Heavily Pigmented Epithelioid Melanoma With Loss of Protein Kinase A Regulatory Subunit-α Expression

Abstract

Heavily pigmented melanocytic neoplasms are genotypically and phenotypically diverse. Recently, a subset of this histopathologic spectrum was shown to harbor recurrent genetic alterations in the gene-encoding protein kinase A regulatory subunit-α (PRKAR1A). To date, no histopathologic descriptions of melanomas arising from this pathway have been described. We present a case of a darkly pigmented papule arising on the posterior neck of a 28-year-old man. Microscopically, the heavily pigmented compound melanocytic proliferation was centered in the dermis with permeation into the superficial subcutis. Tumor cells were arranged in large confluent nests and fascicles and lacked maturation with descent. The epithelioid melanocytes were characterized by enlarged vesicular nuclei with prominent nucleoli, nuclear pleomorphism, and plentiful gray-brown granular cytoplasm. Mitotic figures were readily identified. By immunohistochemistry, melanocytes were positive for mutant BRAF V600E and showed loss of Prkar1α and p16 expression. A multiplex MART-1/tyrosinase/phosophohistone-H3 immunostain demonstrated an increased mitotic index in melanocytes. The combination of highly atypical cytomorphology and architecture, increased mitoses, and p16 expression loss compelled the diagnosis of melanoma. Overall, we present the first clinicopathologic description of a PRKAR1A-inactivated melanoma to highlight morphological features and discuss mimics that may enter the differential diagnosis.

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

“…In the case presented, NGS identified a BRAF V600E mutation in the tumor, consistent with recent evidence describing the BRAF V600E immunostain as highly reliable and correlative with sequencing . In tandem with loss of p16, this BRAF driver mutation was recently described in a heavily pigmented epithelioid melanoma in a 28‐year‐old man . CDKN2A , GNAQ , GNA11 , and BAP‐1 mutations were not detected by NGS in the PSM described in this report.…”

“…However, mutations involving PRKAR1A may also be observed in benign and malignant melanotic schwannomas as well as a subset of melanomas including spitzoid melanomas . In addition, loss of Prkar1α expression was recently identified in a heavily pigmented epithelioid melanoma . Thus, loss of expression of Prkar1α, with or without corresponding PRKAR1A mutation, is supportive but not diagnostic of PEM and cannot be used to exclude the diagnosis of melanoma.…”

“…Other genetic alterations in specific genes relevant to melanocyte oncogenic transformation were not identified in this case. Table summarizes immunohistochemistry (IHC) for PrkaR1α, BRAF V600E, and p16 expression and molecular studies in PSMs and PEM …”

“…PSMs comprise a diverse group of tumors, most often typified by a proliferation of large epithelioid melanocytes with marked nuclear pleomorphism and prominent nucleoli, abundant deep pigmentation and melanophages, vertical orientation with folliculocentricity and involvement of the entire dermis (and sometimes subcutis). Necrosis and mitotic activity are variable . Rather than a singular entity, PSM encompasses a heterogeneous spectrum including PEM‐like melanomas, blue‐nevus‐like melanomas associated with GNAQ , GNA11 , BAP1 , and SF3B1 mutations, and melanomas associated with BRAF mutations .…”

“…Necrosis and mitotic activity are variable . Rather than a singular entity, PSM encompasses a heterogeneous spectrum including PEM‐like melanomas, blue‐nevus‐like melanomas associated with GNAQ , GNA11 , BAP1 , and SF3B1 mutations, and melanomas associated with BRAF mutations . Aggressive disease due to PSMs has rarely been documented, with four previously reported cases associated with fatal outcome .…”