Molecular Profiling of Multiple Primary Merkel Cell Carcinoma to Distinguish Genetically Distinct Tumors From Clonally Related Metastases

Abstract

IMPORTANCE Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma. In rare cases, the development of an additional cutaneous MCC tumor is clinically consistent with a second primary MCC tumor rather than a cutaneous metastasis, which has important treatment and prognostic implications. OBJECTIVE To evaluate genetic relatedness in 4 cases with the clinical diagnosis of multiple primary MCCs. DESIGN, SETTING, AND PARTICIPANTS In this case series, 7 cases of clinically designated multiple primary MCC were identified; 4 cases met inclusion criteria for next-generation sequencing (NGS) analysis. Mutations, copy number alterations, and Merkel cell polyomavirus (MCPyV) sequence were analyzed and compared between clinically designated multiple primary tumors to characterize genetic relatedness and hence assess clonality. Patients with clinically designated multiple primary MCC were identified from the multidisciplinary MCC Program at the University of Michigan, a tertiary care center. MAIN OUTCOMES AND MEASURES Four cases of clinically designated multiple primary MCC were characterized by tumor sequencing and targeted MCPyV sequencing to distinguish independent primary tumors from related metastases. RESULTS Overall, 4 patients in their 70s or 80s were included and analyzed. Cases 1 and 4 were verified as genetically distinct primary tumors and did not harbor similar copy number alterations or demonstrate significant mutational overlap. Cases 2 and 3 were designated as clonally related based on overlapping copy number alterations. In clonally related tumors, chromosomal copy number changes were more reliable than mutations for demonstrating clonality. Regardless of clonality, we found that MCPyV status was concordant for all tumor pairs and MCPyV positive tumors harbored predominatly subclonal mutations. CONCLUSIONS AND RELEVANCE Our findings suggest that patients with MCC may develop a second genetically distinct primary tumor; in this case, the subsequent tumor is likely to develop through similar mechanisms of pathogenesis, either MCPyV-mediated or ultraviolet light-mediated. Next-generation sequencing analysis of chromosomal copy number changes and mutations is useful in distinguishing multiple primary MCCs from progression of MCC clinically resembling multiple primaries, allowing appropriate staging of the patient.

Epidemiology, biology and therapy of Merkel cell carcinoma: conclusions from the EU project IMMOMEC

“…type 1 “immune resistant” (high TIL/high PD-L1) and type 2 “immune ignorant” (low TIL/low PD-L1). Mutation burden is higher in type 1 non-viral MCC, consistent with the notion that a higher neoantigen load exists within more densely infiltrated tumors [47–53] (Fig. 2b).…”

A case of combined Merkel cell carcinoma and squamous cell carcinoma: Molecular insights and diagnostic pitfalls

“…We build upon previous observations that chromosomal copy number analysis is useful for demonstrating MCC clonality. 4 , 8 Our findings suggest that, at least in the current case, SCC and MCC may coexist as a result of collision rather than divergent differentiation of a single neoplasm. We propose that concurrent SCC is not a reliable feature for favoring a primary MCC, as collision is possible in a patient with high NMSC burden.…”

“… 1 Different MCPyV status between 2 tumors would support them to be unrelated (metachronous primaries); however, in practice, this may not be a useful test, as patients with multiple primary MCC tumors tend to consistently have either MCPyV-driven or photo damage–associated tumors. 4 Molecular studies can distinguish clonally related MCC metastases from independent primary tumors. 4 , 5 , 6 , 7 , 8 In our case, SNP array found clonal identity between 2 foci of MCC.…”

“… 4 Molecular studies can distinguish clonally related MCC metastases from independent primary tumors. 4 , 5 , 6 , 7 , 8 In our case, SNP array found clonal identity between 2 foci of MCC. By contrast, the associated SCC had a distinct, nonoverlapping set of chromosomal copy number changes, compatible with an unrelated neoplasm.…”

“…In approximately 1% to 2% of patients with MCC, a second MCC tumor will arise that is clinically compatible with a new primary MCC. 1 , 4 In such cases, molecular analyses may be useful in distinguishing a second primary MCC tumor from a distant cutaneous metastasis. 4 , 5 , 6 , 7 , 8 …”