Merkel Cell Carcinoma of Unknown Primary: Immunohistochemical and Molecular Analyses Reveal Distinct UV-Signature/MCPyV-Negative and High Immunogenicity/MCPyV-Positive Profiles

Abstract

Background: Merkel cell carcinomas of unknown primary (MCC-UPs) are defined as deep-seated tumors without an associated cutaneous tumor. Although the distinction has important clinical implications, it remains unclear whether these tumors represent primary tumors of lymph nodes or metastatic cutaneous primaries. Methods: We compared the immunohistochemical profiles of four groups of MCCs (Merkel cell polyomavirus (MCPyV)-positive UP, MCPyV-negative UP, MCPyV-positive known primary (KP), and MCPyV-negative KP) using B-cell and pre-B-cell markers, cell cycle regulating proteins, follicular stem cell markers, and immune markers, and performed next generation and Sanger sequencing. Results: Virus-positive and virus-negative MCC-UPs exhibited an immunoprofile similar to virus-positive and virus-negative primary cutaneous MCCs, respectively. MCC-UP tumors (both virus-positive and -negative) were immunogenic with similar or even higher tumoral PD-L1 expression and intratumoral CD8 and FoxP3 infiltrates in comparison to MCPyV-positive cutaneous tumors. In addition, similar to primary cutaneous MCCs, MCPyV-negative MCC-UPs exhibited UV signatures and frequent high tumor mutational burdens, whereas few molecular alterations were noted in MCPyV-positive MCC-UPs. Conclusions: Our results showed distinct UV-signatures in MCPyV-negative tumors and high immunogenicity in MCPyV-positive tumors. Although additional studies are warranted for the MCPyV-positive cases, our findings are supportive of a cutaneous metastatic origin for MCPyV-negative MCC-UP tumors.

Clinical-Pathological Evaluation and Prognostic Analysis of 228 Merkel Cell Carcinomas Focusing on Tumor-Infiltrating Lymphocytes, MCPYV Infection and ALK Expression

“…Fourteen of our cases presenting with macroscopic nodal disease lacked any evidence of a skin primary tumor (MCC of unknown primary, MCC-UP), and presented with a mean age at diagnosis of 65 years, which was significantly lower compared to the age at diagnosis of MCC with known primary skin lesion. This is in line with previous reports observing a similar mean age at diagnosis [69,70] as well as a lower median age in the MCC-UP subgroup [71]. In apparent contrast with our results, no significant differences in demographics of MCC-UP was reported in the largest published series, but age was investigated considering a cutoff of 65 years (and not as a continuous variable), thus possibly explaining our diverging results [72].…”

“…Nevertheless, in a recent review, rare cases of MCC-UP arising in the setting of immunosuppression have been described and found to be prevalently characterized by a negative viral status and worse prognosis [74]. It remains however unlikely that such tumors actually arise as a primary lymph node disease; in fact, evidence of UV-mutational signatures and high mutational burdens have been extensively reported in MCPyV-MCC-UP, both in immunocompetent and immunosuppressed patients [71][72][73].…”

The impact of merkel cell polyomavirus positivity on prognosis of merkel cell carcinoma: A systematic review and meta-analysis

“…Most studies suggest that MCC may have a majority (80%) MCPyV-positive subtype and another minority (20%) MCPyVnegative subtype (27). In addition to MCPyV infection, UV exposure is a significant risk factor for MCC, and it has the potential to trigger genetic mutations, which would lead to immunosuppression (2,9,28,(34)(35)(36). Enrichment of UVinduced mutations detected in most MCPyV-negative MCC and not identified in MCPyV-positive MCC (28,(34)(35)(36).…”

“…In addition to MCPyV infection, UV exposure is a significant risk factor for MCC, and it has the potential to trigger genetic mutations, which would lead to immunosuppression (2,9,28,(34)(35)(36). Enrichment of UVinduced mutations detected in most MCPyV-negative MCC and not identified in MCPyV-positive MCC (28,(34)(35)(36). Thus, the possibility of MCPyV-negative MCC deriving from UVdriven pathways is high.…”

Merkel Cell Carcinoma from Molecular Pathology to Novel Therapies

“…Both virus-positive and -negative MCC-UP are immunogenic with high intratumoral PD-L1 expression as well as intratumoral CD8 and FoxP3 infiltrates. Moreover, MCPyV-negative MCC-UP tumors present typical UV signatures and high tumor mutational burden, and in contrast, low numbers of mutations are found in MCPyV-positive MCC-UPs [16].…”