Combined Merkel Cell Carcinoma and Squamous Cell Carcinoma: A Systematic Review

Abstract

Combined Merkel cell carcinoma (MCC) and squamous cell carcinoma (SCC) have classically been regarded as more aggressive than conventional, pure, Merkel cell polyomavirus (MCPyV)-positive MCC. It is still unknown whether combined MCC and SCC are more aggressive than pure, MCPyV-negative MCC, and the origin of both the SCC and MCC elements of these combined tumors has not been elucidated. The main objective of this systematic review was to assess whether combined MCC and SCC tumors are associated with a worse prognosis than pure MCC; the secondary goals were the characterization of the clinical and histopathological features of these combined neoplasms. A total of 38 studies, including 152 patients, were selected for review. In total, 76% of the cases were MCPyV-negative, whereas 4% were MCPyV-positive. The most frequent histopathological pattern was that of an SCC in situ combined with a dermal MCC (36%), followed by both an in situ and invasive SCC combined with a dermal MCC (20%). Forty-seven percent of all cases fitted in the morphology of the so-called "collision tumors". Three combined MCC cases that would fit in the morphological category of collision tumors presented both squamous and neuroendocrine elements in their respective nodal metastases. The mean overall survival was 36 months, comparable to that of pure, MCPyV-negative MCC. This review found similarly aggressive behavior for combined MCC and SCC and pure, MCPyV-negative MCC. Preliminary data strongly suggest that all MCPyV-negative MCC tumors, whether combined or pure, are part of a common spectrum.

Keywords: Merkel cell carcinoma; Merkel cell polyomavirus; combined Merkel cell carcinoma; combined squamous cell carcinoma and Merkel cell carcinoma; divergent Merkel cell carcinoma.

Figure 1

The flow chart with the different phases of the systematic literature search and selection of studies included in this review. The total number of search results was 1014 records. After elimination of duplicates (173), another 784 studies were excluded based on title and abstract screening, and finally, 14 studies were excluded after full-text assessment. Thus, the study selection resulted in a total of 38 relevant articles included in the present review of combined MCC and SCC (Supplementary Table S2).

Figure 2

Combined MCC and SCC are classically depicted as a collision tumor. (A,B) (×200, original magnification) the neuroendocrine (green arrows) and squamous (yellow arrows) components of the tumor can be seen closely together, with sheets of small, basophilic tumoral cells intermingled with nests of atypical, squamous cells; (C,D) (×400, original magnification). A closer view highlights the dermal invasion of sheets of small, monomorphic, basophilic, tumoral cells (green arrows), as well as large nests of atypical squamous cells (yellow arrows). Both elements appear closely together, without areas of clear transition from one component to the other.

Figure 3

Combined MCC and SCC typically described as MCC with divergent differentiation. (A,B) (×200, original magnification) diffuse dermal invasion by sheets of small, basophilic, neuroendocrine cells (green arrows), with areas of abrupt transition into nests of atypical, squamous cells (yellow arrows); (C,D) (×400, original magnification). A closer view highlights the abrupt transition of the neuroendocrine cells (green arrows) into the squamous component (yellow arrows).

Figure 4

Immunohistochemical panel of combined MCC and SCC: (A) (×40, original magnification) shows a panoramic view of a dense, basophilic, dermal tumor; (B) (×200, original magnification) shows a closer view and highlights areas of abrupt transition into nests of squamous cells; (C) (×40, original magnification) the squamous nests show positive staining with CKAE1/AE3, whereas the basophilic, neuroendocrine cells remain negative; (D) (×200, original magnification) a closer view of the positive squamous nests; (E) (×40, original magnification) the tumor shows diffuse positive staining with synaptophysin; (F) (×200, original magnification) a closer view highlights intense positive staining for the neuroendocrine cells, whereas the squamous nests remain negative.

Figure 5

Morphological classification of combined MCC (green arrows) and SCC (yellow arrows) tumors. (A) (×400 original magnification) dermal MCC associated with intraepidermal SCC. (B) (×400 original magnification) Intraepidermal MCC associated with intraepidermal SCC. (C) (×400 original magnification) Intraepidermal and dermal MCC. (D) (×400 original magnification) Dermal MCC and SCC. (E) (×200 original magnification) Dermal MCC associated with intraepidermal and dermal SCC. (F) (×400 original magnification) Intraepidermal and dermal MCC associated with intraepidermal and dermal SCC.