Neuroendocrine neoplasms of the digestive system: challenges of biopsy diagnosis

The diagnosis of digestive neuroendocrine neoplasms (NENs) is increasingly being made on endoscopic biopsies and endoscopic ultrasound-guided fine-needle aspiration/biopsy (EUS-FNA/FNB) or ultrasound biopsies taken from metastases. Although current classification systems provide a robust and elaborate framework for categorizing NENs, their application to limited tissue biopsy samples often remains challenging. A major challenge is the accurate distinction between well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs), which is essential because of their markedly different prognostic and therapeutic implications. Additional challenges include reliable Ki-67 assessment, recognition of intratumoral heterogeneity, and identification of mixed neoplasms, including mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) and amphicrine-like carcinoma (ALC)-a recently introduced and still poorly characterized category-and assignment of the primary site in metastatic disease using organ-associated immunohistochemical markers. Site-specific differences in morphology and immunophenotype further complicate biopsy interpretation and require integration of histological, immunohistochemical, clinical, and radiological findings. Although morphology remains the cornerstone of diagnosis, molecular testing is increasingly used in difficult cases to identify predictive biomarkers and potentially actionable genomic alterations. This review focuses on a practical biopsy-oriented diagnostic approach, discusses major diagnostic pitfalls, controversial and emerging concepts, and highlights the clinicopathological features of NENs across the digestive tract.