Evidence of proliferative activity in human Merkel cells: implications in the histogenesis of Merkel cell carcinoma

Abstract

The cellular origin of Merkel cell carcinoma (MCC) is controversial. We previously hypothesized that MCC originates from hair follicle stem cells or Merkel cell (MC) progenitors residing within the hair follicle bulge. Examination of three cases of combined MCC led to the unexpected discovery that numerous keratin 20 (CK20)-positive MCs within the squamous cell carcinoma (SCC) component of combined MCC appeared morphologically normal with dendritic and oval shapes. Moreover, one extremely rare case of combined SCC and MCC showed both intra-epidermal and dermal MCCs. These three cases represent the first documentation of MC hyperplasia in MCC, besides various benign follicular neoplasms associated with MC hyperplasia. Therefore, to elucidate the proliferating potential of MCs and their histogenetic relationship with MCCs, we further investigated these cases based on pathological observations. We identified numerous cells co-expressing CK20 and the proliferation marker Ki-67, identical to the morphological and immunohistochemical features of normal MCs. This finding indicated that MCs can no longer be considered as pure post-mitotic cells. Instead, they have proliferative potential under specific conditions in the diseased or wounded skin, or adjacent to various skin tumors, including MCC. Intimate co-existence of two malignant cell components composed of intradermal and intra-epidermal MCCs, with the proliferation of normal-appearing MCs in the same lesion, lends support to the hypothesis that MCs and MCC cells are derived from MC progenitors residing within the hair follicle bulge. Specifically, MCCs are derived from transformed MC progenitors with potential for dual-directional differentiation towards neuroendocrine and epithelial lineages.