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2018 WHO classification of melanoma

2018 WHO classification of melanoma
  Low UV radiation exposure/CSD High UV radiation exposure/CSD Low to no (or variable/incidental) UV radiation exposure/CSD
Pathway I II III IV V VI VII VIII IX
Endpoint of pathway Low-CSD melanoma/SSM High-CSD melanoma/LMM Desmoplastic melanoma Malignant Spitz tumor/Spitz melanoma Acral melanoma Mucosal melanoma Melanoma in congenital nevus Melanoma in blue nevus Uveal melanoma
Benign neoplasms (nevi) Nevus

?

IMP

?

IMP		 Spitz nevus

?

Acral nevus

?

Melanosis		 Congenital nevus Blue nevus

?

Nevus
Intermediate/low-grade dysplasias and melanocytomas Low-grade dysplasia BAP1-inactivated nevus Deep penetrating nevus  

?

IAMP/dysplasia

?

IAMP/dysplasia		 Atypical Spitz tumor (melanocytoma) IAMP/ dysplasia Atypical melanosis/dysplasia/IAMPUS Nodule in congenital nevus (melanocytoma) (Atypical) cellular blue nevus (melanocytoma) ?
Intermediate/high-grade dysplasias and melanocytomas High-grade dysplasia/MIS BAP1-inactivated melanocytoma/MELTUMP Deep penetrating melanocytoma/MELTUMP Pigmented epithelioid melanocytoma/MELTUMP Lentigo maligna (MIS) MIS STUMP/MELTUMP Acral MIS Mucosal MIS MIS in congenital nevus Atypical cellular blue nevus ?
Malignant neoplasms Low-CSD melanoma/SSM (VGP) Melanoma in BAP1-inactivated nevus (rare) Melanoma in deep penetrating nevus (rare) Melanoma in pigmented epithelioid melanocytoma (rare) LMM (VGP) Desmoplastic melanoma Malignant Spitz tumor/Spitz melanoma (tumorigenic) Acral melanoma (VGP) Mucosal lentiginous melanoma (VGP) Melanoma in congenital nevus (tumorigenic) Melanoma in blue nevus (tumorigenic) Uveal melanoma
Common mutations* BRAFV600E or NRAS

BRAF or NRAS

plus

BAP1Δ

BRAF, MAP2K1, or NRAS

plus

CTNNB1 or APCΔ

BRAF

plus

PRKAR1AΔ; or PRKCA		 NRAS; BRAF (non-V600E); KIT; or NF1Δ NF1Δ; ERBB2◊; MAP2K1◊; MAP3K1◊; BRAF◊; EGFR◊; MET◊ HRAS; ALK§; ROS1§; RET§; NTRK1§; NTRK3§; BRAF§; or MET§ KIT; NRAS; BRAF; HRAS; KRAS; NTRK3§; ALK§; or NF1Δ KIT, NRAS, KRAS; or BRAF NRAS; BRAFV600E (small lesions); or BRAF§ GNAQ; GNA11; or CYSLTR2 GNAQ; GNA11; CYSLTR2; or PLCB4
TERT‡; CDKN2AΔ; TP53Δ; PTENΔ       TERT‡; CDKN2AΔ; TP53Δ; PTENΔ; RAC1 TERT‡; NFKBIE‡; NRAS; PIK3CA; PTPN11 CDKN2AΔ CDKN2AΔ; TERT‡; CCND1◊; GAB2◊ NF1; CDKN2AΔ; SF3B1¥; CCND1◊; CDK4◊; MDM2◊   BAP1Δ; EIF1AX¥; SF3B1¥ BAP1Δ; SF3B1¥; EIF1AX¥
Melanocytoma is a tumorigenic neoplasm of melanocytes that generally has increased cellularity and/or atypia (compared with a common nevus) and an increased (although generally still low) probability of neoplastic progression. Tumorigenic means forming a mass of neoplastic cells.

CSD: cumulative sun damage; IAMP: atypical intraepidermal melanocytic proliferation; IAMPUS: atypical intraepidermal melanocytic proliferation of uncertain significance; IMP: intraepidermal melanocytic proliferation without atypia; LMM: lentigo maligna melanoma; low/high CSD melanoma: melanoma in skin with a low/high degree of cumulative sun damage; MELTUMP: melanocytic tumor of uncertain malignant potential; MIS: melanoma in situ; SSM: superficial spreading melanoma; STUMP: spitzoid tumor of uncertain malignant potential; UV: ultraviolet; VGP: vertical growth phase (tumorigenic and/or mitogenic melanoma); WHO: World Health Organization.

* Common mutations in each pathway are listed; mutations already identified in benign or borderline low lesions are shown in bold.

¶ Gain-of-function mutation.

Δ Loss-of-function mutation.

◊ Amplification.

§ Rearrangement.

¥ Change-of-function mutation.

‡ Promoter mutation.
Reproduced with permission from: WHO Classification of Tumours Editorial Board. Skin tumours [Internet]. Lyon (France): International Agency for Research on Cancer; 2020. (WHO classification of tumours series, 4th ed.; vol. 11). Available from: https://tumourclassification.iarc.who.int/. Copyright © David Elder, MBChB.
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