Merkel cell carcinoma with divergent differentiation: histopathological and immunohistochemical study of 15 cases with PCR analysis for Merkel cell polyomavirus

Abstract

Merkel cell carcinoma with divergent differentiation is a highly aggressive tumour that might be difficult to recognize, owing to its wide histological variability. Negativity for MCV suggests that the virus is not implicated in the development of this subtype of MCC.

Comment on “Diffuse TTF-1 expression in a case of Merkel cell carcinoma”

“…However, since the first description of TTF-1 positive MCC in 2008 [2,3], a few such cases have been reported. If combined MCC is included, expression of TTF-1 seems not to be infrequent, as in the largest published series 4/15 (27%) presented expression of TTF-1 [4]. In our report, TTF-1 expression was present to a variable extent in 4/5 (80%) cases, and peculiarly in two cases also in the squamous cell carcinoma component [1].…”

“…In our report, TTF-1 expression was present to a variable extent in 4/5 (80%) cases, and peculiarly in two cases also in the squamous cell carcinoma component [1]. Combined MCC differs in many aspects from the conventional MCC: being Merkel cell polyomavirus (MCPV) negative, showing high expression of p53 and a low level of Rb1 and a much higher number of mutations [4,5,6]. MCPV-negative MCCs overlap to some extent in biology and genetics with the combined MCC, as they present TP53 mutations and a high mutation phenotype, with the majority of them showing a UV-signature pattern with C > T transitions [5,7,8].…”

Pure versus combined Merkel cell carcinomas: immunohistochemical evaluation of cellular proteins (p53, Bcl-2, and c-kit) reveals significant overexpression of p53 in combined tumors

“…In a recent large series of cases of MCC, expression of Bcl-2 correlated significantly with improved overall survival [10]. Given suggestions from our own work [12] and that of others [3] that combined tumors behave more aggressively than their pure counterparts, we sought a previously unexplored inverse relationship between Bcl-2 expression and a combined morphology but found none. Prompted by the therapeutic success of tyrosine kinase inhibitors in neoplasms such as gastrointestinal stromal tumors, which harbor activating mutations of the KIT or platelet-derived growth factor receptor α genes, with corresponding expression of cytoplasmic c-kit, several investigators have explored this avenue in MCC.…”

“…We know that Merkel cell polyomavirus (MCPyV) plays an oncogenic role in a significant majority (N80%) of cases [1]. Moreover, the tumors, formerly regarded as neuroendocrine carcinomas, have been found to display morphological diversity in a minority (b20%) of instances [2][3][4]. Hence, MCCs can be subcategorized (1) according to their viral status, MCPyV positive or MCPyV negative, and (2) according to their morphology, pure neuroendocrine or combined tumors (displaying neuroendocrine and other phenotypic elements).…”

Cytokeratin 20-negative Merkel cell carcinoma is infrequently associated with the Merkel cell polyomavirus

“…31 Merkel cell carcinoma with squamous elements or coexisting squamous cell carcinoma is often Merkel cell polyomavirus negative. 12,23,25,[33][34][35][36] Recent findings indicate that Merkel cell polyomavirusnegative tumors may be associated with RB1 inactivating mutations 37 and (in a subset) PIK3CA activating mutations. 38 Hence, although additional study is needed to clarify differences between Merkel cell polyomavirus-positive and Merkel cell polyomavirus-negative tumors, current data suggest that molecular differences exist that may have implications for immune-based or targeted therapy.…”