Distant metastasis due to heavily pigmented epithelioid melanoma with underlying BRAF V600E, NOTCH1, ERBB3, and PTEN mutations

Abstract

Pigment-synthesizing melanoma (PSM) describes a morphologically and genetically diverse group of melanomas. In contrast, pigmented epithelioid melanocytoma (PEM) encompasses a spectrum of indolent tumors now classified as borderline/intermediate melanocytic tumors. Herein, we report a case of widely metastatic heavily pigmented epithelioid melanoma with fatal outcome in a 36-year-old woman. Nextgeneration sequencing identified somatic (tumoral) mutations in BRAF V600E, PTEN, NOTCH1, and ERBB3. By contrast, GNAQ and GNA11 were wild type. Prkar1α and p16 expression were maintained. Identification of mutations in NOTCH1 and ERBB3 may support the diagnosis of heavily pigmented epithelioid melanoma. In contrast, PRKCA fusion genes and PRKAR1A mutations support the diagnosis of PEM. Given the heterogeneity, potential overlap (loss of Prkar1α expression), and evolving genetic profiles of these two distinct groups of tumors, careful appraisal of molecular profiles in the light of histomorphology and clinical history is necessary for distinction between PEM and PSMs including heavily pigmented epithelioid melanomas, with significant potential impact on prognosis and therapy. K E Y W O R D S BRAF V600E, ERBB3, next-generation sequencing, NOTCH1, pigmented epithelioid melanocytoma, pigment-synthesizing melanoma, PTEN

Two congenital cases of pigmented epithelioid melanocytoma with unique clinical and genetic features

“…Pigmented epithelioid melanocytomas was first defined in 2004 as an umbrella term for borderline melanocytic lesions encompassing animal-type melanomas, Carney complex's epithelioid blue nevus (EBN), and pigment synthesizing melanoma [1]. Historically, all these terms have all been lumped, but a PEM-like pigmented fatal melanoma that was categorized as pigment synthesizing menlanoma has been reported [2]. Since then, further research has defined the variable genetic drivers of PEM, including a subset with PRKCA fusion transcripts [3].…”