Merkel cell carcinoma: updates in tumor biology, emerging therapies, and preclinical models

Abstract

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma thought to arise via either viral (Merkel cell polyomavirus) or ultraviolet-associated pathways. Surgery and radiotherapy have historically been mainstays of management, and immunotherapy has improved outcomes for advanced disease. However, there remains a lack of effective therapy for those patients who fail to respond to these established approaches, underscoring a critical need to better understand MCC biology for more effective prognosis and treatment. Here, we review the fundamental aspects of MCC biology and the recent advances which have had profound impact on management. The first genetically-engineered mouse models for MCC tumorigenesis provide opportunities to understand the potential MCC cell of origin and may prove useful for preclinical investigation of novel therapeutics. The MCC cell of origin debate has also been advanced by recent observations of MCC arising in association with a clonally related hair follicle tumor or squamous cell carcinoma in situ. These studies also suggested a role for epigenetics in the origin of MCC, highlighting a potential utility for this therapeutic avenue in MCC. These and other therapeutic targets form the basis for a wealth of ongoing clinical trials to improve MCC management. Here, we review these recent advances in the context of the existing literature and implications for future investigations.

Keywords: Merkel cell carcinoma (MCC); UV signature; clinical trial; epigenetics; immunotherapy; mouse model; neuroendocrine carcinoma (NEC); viral tumorigenesis.

Figure 1

Morphologic and immunophenotypic features of Merkel cell carcinoma. (A) Expansile blue cell tumor occupying dermis with extension into subcutis (hematoxylin and eosin [H&E], 0.7x. (B) Small round cell tumor with neuroendocrine chromatin, mitotic activity, and crush artifact (H&E, 40x). (C) Cytokeratin 20 displays distinctive paranuclear dot labelling. (Chromogen DAB, counterstain hematoxylin, 40x). (D) Neuroendocrine marker Chromogranin A is immunohistochemically expressed in most cases (Chromogen DAB, counterstain hematoxylin, 40x). (E ) Neurofilament immunohistochemistry displays paranuclear dot labelling and provides a more specific marker than cytokeratin 20 for MCC (Chromogen DAB, counterstain hematoxylin, 40x). (F) RNA in situ hybridization for the MCPyV T-antigen transcript in a virus-positive MCC (Chromogen DAB, counterstain hematoxylin, 80x).

Figure 2

Candidates for MCC cell of origin. (Left) Proposed candidates for VP-MCC include many diverse cell types, especially UV-shielded dermal populations such as follicular epithelial cells and precursors, and non-epithelial lineages including neuronal, fibroblast, and pre-pro B-cells. By contrast, direct observations from human tumors strongly suggest epidermal keratinocytes to be the precursors for VN-MCC. In either scenario, lineage reprogramming (with an as-yet unknown trigger) would be required for a shift to the Merkel cell phenotype in addition to malignant transformation.

Figure 3

Mouse models of MCC. (Top panel) Mouse models of MCC utilizing xenografts of human MCC include patient-derived xenograft models in immune compromised mice, and cell line xenografts in immune compromised or humanized mice. Of these, only humanized mice allow for assessment of antitumor immune response. (Bottom panel) Generation of a murine virus positive (VP) MCC tumor required genetically engineered mice expressing MCC oncoproteins (TAgs) accompanied by ATOH1 for neuroendocrine reprogramming, and inactivation of p53. The resulting tumors can be studied in immune competent mice, allowing for studies of antitumor immunity (such as for immunotherapy). There is currently no virus negative (VN) MCC mouse model, however such a model would presumably require inactivation of the Trp53 and RB1 tumor suppressor genes similar to human VN-MCC tumors. Generation of congenic mouse cell lines from VP and VN GEMMs would allow pre-clinical therapeutic studies in an immune competent syngeneic model. Examples in gray have not yet been reported.