Subtitle: The WHO pathway classification of melanoma, from UV damage and mutational burden to BRAF, NRAS, NF1, KIT, GNAQ/GNA11 and BAP1, with virtual slides, precursor lesions, targeted therapy and 10 case-based MCQs.

Author: PathologyMCQ Editorial Board

Category: Dermatopathology / Molecular Pathology

Last Updated: October 2026

Read Time: 10 minutes

At-a-Glance

• Framework: the WHO classifies melanoma into 9 pathways by sun exposure (cumulative sun damage, CSD), anatomical site, precursor lesion and driver genes.
• Sun-associated (I to III): low-CSD (BRAF V600E), high-CSD (NRAS, NF1, KIT, non-V600E BRAF) and desmoplastic (NF1, very high mutational burden).
• Not sun-associated (IV to IX): Spitz (HRAS or kinase fusions), acral and mucosal (KIT, NRAS, amplifications), congenital naevus (NRAS), blue naevus and uveal (GNAQ/GNA11, BAP1).
• Why it matters: BRAF+MEK inhibitors for BRAF V600, KIT inhibitors for KIT-mutant tumours, and better checkpoint-inhibitor responses in high mutational burden tumours.

The 9 WHO Melanoma Pathways

The WHO groups melanomas by how much sun damage the skin has had and where they arise. Each pathway has its own precursor, driver genes and behaviour.

Pathways I to IIIAssociated with sun exposure

I · Low-CSDSuperficial spreadingBRAF V600ETrunk and limbs, intermittent sun; arises from naevi; TERT, CDKN2A later

II · High-CSDLentigo maligna melanomaNRAS, NF1, KIT, BRAF non-V600EHead and neck of older adults with solar elastosis; high UV mutational load

III · DesmoplasticDesmoplastic melanomaNF1 lossHighest UV mutational burden; MAPK activators such as ERBB2, MAP2K1

Key idea: more cumulative sun damage means more UV mutations, fewer BRAF V600E and more NF1, NRAS and KIT alterations.

Pathways IV to IXNot consistently associated with sun exposure

IV · SpitzSpitz melanomaHRAS or kinase fusionsALK, ROS1, NTRK1/3, RET, MET, BRAF fusions; CDKN2A loss in malignant cases

V · AcralAcral melanomaKIT, NRAS, BRAFPalms, soles, nail beds; CCND1 and KIT amplification; low point-mutation burden

VI · MucosalMucosal melanomaKIT, NRAS, SF3B1Sinonasal, oral, anorectal, vulvovaginal; many copy-number changes

VII · Congenital naevusMelanoma in congenital naevusNRAS Q61Large and giant congenital naevi; often deep, dermal origin

VIII · Blue naevusMelanoma in blue naevusGNAQ, GNA11, CYSLTR2Scalp is a common site; BAP1 loss marks progression

IX · UvealUveal melanomaGNAQ, GNA11BAP1, SF3B1 or EIF1AX define risk; monosomy 3 predicts liver spread

Key idea: sun-shielded melanomas have low UV mutational burden and are driven by kinase mutations, fusions or copy-number changes instead.

Virtual Slides: Four Pathways

Four real melanomas from different pathways. Switch between the tabs and read the note below each slide. Where a slide has annotated regions, tap one to zoom straight to it.

UV Damage and Mutational Burden

• UV signature: UV light causes C>T transitions at dipyrimidine sites. Melanomas on sun-damaged skin carry thousands of these mutations.
• Gradient: desmoplastic and high-CSD melanomas have the highest tumour mutational burden (TMB); low-CSD is intermediate; acral, mucosal and uveal melanomas have the lowest.
• Histological marker: solar elastosis in the adjacent dermis is how the pathologist estimates cumulative sun damage.
• Clinical link: high-TMB melanomas make more neoantigens and generally respond better to checkpoint inhibitors; acral, mucosal and uveal melanomas respond less well.

Pathways, Precursors and Drivers

Two related groups worth knowing: BAP1-inactivated melanocytic tumours (BRAF or NRAS mutation plus BAP1 loss, epithelioid cells, may signal a germline BAP1 syndrome) and deep penetrating melanocytic tumours (beta-catenin or PRKAR1A pathway plus a MAPK driver).

From Naevus to Melanoma

For pathway I, the stepwise model is the best studied. Each step adds a genetic hit.

Uveal Melanoma

• Drivers: GNAQ or GNA11 mutation in about 90%, with CYSLTR2 or PLCB4 in the rest. These activate G-protein signalling, not the classic BRAF route.
• Risk genes (mutually exclusive): BAP1 loss with monosomy 3 = high risk of early liver metastasis; SF3B1 = intermediate, late metastasis; EIF1AX = low risk.
• Pathology test: BAP1 immunohistochemistry (loss of nuclear staining) is a practical surrogate for BAP1 inactivation.
• Treatment: responds poorly to BRAF inhibitors and standard checkpoint inhibitors; tebentafusp is an option for HLA-A*02:01-positive metastatic disease.

Familial Melanoma

• CDKN2A (p16): the commonest high-penetrance gene in melanoma-prone families; also linked to pancreatic cancer.
• CDK4: rare; mimics CDKN2A families.
• BAP1 tumour predisposition syndrome: BAP1-inactivated melanocytic tumours, uveal and cutaneous melanoma, mesothelioma, renal cell carcinoma.
• Others: MITF E318K, POT1 and other telomere genes; MC1R variants modify risk in fair-skinned people.

Testing and Targeted Therapy

Molecular testing is usually done for stage III and IV melanoma. Checkpoint inhibitors are used regardless of BRAF status, so BRAF testing guides the targeted option rather than eligibility for immunotherapy.

Test Yourself: 10 MCQs

Exam Pearls

• Low-CSD = BRAF V600E; high-CSD and desmoplastic = NF1, NRAS, KIT and non-V600E BRAF.
• Desmoplastic melanoma has the highest TMB and good immunotherapy response; S100/SOX10 positive, often Melan-A and HMB-45 negative.
• Spitz tumours: HRAS or kinase fusions, not BRAF V600E.
• Acral and mucosal: KIT, NRAS and amplifications; low TMB.
• Blue naevus and uveal: GNAQ/GNA11; BAP1 loss with monosomy 3 means liver metastasis risk.
• Large congenital naevi: NRAS Q61.
• BRAF V600E metastatic melanoma: BRAF plus MEK inhibitors.

Video lesson

Melanoma genetics, explained

The WHO pathways, driver genes and their clinical use in one video.

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References

• Elder DE, Massi D, Scolyer RA, Willemze R, eds. WHO Classification of Skin Tumours. 4th ed. IARC; 2018.
• Bastian BC. The molecular pathology of melanoma: an integrated taxonomy of melanocytic neoplasia. Annu Rev Pathol. 2014;9:239–271.
• Cancer Genome Atlas Network. Genomic classification of cutaneous melanoma. Cell. 2015;161:1681–1696.
• Hayward NK, et al. Whole-genome landscapes of major melanoma subtypes. Nature. 2017;545:175–180.
• Robertson AG, et al. Integrative analysis identifies four molecular and clinical subsets in uveal melanoma. Cancer Cell. 2017;32:204–220.