Clinical-Pathological Evaluation and Prognostic Analysis of 228 Merkel Cell Carcinomas Focusing on Tumor-Infiltrating Lymphocytes, MCPYV Infection and ALK Expression

Abstract

Merkel cell carcinoma is a rare and aggressive primary neuroendocrine carcinoma of the skin, whose pathogenesis can be traced back to UV radiation damage or Merkel cell polyomavirus (MCPyV) infection. Despite some improvements on the characterization of the disease partly due to its increased incidence, crucial pathogenetic and prognostic factors still need to be refined. A consecutive series of 228 MCC from three hospitals in Turin was collected with the aim of both analyzing the apparent increase in MCC incidence in our area and investigating the distribution and prognostic role of clinical-pathological parameters, with a focus on MCPyV status, ALK tumor expression and tumor infiltrating lymphocytes (TILs). Review of morphology and conventional immunohistochemical staining was possible in 191 cases. In 50 cases, the expression of the novel neuroendocrine marker INSM1 was additionally assessed. Fourteen cases of MCC of unknown primary skin lesion were identified and separately analyzed. While confirming an exponential trend in MCC incidence in the last decades and providing a description of histological and cytological features of a large series of MCC, the present study concludes that 1) INSM1 is a highly sensitive marker in both skin and lymph node primary MCC; 2) positive MCPyV status, brisk TILs and lower tumor size and thickness are independent positive prognostic parameters, and the combination of the former two may provide a novel tool for prognostic stratification; 3) ALK is expressed 87% of MCC and associated with positive viral status, and could represent a prognostic biomarker, if validated in larger series.

Keywords: ALK expression; INSM1 expression; Merkel cell carcinoma; Merkel cell polyomavirus; Tumor-infiltrating lymphocytes.

Fig. 1

Morphological features of Merkel cell carcinoma with large-cell cytotype and brisk intratumoral tumor infiltrating lymphocytes (a), hematoxylin–eosin, magnification 200x). ALK immunohistochemical staining, score 3 (b), and MCPyV immunohistochemistry highlighting positive viral status (c). INSM-1 immunohistochemistry with strong nuclear expression in the majority of tumor cells (d)

Fig. 2

Lower Breslow thickness (a), presence of TILs (b), positive viral status (c) and lower tumor stage (d) are associated with longer DSS by multivariate analysis; larger tumor size (e) and increased score of ALK immunohistochemical expression (f) are associated with shorter DFI by multivariate analysis

Fig. 3

Both a linear model (a) and a generalized linear model (b) demonstrate an increase in MCC diagnoses from 1980 to 2021 in the city of Turin