"Paraneoplastic syndromes secondary to Νeuroendocrine Νeoplasms"

Paraneoplastic syndromes (PNS) represent uncommon but clinically significant manifestations of neuroendocrine neoplasms (NENs) arising from ectopic hormone secretion, aberrant peptide processing, cytokine-mediated effects, or immune-mediated mechanisms. Although NENs are intrinsically capable of producing bioactive substances leading to PNS, the true prevalence of PNS in NENs remains uncertain and is likely underestimated. Paraneoplastic manifestations may precede tumor diagnosis, represent the first indication of an otherwise occult neoplasm, or emerge during disease progression, thereby providing valuable diagnostic, prognostic, and therapeutic information. Endocrine PNS, including ectopic adrenocorticotrophic hormone secretion, carcinoid syndrome, paraneoplastic hypercalcemia, syndrome of inappropriate antidiuretic hormone secretion, hypoglycemia and ectopic acromegaly, account for the majority of cases, whereas neurological PNS are rarer and predominantly associated with high-grade neuroendocrine carcinomas (NECs). Recent advances in molecular biology have revealed the importance of neuroendocrine lineage plasticity, transcriptional dysregulation, epigenetic reprogramming, and abnormal prohormone processing in the pathogenesis of these syndromes. Concurrently, improvements in biochemical testing, functional imaging, liquid biopsy technologies, and molecular profiling have enhanced diagnostic accuracy and disease monitoring. Management requires a multidisciplinary approach combining syndrome-directed therapies with tumor-targeted interventions, including surgery, somatostatin analogs, peptide receptor radionuclide therapy, targeted agents, specific chemotherapy regimens and emerging immunotherapeutic strategies. Despite substantial progress, significant gaps remain regarding epidemiology, accurate biomarkers, prognostic significance, and optimal management. This review summarizes current knowledge on pathophysiology, clinical spectrum, diagnosis, prognostic implications, and treatment of PNS associated with gastroenteropancreatic and lung NENs, while highlighting future research priorities and unmet clinical needs.