Epidemiology of Merkel Cell Polyomavirus Infection and Merkel Cell Carcinoma

Abstract

Merkel cell polyomavirus (MCPyV) is a ubiquitous virus replicating in human dermal fibroblasts. MCPyV DNA can be detected on healthy skin in 67−90% of various body sites, and intact virions are regularly shed from the skin. Infection occurs early in life, and seropositivity increases from 37 to 42% in 1- to 6-year-olds to 92% in adults. Merkel cell carcinoma (MCC) is a rare but very aggressive neuroendocrine tumor of the skin. It develops mainly on sun-exposed areas as a fast-growing, reddish nodule. Two MCC entities exist: about 80% of MCC are MCPyV-associated. Tumorigenesis is driven by viral integration into the host genome and MCPyV oncogene expression. In MCPyV-negative MCC, UV radiation causes extensive DNA damage leading to the deregulation of the cell cycle. In recent decades, MCC incidence rates have increased worldwide, e.g., in the United States, from 0.15 in 1986 to 0.7/100,000 in 2016. Risk factors for the development of MCC include male sex, older age (>75 years), fair skin, intense UV exposure, and immunosuppression. Projections suggest that due to aging populations, an increase in immunosuppressed patients, and enhanced UV exposure, MCC incidence rates will continue to rise. Early diagnosis and prompt treatment are crucial to reducing high MCC morbidity and mortality.

Keywords: MCC; MCPyV; Merkel cell carcinoma; Merkel cell polyomavirus; epidemiology.

Figure 1

MCPyV seroprevalence in percent by age group in years. Data from Kean et al. 2009 [17] (*only antibodies against MCPyV isolate 339 are shown), Nicol et al 2013 [25], Kamminga et al. 2018 [23], and Jeles at al. 2022 [24].

Figure 3

Advanced Merkel cell carcinoma in an 82-year-old patient. MCC appears as pink to reddish-livid and sometimes skin-colored, often fast-growing, and painless, shiny nodules or plaques. The main features are described by the acronym AEIOU: asymptomatic, (rapidly) expanding nodules, immunosuppressed, older than 50 years, and UV radiation exposure [50]. (a) Merkel cell carcinoma above the right eye covering the eyebrow. Clinically, a large, ulcerated tumor nodule, between 3 and 4 cm in diameter, with central erosions and hemorrhagic crusts is seen. According to the patient, the tumor developed within a few months. (b) The histology of Merkel cell carcinoma is shown in (a). Proliferates of small to medium-sized, hyperchromatic, densely arranged, monomorphic basophilic cells with disrupted chromatin scaffolds and mitoses are seen (Hematoxylin-eosin stain, original magnification, 100:1). (c) Immunohistochemical staining with the anti-MCPyV large T-antigen mouse monoclonal antibody CM2B4 (Santa Cruz Biotechnology, Inc., Santa Cruz, California, United States, 200 µg/mL). Strong expression (brown stained cells) of the large T antigen in tumor cells is visible (original magnification, 100:1).

Figure 2

UV radiation-induced and MCPyV-induced MCC. Exposure of the skin to UV radiation (top) or integration of MCPyV DNA into the cellular genome (bottom) can induce neuroendocrine transdifferentiation and give rise to two different MCC entities. * The cell of origin for MCPyV-positive MCC is currently under debate. LT: large T-antigen; Rb: retinoblastoma protein; Figure created with BioRender.com (accessed on 5 October 2022).

Figure 4

MCC incident rates per 100,000 per year in the US between 1986 and 2016 according to the surveillance, epidemiology, and end results (SEER) program (Data from [79] and SEER report 2018 [57].

Figure 5

Most common body sites for MCC in percent. MCC are most commonly located on the head and neck (43–54%), followed by the upper and lower extremities (see text for references). Figure created with BioRender.com accessed on 13 December 2022.