large T protein
Cell of origin Although MCC was initially named for the
Merkel cell due to histologic and physiologic similarities between MCC and Merkel cells, the cellular progenitor of MCC has been a heavily debated question. Merkel cells are highly specialized cells that act as pressure receptors in the epidermis. The origin of Merkel cells themselves is debated and proposed to be derived from neural crest cells or epidermal progenitors. MCC is similar to Merkel cells in its histological appearance (see below: Diagnosis) and shares many
immunohistochemical markers with Merkel cells, including epidermal marker
cytokeratin 20 and neuroendocrine markers
synaptophysin and
chromogranin A. Furthermore, the ion channel
Piezo2 and transcription factor
Atoh1, both specific to Merkel cells, are also expressed by MCC. Instead, it has been proposed the MCC may originate from a Merkel cell precursor, at which point it gains features similar to those of Merkel cells. One such precursor is the human fibroblast. Evidence for a fibroblast precursor includes its location in the
dermis, which is thought to be the primary site of origin for MCC. Additionally,
in vitro experiments have demonstrated that fibroblasts not only support
Merkel cell polyomavirus (MCV) infection but can be induced into having a MCC phenotype by the expression of viral proteins. However, others have argued that MCC likely derives from an epithelial precursor cell due to its frequent presence in mixed tumors including epithelial neoplasms such as squamous cell carcinoma. While epithelial cells are not typically found in the dermis, hair follicles include epithelial cells that have been shown to have oncogenic potential, and have therefore been proposed as a possible site for a MCC precursor. Finally, the presence of B-cell surface markers on MCC in addition to the high correlation between MCC and B-cell lymphomatous cancers have also led to suggestions that MCC may share a progenitor with B-cells. Because of the differences in physiology and prognosis between MCV+ and MCV- MCC (see below), however, some have suggested that these two subtypes of MCC may derive from different progenitor cells. Several factors are involved in the pathophysiology of MCC, including MCV, ultraviolet radiation (UV) exposure, and weakened immune function.
Merkel cell polyomavirus The
MCV is a small double-stranded DNA virus that is believed to contribute to the development of the majority of MCC. About 80% of MCC tumors are infected with MCV, with the virus integrated into the host genome in a
monoclonal pattern. Since then, studies have demonstrated integration of the MCV genome into the genome of MCC tumor cells. Central to the understanding of the pathogenicity of MCV are two viral proteins expressed in infected cells known as the
large tumor antigen (LT) and
small tumor antigen (sT). Normally, patients infected with MCV show low levels of antibodies to the LT protein, perhaps due to a nuclear localization domain in its C-terminal that limits its cellular dispersion. However, integration of the viral genome into the host genome can result in truncation of the LT protein proximal to this domain. This serves two oncogenic purposes: first, it prevents successful viral replication that would culminate in the lysis of the infected cell. Second, it redistributes the LT protein to the cytoplasm, where it can interact with cytoplasmic signaling. The N-terminal LXCXE motif of the LT protein has been shown to interact with known oncogene
Rb and is conserved in other cancer-causing viruses. This is suspected to be due to the inability of the body to defend itself from infection by or reactivation of MVC. The body of data indicating the importance of immune function in MCC pathogenesis has been exploited for the development of immunotherapies discussed below. ==Diagnosis==