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.

Mast cell density in Merkel cell carcinoma and its correlation with prognostic features and MCPyV status: a pilot study

“…Another important aspect we addressed in our paper relates to the status of MCPyV; the current literature is in agreement that MCPyV-positive cases have a more favorable prognosis than non-MCPyV-related cases [ 35 – 37 ]. Different hypotheses have been advanced to explain these data, including the fact that MCPyV-negative MCCs have a higher number of chromosomal aberrations [ 8 , 39 , 40 ], a greater nucleotide mutation burden [ 8 , 38 ], and a higher number of mutations in known oncogenic pathways including PI3K/pAKT, P53, and RB1 [ 8 , 41 ], as well as postulating that virus-driven oncogenesis is able to be more immunogenic and thus stimulate a more vigorous response from the immune system [ 41 , 42 ].…”

“…Regarding this latter type of MCC, the most frequent mutations are of the tumor suppressor genes RB1 and TP53 but also mutations promoting the activation of the PI3K pathway (HRAS and KRAS) and inactivation of the Notch pathway that is another critical oncogenic event [ 6 ]. In terms of topography, MCC usually favors the head–neck region (50%) (particularly the eyelid and periorbital region) and upper extremities (40%) and often presents as a firm, painless, nodular or plaque-like, flesh-colored to red–violet lesion, which can sometimes grow very rapidly to the point of causing ulceration, bleeding, and necrosis [ 5 , 7 , 8 ].…”

Mast Cells density in relation to recurrency, lymphovascular Invasion and MCPyV status in Human Merkel Cell Carcinoma: a descriptive study with prognostic implications

“…Histopathologically, the tumor presents as so-called 'blue nodule' in the dermis and/or subcutis and consists of cellular elements that may be small or intermediate to large cells, the nuclei of which characteristically display the ne granular 'salt-and-pepper' appearance of chromatin, with frequent nuclear moulding [2,11]. An example of histopathological features is reported in Fig.…”

“…In terms of immunohistochemistry, MCC cells are positive for epithelial markers such as CK-CAM5.2, CKAE1-AE3, CK20, CK34BetaE12, BerEP4 and Epithelial membrane Antigen (EMA), PIEZO2 [12], with some cases showing positivity for CK7 along with markers of neuroendocrine differentiation including Chromogranin A (CgA), Synaptophysin (Syn) and CD56 (NCAM1). It is also important to mention that positivity for CK20 is de ned as 'dot-like' and is a reliable speci c sign for the diagnosis of MCC [11,13]. An example of CK20 is reported in Fig.…”