"Pathway Leap": A New Molecular Phenomenon to Consider in the Pathogenesis of Melanocytic Tumors

The current WHO classification of melanocytic tumors distinguishes 9 pathogenic routes. This classification is based on the conceptual interpretation that melanocytic tumors evolve from benign counterparts, accumulating mutations, eventually developing into melanomas with metastatic and potentially lethal capacity. In this article, we present a molecular study of 2 melanocytic tumors that suggest a "leap" from pathogenic routes IV to I.

Two recent melanocytic tumors were selected, each exhibiting 2 contiguous melanocytic populations of distinct morphology, without separation between them. One population corresponded to a common melanocytic nevus (with morphology consistent with route I), while the other population displayed epithelioid morphology, consistent with route IV. Immunohistochemical studies were performed in both cases, as well as molecular studies using PCR to search for mutations in the NRAS and BRAF genes. For the molecular study, both populations were manually separated by microdissection.

In both cases, the melanocytic population consistent with route I showed a BRAF mutation. In both cases, the epithelioid population did not present a BRAF mutation. No NRAS mutations were observed in any of the populations.

These findings suggest the existence of a molecular phenomenon of "leap" between pathways, which we have termed "pathway leap." This could explain the enigmatic group of tumors that the WHO classifies under the heading of "combined nevi." This group could be more frequent than suspected, because microdissection is not a technique commonly used in the daily diagnosis of melanocytic tumors.