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- Presentation
Molecular Diagnosis of Melanocytomas and Nevi: Genetic Drivers, Classification, and Targeted Therapy
Description
The speaker, a UCSF dermatologist and dermatopathologist, discusses how molecular genetics is reshaping the diagnosis and classification of melanocytic lesions, especially nevi and melanocytomas. She explains that melanocytomas are generally nevi with an additional pathogenic alteration beyond the initiating mutation, making them higher risk than ordinary nevi but not fully malignant; this creates management challenges because the exact progression risk is unclear. The talk reviews major genetic drivers across lesion types: common acquired nevi are usually driven by BRAF V600E or NRAS mutations, blue nevi by GNAQ/GNA11 and sometimes PKC-related fusions, and Spitz nevi by HRAS mutations or diverse kinase fusions, which help explain their varied histology. She presents examples showing how molecular findings correlate with pathology and clinical behavior, including PKC-fusion lesions with fibrotic, archipelago-like histology; BRAF-fusion giant congenital nevi with desmoplasia and multiple nodules; and cases where targeted therapy such as MEK inhibition or ROS inhibition reduced symptomatic lesions. She then focuses on melanocytoma subtypes, including BAP1-inactivated melanocytoma, Wnt-activated/deep penetrating melanocytoma with beta-catenin activation, PRKAR1A-inactivated melanocytoma, and CDKN2A-inactivated Spitz melanocytoma, emphasizing how genetics clarifies morphology and helps avoid overcalling melanoma. The speaker also notes that dysplastic nevi may represent multiple molecular pathways and that molecular testing can reveal distinctions not visible by eye. Finally, she reviews diagnostic platforms for DNA, RNA, proteins, and copy-number changes, and highlights emerging targeted inhibitors for rare fusions and mutations, including a melanoma case responding to a ROS1 inhibitor.
View moreConclusions
- Melanocytomas appear to represent an intermediate genetic and clinical state between common nevi and melanoma, marked by additional pathogenic alterations beyond the initiating nevus mutation.
- Different melanocytic tumor subtypes are driven by distinct initiating events, such as GNAQ/GNA11 in blue nevi, BRAF in common nevi, and diverse kinase fusions in Spitz nevi.
- Molecular classification can explain why many melanocytic lesions look similar histologically yet behave differently, and it may reduce overcalling benign lesions as melanoma.
- PKC-fusion melanocytic tumors define a newly recognized class that can mimic other nevi, may be congenital or acquired, and are often benign but sometimes clinically difficult because of their size or location.
- BRAF fusions are an important driver in a subset of giant congenital melanocytic nevi and may be suggested by desmoplasia, numerous nodules, microsatellites, and pruritus.
- Targeted therapy can benefit some large but nonmalignant melanocytic lesions, as shown by symptomatic improvement and tumor shrinkage with MEK inhibition or ROS1 inhibition in selected cases.
- BAP1-inactivated melanocytomas are defined by a two-hit tumor suppressor loss and a characteristic epithelioid, glassy cytomorphology with lymphocytic infiltrates.
- Wnt-activated or deep penetrating melanocytomas are common because a single activating beta-catenin pathway alteration can create a distinctive deeply infiltrative pigmented lesion.
- Some lesions that appear histologically like dysplastic nevi may actually belong to different molecular pathways, including lesions with TERT promoter mutations or other melanocytoma-associated alterations.
- CDKN2A-inactivated Spitz melanocytomas show that even tumors with Spitz-like morphology can harbor secondary alterations that justify a melanocytoma diagnosis rather than melanoma.
- No single histologic feature is sufficient to distinguish all benign from malignant melanocytic lesions, so integrating morphology with DNA, RNA, protein, and copy-number testing is increasingly necessary.
- As targeted inhibitors expand for rare driver alterations, melanocytic tumor genetics may increasingly guide both diagnosis and treatment, including in selected melanomas with actionable fusions or mutations.
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