MCC is a rare skin tumor whose reported incidence has tripled in the past 2 decades.1,17
It affects predominantly the White population, men more often than women.2,7,16
MCC tends to affect the elderly, with a median age at presentation of 69 years.2
It is associated with chronic sun-damage2,7,16
The latter includes HIV-associated or lymphoma-associated immunosuppression and patients after solid organ transplantation or undergoing chemotherapy.9,16,26,32
Recently, Feng et al13
identified MCV as a novel polyomavirus clonally integrated into the genome of MCCs. Eight of 10 tumor samples were found to contain the virus. Subsequent studies confirmed this association. The frequency of detection of MCV by PCR in tumor ranged from as low as 24% in a small sample of Australian patients15
to 70% to 85% in North American and European patients.6,13,15,20
In our current series, 88% of all MCC were positive for MCV by PCR. Differences in MCV detection rates may be related to different patient populations, technical reasons, or diagnostic criteria of suspected lesions.
The sensitivity of MCV detection by IHC using mAb CM2B4, which was generated against a predicted antigenic epitope on the Merkel cell polyomavirus encoded T antigen, was less than by qPCR (67% vs. 88%, respectively). However, the antibody stained the majority of PCR-positive tumors (77%). The specificity of the immunohistochemical labeling was high. All tumors, which were immunoreactive for CM2B4 were positive for MCV by PCR.
Positive staining was typically homogenous strong nuclear labeling of the majority of tumor cells. However, in a subset of cases, only a portion of the tumor cells was positive. Adjacent normal skin tissue was consistently negative for CM2B4.
There was no apparent association of MCV detection with anatomic site/mode of sun exposure and major clinical immune suppression of the patients. This is not a surprise. Less than 10% of MCC occur in patients with major immunosuppression, such as HIV, associated lymphoma or status postorgan transplantation.16
As the majority of MCCs had previously been found to be positive for MCV,6,13,20
it was already evident that MCV-associated MCC could not be restricted to severely immunosuppressed patients. Similarly, given the high frequency of MCV in MCC and the known anatomic distribution of the tumor,2
it was also expected that MCV could be found in tumors of both sun-exposed and sun-protected sites.
With regard to its potential diagnostic use, our findings suggest that mAb CM2B4 will likely emerge as a valuable adjunct reagent for the differential diagnosis of MCC from histologic mimics, in particular for the distinction of MCC from a cutaneous metastasis of a pulmonary neuroendocrine carcinoma, when current panels of immunomarkers do not allow a definitive diagnosis.8,10,11,19,22,25,27
None of the 26 neuroendocrine carcinomas of the lung, which we examined in this series, labeled with CM2B4. Further investigations, however, are needed to examine the sensitivity and specificity of CM2B4 on a larger set of tumors, especially neuroendocrine carcinomas from sites other than skin and lung.
Although our results support prior observations that the majority of primary cutaneous neuroendocrine carcinomas are associated with MCV, not all of them are. Lack of virus detection may in part be due to technical reasons, for example, tissue preservation of the specimen, or virus mutation that does not permit PCR-amplification with the primers used, and/or may also lead to lack of immunoreactivity for CM2B4. However, it is also possible that there is a subset of primary cutaneous neuroendocrine carcinomas, which may not be associated with MCV. Consequently, primary cutaneous neuroendocrine carcinomas may be divided into 2 broad categories—MCV-positive type, representing the majority of case, and MCV-negative type.
It is of interest in this regard that none of the 7 combined cutaneous squamous and neuroendocrine carcinomas were immunoreactive with CM2B4. Furthermore, the one PCR-negative primary tumor turned out to be a combined squamous and neuroendocrine carcinoma. Such combined tumors are rare and account for only a minor portion of MCCs. Population-based data are lacking. In the patient review of 29 cases of MCC, Walsh36
found 3 tumors, in which MCC was associated with a superficial squamous cell carcinoma. In the institutional data set of Merkel cell tumors from MSKCC, approximately 5% of patients with a diagnosis of MCC have a neuroendocrine tumor that is associated with a superficial invasive squamous cell carcinoma (KJ Busam, unpublished observations). Although it is difficult to draw definitive conclusions from such as small sample size, it is tempting to speculate that neuroendocrine carcinomas arising in association with a squamous cell carcinoma may develop via a MCV-independent pathway and are different from “classic” MCCs. One may also question whether or not such combined MCV-negative tumors should be designated as “MCC.”
Historically, pathologists have classified the combined tumors as variants of MCC, because phenotypically, they are primary cutaneous carcinomas with a predominant neuroendocrine phenotype (ie, after the differentiation pathway of Merkel cells). Except for the associated presence of a (usually minor) superficial squamous cell carcinoma component, the histologic and immunohistochemical features of the dominant tumor component are indistinguishable from de novo “pure” MCC.4,18,34,36
Furthermore, the combined tumors tend to behave clinically similar to pure MCCs,36
and their metastases tend to have a pure neuroendocrine appearance. It is of interest that among the patients with combined tumors, the proportion of those with chronic lymphocytic leukemia was higher than expected,16
but this may be related to referral bias to a large cancer center.
In conclusion, our study documents that MCCs frequently express MCV at the molecular and the protein level, with a good correlation of PCR-based and immunohistochemical detection methods. Immunostaining with mAb CM2B4 detects MCV-associated protein the majority of Merkel cell tumors, but not in pulmonary neuroendcorine tumors. Although a broader spectrum of tumors from many different anatomic sites need to be tested, our findings suggest that CM2B4 may be a useful reagent for the diagnosis of MCC. Interestingly, not all primary or metastatic cutaneous neuroendocrine carcinomas appear to be MCV-positive suggesting some biologic heterogeneity in this tumor family.