Track

Clinical Studies

Abstract

Introduction: Metastatic neuroendocrine neoplasms can arise from diverse organs and exhibit an overlapping microscopic appearance, complicating the diagnostic process. To address this diagnostic ambiguity, we analyzed comprehensive genomic profiles for mutation burden status and signatures, aiming to uncover genomic characteristics and potential novel therapeutic strategies.

Methods: All consecutive cases of metastatic neuroendocrine neoplasms diagnosed at a single academic institution between 2017 and 2023 were included. Tumors were further categorized by their tumor mutation burden (TMB) status (high: ≥20, intermediate: 6-15, and low ≤ 5 mutations/Mb) by a large cancer mutation panel (Foundationone CDx, Foundation Medicine). Samples with high tumor mutation burden were analyzed based on the published COSMIC guidance to identify specific mutation signatures.

Results: Of 48 enrolled cases (mean age 61.9 years, 60% female), high TMB was identified in 10 samples, intermediate in 10, and low in 28. Notably, all five cases of Merkel cell carcinoma were found within the high TMB group, with four of these exhibiting an ultraviolet mutational signature. In the high TMB group, tobacco signatures were found in lung and unknown primary neuroendocrine carcinomas, while remaining cases, including pancreatic neoplasms, showed temozolomide-associated signatures. Most intermediate and low TMB neuroendocrine metastases originated from the gastrointestinal tract, noncutaneous head and neck, or prostate, with a smaller number (n=3) from pancreatic and lung neuroendocrine neoplasms.

Conclusion: Our study demonstrated that high TMB and ultraviolet signatures were only observed in Merkel cell carcinomas, suggesting their potential role in guiding diagnosis and treatment for this subset of neuroendocrine neoplasms.