Merkel-cell carcinoma

Merkel cell carcinoma (MCC) is an aggressive skin cancer occurring in about three thousand persons per year in the United States. It is also known as cutaneous APUDoma, primary neuroendocrine carcinoma of the skin, primary small-cell carcinoma of the skin, and trabecular carcinoma of the skin. Factors involved in the development of MCC include the Merkel cell polyomavirus (MCPyV or MCV), a weakened immune system, or exposure to ultraviolet radiation. Merkel cell carcinoma usually arises on the head, neck, and extremities, as well as in the perianal region and on the eyelid. It ‘most often presents in an older white population with a male predominance'; 'median age of presentation falls within the late seventh decade, despite a broad age range (fourth to tenth decades).’ MCC is less common in children.

Signs and symptoms

Merkel cell carcinoma (MCC) usually presents as a firm nodule (up to 2 cm diameter) or mass (>2 cm diameter). These flesh-colored, red, or blue tumors typically vary in size from 0.5 cm (less than one-quarter of an inch) to more than 5 cm (2 inches) in diameter and may enlarge rapidly. Tumors can present as painless, tender or itchy, and other MCC manifestations as papules or plaques have also been reported. Although MCC may arise almost anywhere on the body, it is most commonly found in sun-exposed areas such as the head, neck, or extremities. Five key attributes of MCC were summarized in 2008 in the acronym AEIOU (Asymptomatic/lack of tenderness, Expanding rapidly, Immune suppression, Older than 50 years, and Ultraviolet-exposed site on a person with fair skin). Ninety percent of MCC's have three or more of those features. MCC is sometimes mistaken for other histological types of cancer, including basal cell carcinoma, squamous cell carcinoma, melanoma, lymphoma, and small cell carcinoma, or as a benign cyst. Merkel cell carcinomas have been described in children, but pediatric cases are very rare. Merkel cell cancers tend to invade locally, infiltrating the underlying subcutaneous fat, fascia, and muscle, and typically metastasize early in their natural history, most often to the regional lymph nodes. MCCs also spread aggressively through the blood vessels to many organs, particularly to the liver, lung, brain, and bone.

Pathophysiology

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. However, Merkel cells are post-mitotic cells with a low probability of cancerous transformation. Additionally, they have not been shown to support Merkel cell polyoma virus infection, which is believed to drive oncogenesis in approximately 80% of 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.

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