Original contributionThe spectrum of Merkel cell polyomavirus expression in Merkel cell carcinoma, in a variety of cutaneous neoplasms, and in neuroendocrine carcinomas from different anatomical sites☆,☆☆,
Introduction
Merkel cell carcinoma (MCC) is synonymous with primary neuroendocrine carcinoma of the skin. Although Toker [1] originally described and designated this tumor as trabecular carcinoma in 1972, MCC histogenesis and pathogenesis remained elusive for many years. This tumor was initially thought to be of sudoriferous or eccrine origin, but subsequent ultrastructural identification of tumoral neurosecretory granules similar to those of native cutaneous neuroendocrine cells (Merkel cells) led to the eponym Merkel cell carcinoma. Although most MCCs display pure neuroendocrine differentiation (pure Merkel cell carcinoma [PMCC]), a subset shows combined neuroendocrine and nonneuroendocrine elements (combined Merkel cell carcinoma [CMCC]), most commonly in situ (squamous cell carcinoma in situ [SCCIS]) and invasive squamous cell carcinoma (SCC), actinic keratosis (AK), intratumoral squamous differentiation, and rarely basal cell carcinoma (BCC) [2], [3]. This not-infrequent observation of CMCCs evoked theories of epidermal stem cell derivation for MCCs and shared etiologic factors with non-MCC cutaneous neoplasms—most notably UV radiation and squamous neoplasia [2], [3]. Indeed, MCC typically occurs on sun-exposed skin, but it is the tumor predilection for the elderly and immunosuppressed individuals such as human immunodeficiency virus and organ transplantation patients that compelled researchers to search for an oncogenic virus [4], [5]. Since 2008, Feng et al [6] and multiple independent investigators have confirmed the presence and clonal integration of a new polyomavirus, aptly named Merkel cell polyomavirus (MCV), in a proportion of MCCs from geographically diverse populations [6], [7], [8], [9]. These findings suggest viral-induced oncogenesis.
To date, the most common method for MCV detection has been polymerase chain reaction (PCR)–based tests, but the few immunohistochemical (IHC) studies that have examined MCV protein expression via MCV large T (LT) antigen detection in MCC and other tumors have yielded interesting results [10], [11], [12], [13]. Notably, Busam et al [10] demonstrated MCV LT antigen expression in 67% to 75% of MCCs with pure neuroendocrine morphology (PMCC) contrasting with lack of viral protein expression in 7 cases of combined squamous and neuroendocrine carcinoma (CMCC). Along the same lines, Kuwamoto et al [11] did not identify MCV DNA or protein expression in 4 cases of CMCC. Together, these findings suggest that a subset of MCC may develop independently of MCV. Busam et al [10] concluded that IHC detection of MCV using the novel monoclonal antibody CM2B4 was less sensitive than PCR (67% versus 88%, respectively) but still highly specific. This study also showed that pulmonary neuroendocrine carcinoma, a known histologic mimic of MCC, can be reliably distinguished from MCC by an absence of MCV LT antigen expression [10]. Finally, PCR-based MCV detection rates in non-MCC tissue including normal tissue, tumors from different anatomical sites, and tissue derived from patients with variable immune function have been inconsistent [6], [14], [15], [16], [17], [18]. In contrast, the findings by IHC have been consistently negative [13], [15], with the exception of 2 cases of epidermodysplasia verruciformis (EV)–related cutaneous lesions [17] and 2 cases of cutaneous SCC [18].
Intrigued by the apparent discrepancies in the literature and the relative paucity of MCV IHC studies, we sought to use CM2B4, the novel monoclonal antibody known to target MCV LT antigen, to (1) determine the frequency of MCV protein expression in cohorts of PMCC and CMCC, (2) compare patterns of MCV expression in primary MCCs and corresponding tumor metastases, and (3) investigate the prevalence of MCV expression in pulmonary and gastrointestinal (GI) neuroendocrine tumors (NETs) and various non-MCC cutaneous lesions derived from MCC patients, non-MCC patients, and individuals with altered immune function.
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Patients and samples
The study was approved by the Capital Health Research Ethics Board, Halifax, Nova Scotia, Canada. A total of 142 study cases were identified through a search of laboratory computer records and review of a previously published case series of MCCs [2]. All cases were diagnosed between 1989 and 2010, and only those with available paraffin-embedded tissue samples were included in the study. When possible, cases were age-, sex-, and site-matched across the different study groups. Clinical
Results
The clinical characteristics and primary MCC immunohistochemistry results for PMCC and CMCC patients are summarized in Table 1, Table 2, respectively. Both groups showed a slight male predominance, but the mean age was 78 years (range, 50-94 years) in the PMCC group compared with 74 years (range, 48-86 years) in the CMCC group. Moreover, although only 12 (44%) of 27 primary PMCCs arose in the highly sun-exposed region of the head and neck, 12 (80%) of 15 primary CMCCs occurred at this site.
Discussion
MCV is a newly discovered human virus that displays many features of an oncogenic virus. Specifically, MCV shows a clonal pattern of integration into MCC tumor genome and encodes a mutated LT antigen with oncogenic properties [6], [12], [19]. The recent discovery of this virus has shed new light on MCC pathogenesis, but a great deal remains to be learned about the role MCV plays in the development of MCC and other tumors.
First, although many independent investigators have detected MCV in MCCs
Acknowledgments
The authors gratefully acknowledge the support of the Capital Health Research Fund and the excellent technical assistance provided by Pam Travers and Dr. Geoffrey Rowden. We would also like to thank Dr. Yuan Chang (University of Pittsburgh) for generously sharing the CM2B4 antibody for our initial tissue trials.
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This work was supported by the Capital Health Research Fund.
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The authors have no conflict of interest to disclose.
Presented in part at the 100th annual meeting of the United States and Canadian Academy of Pathology, San Antonio, Texas, February 26-March 4, 2011.