953;6(1):1-45.

• 8. Allen AC, Spitz S. Histogenesis and clinicopathologic correlation of nevi and malignant melanomas; current status. AMA Arch Derm Syphilol. 1954;69(2):150-71.

• 9. Elder DE, Massi D, Scolyer RA, Willemze R. WHO Classification of Skin Tumours. 4th ed. Lyon: IARC; 2018.

• 10. Viros A, Fridlyand J, Bauer J, Lasithiotakis K, Garbe C, Pinkel D, et al. Improving melanoma classification by integrating genetic and morphologic features. Plos Med. 2008;5(6):e120.

• 11. Eroglu Z, Zaretsky JM, Hu-Lieskovan S, Kim DW, Algazi A, Johnson DB, et al. High response rate to PD-1 blockade in desmoplastic melanomas. Nature. 2018;553(7688):347-50.

• 12. Wiesner T, He J, Yelensky R, Esteve-Puig R, Botton T, Yeh I, et al. Kinase fusions are frequent in Spitz tumours and spitzoid melanomas. Nature communications. 2014;5:3116.

• 13. VandenBoom T, Quan VL, Zhang B, Garfield EM, Kong BY, Isales MC, et al. Genomic Fusions in Pigmented Spindle Cell Nevus of Reed. The American journal of surgical pathology. 2018;42(8):1042-51.

• 14. Moon KR, Choi YD, Kim JM, Jin S, Shin MH, Shim HJ, et al. Genetic Alterations in Primary Acral Melanoma and Acral Melanocytic Nevus in Korea: Common Mutated Genes Show Distinct Cytomorphological Features. J Invest Dermatol. 2018;138(4):933-45.

• 15. Hayward NK, Wilmott JS, Waddell N, Johansson PA, Field MA, Nones K, et al. Whole-genome landscapes of major melanoma subtypes. Nature. 2017;545(7653):175-80.

• 16. Bastian BC, Xiong J, Frieden IJ, Williams ML, Chou P, Busam K, et al. Genetic changes in neoplasms arising in congenital melanocytic nevi : differences between nodular proliferations and melanomas. Am J Pathol. 2002;161(4):1163-9.

• 17. Griewank KG, Muller H, Jackett LA, Emberger M, Moller I, van de Nes JA, et al. SF3B1 and BAP1 mutations in blue nevus-like melanoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2017;30(7):928-39.

• 18. Dasu MR, Barrow RE, Hawkins HK, McCauley RL. Gene expression profiles of giant hairy naevi. J Clin Pathol. 2004;57(8):849-55.

• 19. Shain AH, Yeh I, Kovalyshyn I, Sriharan A, Talevich E, Gagnon A, et al. The Genetic Evolution of Melanoma from Precursor Lesions. N Engl J Med. 2015;373(20):1926-36.

• 20. Tsao H, Bevona C, Goggins W, Quinn T. The transformation rate of moles (melanocytic nevi) into cutaneous melanoma: a population-based estimate. Arch Dermatol. 2003;139(3):282-8.

• 21. Gerami P, Li G, Pouryazdanparast P, Blondin B, Beilfuss B, Slenk C, et al. A highly specific and discriminatory FISH assay for distinguishing between benign and malignant melanocytic neoplasms. Am J Surg Pathol. 2012;36(6):808-17.

• 22. Clarke LE, Flake DD, Busam K, Cockerell C, Helm K, McNiff J, et al. An independent validation of a gene expression signature to differentiate malignant melanoma from benign melanocytic nevi. Cancer. 2017;123(4):617-28.