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Melanocytic Skin Neoplasms

What Lesson From Genomic Aberrations?

Urso, Carmelo MD

The American Journal of Dermatopathology: September 2019 - Volume 41 - Issue 9 - p 623–629
doi: 10.1097/DAD.0000000000001341
CME Article

Abstract: Studies on the genomic aberrations in melanocytic neoplasms have shown a complex genomic landscape. In nevi and melanomas, a MAP-kinase pathway activation was generally found, produced by different chromosomal aberrations, including BRAF, NRAS, HRAS, GNAQ, GNA11, BAP1, CTNNB1, MAP2K1, PRKAR1A, and NF1 mutations, and ALK, ROS1, NTRK1, RET, MET, BRAF, NTRK3, and PRKCA fusions. Melanomas also showed a variable number of additional mutations ablating tumor-suppression mechanisms and activating other oncogenic pathways, including CDKN2A loss, PTEN loss, as well as TP53 and TERT-promoter mutations. Moreover, borderline melanocytic tumors displayed the same chromosomal aberrations, but more mutations than nevi and fewer than melanomas. In this context, the notion that melanocytic neoplasms can be classified as benign/malignant is hardly supportable, because all neoplasms harbor a certain number of mutations and the progression risk, that is, the malignant potential, is related and proportional to the burden of pathogenic mutations. Moreover, from the genomic analysis, in parallel to the current diagnostic categories of “nevi,” “melanomas,” and “melanocytomas,” some aggregations or classes of tumors based on the characteristic types of driver mutations/fusions emerge as possible and more rationale, including Spitzoid neoplasms, blue neoplasms, BAP1-inactivated melanocytic neoplasms, deep penetrating melanocytic neoplasms, pigment-synthesizing melanocytic neoplasms, and “common” melanocytic neoplasms. Each of these classes, showing the same driver mutations/fusions, demonstrates to have the same pathogenesis and may be genetically considered as a single tumor, although with a variable amount of progression risk. Histologic features, being an expression of the mutational state, could be used to obtain an approximate risk assessment in each single tumor.

Scientific Director, Dermatopathology Study Center of Florence, Florence, Italy.

Correspondence: Carmelo Urso, MD, Dermatopathology Study Center of Florence, Via Della Cernaia, 88, I-50129 Florence, Italy (e-mail:

All authors and staff in a position to control the content of this CME activity and their spouses/life partners (if any) have disclosed that they have no financial relationships with, or financial interests in, any commercial organizations relevant to this educational activity.

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