<unk>  (arrow) infiltrating skin tissue, stained brown for<unk>  cell polyomavirus large T protein. Cell of origin Although<unk>  was initially named for the<unk>  cell due to histologic and physiologic similarities between<unk>  and<unk>  cells, the cellular progenitor of<unk>  has been a heavily debated question.<unk>  cells are highly specialized cells that act as pressure receptors in the epidermis. The origin of<unk>  cells themselves is debated and proposed to be derived from neural crest cells or epidermal progenitors.<unk>  is similar to<unk>  cells in its histological appearance (see below: Diagnosis) and shares many immunohistochemical markers with<unk>  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<unk>  cells, are also expressed by<unk> . However,<unk>  cells are post-mitotic cells with a low probability of cancerous transformation. Additionally, they have not been shown to support<unk> -cell polyoma virus infection, which is believed to drive oncogenesis in approximately 80% of<unk> . Instead, it has been proposed the<unk>  may originate from a<unk>  cell precursor, at which point it gains features similar to those of<unk>  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<unk> . Additionally, in vitro experiments have demonstrated that fibroblasts not only support MCV infection but can be induced into having a<unk>  phenotype by the expression of viral proteins. However, others have argued that<unk>  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<unk>  precursor. Finally, the presence of B-cell surface markers on<unk>  in addition to the high correlation between<unk>  and B-cell lymphomatous cancers have also led to suggestions that<unk>  may share a progenitor with B-cells. Because of the differences in physiology and prognosis between MCV+ and MCV-<unk>  (see below), however, some have suggested that these two subtypes of<unk>  may actually derive from different progenitor cells. Several factors are involved in the pathophysiology of<unk> , including a virus called<unk>  cell polyomavirus (MCV), ultraviolet radiation (UV) exposure, and weakened immune function.<unk>  cell polyomavirus The MCV is a small double-stranded DNA virus that is believed to contribute to the development of the majority of<unk> . About 80% of<unk>  tumors are infected with MCV, with the virus integrated into the host genome in a monoclonal pattern. However, the majority of people with MCV infection do not develop<unk> : MCV is a ubiquitous virus and infection commonly occurs during childhood but remains asymptomatic throughout an individual's lifetime.<unk>  was first believed to be associated with MCV when it was observed to occur at a much higher rate in HIV patients during the 1980s. Since then, studies have demonstrated integration of the MCV genome into the genome of<unk>  tumor cells. Central to the our 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 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. Studies suggest that LT may also preserve cell proliferation signals such as c-Myc and cyclin E and cause DNA injury to the p53 tumor suppressor. Meanwhile, sT has been shown to induce cell proliferation through hyper-phosphorylation of the translation initiator 4EBP1 as well as inhibition of a ubiquitin ligase complex responsible for degradation of cellular proliferation signals. sT also contains a region known as the LT stabilization domain (LSD), which potentiates the LT protein's oncogenic function. Unlike LT,<unk>  samples have been identified that express sT alone, and sT expression in fibroblasts has been shown to cause<unk>  phenotype development. UV light About 20% of<unk>  tumors are MCV negative. In contrast to MCV-induced<unk> , these tumors tend to have much higher mutational burdens with mutational signatures characteristic of UV damage. Genes frequently mutated in MCV-negative<unk>  include p53 and Rb, among others. The link between<unk>  and UV exposure has been demonstrated through various epidemiological studies indicating a higher incidence of<unk>  in fair-skinned people in areas of high UV exposure, as well as among those receiving UV phototherapy. The typical distribution of<unk>  in sun-exposed regions and its co-occurrence with other skin cancers also indicate that UV exposure is a contributing factor to<unk>  development. It is unclear whether this is through direct mutational impact, immune down-regulation, or some combination of the two. Immunosuppression The incidence of<unk>  is increased in conditions with defective immune functions such as malignancy, HIV infection, and organ transplant patients, etc. Conversely, patients with brisk immune response have been shown to have improved prognoses. 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<unk>  pathogenesis has been exploited for the development of immunotherapies discussed below.
Merkel-cell carcinoma
Basal-cell carcinoma
Lymphoepithelioma
Trichoepithelioma
Angiokeratoma
Onychomatricoma
Sebaceous carcinoma
Generalized trichoepithelioma