Neuroendocrine Tumors of Unknown Primary: A Review of the Diagnosis and Treatment

Neuroendocrine tumors of unknown primary (NET-UPs) represent a diagnostically and therapeutically challenging subset of neuroendocrine neoplasms. Despite advances in imaging and molecular profiling, up to 13% of metastatic NETs lack an identifiable origin at presentation. This review examines the multimodal diagnostic strategies for NET-UPs, highlighting the integration of cross-sectional imaging, receptor-based PET imaging, immunohistochemistry, and surgical exploration. While 68 Ga-DOTATATE PET/CT remains the preferred imaging modality for well-differentiated tumors, intraoperative small bowel palpation offers the highest diagnostic yield when imaging is inconclusive. Immunohistochemical markers, including second generation neuroendocrine stains and transcription factor profiles, aid in classifying tumor origin and differentiation. Management of NET-UPs is largely guided by tumor grade and somatostatin receptor status. Well-differentiated, receptor-positive tumors are treated with somatostatin analogues, with peptide receptor radionuclide therapy used in progressive disease. Despite therapeutic advancements, optimal sequencing and combination strategies remain areas of ongoing investigation. Given the clinical heterogeneity of NET-UPs, sustained multidisciplinary collaboration is critical to optimizing outcomes in this complex and increasingly prevalent disease.