“Paradoxical” p16 overexpression in cutaneous melanoma: Molecular and immunohistochemical analysis of a rare phenomenon with a focus on cell cycle regulatory molecules

Our understanding of the mutational landscape of cutaneous melanoma (CM) has made significant progress in the past several years [1], [2], [3]. One of the most relevant genetic alterations in CM is the biallelic inactivation/loss-of-heterozygosis (LOH) of cyclin-dependent kinase inhibitor 2 A (CDKN2A) encoding the tumor suppressor proteins p16 and p14arf [1], [2], [3], [4], [5], [6], [7], [8]. Specifically, LOH of CDKN2A, through different molecular mechanisms spanning from heterozygous/homozygous deletions and promoter hyper-methylation to missense and truncating mutations has been identified as a distinctive feature of invasive, advanced-stage and/or metastatic CM [1], [2], [3], [4], [5], [6], [7], [8]. Consequently, immunohistochemical identification of p16 loss has been adopted in the routine practice for the differential diagnosis between CM and cutaneous nevi (CN) [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19]. We recently reported an exceptionally rare case of a dermal/deep-seated melanoma arising in giant congenital nevus (DDM-GCN) showing unexpected immunohistochemical overexpression of p16 combined with immunohistochemical loss of p53 and tumor protein 53 (TP53) mutation [20]. We hypothesized the existence of cases of CM with a peculiar combination of genetic mutations and alterations of the cell cycle regulatory molecules (CCRM) that biologically interact with p16, resulting in paradoxical p16 overexpression. Thus, we retrospectively analyzed p16 expression in CM cases to identify those with overexpression of the protein, and here report their prevalence, clinicopathologic features, immunohistochemical melanocytic marker and CCRM (p53, p21, Cyclin D1, Rb) profiles, and genetic alterations identified using a laboratory-developed multi-gene next generation sequencing (NGS) panel [21].

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