胰腺神经内分泌肿瘤的分子遗传学：PathologyOutlines 专题全文Molecular genetics of pancreatic neuroendocrine neoplasms (PathologyOutlines topic; Textbook Updates 15 October 2026)

Scope: Full PathologyOutlines topic “Molecular genetics of pancreatic neuroendocrine neoplasms” with histologic images (Textbook Updates 15 October 2026).

Definition / general

• Pancreatic neuroendocrine neoplasms (PanNENs) are classified into 3 groups by WHO tumor classification: pancreatic neuroendocrine tumors (PanNETs), pancreatic neuroendocrine carcinomas (PanNECs) and mixed neuroendocrine nonneuroendocrine neoplasms (MiNENs)
  • PanNET: well differentiated neoplasm; graded into 3 tiers (G1, G2 and G3) based on mitotic count and Ki67 proliferation
  • PanNEC: poorly differentiated and high grade; subclassified as small cell (SCNEC) or large cell (LCNEC) types
• From a genetic point of view, PanNET, PanNEC and MiNEN show different genetic and epigenetic alterations and expression profiles

Essential features

• ~40% of PanNETs harbor mutations in MEN1, DAXX and ATRX (Endocr Pathol 2025;36:44)
• PanNECs most commonly harbor mutations in TP53 and RB1 and may acquire KRAS mutations similar to pancreatic ductal adenocarcinomas
• Mutation landscape of MiNENs generally reflects the genetic alterations present in each specific neoplastic component

Terminology

• Pancreatic neuroendocrine neoplasms
• Pancreatic neuroendocrine tumor
• Pancreatic neuroendocrine carcinoma
• Mixed neuroendocrine non-neuroendocrine neoplasm

ICD coding

• ICD-O
  • 8240/3 - neuroendocrine tumor, grade 1 (pNET G1)
  • 8249/3 - neuroendocrine tumor, grade 2 or grade 3 (pNET G2 / G3)
  • 8154/3 - mixed endocrine and exocrine tumor, malignant
  • 8246/3 - neuroendocrine carcinoma, NOS
• ICD-10
  • C25.9 - malignant neoplasm of pancreas, unspecified
  • C25.4 - malignant neoplasm of endocrine pancreas
• ICD-11
  • 2C10.1 - neuroendocrine neoplasms of the pancreas

Somatic mutations

• PanNETs
  • Most common mutations: ATRX, DAXX and MEN1 (Hum Pathol 2024;150:51, Nat Commun 2018;9:4158)
  • Other recurrent mutations: chromatin remodeling and telomere maintenance (ARID1A, SMARCA4), histone modification (MLL3, SETD2), DNA damage repair (MUTYH, CHEK2, BRCA2, ATM), mTOR signaling pathway (TSC1, TSC2, PTEN, DEPDC5), hypoxia inducible factor (HIF) signaling pathway (EPAS2, VHL) and others including cell cycle regulators such as CDKN1A and CDKN1B
  • Rare mutations: TP53 and RB1
  • Nearly absent mutations: KRAS and SMAD4 (Nature 2017;543:65, Cancer Discov 2022;12:692, Front Oncol 2022;12:967071, Virchows Arch 2026;488:45)
• PanNECs
  • Most common mutations: TP53, RB1, KRAS (World J Gastroenterol 2022;28:1009, Cancer Discov 2022;12:692, Hum Pathol 2018;77:70)
  • Less common mutations: BRAF, APC and others
  • Typically absent mutations: MEN1, telomere alteration (DAXX / ATRX), DNA damage repair (MUTYH, CHEK2, BRCA2), chromatin remodeling (ARID1A, SMARCA4) and PI3K / mTOR signaling (EWSR1 fusions, PTEN, HIF1A / EPAS2) pathways
• MiNENs
  • Mixed ductal adenocarcinoma neuroendocrine carcinomas: genetic alterations of both conventional ductal adenocarcinomas (KRAS, CDKN2A, TP53, SMAD4) and of PanNECs (TP53 and RB1)
  • Mixed acinar neuroendocrine carcinomas: changes similar to pure acinar cell carcinomas (APC / β catenin pathway alterations, BRAF rearrangements, DNA repair defects and BRCA pathway defects)

Germline mutations / genetic syndromes

• Familial nonfunctional PanNETs
  • Most common mutations: MEN1 (multiple endocrine neoplasia type 1), VHL (von Hippel-Lindau), TSC1 / TSC2 (tuberous sclerosis) and NF1 (neurofibromatosis type 1)
  • CDKN1B (MEN4 syndrome) and MAX (MEN5 syndrome)
  • GCGR (glucagon cell hyperplasia and neoplasia [GCHN])
  • Germline mutation in MUTYH has been reported
• Familial functional PanNETs
  • MAFA related familial insulinomatosis: specific mutation p.S64F in MAFA
  • Insulinomas: rarely seen in MEN1, NF1 and tuberous sclerosis syndromes
  • Glucagonomas: 10% are associated with MEN1 syndrome
  • Somatostatinomas: MEN1, VHL, rarely NF1 syndromes
  • Gastrinomas: MEN1, NF1 / NF2, tuberous sclerosis syndromes
  • Ectopic hormone producing PanNETs: MEN1 and VHL syndromes

Transcriptomics / epigenetic changes

• Multiomics data, such as RNA expression and DNA methylation profiling, can help distinguish PanNETs from PanNECs (Nature 2017;543:65, Cancer Discov 2022;12:692, Front Oncol 2022;12:967071, Virchows Arch 2026;488:45)
• Aberrant DNA methylation in PanNETs is associated with more aggressive tumor behavior, progression and metastasis (Lancet Oncol 2020;21:e431)
  • Global DNA hypomethylation: PanNETs with DAXX / ATRX mutations exhibit global DNA hypomethylation, driving alternative lengthening of telomeres (ALT) and chromosomal instability (CIN) (Endocr Relat Cancer 2015;22:L13, Endocr Relat Cancer 2017;24:137)
  • Hypermethylation of tumor suppressor genes: most commonly RASSF1A, CDKN2A / TP16, MGMT and RAR beta (Ann Surg 2003;238:423)
• PanNECs may cluster into ductal and acinar types by expression profiling (Cancer Discov 2022;12:692)

Diagrams / tables

Molecular genetic features of PanNETs and PanNECs Feature PanNETs PanNECs Genomic instability Low High Most common somatic mutations MEN1, DAXX, ATRX TP53, RB1 Somatic alterations in progressed PanNET TP53, RB1, CDKN2A Gene fusions KMT2A::BCOR, EWSR1::BEND2 NTRK1::CCDC19, ETV6::NTRK3 RNA expression Can help differentiate PanNETs and PanNECs DNA methylation

References: Front Oncol 2022;12:967071, Virchows Arch 2026;488:45, Hum Pathol 2024;150:51, Nat Commun 2018;9:4158, World J Gastroenterol 2022;28:1009, Cancer Discov 2022;12:692, Hum Pathol 2018;77:70, Mod Pathol 2023;36:100065, Pathol Int 2022;72:411, Cancer Res 2020;80:3620, NPJ Precis Oncol 2025;10:7, Gastroenterology 2018;154:2060, Virchows Arch 2023;482:507, Nature 2017;543:65, Front Oncol 2023;12:1031396, Oncotarget 2018;9:35809

Clinical features

• PanNETs typically present at a median age of 57 years; can be functional (20 - 30%) or nonfunctional (70 - 80%), with the former often manifesting early with hormone related symptoms (Pancreas 2025;54:e423)
• PanNECs present more aggressively with rapid symptom onset; almost always nonfunctional and present with symptoms related to tumor bulk or metastatic disease (Radiographics 2020;40:1240, World J Gastroenterol 2022;28:1009)

Prognostic factors

• In PanNETs, DAXX / ATRX loss is often associated with high grade (G3) progression, metastatic potential and recurrence (Nat Commun 2018;9:4158, Am J Surg Pathol 2016;40:1192, Gut 2022;71:961)
• TP53 mutations can be acquired during high grade transformation of PanNETs and are typically mutually exclusive with CDKN2A alterations in this group (Mod Pathol 2023;36:100065)
• Epigenetic changes / aberrant methylation of certain genes or their promoters, such as CDKN2A and MGMT, are associated with aggressive behavior and poor prognosis in PanNETs (Gastroenterology 2018;154:2060, J Clin Endocrinol Metab 2003;88:1367)
• Mutations in exon 3 of VHL in familial PanNETs, particularly at codons 161 / 167, confer a higher risk of metastasis (Endocr Relat Cancer 2018;25:783)

Case reports

• 45 year old woman with pancreatic tumor and multiple liver metastases (J Clin Med 2025;14:4432)
• 69 year old man presented with weight loss and deterioration of diabetes mellitus (Front Med (Lausanne) 2022;9:951834)
• 81 year old man with abdominal pain, nausea, loose stools and episodic flushing (J Clin Med 2023;12:6617)

Treatment

• Somatostatin analogues (octreotide, lanreotide, etc.) target somatostatin receptors (SSTRs) and represent the most widely used therapy, as ~70% of PanNETs express SSTRs (Endocr Relat Cancer 2008;15:701)
• Everolimus, an mTOR inhibitor, is used in the treatment of PanNETs (Cancers (Basel) 2020;12:1988)
• Belzutifan, a specific HIF-2α inhibitor, has been approved for the treatment of VHL disease and its related tumors (Clin Cancer Res 2022;28:4843)

Microscopic (histologic) description

• PanNETs: well differentiated tumors with nested, organoid and trabecular architecture; uniform nuclei with mild atypia
• PanNECs: poorly differentiated carcinomas with expansile and irregular nests to solid structures containing necrosis (single cell or in large areas), more nuclear atypia; can be classified as small or large cell type (Am J Clin Pathol 2025;163:804, Histopathology 2018;72:168, Am J Surg Pathol 2016;40:1192)
• VHL mutated PanNETs: may show features of nuclear atypia, clear cell change, oncocytic change, hypervascularity, islet dysplasia and cystic morphology

Microscopic (histologic) images

Contributed by Yan Hu, M.D., Ph.D. and Wei Chen, M.D., Ph.D.

Additional references

• WHO Classification of Tumours Editorial Board: Endocrine and Neuroendocrine Tumours, 5th Edition, 2025

Practice question #1

What is a distinct morphology of VHL related pancreatic neuroendocrine tumors (PanNETs)?

1. Clear cell change
2. Ductal
3. Islet hyperplasia
4. Poorly differentiated

Practice answer #1

A. Clear cell change. Clear cell change is a characteristic morphologic change of VHL related PanNETs. VHL related PanNETs exhibit both common PanNET morphology and their unusual features. Those features include nuclear atypia, clear cell change, oncocytic cytology and hypervascularity, which is due to the pseudohypoxic state caused by activation of hypoxia inducible factor (HIF). Answer C is incorrect because islet hyperplasia shows an increased number of islets, which are associated with nesidioblastosis, MEN1 and VHL syndromes, among others. Answers B and D are incorrect because ductal morphology and poorly differentiated morphology are commonly seen in pancreatic neuroendocrine carcinomas, large cell type.

Reference: Molecular genetics of pancreatic neuroendocrine neoplasms

Practice question #2

An endoscopic ultrasound (EUS) pancreatic mass biopsy from a 74 year old man demonstrates a high grade pancreatic neuroendocrine carcinoma (PanNEC). What is the most commonly mutated gene in PanNECs?

1. ATRX
2. DAXX
3. MEN1
4. TP53

Practice answer #2

D.TP53. TP53 is the most commonly mutated gene in PanNECs. The other most common mutations in PanNECs are RB1 and KRAS. Answers A, B and C are incorrect because PanNECs typically lack mutations in ATRX, MEN1 and DAXX, which are among the most frequently altered genes in pancreatic neuroendocrine tumors (PanNETs).

Reference: Molecular genetics of pancreatic neuroendocrine neoplasms