Atsuko Kasajima

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.

Mixed neuroendocrine/non‐neuroendocrine neoplasms (MiNEN) of the digestive system are rare epithelial malignancies characterised by the coexistence of neuroendocrine and non‐neuroendocrine neoplasm components within the same lesion, where each component must account for at least 30% of the total tumour cell population. Despite growing recognition, MiNEN remain diagnostically and therapeutically challenging because of marked morphological heterogeneity, biological plasticity, and limited evidence guiding management. Recent molecular studies support a common clonal origin with subsequent divergent differentiation, although the mechanisms underlying progression and treatment resistance remain incompletely understood. This ENETS position statement summarises current evidence and expert opinion regarding the diagnosis and treatment of digestive MiNEN, focusing on major controversies in pathology, molecular biology, imaging, and management. Key diagnostic issues include the arbitrary 30% cutoff defining MiNEN, sampling limitations in biopsy specimens, intra‐tumoural heterogeneity, and the distinction between amphicrine and collision neoplasms. Molecular profiling increasingly demonstrates shared genomic alterations between distinct components and may identify potentially actionable targets, including high level of microsatellite instability (MSI‐high) or deficient mismatch repair (dMMR) and V‐RAF murine sarcoma viral oncogene homolog B1 ( BRAF ) alterations in selected cases. Clinical management should be individualised according to anatomical site, stage, differentiation and proliferation of each component, and the histology of metastatic disease when available. Surgery is the main potentially curative approach for localised resectable disease. Perioperative and metastatic systemic treatments are extrapolated predominantly from site‐specific adenocarcinoma and poorly differentiated neuroendocrine carcinoma (NEC) practice; no regimen has been prospectively established as superior specifically for MiNEN. Given the rarity and complexity of MiNEN, multidisciplinary management in expert centres, centralised pathological review, and international collaborative registries are essential to improve diagnostic standardisation and optimise treatment strategies.

Background: Well-differentiated pancreatic neuroendocrine tumors (PanNETs) develop in ~80% of patients with multiple endocrine neoplasia type 1 (MEN1) and remain the leading cause of MEN1-related mortality. Whether MEN1-associated PanNETs display distinct clinicopathologic or prognostic characteristics compared with non-MEN1 PanNETs remains incompletely defined. Methods: We retrospectively reviewed clinical, pathological, and outcome data from 817 patients who underwent surgical resection for well-differentiated PanNETs, including 39 MEN1-associated and 778 non-MEN1 PanNETs, with a total of 7752 person-years of follow-up. Tumor characteristics, stage, and survival outcomes were compared between two groups. Results: MEN1-associated PanNETs represented 4.8% of the cohort and included both functional and non-functional tumors. Patients with MEN1 more frequently had functional tumors, with insulinomas and gastrinomas predominating. Patients with MEN1 were significantly younger at surgery. Tumor size and grade distribution were similar between the two groups, although tumors >2 cm were more prevalent in patients with MEN1. MEN1-associated tumors demonstrated significantly lower rates of lymphovascular and perineural invasion, but similar rates of lymph node metastasis and stage III disease when only lymph node metastases attributable to a pancreatic primary were included. Long-term overall survival, disease-specific survival, and cumulative incidence of relapses did not differ significantly between MEN1 and non-MEN1 patients. Conclusions: In this retrospective cohort of surgically resected, well-differentiated PanNETs, MEN1-associated tumors exhibited similar histologic grade and tumor size distributions to non-MEN1 PanNETs. MEN1 status was associated with a higher prevalence of functional tumors and lymph node metastases, but lower rates of vascular and perineural invasion. Despite these features, no statistically significant differences in long-term overall survival, disease-specific survival, or cumulative incidence of relapse were observed between surgically resected patients with and without MEN1, though the study was underpowered to detect modest differences.

About 10% of neuroendocrine tumors (NETs) can occur in the context of several different hereditary tumor syndromes, and, in a not negligible number of cases, their diagnosis precedes the clinical identification of the hereditary syndrome. In this context, the role of a pathologist can be crucial in identifying these sentinel cases. Indeed, early recognition of inherited NETs has significant clinical value, both for guiding therapeutic strategies and for managing at-risk family members. Modern pathologists play a central role not only in the accurate diagnosis and subtyping of NETs but also in recognizing specific morphologic features that may point to a germline etiology. When morphology does not show peculiar features suggestive of a hereditary context, integrating morphology with clinical context may, however, help identify appropriate genetic testing. In the present paper, we provide an organ-based overview of the most important morphologic and immunohistochemical features, along with their molecular correlates, of pituitary, parathyroid, thoracic, and digestive NETs arising in the context of hereditary tumor syndromes.

The increasing use of immune checkpoint inhibitors (ICI) has led to recognition of a broad spectrum of treatment‐associated inflammatory adverse events, including pancreatic injury. Histological overlap between ICI associated pancreatic injury (ICIPI) and so‐called autoimmune pancreatitis (AIP) has been suggested in isolated reports, but the extent and detailed histopathological features of this overlap remain poorly characterized. The aim of this study was to describe the clinicopathological and histological features of rare ICIPI cases with available tissues and to compare these findings with established histological patterns of AIP. Data were available for five cases. All patients except one were female. ICIPI occurred between 182–580 days after initiation of ICI therapy. All patients had received a combination ICI treatment (e.g., Ipilimumab + Nivolumab). Peak serum lipase levels ranged from 4 to 41 (µkat/L). Computed tomography demonstrated radiologic features consistent with autoimmune pancreatitis (AIP) in four cases, whereas one case raised suspicion of a metastatic lesion. Three patients were treated with steroids, following which pancreatitis (lipase and imaging) resolved. Two patients developed pancreatic atrophy or exocrine insufficiency. Two patients underwent surgical resection because of suspected cancer metastasis. Fine needle biopsy showed only nonspecific atrophy and mild chronic inflammation. In contrast, both surgical specimens demonstrated marked histological overlap with type 2 AIP, including duct‐centric inflammatory changes and granulocytic epithelial lesions, whereas increased IgG4‐positive plasma cells or other features characteristic of type 1 AIP were not identified. Our results, together with the limited published literature, suggest that ICIPI may encompass a heterogeneous spectrum of histological changes, with substantial overlap with type 2 AIP in a subset of cases. Recognition of these overlapping features is important in the histopathological diagnosis of pancreatic inflammatory lesions in patients receiving ICI therapy. Treatment of ICIPI should follow NCCN recommendations. The risk of developing a pancreatic exocrine insufficiency needs to be observed.

Background: Well-differentiated pancreatic neuroendocrine tumors (PanNETs) develop in ~80% of patients with multiple endocrine neoplasia type 1 (MEN1) and remain the leading cause of MEN1-related mortality. Whether MEN1-associated PanNETs display distinct clinicopathologic or prognostic characteristics compared with sporadic PanNETs remains incompletely defined. Methods: We retrospectively reviewed clinical, pathological, and outcome data from 817 patients who underwent surgical resection for well-differentiated PanNETs, including 39 MEN1-associated and 778 non-MEN1 tumors, with a total of 7,752 person-years of follow-up. Tumor characteristics, stage, and survival outcomes were compared between two groups. Results: MEN1-associated PanNETs represented 4.8% of the cohort and included both functional and non-functional tumors. Patients with MEN1 more frequently had functional tumors, with insulinomas and gastrinomas pre-dominating. Patients with MEN1 were significantly younger at surgery. Tumor size and grade distribution were similar between two groups, although tumors >2 cm were more prevalent in patients with MEN1. MEN1-associated tumors demonstrated significantly lower rates of lymphovascular and perineural invasion, but similar rates of lymph node metastasis and stage III disease when only lymph node metastases attributa-ble to a pancreatic primary were included. Long-term overall survival, disease-specific survival, and cumula-tive incidence of relapses did not differ significantly between MEN1 and non-MEN1 patients. Conclusions: Surgically resected MEN1-associated PanNETs show comparable histologic grade and tumor size to sporadic PanNETs. MEN1 is associated with more functional tumors and lymph node metastases, but less vascu-lar/perineural invasion. Despite these features, long-term overall survival, disease-specific survival and cu-mulative incidence of relapse are comparable between surgically resected patients with and without MEN1.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplasms encompassing both well differentiate neuroendocrine tumors (NETs), and poorly differentiated neuroendocrine carcinomas (NECs). This classification is supported by distinct histological, clinical, and molecular profiles. NETs are typically slow-growing and hormone-producing, with organoid architecture and frequent associations with hereditary syndromes such as multiple endocrine neoplasia type 1 (MEN1) and von Hippel-Lindau (VHL) disease. In contrast, NECs are highly malignant, rapidly proliferating tumors characterized by mutations in adenocarcinoma-driver genes and in addition to TP53 mutations and RB1 inactivation, without hereditary links to endocrine tumor syndomes. Recent WHO classifications introduced site-specific grading systems, including NET G3 in the digestive, urogenital, gynecological and head and neck organs. There is growing evidence of progression from NET G1 to G3 with occasionally NEC-like features via acquired TP53 mutations. Advances in transcription factor profiling related to hormonal expression, molecular alterations resulted in further subtyping especially in pancreatic, pulmonary, and pituitary NETs. These tools support more precise treatment strategies. Genomic studies focusing on pancreatic NETs highlighted mutations in MEN1, DAXX, ATRX , and targets in mTOR pathway. NECs display higher tumor mutation burdens and harbor various actionable alterations. Approximately 5–10% of NETs are associated with hereditary syndromes, though recent findings suggest germline pathogenic variants, which were present in additional 5% of apparently sporadic NETs and NECs, requiring further study. An integrated histological, molecular, and clinical approach is essential to improve the classification, prognostication, and management of NENs, while recognizing the distinct biology of individual subtypes.

INTRODUCTION: Pancreatic neuroendocrine tumors (PanNETs) are rare, but their incidence has been increasing. PanNETs are usually diagnosed based on typical radiological and pathological findings. However, some exhibit unusual findings; therefore, we need to consider these and make a diagnosis through multidisciplinary evaluation. In this report, we present a case of PanNET that was challenging to diagnose preoperatively.CASE PRESENTATION: A man in his 70s with a prior diagnosis of intrahepatic cholangiocarcinoma (iCCA) was referred to our hospital (Kyoto University Hospital) for suspected recurrence of multiple intrahepatic metastases. MRI showed space-occupying lesions in the liver and a 2.7-cm hyperintense mass in the uncinate process of the pancreas. Adenocarcinoma was diagnosed by endoscopic US-guided tissue acquisition (EUS-TA) of the pancreatic lesion. Accordingly, the patient underwent neoadjuvant chemotherapy followed by pancreatoduodenectomy. However, postoperative histological and immunohistochemical evaluations of the surgically resected specimen revealed G2 PanNET with an unusual acinar structure that was not considered preoperatively.CONCLUSIONS: This case highlights the diagnostic challenge of unusual PanNETs that presented radiologically and pathologically with unusual features. A multidisciplinary evaluation and awareness of PanNETs with unusual features are essential for accurate diagnosis.