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.

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. However, the majority of people with MCV infection do not develop MCC: MCV is a ubiquitous virus and infection commonly occurs during childhood but remains asymptomatic throughout an individual's lifetime.

MCC 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 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. 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 the inhibition of a ubiquitin ligase complex responsible for the 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, MCC samples have been identified that express sT alone, and sT expression in fibroblasts has been shown to cause MCC phenotype development.

UV light About 20% of MCC tumors are MCV negative. In contrast to MCV-induced MCC, these tumors tend to have much higher mutational burdens with mutational signatures characteristic of UV damage. Genes frequently mutated in MCV-negative MCC include p53 and Rb, among others. The link between MCC and UV exposure has been demonstrated through various epidemiological studies indicating a higher incidence of MCC in fair-skinned people in areas of high UV exposure, as well as among those receiving UV phototherapy. The typical distribution of MCC in sun-exposed regions and its co-occurrence with other skin cancers also indicate that UV exposure is a contributing factor to MCC development. It is unclear whether this is through direct mutational impact, immune down-regulation, or some combination of the two.

Immunosuppression The incidence of MCC 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 MCC pathogenesis has been exploited for the development of immunotherapies discussed below.

Diagnosis

Diagnosis of MCC begins with a clinical examination of the skin and lymph nodes to determine suspicious areas for further investigation. Definitive diagnosis requires examination of biopsy tissue to identify its histopathologic features. An ideal biopsy specimen is either a punch biopsy or a full-thickness incisional biopsy of the skin including full-thickness dermis and subcutaneous fat. On light microscopy, MCC shows basaloid tumor nests with neuroendocrine features ("salt and pepper" chromatin, scarce cytoplasm, and brisk mitotic activity). In addition to standard examination under light microscopy, immunohistochemistry (IHC) is also generally required to differentiate MCC from other morphologically similar tumors such as skin metastases of small cell lung cancer, the small cell variant of melanoma, various cutaneous leukemic/lymphoid neoplasms, and Ewing's sarcoma. Neuroendocrine molecular markers such as synaptophysin or chromogranin A are characteristic of MCC and other neuroendocrine tumors, while other markers such as PAX5 or cytokeratin 20 can distinguish MCC from these tumors. Longitudinal imaging may also help in ruling out a diagnosis of metastatic small cell lung cancer. Once an MCC diagnosis is made, a sentinel lymph node biopsy as well as imaging are recommended as a part of the staging process, which determines prognosis and subsequent treatment options. Imaging may include positron emission tomography or CT scan.

Prevention Sunlight exposure is thought to be one of the causes of Merkel cell carcinoma (MCC). The World Health Organization, American Academy of Dermatology, and Skin Cancer Foundation recommend the following measures to prevent excessive UV exposure and skin cancer: Limiting sun exposure between the hours of 10 am and 4 pm, when UV rays are the strongest Seeking shade when UV rays are most intense Wearing sun-protective clothing including a wide-brim hat, sunglasses, and tightly woven, loose-fitting clothing Using sunscreen Avoiding tanning beds and artificial UV exposure

Treatment

Merkel cell carcinoma is typically treated with surgery and radiation; immunotherapy is used in advanced disease. If an affected person is being treated with immunosuppressive drugs, they are reduced as much as possible.

Surgery Surgical resection is typically performed before other treatments, if possible. The type of surgery used may be a simple wide excision or a more specialized technique like Mohs surgery, depending on the individual. Part of the staging process – sentinel lymph node biopsy – is often performed at the same time.

Radiation

Radiation therapy is the primary management of Merkel cell carcinoma (MCC). The largest studies to date, from Australia, demonstrated that radiotherapy alone achieves equal outcomes with upfront or neoadjuvant surgery followed by radiation therapy. The role of surgery is largely historical and relegated to biopsy. There have been no head-to-head trials comparing the two treatment strategies, and in the absence of this, surgeons tend to most commonly perform excisional biopsy prior to referring for radiation therapy to eradicate MCC. MCC is exquisitely radiosensitive. The conclusion amongst published studies in the Radiation Oncology community is that MCC should be managed ideally with radiation therapy alone.

Chemotherapy