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

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.

Current data on neuroendocrine tumors (NETs) of the gallbladder and cystic duct (GB-NETs) are highly limited, and the available evidence, largely derived from cancer registry data, suggests that these tumors exhibit a substantially more aggressive clinical behavior than NETs arising at other anatomical sites. We analyzed 26 GB-NETs. Female-to-male ratio: 1.9:1; median age: 50 years. They were typically incidental small (median: 0.8 cm, range: 0.08–2.3 cm) tumors, with 81

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 (NEN) comprise well-differentiated neuroendocrine tumours (NET) and neuroendocrine carcinomas (NEC), whose distinction is clinically critical. Although c-MYC alterations have been implicated in NEC pathogenesis, its expression across NEC subtypes and anatomical sites, as well as in NET, remains incompletely defined. We analysed c-MYC immunohistochemically in 1380 resected NEN using the immunoreactive score (IRS: negative 0–1, weak 2–3, moderate 4–8, strong 9–12). Overall, c-MYC positivity (IRS ≥ 2) was observed in 13.3% of NEN. Expression was detected in 43% of NEC (164/381), including strong staining in 19.4%, whereas it was rare in NET and pulmonary carcinoids (20/999; 2%; p ≤ 0.001 ). Within NEC, c-MYC expression was enriched in LCNEC and MiNEN compared with SCNEC and Merkel cell carcinoma ( p ≤ 0.001 ) and occurred more often in gastroenteropancreatic than in pulmonary NEC (57.6% vs. 37.3%; p ≤ 0.001 ). Among NET, G3 tumours showed the highest positivity rate (6/35; 17.1%), although this was significantly lower than in NEC ( p ≤ 0.001 ), with strong expression observed in only one NET G3 (2.9%). No association between c-MYC expression and survival was identified in either NEC or NET. Our study confirms c-MYC expression as a common event in NEC and highlights differences across histological subtypes and anatomical sites, while demonstrating its absence in most low-proliferative NET. A subset of NET G3 tumours exhibits weak to moderate c-MYC expression at levels far below those seen in NEC, suggesting that strong c-MYC positivity may support an NEC classification in borderline cases but does not represent a definitive discriminatory marker.

Neuroendocrine tumors (NETs) associated with the intrapancreatic bile duct are rare and poorly characterized. Their relationship to conventional pancreatic neuroendocrine tumors (PanNETs) and to neuroendocrine cells of the periampullary and peribiliary regions remains unclear. A total of 199 resected NETs from the pancreas were evaluated for anatomical location and intrapancreatic bile duct narrowing. Transcription factor and hormone expression were assessed by whole-slide immunohistochemistry. For comparison, 22 duodenal NETs, 6 ampullary NETs and non-neoplastic duodenal, ampullary, and bile duct tissues were examined. Nineteen tumors (10%) were associated with bile duct narrowing, including 11 lower (periampullary) and 8 upper bile duct lesions. Compared with NETs without bile duct narrowing, these tumors were exclusively non-functioning, occurred more frequently in women and exhibited higher Ki-67 indices. Lower bile duct-narrowing tumors were associated with shorter progression-free survival. All but one bile duct-narrowing tumor expressed PDX1 (18/19, 95%), whereas CDX2 expression was observed in 73% (8/11) of lower bile duct-narrowing tumors. These tumors frequently expressed gastrin (73%) and somatostatin (73%), occasionally serotonin (27%), and lacked glucagon and insulin expression. Their transcription factor and hormone expression profiles closely resembled those of duodenal NETs and neuroendocrine cells of periampullary and peribiliary glands and differed from those of conventional PanNETs. Bile duct-narrowing NETs from the pancreas, particularly those involving the lower bile duct, represent a distinct clinicopathological subgroup characterized by a PDX1-positive, frequently CDX2-positive phenotype and enrichment for gastrin and somatostatin expression. Their resemblance to duodenal NETs and periampullary/peribiliary neuroendocrine cells supports a shared differentiation program and suggests a possible non-islet cell origin.

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.

Delta-like ligand 3 (DLL3) is frequently expressed in pulmonary small cell neuroendocrine carcinoma (SCNEC) and has emerged as a promising therapeutic target. However, limited data on DLL3 expression in other neuroendocrine neoplasms (NEN), such as extrapulmonary SCNEC, large cell neuroendocrine carcinomas (LCNEC), mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN), gastroenteropancreatic neuroendocrine tumours (GEP-NET), and pulmonary carcinoids, impedes an estimation if other types of NEN might be suitable candidates for anti-DLL3 therapies. We evaluated DLL3 expression in 1294 NEN and 479 non-neuroendocrine carcinomas, correlating the findings with histological subtypes, tumour localisation, and overall survival (OS). Furthermore, we explored the concordance of DLL3 expression during metastatic progression in 67 paired primary NEN and metastases. DLL3 expression was significantly higher in NEC (64.0%) compared to GEP-NET and pulmonary carcinoids (10.1%, p < 0.001), particularly in SCNEC (80.4%), followed by LCNEC (62.6%) and MiNEN (28.6%). DLL3 was common in pulmonary carcinoids (41.5%), but rare in GEP-NET (5.1%) and non-neuroendocrine carcinomas (1.3%). Overall DLL3 expression was highly concordant between metastases and corresponding primary NEN (92.5%, p < 0.001). In univariable analyses, DLL3-expressing pulmonary carcinoids (p = 0.005) and GEP-NET (p = 0.018) were associated with decreased OS, but this was not retained in multivariable analyses adjusting for stage and grade (p = n. s.). No prognostic impact was observed in pulmonary (p = 0.708) or GEP-NEC (p = 0.87). Our study highlights significant differences in DLL3 expression across NEN subtypes and localisations, with largely concordant expression in metastases. DLL3-based therapies may be effective in many NEC and pulmonary carcinoids, while DLL3 appears to be a minor therapeutic target for GEP-NET and non-neuroendocrine carcinomas.

Aims/hypothesisCystic fibrosis (CF) is associated with pancreatic exocrine insufficiency (PEI) early in life and diabetes in at least 50% of adults. Underlying CF-related changes within the pancreas remain incompletely understood due to scarcity of available human tissue, protracted disease course and absence of robust and reproducible analytical approaches. This study aimed to develop and apply a systematic analysis cross-sectionally to CF pancreatic tissue samples to construct a timeline of exocrine and endocrine changes with progressive disease.MethodsThrough a pathologist-led iterative approach, a light-microscopy semi-quantitative scoring system and artificial-intelligence-driven quantitative image analysis for individual pancreatic variables were developed. These were applied to human pancreatic tissue from 29 CF and 58 control donors without pancreatic disease.ResultsRapid loss of acinar tissue with virtually complete absence and replacement by adipocytes by the age of 7 years was confirmed. Ductal blockage by thickened secretions was associated with increasing ductal dilatation accompanied by periductal fibrosis, followed by ductal loss with involution of associated fibrosis in parallel with increasing adipocyte proportional area. Remaining ducts were relatively small, surrounded by residual fibrosis. Islets became increasingly clustered, initially surrounded by pancreatic stellate cells and fibrosis, then disorganised by interposing fibrotic tissue between endocrine cell regions and surrounded by residual collagen stranding in a 'lipotic' pancreas. Overall islet mass was not reduced but proportional beta cell area was reduced from birth without further loss over the course of progressive disease.Conclusions/interpretationThe natural history of pancreatic CF progresses rapidly from duct blockage and dilatation associated with periductal fibrosis to global fat replacement in keeping with early onset of PEI in the majority of affected individuals. Beta cell proportional area is reduced at birth before clinical evidence of pancreatic endocrine dysfunction without significant further loss of islet/beta cell mass with age. Increasing islet disorganisation and intra-islet collagen deposition in older donors temporo-spatially implicates fibrosis in and around the islet as being aetiologically important in the development of CF-related diabetes.

Recent studies have shown that pulmonary neuroendocrine tumor (NET) subgroups, defined by the transcription factors OTP and ASCL1, correlate with age, sex, and tumor location. Their relationships with histology and hormone production, however, remain unclear. We analyzed 170 pulmonary NETs classified by OTP (O) and ASCL1 (A) expression into four groups: O + /A + , O + /A-, O-/A + , and O-/A-. Subgroups were assessed for histology, hormone expression, therapy-related markers, outcomes, and matched metastases. Among 152 resected primaries, O + /A + tumors (38%) were most frequent, occurring mainly in females (median age 72 years), and typically showed central or peripheral location, solid/spindle morphology with diffuse gastrin-releasing peptide (GRP), and focal ACTH/calcitonin. They also showed strong DLL3 expression and pronounced neuroendocrine cell hyperplasia. O + /A- tumors (23%) occurred predominantly in females (median age 56 years) with solid/trabecular patterns, occasional/ACTH, and strong SSTR2A/5 expression. O-/A- tumors (25%) were more common in males (median age 70 years), often central with solid/trabecular or oncocytic histology, serotonin expression (24%), and frequently SSTR2A-positivity. O-/A + tumors (14%) occurred across both sexes (median age 58 years), were centrally located, and solid, sometimes oncocytic features with moderate DLL3/SSTR2A expression. Metastases mirrored their primaries in transcription factor and hormone profiles. In the univariate analysis, OTP-negative tumors were associated with poorer disease-free survival (DFS). However, the multivariate analysis identified Ki67-based WHO grades (G1-G3) as the only independent prognostic factors. In conclusion, integrating OTP and ASCL1 refines pulmonary NET classification into four histologically and biologically distinct subgroups, providing additional insight into tumor heterogeneity. O + /A + tumors showed solid-spindle features and diffuse GRP and frequent ACTH expression, trabecular patterns characterized ASCL1-negative tumors, while oncocytic histology predominated in OTP-negative tumors, highlighting their role in defining tumor heterogeneity.

Gastric, duodenal and rectal neuroendocrine tumours (NETs) are increasingly detected due to advances in endoscopic imaging. While international guidelines provide criteria for endoscopic management, several aspects remain controversial due to limited high-quality evidence. This position paper, developed by an expert panel, aims to clarify these unresolved issues and provide consensus-based recommendations. The primary objective of this position paper is to critically analyse and address key controversies in the endoscopic management of gastro-duodenal-rectal NETs. These include the optimal selection of endoscopic resection techniques, the significance of R1 resections, pathological assessment and surveillance strategies. Special attention is given to site-specific challenges, including the role of Ki-67 in type 1 gastric NETs, the management of multiple gastric lesions, the feasibility of endoscopic resection for type 3 gastric NETs and the limitations of advanced endoscopic techniques in the duodenum. This position paper was developed using an Expert Panel Consensus methodology. Topics were identified during the 2024 ENETS Advisory Board meeting and addressed through a structured literature review. Evidence was critically appraised, and expert discussions were conducted to identify key points. By reviewing controversial aspects of endoscopic management, this position paper will provide practical guidance to optimise decision-making and improve outcomes for patients with gastro-duodenal-rectal NETs. Multidisciplinary evaluation remains crucial to tailoring treatment strategies based on tumour characteristics, patient factors and procedural risks.

The clinical behavior of well-differentiated pancreatic neuroendocrine tumors (PanNETs) is difficult to predict. In order to define, more accurately, prognosticators for patients with a surgically resected PanNET, the pathologic features and Ki-67 immunolabeling indexes of PanNETs resected from 904 consecutive patients at an academic tertiary care hospital were correlated with patient outcome. The mean patient age at surgery was 56.6 years (SD 14.0), 477 were male (52.8%), and 7882 person-years of follow-up were obtained (mean 8.8 years, SD 6.5). The 10-year survival was 81% (95% CI: 77,86%) for patients with G1 PanNETs (Ki-67 <3%), 68% (95% CI: 61,76%) for patients with G2a PanNETs (Ki-67 3 - <10%), 44% (95% CI: 29,66%) for patients with G2b PanNETs (Ki-67 of 10%- ≤20%), and 23% (95% CI: 8,61%) for patients with G3 PanNETs. Vascular invasion (HR 3.0, p <0.0001), tumor size ≥ 2 cm (HR 2.88, p <0.0001), perineural invasion (HR 2.42, p<0.0001), and positive margins (HR 2.18, p <0.0001) were associated with worse overall survival. Insulinoma (HR 0.34, p=3e-04), sclerosing variant (HR 0.47, p=0.05), and cystic variant (HR 0.61, p=0.05) were associated with improved overall survival. T, N and M stages were all statistically significant classifiers of overall survival. Similar associations were found with respect to disease relapse. There was a significant (P<0.001) increase in the proportion of patients diagnosed with stage I vs stage IV disease over time. This study supports the classification of PanNETs into four grades (G1, G2a, G2b, and G3) based on Ki-67 labeling, which allows a more accurate prognostic assessments of patients.