Table 2.

The WHO 2018 classification of melanoma according to pathways.

Relationship with sun exposure/sun damage	Pathway n.	Subtype	Genetic hallmarks
Melanomas arising in sun-exposed skin	1	Low-CSD melanoma/superficial spreading melanoma	High frequency of BRAF p.V600 mutations (7–9)
	2	High-CSD melanoma (including lentigo maligna melanoma and high-CSD nodular melanoma)	Predominating mutually exclusive NF1, NRAS, other BRAF (non-p.V600E), and perhaps KIT mutations (7–9)
	3	Desmoplastic melanoma	Recurrent inactivating NF1 mutations, NFKBIE promoter mutations, and several different activating mutations in the MAPK pathway (e.g.: MAP2K1) (9–11)
Melanomas arising at sun-shielded sites or without known etiological associations with UV radiation exposure	4	Malignant Spitz tumor (Spitz melanoma)	Mutations in HRAS and kinase fusions in ROS1, NTRK1, NTRK3, ALK, BRAF, MET, and RET; CDKN2A homozygous deletion, TERT promoter mutations and MAP3K8 fusions/truncating mutations only in aggressive or lethal variants (7, 12–15)
	5	Acral melanoma (including nodular melanoma in acral skin)	Multiple amplifications of CCND1, KIT, and TERT; mutations of BRAF, NRAS, and KIT; kinase fusions of ALK or RET in a few cases (7, 8)
	6	Mucosal melanoma	Numerous copy number and structural variations; uncommonly, KIT and NRAS mutations (16)
	7	Melanoma arising in congenital nevus	In large to giant congenital nevi: NRAS mutation; in small to medium-sized congenital nevi, BRAF mutations (17, 18)
	8	Melanoma arising in blue nevus	Initiating mutations in the Gαq signalling pathway (GNAQ, GNA11, CYSLTR2, PLCB4); monosomy 3 (associated with loss of BAP1) and chromosome 8q gains in aggressive cases; additional secondary copy number aberrations in SF3B1 and EIF1AX (7, 19)
	9	Uveal melanoma	Mutually exclusive mutations in the Gαq pathway (GNAQ, GNA11, PLCB4, CYSLTR2); BAP1, SF3B1, and EIF1AX mutations during progression (16)