Merkel cell polyomavirus

Merkel cell polyomavirus (MCPyV) is a small non-enveloped DNA virus that lives harmlessly on the skin of most people and is, in clinical terms, important for a single reason: it causes about 80 per cent of cases of Merkel cell carcinoma, an aggressive neuroendocrine cancer of the skin. It is the only human polyomavirus with a proven causal role in a human cancer, and it causes that cancer not by the usual viral life cycle but by integrating into the host genome and expressing a crippled version of its main oncoprotein. The virus is a near-universal component of the skin flora acquired in childhood; the cancer it can cause is rare and falls overwhelmingly on the elderly and the immunosuppressed, on skin that has had heavy sun exposure. Its discovery in 2008 by the laboratory that had earlier found Kaposi sarcoma-associated herpesvirus, and the subsequent success of immune checkpoint inhibitors against the cancer, have made it one of the most instructive of the human tumour viruses.

Discovery and historical significance

Merkel cell polyomavirus was discovered in 2008 by Feng, Shuda, Chang and Moore, who used digital transcriptome subtraction to search Merkel cell carcinoma tissue for foreign sequences and found a previously unknown polyomavirus integrated into the tumour genome. It was the first polyomavirus shown to cause a human cancer and the fifth human polyomavirus described. The same laboratory, that of Chang and Moore, had earlier discovered Kaposi sarcoma-associated herpesvirus, so the find extended a notable line of tumour-virus discovery. The recognition that the viral genome is clonally integrated in the tumour, and that the integrated virus expresses a mutated large T antigen, established the causal link and made Merkel cell carcinoma a model of polyomavirus oncogenesis.

Classification, structure, and genome

Merkel cell polyomavirus belongs to the family Polyomaviridae, genus Alphapolyomavirus, with the current International Committee on Taxonomy of Viruses species name Alphapolyomavirus quintihominis (formerly Human polyomavirus 5). It is a typical polyomavirus: a non-enveloped icosahedral particle about 40 to 45 nanometres across, built from 72 pentamers of the major capsid protein VP1, enclosing a circular double-stranded DNA genome of about 5,000 base pairs. The genome carries an early region encoding the large T and small t antigens and a late region encoding the capsid proteins. The large T antigen retains the LXCXE motif that binds the retinoblastoma protein but, unlike the large T antigens of BK and JC viruses, does not bind p53.

Replication cycle

As a commensal of healthy skin the virus replicates by the standard polyomavirus route, large T antigen driving the cell into S phase and the genome replicating in the nucleus. The clinically important behaviour is a departure from that cycle. In Merkel cell carcinoma the viral genome is integrated, clonally, into the host chromosome, and integration is accompanied by a truncating mutation of the large T antigen: the part that retains retinoblastoma-binding and drives proliferation is preserved, while the helicase and origin-binding domains needed to replicate viral DNA are lost. The integrated virus therefore can no longer complete its life cycle, and it transforms the cell precisely because it can only drive proliferation and not replicate. The small t antigen, which is also expressed, contributes by binding the cellular phosphatase PP2A and stabilising a MYCL-containing transcription complex that activates growth-promoting genes.

Pathogenesis

The virus persists asymptomatically on the skin of almost everyone, shed from the skin surface as part of the normal flora. Oncogenesis is a rare accident. When the genome integrates into a cell and expresses the truncated large T antigen together with small t antigen, the two viral proteins together drive the unrestrained proliferation of a Merkel-cell-like neuroendocrine cell, producing Merkel cell carcinoma. Because the oncoproteins are foreign, the tumour is immunogenic, which is why it arises disproportionately when immune surveillance is weak, in the elderly, in transplant recipients, in people with HIV and in those with chronic lymphocytic leukaemia, and why restoring or unleashing the T-cell response is therapeutically effective. About 80 per cent of Merkel cell carcinomas are caused by Merkel cell polyomavirus through this mechanism (virus-positive tumours); the remaining 20 per cent are virus-negative and arise instead from heavy ultraviolet mutagenesis, with a high mutational burden and inactivation of the retinoblastoma and p53 pathways, and these virus-negative tumours behave more aggressively.

Epidemiology

Merkel cell polyomavirus is acquired in childhood and is ubiquitous: adult seroprevalence is on the order of 60 to 80 per cent, and the virus is detectable on the skin of most healthy people. Merkel cell carcinoma is rare, with an incidence of roughly 0.2 to 0.8 per 100,000 per year, but the incidence is rising with an ageing population and greater ultraviolet exposure. The risk factors are consistent: advanced age, fair sun-damaged skin, and immunosuppression of any cause, including organ transplantation, HIV and haematological malignancy.

Natural history

Primary infection is silent and is followed by lifelong, harmless carriage on the skin. In the great majority of people nothing further happens. Merkel cell carcinoma is a rare late event that depends on the convergence of viral integration, an ageing or immunosuppressed host and accumulated skin damage, which is why it is a cancer of older and immunocompromised people rather than of the young and well.

Clinical presentations and complications

The clinically significant disease is Merkel cell carcinoma. It presents as a firm, painless, rapidly enlarging red or violet nodule on sun-exposed skin, most often of the head, neck or limbs, in an older person. The features are captured by the mnemonic AEIOU: asymptomatic, expanding rapidly, immunosuppressed, older than 50 years, and ultraviolet-exposed fair skin. It is an aggressive cancer that spreads readily to regional lymph nodes and then to distant sites, and untreated or advanced disease carries a poor prognosis.

Diagnosis

Diagnosis is made on skin biopsy. The histology is of a small round blue cell tumour with neuroendocrine features, identified by a characteristic dot-like (paranuclear) cytokeratin 20 staining pattern together with neuroendocrine markers such as synaptophysin and chromogranin, which distinguish it from other small blue cell tumours such as metastatic small cell lung carcinoma. The virus can be demonstrated in the tumour by immunohistochemistry for the large T antigen or by PCR. Circulating antibodies to the viral oncoproteins are a useful biomarker of tumour burden and can be followed to detect recurrence. Imaging is used for staging.

Management

Localised Merkel cell carcinoma is treated by wide surgical excision with sentinel lymph node biopsy, and the tumour is radiosensitive, so radiotherapy is widely used to the primary site and nodal basin. The major advance in advanced disease is immunotherapy: immune checkpoint inhibitors directed at the PD-1 and PD-L1 pathway reinvigorate T cells against the viral and tumour antigens and have become the standard treatment for metastatic disease, displacing cytotoxic chemotherapy. Where immunosuppression is contributing, reducing it assists the response. These are principles of management; the specific regimens are the province of oncology.

Prevention and public health

Vaccination

There is no vaccine against Merkel cell polyomavirus, and because the virus is a near-universal skin commensal there is no prospect of preventing infection. Prevention is therefore directed at the cancer rather than the virus: protection from ultraviolet radiation, and vigilance for new or rapidly growing skin nodules in older and immunosuppressed people, in whom early detection improves outcome.

South African context

Merkel cell carcinoma is uncommon in South Africa and has no dedicated surveillance, but two local factors are relevant: high ambient ultraviolet exposure, particularly in fair-skinned individuals, and the large population living with HIV, in whom the cancer occurs at increased frequency and at younger ages than in the immunocompetent elderly. Diagnosis and management rest with tertiary dermatology, pathology and oncology services, and the immunohistochemical and molecular tests used to confirm the diagnosis are concentrated in those centres.

References and recommended reading

• DeCaprio JA, Imperiale MJ, Hirsch HH. Polyomaviridae. In: Howley PM, Knipe DM, Damania BA, Cohen JI, eds. Fields Virology: DNA Viruses. 7th ed. Wolters Kluwer; 2022:1-44. The primary reference for the virology and the oncogenic mechanism.
• Greenlee JE, Hirsch HH. Polyomaviruses. In: Richman DD, Whitley RJ, Hayden FG (eds.), Clinical Virology, 4th edition. ASM Press; 2016. The clinical account of Merkel cell carcinoma.
• Moshiri AS, Doumani R, Yelistratova L, et al. Polyomavirus-negative Merkel cell carcinoma: a more aggressive subtype based on analysis of 282 cases using multimodal tumor virus detection. Journal of Investigative Dermatology. 2017;137(4):819-827. The source for the proportion of virus-positive tumours (about 80 per cent) and the more aggressive course of virus-negative disease.