Pancreatic Neuroendocrine Tumor

1. Disease Information

1.1 What is the disease?

PanNETs are pancreatic tumors of neuroendocrine lineage, clinically classified as functional (hormone-secreting, syndrome-producing) or non-functioning (no hormone syndrome; majority) (sulciner2023surgicalmanagementof pages 1-2, sulciner2023surgicalmanagementof pages 2-5). In a recent hereditary-syndrome review, “roughly 30% are functioning” while most are non-functioning (papadopouloumarketou2024hereditarysyndromesassociated pages 1-3).

Direct abstract quote (definition/overview): - “Pancreatic neuroendocrine tumors (PNETs) are relatively uncommon malignancies, characterized as either functional or nonfunctional secondary to their secretion of biologically active hormones.” (Sulciner & Clancy, Cancers, 2023-03-30; DOI:10.3390/cancers15072006) (sulciner2023surgicalmanagementof pages 1-2)

1.2 Key identifiers (ontology/coding)

Available in retrieved sources/tools during this run - MONDO (subtypes): - Non-functional pancreatic neuroendocrine tumor: MONDO_0004334 (OpenTargets mapping in context) (papadopouloumarketou2024hereditarysyndromesassociated pages 1-3) - Functional pancreatic neuroendocrine tumor: MONDO_0023206 (OpenTargets mapping in context) (papadopouloumarketou2024hereditarysyndromesassociated pages 1-3)

Not recovered from the currently retrieved sources/tools (will require explicit ontology lookups outside this run) - ICD-10 / ICD-11, MeSH ID, Orphanet ORPHA code, and a MONDO ID for the parent concept “pancreatic neuroendocrine tumor” were not directly available in the accessible documents returned by the tools in this session.

1.3 Common synonyms / alternative names

• Pancreatic neuroendocrine tumor (PanNET)
• Pancreatic neuroendocrine tumour
• pNET / PNET
• Pancreatic neuroendocrine neoplasm (PanNEN; sometimes used in GEP-NEN context)
• Functioning pancreatic NET vs non-functioning pancreatic NET (sulciner2023surgicalmanagementof pages 1-2, papadopouloumarketou2024hereditarysyndromesassociated pages 1-3)

1.4 Evidence provenance (individual vs aggregated)

The evidence summarized here derives predominantly from aggregated disease-level resources (systematic reviews/meta-analyses and clinical practice guidelines) plus selected primary clinical trials and sequencing studies (andersen2024welldifferentiatedg1and pages 1-2, taherifard2024efficacyandsafety pages 1-3, partelli2024neoadjuvant177ludotatatefor pages 1-2, jiang2024multiregionwesof pages 1-2).

2. Etiology

2.1 Causal factors (genetic/mechanistic)

Most PanNETs are sporadic, but a clinically important fraction occurs in monogenic tumor syndromes (papadopouloumarketou2024hereditarysyndromesassociated pages 1-3, andersen2024welldifferentiatedg1and pages 1-2).

Quantitative hereditary burden: - “About 17% of PanNETs … develop in the context of monogenic familial tumor syndromes” (Papadopoulou-Marketou et al., Cancers, 2024-05-31; DOI:10.3390/cancers16112075) (papadopouloumarketou2024hereditarysyndromesassociated pages 1-3).

2.2 Risk factors

Genetic risk factors (hereditary syndromes; germline variants)

Authoritative 2024 review synthesis indicates hereditary PanNETs most often occur in: - MEN1 (MEN1 gene; tumor suppressor menin) - VHL (VHL) - TSC (TSC1/TSC2) - NF1 (NF1) - MEN4 (CDKN1B/p27Kip1) (papadopouloumarketou2024hereditarysyndromesassociated pages 1-3, papadopouloumarketou2024hereditarysyndromesassociated pages 14-16)

MEN1-specific quantitative penetrance/risk (from 2024 review): - MEN1 prevalence: 3–10/100,000, with “>95% of mutation carriers develop manifestations by age 50” (papadopouloumarketou2024hereditarysyndromesassociated pages 4-6). - “Lifetime risks” in MEN1: primary hyperparathyroidism 95%, duodenopancreatic NETs 80%, pituitary adenomas 50% (papadopouloumarketou2024hereditarysyndromesassociated pages 4-6). - Pancreatic NETs occur “in up to 80% of MEN1 patients” (papadopouloumarketou2024hereditarysyndromesassociated pages 4-6).

Direct abstract quote (screening recommendation): - “Genetic screening is recommended in childhood, and diagnostic screening starts often in adolescence, even in asymptomatic mutation carriers.” (Papadopoulou-Marketou et al., Cancers, 2024-05-31; DOI:10.3390/cancers16112075) (papadopouloumarketou2024hereditarysyndromesassociated pages 1-3)

Non-genetic (environmental/lifestyle) risk factors

No high-quality, PanNET-specific environmental or lifestyle risk-factor evidence was identified in the retrieved 2023–2024 sources used in this run. This is a known evidence gap relative to more common pancreatic cancers.

2.3 Protective factors

No PanNET-specific protective factors with quantitative support were identified in the retrieved sources.

2.4 Gene–environment interactions

No PanNET-specific gene–environment interaction data were identified in the retrieved sources.

3. Phenotypes

3.1 Core clinical phenotypes

• Non-functioning PanNETs: majority; may be asymptomatic and incidentally detected on imaging (sulciner2023surgicalmanagementof pages 2-5).
• Functioning PanNETs: ~30% overall; may present with hormone-specific syndromes; insulinomas are frequent in MEN1/TSC; VHL-associated PanNETs are “almost exclusively nonfunctioning” (papadopouloumarketou2024hereditarysyndromesassociated pages 1-3).

3.2 Functional syndromes (examples)

The retrieved corpus did not include a dedicated clinical phenotype frequency table for individual functional syndromes (insulinoma, gastrinoma, glucagonoma, VIPoma, somatostatinoma). However, hereditary review context indicates syndrome-specific enrichment (e.g., insulinomas in MEN1/TSC) (papadopouloumarketou2024hereditarysyndromesassociated pages 1-3).

3.3 Laboratory abnormalities (examples)

• Chromogranin A (CgA) is commonly used as a biochemical marker; a temozolomide meta-analysis reports >50% CgA decline in 44.9% of treated advanced pNET patients (pooled estimate) (taherifard2024efficacyandsafety pages 1-3).

3.4 HPO term suggestions (non-exhaustive; for knowledge base normalization)

These are ontology mapping suggestions (not extracted from the cited papers): - Nonfunctioning tumor presentation: Abdominal pain (HP:0002027), Weight loss (HP:0001824), Jaundice (HP:0000952) (mass effect), Incidental finding (no single HPO term; often represented via clinical annotation rather than HPO). - Insulinoma syndrome: Hypoglycemia (HP:0001943), Neuroglycopenia (HP:0002187), Confusion (HP:0001289). - Gastrinoma/Zollinger–Ellison: Peptic ulcer (HP:0002592), Diarrhea (HP:0002014). - Glucagonoma syndrome: Necrolytic migratory erythema (HP:0031223), Diabetes mellitus (HP:0000819).

4. Genetic / Molecular Information

4.1 Somatic driver landscape (well-differentiated G1/G2 PanNETs)

A 2024 systematic review/meta-analysis of expanded DNA sequencing (225 tumors) reported the following recurrent alterations: - MEN1: altered in 42% (95/225) - DAXX: 16% (37/225) - ATRX: 12% (27/225) and DAXX alterations occurred more frequently with MEN1 mutations (p<0.05) (Andersen et al., Frontiers in Endocrinology, 2024-05-30; DOI:10.3389/fendo.2024.1351624) (andersen2024welldifferentiatedg1and pages 1-2).

4.2 Germline predisposition genes (examples from sequencing meta-analysis + hereditary review)

• MEN1, VHL, PTEN, CDKN1B, BRCA2, CHEK2, MUTYH (andersen2024welldifferentiatedg1and pages 1-2, papadopouloumarketou2024hereditarysyndromesassociated pages 4-6, papadopouloumarketou2024hereditarysyndromesassociated pages 14-16).

4.3 Pathways and mechanistic themes

• Chromatin remodeling / telomere biology (MEN1, DAXX/ATRX)
• PI3K/AKT/mTOR axis (TSC1/2, PTEN; enriched in subsets and clinically actionable) (andersen2024welldifferentiatedg1and pages 1-2, jiang2024multiregionwesof pages 7-12)
• RTK/RAS-related signaling differences noted particularly in non-functioning tumors in the sequencing meta-analysis (andersen2024welldifferentiatedg1and pages 1-2).

4.4 Metastatic disease evolution and immune microenvironment (2024 multi-region WES)

A 2024 multiregion WES study of treatment-naïve metastatic PanNET (10 patients) sequenced 29 primary samples, 31 lymph node metastases, and 15 liver metastases, reporting that MEN1/DAXX mutations may act as early drivers and that cases with MEN1/DAXX/ATRX mutations had longer median overall survival (median not reached vs 43.63 months; p=0.047) (Jiang et al., Cell Communication and Signaling, 2024-03-15; DOI:10.1186/s12964-024-01545-6) (jiang2024multiregionwesof pages 1-2). The same work reports metastatic lesions (particularly in MEN1/DAXX-mutant cases) showing a more immunosuppressive environment by multiplex IHC (jiang2024multiregionwesof pages 1-2).

4.5 GO / CL term suggestions (mechanism and cell types)

Ontology mapping suggestions (not extracted verbatim from papers): - GO biological processes: “mTOR signaling” (GO:0031929), “chromatin organization” (GO:0006325), “DNA repair” (GO:0006281), “cell proliferation” (GO:0008283), “angiogenesis” (GO:0001525). - Cell Ontology (CL) candidates: pancreatic endocrine cell populations including pancreatic alpha cell (CL:0000171), pancreatic beta cell (CL:0000169), and broader neuroendocrine cell (CL:0000160).

5. Environmental Information

No PanNET-specific environmental toxins, infectious etiologies, or strong lifestyle risk/protective factors were supported by the retrieved evidence in this run.

6. Mechanism / Pathophysiology (causal chain)

6.1 Current understanding (integrated)

A parsimonious mechanistic chain consistent with recent human sequencing evidence is: 1) Initiating genetic events (sporadic somatic or hereditary germline + second-hit), frequently involving MEN1 and chromatin remodeling genes (MEN1/DAXX/ATRX) (andersen2024welldifferentiatedg1and pages 1-2, papadopouloumarketou2024hereditarysyndromesassociated pages 4-6). 2) Pathway dysregulation (e.g., PI3K/AKT/mTOR alterations in subsets; additional pathway divergence between functional and non-functional tumors) leading to neuroendocrine tumor growth and heterogeneity (andersen2024welldifferentiatedg1and pages 1-2, jiang2024multiregionwesof pages 7-12). 3) Phenotypic divergence into functional hormone-secreting vs nonfunctioning tumors, and across WHO grades (Ki-67-based) that strongly influence prognosis and imaging phenotype (SSTR vs FDG) (sulciner2023surgicalmanagementof pages 1-2, pellegrino2023diagnosticmanagementof pages 5-6). 4) Metastatic progression often to liver/lymph nodes, with genomic and immune microenvironment heterogeneity; metastatic lesions may be more immunosuppressive (jiang2024multiregionwesof pages 1-2).

7. Anatomical Structures Affected

7.1 Organ and system level (UBERON suggestions)

• Primary site: Pancreas (UBERON:0001264).
• Common metastatic/secondary sites in clinical literature: Liver (UBERON:0002107) (noted as a major site of metastatic disease and a central focus for imaging and surgery) (sulciner2023surgicalmanagementof pages 12-14).

7.2 Tissue/cell level

• PanNETs are derived from endocrine/neuroendocrine cellular lineages in the pancreas (sulciner2023surgicalmanagementof pages 1-2).

8. Temporal Development

8.1 Onset

• Hereditary PanNETs present younger and are often multiple/multifocal (MEN1 particularly) (papadopouloumarketou2024hereditarysyndromesassociated pages 1-3).

8.2 Progression and staging

• WHO grade (Ki-67/mitotic index) is a primary determinant of clinical behavior and prognosis (sulciner2023surgicalmanagementof pages 1-2).

9. Inheritance and Population

9.1 Epidemiology

• PanNETs are ~1–2% of pancreatic cancers and reported incidence is 0.48 per 100,000 per year (Papadopoulou-Marketou et al., 2024) (papadopouloumarketou2024hereditarysyndromesassociated pages 1-3).

9.2 Inheritance patterns (subset)

• Syndromic forms are typically autosomal dominant (e.g., MEN1, VHL, NF1, TSC, MEN4) with high penetrance (papadopouloumarketou2024hereditarysyndromesassociated pages 4-6, papadopouloumarketou2024hereditarysyndromesassociated pages 3-4).

10. Diagnostics

10.1 Pathology and grading

WHO-grade cutoffs commonly used in current practice: - G1: Ki-67 <3% - G2: Ki-67 3–20% - G3: Ki-67 >20% (sulciner2023surgicalmanagementof pages 1-2).

10.2 Morphologic imaging (real-world implementations)

A radiology review summarizing major guidelines notes that the “correct diagnostic management … includes a combination of morphological and functional evaluations,” with: - ENETS-recommended contrast-enhanced CT for diagnostic workup and staging, - MRI including DWI for liver/pancreas/bone/brain assessment, - US/CEUS for liver metastases detection/characterization and biopsy guidance, - EUS as highly sensitive for pancreatic lesion detection and biopsy (pellegrino2023diagnosticmanagementof pages 1-2, pellegrino2023diagnosticmanagementof pages 11-13).

Quantitative performance examples: - Multiphasic contrast CT sensitivity ≈82%, specificity 96% (sulciner2023surgicalmanagementof pages 2-5). - MRI sensitivity 93%, specificity 88% (sulciner2023surgicalmanagementof pages 2-5). - For small pancreatic NENs: EUS sensitivity 86% and specificity 92%; CT may miss 68.4% of lesions <10 mm (pellegrino2023diagnosticmanagementof pages 11-13).

10.3 Functional imaging (SSTR PET and FDG PET)

SSTR PET practice standard (2023 SNMMI/EANM guideline)

SSTR PET has largely supplanted 111In-pentetreotide imaging and is used for staging, localization, PRRT selection, and standardized reporting/QC (hope2023snmmiprocedurestandardeanm pages 1-2, hope2023snmmiprocedurestandardeanm pages 2-3). The guideline explicitly notes: - “68Ga-DOTATATE approved by the Food and Drug Administration (FDA) in 2016, 68Ga-DOTATOC approved by the European Medicines Agency in 2016 and the FDA in 2019, and 64Cu-DOTATATE approved by the FDA in 2020.” (Hope et al., J Nucl Med, 2023-02-01; DOI:10.2967/jnumed.122.264860) (hope2023snmmiprocedurestandardeanm pages 1-2)

Administered-activity guidance examples: - 68Ga-DOTATATE: 2 MBq/kg up to 200 MBq - 68Ga-DOTATOC: ~148 MBq - 64Cu-DOTATATE: 148 MBq (hope2023snmmiprocedurestandardeanm pages 3-4).

Diagnostic performance and grade dependence

• 68Ga-DOTATATE/DOTANOC PET/CT sensitivity 93%, specificity 91%; detection ~95% for G1, 87.5% for G2, 37.5% for G3 (sulciner2023surgicalmanagementof pages 2-5).
• FDG PET can complement SSTR PET to identify higher-grade or SSTR-negative disease (hope2023snmmiprocedurestandardeanm pages 5-6).

10.4 Biomarkers

• Chromogranin A is frequently used, with a reported >50% decline in 44.9% of patients in temozolomide-based regimen studies (pooled) (taherifard2024efficacyandsafety pages 1-3).

10.5 Genetic testing strategy (implementation-oriented)

• Germline evaluation is strongly indicated when clinical features suggest hereditary syndromes (e.g., MEN1) and for first-degree relatives; MEN1 genetic testing starting in childhood (e.g., age 5) is described in the hereditary syndromes review (papadopouloumarketou2024hereditarysyndromesassociated pages 4-6).

11. Outcome / Prognosis

11.1 Prognostic role of grade

• “Median overall survival for patients with grade 1 PNETs is 12 years compared to grade 3 disease with a median survival of 10 months.” (Sulciner & Clancy, 2023) (sulciner2023surgicalmanagementof pages 1-2).

11.2 Imaging correlates of prognosis

• SSTR PET detection varies by grade, with substantially lower detection in G3 disease (sulciner2023surgicalmanagementof pages 2-5).
• FDG uptake is associated with more aggressive disease in G3/high-G2 contexts (radiology and guideline discussions) (pellegrino2023diagnosticmanagementof pages 5-6).

12. Treatment

12.1 Surgery (localized disease; real-world implementation)

Surgery remains the primary curative modality for localized PanNETs (sulciner2023surgicalmanagementof pages 1-2). However, practice is evolving toward selective observation for small, low-risk, non-functioning lesions:

Direct abstract quote (active surveillance): - “There is increasing data to suggest small, nonfunctional PNETs (less than 2 cm) are appropriate follow with nonoperative active surveillance.” (Sulciner & Clancy, 2023) (sulciner2023surgicalmanagementof pages 1-2)

Guideline convergence summarized in the surgical review includes: - NANETS: observation for <1 cm (and individualized 1–2 cm) - NCCN: observation ≤2 cm (stronger evidence ≤1 cm) - ENETS: surveillance for ≤2 cm if low-grade, asymptomatic, non-suspicious imaging (sulciner2023surgicalmanagementof pages 10-11).

12.2 Peptide receptor radionuclide therapy (PRRT) and theragnostics

Neoadjuvant PRRT (2024 NEOLUPANET; phase II)

A multicentre phase II study evaluated neoadjuvant 177Lu-DOTATATE followed by surgery in high-risk, sporadic, well-differentiated non-functioning PanNETs with positive 68Ga-DOTA PET (Partelli et al., Br J Surg, 2024-08-01; DOI:10.1093/bjs/znae178) (partelli2024neoadjuvant177ludotatatefor pages 1-2).

Direct abstract quote (efficacy and safety endpoints): - “A partial radiological response was observed in 18 of 31 patients, and 13 patients had stable disease. Disease progression was not observed.” (partelli2024neoadjuvant177ludotatatefor pages 1-2)

Key outcomes: - Enrolled 31 (March 2020–Feb 2023); 26 completed 4 cycles (partelli2024neoadjuvant177ludotatatefor pages 1-2). - Surgery performed in 29; 24 R0 and 4 R1 resections; 1 unresectable due to vascular involvement (partelli2024neoadjuvant177ludotatatefor pages 1-2). - Postoperative complications: 21/29; severe: 7/29; no postoperative deaths (partelli2024neoadjuvant177ludotatatefor pages 1-2).

ClinicalTrials.gov implementation details (protocol level): - Trial ID NCT04385992, phase II, single arm; 4 cycles 7,400 MBq (200 mCi) every 6–8 weeks with renal-protective amino acid infusion; primary endpoint: 90-day morbidity/mortality after surgery (NCT04385992 chunk 2, NCT04385992 chunk 1).

Supporting visual evidence (trial flow and outcome tables): (partelli2024neoadjuvant177ludotatatefor media 37188ff4, partelli2024neoadjuvant177ludotatatefor media 7fe3253e, partelli2024neoadjuvant177ludotatatefor media 8fe1b3ff)

PRRT combinations (ongoing research direction)

A 2023 NCI NET clinical trials planning report highlights that PRRT approval has raised sequencing and optimization questions (re-treatment, combinations, dosimetry) (piscopo2023diagnosismanagementand pages 2-4).

12.3 Temozolomide-based chemotherapy (advanced disease)

A 2024 systematic review/meta-analysis (14 studies; 441 patients) reported pooled outcomes for temozolomide-based regimens: - ORR 41.2% (95% CI 32.4–50.6%) - DCR 85.3% (95% CI 74.9–91.9%) - >50% chromogranin A decline 44.9% - Serious AEs 23.7% (mainly hematologic) (Taherifard et al., BMC Cancer, 2024-02-14; DOI:10.1186/s12885-024-11926-2) (taherifard2024efficacyandsafety pages 1-3).

12.4 Endoscopic ultrasound (EUS)-guided radiofrequency ablation (RFA)

A 2023 systematic review/meta-analysis of EUS-RFA (19 studies; 183 patients; 196 lesions) reported very high pooled clinical efficacy:

Direct abstract quotes (definitions and results): - Clinical success definition: “the disappearance of clinical symptoms for functional (F-) PanNETs and as complete ablation per nonfunctional (NF)-PanNETs.” (armellini2023efficacyandsafety pages 1-2) - Outcomes: “Pooled estimates for the overall AE rates for the clinical efficacy were 17.8% (95% CI 9.1–26.4%) and 95.1% (95% CI 91.2–98.9%) for F-PanNETs and 24.6% (95% CI 7.4–41.8%) and 93.4% (95% CI 88.4–98.4%) for NF-PanNETs.” (Armellini et al., Medicina, 2023-02-03; DOI:10.3390/medicina59020359) (armellini2023efficacyandsafety pages 1-2)

12.5 Liver-directed and metastatic surgery (selected patients)

In metastatic settings, retrospective and registry analyses reported improved 5-year overall survival in selected patients undergoing resection (e.g., 56.6% vs 23.9%; 67.9% vs 22.3%) and prolonged median survival after hepatic metastasectomy (median 160 months in a single-institution series) (sulciner2023surgicalmanagementof pages 12-14).

12.6 MAXO term suggestions (treatment normalization)

Ontology mapping suggestions (not extracted verbatim from papers): - Surgical resection (MAXO:0000058) - Active surveillance (MAXO:0000054) - Somatostatin receptor PET imaging (MAXO: imaging procedure; may require local MAXO mapping) - Peptide receptor radionuclide therapy (PRRT) (MAXO:0000146) - Chemotherapy (MAXO:0000059) - Radiofrequency ablation (MAXO:0000500)

13. Prevention

No validated primary prevention interventions or population screening programs were identified in the retrieved PanNET-specific evidence. In hereditary syndromes, prevention is implemented as risk-tailored surveillance beginning in childhood/adolescence for mutation carriers (papadopouloumarketou2024hereditarysyndromesassociated pages 1-3, papadopouloumarketou2024hereditarysyndromesassociated pages 4-6).

14. Other Species / Natural Disease

No comparative natural-disease or cross-species transmission information was identified in the retrieved sources.

15. Model Organisms

A 2024 paper set retrieved in this session includes an immunocompetent mouse model created by combined loss of MEN1, ATRX, and PTEN, intended to model high-grade PanNET biology; however, detailed phenotype recapitulation metrics were not extracted into the current evidence set for citation in this report.

Recent developments (2023–2024) — Expert analysis

1) Theragnostic standardization: 2023 SNMMI/EANM practice guidance formalizes protocol, reporting, and QA expectations for SSTR PET across approved tracers (68Ga-DOTATATE, 68Ga-DOTATOC, 64Cu-DOTATATE), enabling more reproducible staging and PRRT selection in real-world practice and multicenter trials (hope2023snmmiprocedurestandardeanm pages 1-2, hope2023snmmiprocedurestandardeanm pages 3-4).

2) Neoadjuvant PRRT evidence in PanNET: The 2024 NEOLUPANET phase II trial provides direct prospective evidence that neoadjuvant 177Lu-DOTATATE can produce objective responses and allow high rates of margin-negative resections in selected high-risk resectable NF-PanNETs, with substantial postoperative morbidity typical of pancreatic surgery (partelli2024neoadjuvant177ludotatatefor pages 1-2, partelli2024neoadjuvant177ludotatatefor media 37188ff4, partelli2024neoadjuvant177ludotatatefor media 7fe3253e, partelli2024neoadjuvant177ludotatatefor media 8fe1b3ff).

3) Expanding minimally invasive local therapy: 2023 meta-analytic evidence supports EUS-RFA as a high-efficacy local option for selected low-grade functional and non-functional PanNETs, with nontrivial adverse event rates and the need for careful patient selection and expertise (armellini2023efficacyandsafety pages 1-2).

4) Genomics informing stratification: 2024 meta-analysis quantifies core mutation frequencies in G1/G2 PanNETs (MEN1/DAXX/ATRX) and highlights pathway differences in non-functioning tumors; 2024 multiregion WES extends this to metastatic evolution and microenvironment heterogeneity, supporting a future of more precise prognostic and therapeutic stratification (andersen2024welldifferentiatedg1and pages 1-2, jiang2024multiregionwesof pages 1-2).

Summary table of key facts

The following table consolidates the most actionable identifiers, epidemiology, molecular alterations, diagnostic performance, and treatment outcomes from the retrieved evidence:

Table: This table compiles the most decision-relevant identifiers, epidemiology, molecular features, imaging performance, and treatment outcomes for pancreatic neuroendocrine tumors from the retrieved 2023-2024 evidence. It is useful as a compact reference for populating structured disease knowledge base fields.

Limitations of this report (transparency)

• ICD-10/ICD-11, MeSH, and Orphanet identifiers for “pancreatic neuroendocrine tumor” were not directly retrievable via the tools and literature successfully accessed in this run; the report therefore provides partial ontology identifiers (MONDO subtypes) and recommends explicit ontology lookup for completion.
• Environmental/protective factors and gene–environment interactions were not supported by the retrieved evidence set.
• Detailed phenotype frequencies by functional subtype (beyond ≈30% functioning) were not available in the retrieved sources and would require additional dedicated epidemiologic/registry papers.

References

1. (sulciner2023surgicalmanagementof pages 1-2): Megan L. Sulciner and Thomas E. Clancy. Surgical management of pancreatic neuroendocrine tumors. Cancers, 15:2006, Mar 2023. URL: https://doi.org/10.3390/cancers15072006, doi:10.3390/cancers15072006. This article has 42 citations.

2. (papadopouloumarketou2024hereditarysyndromesassociated pages 1-3): Nektaria Papadopoulou-Marketou, Marina Tsoli, Eleftherios Chatzellis, Krystallenia I. Alexandraki, and Gregory Kaltsas. Hereditary syndromes associated with pancreatic and lung neuroendocrine tumors. Cancers, 16:2075, May 2024. URL: https://doi.org/10.3390/cancers16112075, doi:10.3390/cancers16112075. This article has 16 citations.

3. (hope2023snmmiprocedurestandardeanm pages 1-2): Thomas A. Hope, Martin Allen-Auerbach, Lisa Bodei, Jeremie Calais, Magnus Dahlbom, Lisa K. Dunnwald, Michael M. Graham, Heather A. Jacene, Courtney Lawhn Heath, Erik S. Mittra, Chadwick L. Wright, Wolfgang P. Fendler, Ken Herrmann, David Taïeb, and Andreas Kjaer. Snmmi procedure standard/eanm practice guideline for sstr pet: imaging neuroendocrine tumors. The Journal of Nuclear Medicine, 64:204-210, Feb 2023. URL: https://doi.org/10.2967/jnumed.122.264860, doi:10.2967/jnumed.122.264860. This article has 124 citations.

4. (sulciner2023surgicalmanagementof pages 2-5): Megan L. Sulciner and Thomas E. Clancy. Surgical management of pancreatic neuroendocrine tumors. Cancers, 15:2006, Mar 2023. URL: https://doi.org/10.3390/cancers15072006, doi:10.3390/cancers15072006. This article has 42 citations.

5. (andersen2024welldifferentiatedg1and pages 1-2): Kirstine Øster Andersen, Sönke Detlefsen, Klaus Brusgaard, and Henrik Thybo Christesen. Well-differentiated g1 and g2 pancreatic neuroendocrine tumors: a meta-analysis of published expanded dna sequencing data. Frontiers in Endocrinology, May 2024. URL: https://doi.org/10.3389/fendo.2024.1351624, doi:10.3389/fendo.2024.1351624. This article has 10 citations.

6. (taherifard2024efficacyandsafety pages 1-3): Erfan Taherifard, Muhammad Bakhtiar, Mahnoor Mahnoor, Rabeea Ahmed, Ludimila Cavalcante, Janie Zhang, and Anwaar Saeed. Efficacy and safety of temozolomide-based regimens in advanced pancreatic neuroendocrine tumors: a systematic review and meta-analysis. BMC Cancer, Feb 2024. URL: https://doi.org/10.1186/s12885-024-11926-2, doi:10.1186/s12885-024-11926-2. This article has 10 citations and is from a peer-reviewed journal.

7. (partelli2024neoadjuvant177ludotatatefor pages 1-2): Stefano Partelli, Luca Landoni, Mirco Bartolomei, Alessandro Zerbi, Chiara Maria Grana, Ugo Boggi, Giovanni Butturini, Riccardo Casadei, Roberto Salvia, and Massimo Falconi. Neoadjuvant 177lu-dotatate for non-functioning pancreatic neuroendocrine tumours (neolupanet): multicentre phase ii study. The British Journal of Surgery, Aug 2024. URL: https://doi.org/10.1093/bjs/znae178, doi:10.1093/bjs/znae178. This article has 35 citations.

8. (jiang2024multiregionwesof pages 1-2): Yu Jiang, Yi-han Dong, Shi-wei Zhao, Dong-yu Liu, Ji-yang Zhang, Xiao-ya Xu, Hao Chen, Hao Chen, and Jia-bin Jin. Multiregion wes of metastatic pancreatic neuroendocrine tumors revealed heterogeneity in genomic alterations, immune microenvironment and evolutionary patterns. Cell Communication and Signaling : CCS, Mar 2024. URL: https://doi.org/10.1186/s12964-024-01545-6, doi:10.1186/s12964-024-01545-6. This article has 8 citations.

9. (papadopouloumarketou2024hereditarysyndromesassociated pages 14-16): Nektaria Papadopoulou-Marketou, Marina Tsoli, Eleftherios Chatzellis, Krystallenia I. Alexandraki, and Gregory Kaltsas. Hereditary syndromes associated with pancreatic and lung neuroendocrine tumors. Cancers, 16:2075, May 2024. URL: https://doi.org/10.3390/cancers16112075, doi:10.3390/cancers16112075. This article has 16 citations.

10. (papadopouloumarketou2024hereditarysyndromesassociated pages 4-6): Nektaria Papadopoulou-Marketou, Marina Tsoli, Eleftherios Chatzellis, Krystallenia I. Alexandraki, and Gregory Kaltsas. Hereditary syndromes associated with pancreatic and lung neuroendocrine tumors. Cancers, 16:2075, May 2024. URL: https://doi.org/10.3390/cancers16112075, doi:10.3390/cancers16112075. This article has 16 citations.

11. (jiang2024multiregionwesof pages 7-12): Yu Jiang, Yi-han Dong, Shi-wei Zhao, Dong-yu Liu, Ji-yang Zhang, Xiao-ya Xu, Hao Chen, Hao Chen, and Jia-bin Jin. Multiregion wes of metastatic pancreatic neuroendocrine tumors revealed heterogeneity in genomic alterations, immune microenvironment and evolutionary patterns. Cell Communication and Signaling : CCS, Mar 2024. URL: https://doi.org/10.1186/s12964-024-01545-6, doi:10.1186/s12964-024-01545-6. This article has 8 citations.

12. (pellegrino2023diagnosticmanagementof pages 5-6): Fabio Pellegrino, Vincenza Granata, Roberta Fusco, Francesca Grassi, Salvatore Tafuto, Luca Perrucci, Giulia Tralli, and Mariano Scaglione. Diagnostic management of gastroenteropancreatic neuroendocrine neoplasms: technique optimization and tips and tricks for radiologists. Tomography, 9:217-246, Jan 2023. URL: https://doi.org/10.3390/tomography9010018, doi:10.3390/tomography9010018. This article has 22 citations.

13. (sulciner2023surgicalmanagementof pages 12-14): Megan L. Sulciner and Thomas E. Clancy. Surgical management of pancreatic neuroendocrine tumors. Cancers, 15:2006, Mar 2023. URL: https://doi.org/10.3390/cancers15072006, doi:10.3390/cancers15072006. This article has 42 citations.

14. (papadopouloumarketou2024hereditarysyndromesassociated pages 3-4): Nektaria Papadopoulou-Marketou, Marina Tsoli, Eleftherios Chatzellis, Krystallenia I. Alexandraki, and Gregory Kaltsas. Hereditary syndromes associated with pancreatic and lung neuroendocrine tumors. Cancers, 16:2075, May 2024. URL: https://doi.org/10.3390/cancers16112075, doi:10.3390/cancers16112075. This article has 16 citations.

15. (pellegrino2023diagnosticmanagementof pages 1-2): Fabio Pellegrino, Vincenza Granata, Roberta Fusco, Francesca Grassi, Salvatore Tafuto, Luca Perrucci, Giulia Tralli, and Mariano Scaglione. Diagnostic management of gastroenteropancreatic neuroendocrine neoplasms: technique optimization and tips and tricks for radiologists. Tomography, 9:217-246, Jan 2023. URL: https://doi.org/10.3390/tomography9010018, doi:10.3390/tomography9010018. This article has 22 citations.

16. (pellegrino2023diagnosticmanagementof pages 11-13): Fabio Pellegrino, Vincenza Granata, Roberta Fusco, Francesca Grassi, Salvatore Tafuto, Luca Perrucci, Giulia Tralli, and Mariano Scaglione. Diagnostic management of gastroenteropancreatic neuroendocrine neoplasms: technique optimization and tips and tricks for radiologists. Tomography, 9:217-246, Jan 2023. URL: https://doi.org/10.3390/tomography9010018, doi:10.3390/tomography9010018. This article has 22 citations.

17. (hope2023snmmiprocedurestandardeanm pages 2-3): Thomas A. Hope, Martin Allen-Auerbach, Lisa Bodei, Jeremie Calais, Magnus Dahlbom, Lisa K. Dunnwald, Michael M. Graham, Heather A. Jacene, Courtney Lawhn Heath, Erik S. Mittra, Chadwick L. Wright, Wolfgang P. Fendler, Ken Herrmann, David Taïeb, and Andreas Kjaer. Snmmi procedure standard/eanm practice guideline for sstr pet: imaging neuroendocrine tumors. The Journal of Nuclear Medicine, 64:204-210, Feb 2023. URL: https://doi.org/10.2967/jnumed.122.264860, doi:10.2967/jnumed.122.264860. This article has 124 citations.

18. (hope2023snmmiprocedurestandardeanm pages 3-4): Thomas A. Hope, Martin Allen-Auerbach, Lisa Bodei, Jeremie Calais, Magnus Dahlbom, Lisa K. Dunnwald, Michael M. Graham, Heather A. Jacene, Courtney Lawhn Heath, Erik S. Mittra, Chadwick L. Wright, Wolfgang P. Fendler, Ken Herrmann, David Taïeb, and Andreas Kjaer. Snmmi procedure standard/eanm practice guideline for sstr pet: imaging neuroendocrine tumors. The Journal of Nuclear Medicine, 64:204-210, Feb 2023. URL: https://doi.org/10.2967/jnumed.122.264860, doi:10.2967/jnumed.122.264860. This article has 124 citations.

19. (hope2023snmmiprocedurestandardeanm pages 5-6): Thomas A. Hope, Martin Allen-Auerbach, Lisa Bodei, Jeremie Calais, Magnus Dahlbom, Lisa K. Dunnwald, Michael M. Graham, Heather A. Jacene, Courtney Lawhn Heath, Erik S. Mittra, Chadwick L. Wright, Wolfgang P. Fendler, Ken Herrmann, David Taïeb, and Andreas Kjaer. Snmmi procedure standard/eanm practice guideline for sstr pet: imaging neuroendocrine tumors. The Journal of Nuclear Medicine, 64:204-210, Feb 2023. URL: https://doi.org/10.2967/jnumed.122.264860, doi:10.2967/jnumed.122.264860. This article has 124 citations.

20. (sulciner2023surgicalmanagementof pages 10-11): Megan L. Sulciner and Thomas E. Clancy. Surgical management of pancreatic neuroendocrine tumors. Cancers, 15:2006, Mar 2023. URL: https://doi.org/10.3390/cancers15072006, doi:10.3390/cancers15072006. This article has 42 citations.

21. (NCT04385992 chunk 2): Massimo Falconi. Neoadjuvant PRRT With 177Lu-DOTATATE Followed by Surgery for Resectable PanNET. IRCCS San Raffaele. 2020. ClinicalTrials.gov Identifier: NCT04385992

22. (NCT04385992 chunk 1): Massimo Falconi. Neoadjuvant PRRT With 177Lu-DOTATATE Followed by Surgery for Resectable PanNET. IRCCS San Raffaele. 2020. ClinicalTrials.gov Identifier: NCT04385992

23. (partelli2024neoadjuvant177ludotatatefor media 37188ff4): Stefano Partelli, Luca Landoni, Mirco Bartolomei, Alessandro Zerbi, Chiara Maria Grana, Ugo Boggi, Giovanni Butturini, Riccardo Casadei, Roberto Salvia, and Massimo Falconi. Neoadjuvant 177lu-dotatate for non-functioning pancreatic neuroendocrine tumours (neolupanet): multicentre phase ii study. The British Journal of Surgery, Aug 2024. URL: https://doi.org/10.1093/bjs/znae178, doi:10.1093/bjs/znae178. This article has 35 citations.

24. (partelli2024neoadjuvant177ludotatatefor media 7fe3253e): Stefano Partelli, Luca Landoni, Mirco Bartolomei, Alessandro Zerbi, Chiara Maria Grana, Ugo Boggi, Giovanni Butturini, Riccardo Casadei, Roberto Salvia, and Massimo Falconi. Neoadjuvant 177lu-dotatate for non-functioning pancreatic neuroendocrine tumours (neolupanet): multicentre phase ii study. The British Journal of Surgery, Aug 2024. URL: https://doi.org/10.1093/bjs/znae178, doi:10.1093/bjs/znae178. This article has 35 citations.

25. (partelli2024neoadjuvant177ludotatatefor media 8fe1b3ff): Stefano Partelli, Luca Landoni, Mirco Bartolomei, Alessandro Zerbi, Chiara Maria Grana, Ugo Boggi, Giovanni Butturini, Riccardo Casadei, Roberto Salvia, and Massimo Falconi. Neoadjuvant 177lu-dotatate for non-functioning pancreatic neuroendocrine tumours (neolupanet): multicentre phase ii study. The British Journal of Surgery, Aug 2024. URL: https://doi.org/10.1093/bjs/znae178, doi:10.1093/bjs/znae178. This article has 35 citations.

26. (piscopo2023diagnosismanagementand pages 2-4): Leandra Piscopo, Emilia Zampella, Sara Pellegrino, Fabio Volpe, Carmela Nappi, Valeria Gaudieri, Rosa Fonti, Silvana Del Vecchio, Alberto Cuocolo, and Michele Klain. Diagnosis, management and theragnostic approach of gastro-entero-pancreatic neuroendocrine neoplasms. Cancers, 15:3483, Jul 2023. URL: https://doi.org/10.3390/cancers15133483, doi:10.3390/cancers15133483. This article has 14 citations.

27. (armellini2023efficacyandsafety pages 1-2): Elia Armellini, Antonio Facciorusso, and Stefano Francesco Crinò. Efficacy and safety of endoscopic ultrasound-guided radiofrequency ablation for pancreatic neuroendocrine tumors: a systematic review and metanalysis. Medicina, 59:359, Feb 2023. URL: https://doi.org/10.3390/medicina59020359, doi:10.3390/medicina59020359. This article has 63 citations.

28. (jiang2024multiregionwesof pages 4-5): Yu Jiang, Yi-han Dong, Shi-wei Zhao, Dong-yu Liu, Ji-yang Zhang, Xiao-ya Xu, Hao Chen, Hao Chen, and Jia-bin Jin. Multiregion wes of metastatic pancreatic neuroendocrine tumors revealed heterogeneity in genomic alterations, immune microenvironment and evolutionary patterns. Cell Communication and Signaling : CCS, Mar 2024. URL: https://doi.org/10.1186/s12964-024-01545-6, doi:10.1186/s12964-024-01545-6. This article has 8 citations.

29. (pellegrino2023diagnosticmanagementof pages 2-4): Fabio Pellegrino, Vincenza Granata, Roberta Fusco, Francesca Grassi, Salvatore Tafuto, Luca Perrucci, Giulia Tralli, and Mariano Scaglione. Diagnostic management of gastroenteropancreatic neuroendocrine neoplasms: technique optimization and tips and tricks for radiologists. Tomography, 9:217-246, Jan 2023. URL: https://doi.org/10.3390/tomography9010018, doi:10.3390/tomography9010018. This article has 22 citations.

30. (pellegrino2023diagnosticmanagementof pages 8-10): Fabio Pellegrino, Vincenza Granata, Roberta Fusco, Francesca Grassi, Salvatore Tafuto, Luca Perrucci, Giulia Tralli, and Mariano Scaglione. Diagnostic management of gastroenteropancreatic neuroendocrine neoplasms: technique optimization and tips and tricks for radiologists. Tomography, 9:217-246, Jan 2023. URL: https://doi.org/10.3390/tomography9010018, doi:10.3390/tomography9010018. This article has 22 citations.

31. (hope2023snmmiprocedurestandardeanm pages 4-5): Thomas A. Hope, Martin Allen-Auerbach, Lisa Bodei, Jeremie Calais, Magnus Dahlbom, Lisa K. Dunnwald, Michael M. Graham, Heather A. Jacene, Courtney Lawhn Heath, Erik S. Mittra, Chadwick L. Wright, Wolfgang P. Fendler, Ken Herrmann, David Taïeb, and Andreas Kjaer. Snmmi procedure standard/eanm practice guideline for sstr pet: imaging neuroendocrine tumors. The Journal of Nuclear Medicine, 64:204-210, Feb 2023. URL: https://doi.org/10.2967/jnumed.122.264860, doi:10.2967/jnumed.122.264860. This article has 124 citations.

32. (partelli2024neoadjuvant177ludotatatefor pages 2-3): Stefano Partelli, Luca Landoni, Mirco Bartolomei, Alessandro Zerbi, Chiara Maria Grana, Ugo Boggi, Giovanni Butturini, Riccardo Casadei, Roberto Salvia, and Massimo Falconi. Neoadjuvant 177lu-dotatate for non-functioning pancreatic neuroendocrine tumours (neolupanet): multicentre phase ii study. The British Journal of Surgery, Aug 2024. URL: https://doi.org/10.1093/bjs/znae178, doi:10.1093/bjs/znae178. This article has 35 citations.

33. (armellini2023efficacyandsafety pages 2-4): Elia Armellini, Antonio Facciorusso, and Stefano Francesco Crinò. Efficacy and safety of endoscopic ultrasound-guided radiofrequency ablation for pancreatic neuroendocrine tumors: a systematic review and metanalysis. Medicina, 59:359, Feb 2023. URL: https://doi.org/10.3390/medicina59020359, doi:10.3390/medicina59020359. This article has 63 citations.