Genomic and Clinicopathologic Characteristics of PRKAR1A-inactivated Melanomas

Abstract

Melanocytic tumors with inactivation of protein kinase A regulatory subunit-α (PRKAR1A) have large oval nuclei and intense pigmentation. Historically, these tumors have been categorized under various names, including epithelioid blue nevus, pigmented epithelioid melanocytoma (PEM) and animal-type melanoma. Although a subset of PEM harbor BRAF activating mutations and biallelic inactivation of PRKAR1A, there are only a few reports of melanomas, or of tumors with genomic alterations beyond those of PEMs. Herein, we describe the clinicopathologic and genetic features of 8 melanomas and tumors that lack PRKAR1α expression by immunohistochemistry but do not fit with conventional PRKAR1A-inactivated melanocytomas. These tumors tended to affect younger patients than conventional melanomas (median age=38 y) and presented as dark brown/black papules and nodules. Histopathologically, they demonstrated nodularity, sometimes in a background of conventional melanoma, and large vesicular nuclei with prominent nucleoli. With the exception of 1 case, the mitotic index was not significantly elevated. Immunohistochemically, all cases showed loss of PRKAR1α and of p16 expression. Seven tumors underwent massively parallel short read (next-generation) sequencing of a panel of 480 cancer-associated genes. Five tumors demonstrated truncating mutations of PRKAR1A and the 2 in which such mutations were not identified demonstrated loss of heterozygosity of the PRKAR1A locus. Four of the tumors harbored BRAF V600E mutations, and 1 harbored a FAM39B-BRAF gene fusion. Another harbored a GNA11 activating mutation. A MAP kinase activating mutation was not identified in the remaining case. Four tumors displayed TERT promoter mutations and chromosomal copy number changes supporting the diagnosis of melanoma. Two cases without these alterations and were classified as “high-grade PRKAR1A-inactivated melanocytomas”. The 1 case with widespread metastases demonstrated mutations in TP53 and RB1. Overall, we provide the first genetic characterization of PRKAR1A-inactivated melanomas, discuss the differential diagnosis of heavily pigmented epithelioid melanocytic neoplasms, and propose a new nomenclature for such tumors.

BAP1-Inactivated Melanoma Arising From BAP1-Inactivated Melanocytic Tumor in a Patient With BAP1 Germline Mutation: A Case Report and Review of the Literature

“…25,26 To the best of our knowledge, this is the first case of BAP1-inactivated melanoma with TERT-p hot spot mutation. A similar stepwise molecular progression to melanoma in pigmented epithelioid melanocytoma 25 and deep penetrating nevus have been proposed. 27 In conclusion, we report a paradigmatic case of BAP1inactivated melanoma supporting a stepwise progression from a nevus to melanoma through a melanocytoma stage (BIMT) from both histological and molecular viewpoints.…”

“Animal-Type Melanoma/Pigmented Epithelioid Melanocytoma”: History and Features of a Controversial Entity

“…In 2018, Robledo-Sánchez et al [ 2 ] reported a rare case of ATM in a 79-year-old subject who died a few months later from metastatic dissemination. In particular, in recent years, an increasing amount of immunohistochemical and molecular evidence is trying to elucidate the mechanisms of etiopathogenesis; in detail, in two recent works [ 9 , 21 , 22 , 23 , 24 ], Cohen et al have identified an absence of mutation in the codifying gene for the protein PRKAR1A in molecular terms, but demonstrated a loss of immunohistochemical expression of this marker, proposing a possible diagnostic aid for PEMs with respect to lesions that can mimic them as conventional, cellular, or malignant blue nevus and deep penetrating nevus (DPN). Additionally, a recent study showed the presence of GNAQ mutations in PEMs; thus, these studies provided molecular support for the classification of these tumors as variants or blue nevi [ 24 ].…”

The WHO 2018 Classification of Cutaneous Melanocytic Neoplasms: Suggestions From Routine Practice

“…However, several melanocytomas arise de novo (without a preexsisting common nevus): for example, cases of "pure" (noncombined) PEM are also genetically peculiar because often they harbor kinase (most commonly PRKA, but also NTRK1 and NTRK3) (38) fusions as the initiating event. Most of these dermal-based tumors are clinically stable; however, they can display various degrees of histopathological atypia (39)(40)(41)(42). Increasing atypical histopathological features may correlate with increased risk of disease progression ( 43), but available data are too weak because of the relative rarity of these tumors and the need of long-term follow-up data.…”

“…Figure 6 illustrates the clinicopathological features of an ulcerated melanocytic malignancy histopathologically composed of large epithelioid cells with Spitz-like features, but immunohstichemically typifi ed as a " classical" melanoma because of its immunohistochemical positivity to the anti-BRAF mutated protein VE1 antibody. Parenthetically, PEM-like (75,76) and DPN-like melanomas (77, 78) might be differentiated from their "melanocytoma counterpart" based on immunohistochemical and/or genetic findings akin to "classical" melanoma.…”