Milestones in the Staging, Classification, and Biology of Merkel Cell Carcinoma

Abstract

Merkel cell carcinoma (MCC) is an aggressive skin cancer that is causally associated with ultraviolet light exposure and a recently discovered polyomavirus. Before 2010, MCC was staged using any of 5 unique systems in active use. In 2010, a consensus staging system for MCC was adopted worldwide and replaced these systems. This consensus system includes substages that reflect prognostic differences based on whether nodal evaluation was performed by pathologic analysis or clinical assessment alone. MCC-specific disease classification in ICD-9, to be expanded in the upcoming ICD-10, has improved the ability to track and manage this malignancy. Several biomarkers and histopathologic features have been identified that improve understanding of this cancer and may lead to future refinement of the current staging system. In 2008, the Merkel cell polyomavirus was discovered and is now thought to be a critical mechanism of transformation in at least 80% of MCCs. In patients who produce antibodies to the viral T-antigen oncoprotein, the titer increases and decreases with MCC disease burden and can be a clinically useful marker of recurrence. Diverse studies link CD8-positive T-cell function with outcomes in MCC and serve as the rational basis for ongoing trials of therapies to augment cellular immunity. This article reviews basic and translational research insights that will lead to improved staging, prognostic accuracy, and mechanism-based therapy for this often-lethal skin cancer.

Rationale For Immune-Based Therapies in Merkel Polyomavirus-Positive and -Negative Merkel Cell Carcinomas

“…MCPyV oncoproteins are not expressed within MCPyV virions, however, viral integration in the setting of MCC results in persistent intracellular expression of LT and sT, potentially explaining why the presence of oncoprotein antibodies is restricted to MCC patients [41]. Oncoprotein antibody titers have been found to fluctuate with tumor burden and a clinical test monitoring oncoprotein antibody titers is now being used as a tool to monitor disease progression (www.merkelcell.org/sero) [42].…”

Viral Etiology of Merkel Cell Carcinoma:Implications in Diagnosis, Prognosis, Therapy and Prevention

“…Interestingly, Merkel cell polyomavirus (MCPyV), identified in 2008 as a clear first causal agent underlying a human cancer, suggests that healthy human skin harbors resident or transient MCPyV critically capable of neoplastic transformation [7,8]. In this context, MCPyV was recently classified as a 2A carcinogen based on a consensus staging system for MCCs adopted worldwide in 2010, which replaced anyone of the five unique systems in active use [7,8].…”

“…MCPyV, and MCC tumor cells express putative polyomavirus on coprotein small T antigen (sTAg) with robust transforming activity in-vivo as well as a truncated large T antigen (lTAg) [11,13]. In patients who produce antibodies to the viral Tantigen on coprotein, the titer increases and decreases with MCC disease burden and can be a clinically useful marker of recurrence [7]. Importantly, epithelial transformation strictly depends on a recently described MCPyVsTAg domain interaction with Fbxw7, the substrate-binding component of the Skp1/Cullin1/F-box (SCF) protein ubiquitin ligase complex [11].…”

“…PGP 9.5, chromogranin A and several neuropeptides) has suggested that MCCs originate from one of the neurocrest derivatives, most probably Merkel cells, zurHausen et al hypothesized that they could originate from early B cells since they commonly express. Terminal deoxynucleotidyl Transferase (TdT) and Paired Box Protein-5 (PAX5), which are restricted to pro/pre-B cells and pre-B cells when co-expressed under certain physiologic circumstances [3].Interestingly, Merkel cell polyomavirus (MCPyV), identified in 2008 as a clear first causal agent underlying a human cancer, suggests that healthy human skin harbors resident or transient MCPyV critically capable of neoplastic transformation [7,8]. In this context, MCPyV was recently classified as a 2A carcinogen based on a consensus staging system for MCCs adopted worldwide in 2010, which replaced anyone of the five unique systems in active use [7,8].…”

“…In this context, MCPyV was recently classified as a 2A carcinogen based on a consensus staging system for MCCs adopted worldwide in 2010, which replaced anyone of the five unique systems in active use [7,8]. The consensus system that includes sub-stages that reflect prognostic differences based on whether nodal evaluation was performed by histopathology analysis or clinical assessment alone, has improved the ability to track and manage this malignancy [7]. MCPyV, and MCC tumor cells express putative polyomavirus on coprotein small T antigen (sTAg) with robust transforming activity in-vivo as well as a truncated large T antigen (lTAg) [11,13].…”