Pancreatic cancer classification
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahad Hasan, M.D.[2] Aravind Reddy Kothagadi M.B.B.S[3]
Overview
Pancreatic cancer is classified along three independent axes, each with its own prognostic and treatment implications: (1) histologic tumor type and cell of origin according to the WHO classification of digestive system tumors (5th edition, 2019, with 2026 refinements), which separates exocrine neoplasms, dominated by pancreatic ductal adenocarcinoma (PDAC; ~90%), from pancreatic neuroendocrine neoplasms; (2) grade, which for precursor lesions and neuroendocrine tumors now uses simplified, reproducible, proliferation-based tiers; and (3) anatomic extent by the American Joint Committee on Cancer (AJCC) 8th-edition TNM system, which uses separate schemes for exocrine adenocarcinoma and pancreatic neuroendocrine tumors.[1][2][3][4] The most important changes from legacy teaching are the replacement of the three-tier pancreatic intraepithelial neoplasia (PanIN) system by a two-tier (low-grade/high-grade) scheme, Ki-67/mitotic grading of neuroendocrine tumors with recognition of a well-differentiated G3 category distinct from neuroendocrine carcinoma, and a size-based T category with node-count-based N category in AJCC 8.[1][5][3]
Classification
Histologic Classification of Exocrine Neoplasms (WHO)
The WHO classification is based on cell lineage and morphology and is the core element of pathology reporting.[2] Correct subtyping matters because subtypes differ in prognosis, treatment response, and molecular profile.[2]
| Tumor type | Key features |
|---|---|
| Ductal adenocarcinoma (PDAC), NOS | ~90% of pancreatic malignancies; glandular/duct-forming morphology with desmoplastic stroma[2] |
| PDAC subtypes | Colloid (mucinous non-cystic) carcinoma; poorly cohesive/signet ring cell carcinoma; medullary carcinoma; adenosquamous carcinoma; hepatoid carcinoma; undifferentiated carcinoma, including undifferentiated carcinoma with osteoclast-like giant cells (replaces the term "giant cell tumor"); large-cell carcinoma with rhabdoid phenotype[2] |
| Acinar cell carcinoma | <2% of adult pancreatic cancers; acinar differentiation (trypsin, chymotrypsin, BCL10 positive)[2] |
| Mixed carcinomas | Mixed acinar–ductal, mixed acinar–neuroendocrine, and mixed acinar–neuroendocrine–ductal carcinomas[2] |
| Pancreatoblastoma | Most common pancreatic malignancy of childhood; characterized by squamoid nests[2] |
2026 WHO updates:[6]
- Micropapillary carcinoma is now a morphologic pattern rather than a distinct PDAC subtype.
- Hepatoid morphology remains a recognized PDAC subtype but is also acknowledged in well-differentiated neuroendocrine tumors and solid pseudopapillary neoplasms.
- Grading guidance for treatment-naïve PDAC has been expanded.
- Acinar cell cystadenoma has been reclassified as non-neoplastic "acinar cystic transformation."[1]
Precursor Lesions
Pancreatic Intraepithelial Neoplasia (PanIN)
PanIN is a microscopic (<0.5 cm), non-invasive ductal lesion and the principal precursor of PDAC.[7][8] Per the 2014 Baltimore Consensus and the WHO 2019/2026 classifications, PanIN is graded in two tiers, replacing the legacy PanIN-1/2/3 system; the change was driven by better interobserver reproducibility and clinical relevance.[5][9][7]
| Grade | Legacy equivalent | Histology | Clinical significance |
|---|---|---|---|
| Low-grade PanIN | PanIN-1A, 1B, and 2 | Flat or papillary mucinous epithelium; basal or pseudostratified nuclei; mild-to-moderate cytologic atypia | Very common, including in young and otherwise normal pancreata; the vast majority never progress[9][5] |
| High-grade PanIN | PanIN-3 / carcinoma in situ | Complex papillary/micropapillary architecture, cribriforming, budding, loss of nuclear polarity, severe atypia, mitoses | Rare (<5% of benign pancreata); usually adjacent to invasive PDAC; direct precursor of invasive cancer; staged as Tis[9][5][3] |
Other Precursor Neoplasms
- Intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm (MCN), intraductal oncocytic papillary neoplasm (IOPN), and intraductal tubulopapillary neoplasm (ITPN) are all graded on the same two-tier (low-grade vs high-grade) dysplasia scale.[1]
- IOPN and ITPN are now separated from conventional IPMN on the basis of distinct genomics and morphology.[1]
Molecular Progression
KRAS mutation is a near-universal early event in PanIN. CDKN2A loss appears at the low- to high-grade transition. TP53 and SMAD4 inactivation are late events associated with invasion.[9][10]
Pancreatic Neuroendocrine Neoplasms (PanNENs)
PanNENs account for up to ~7% of pancreatic tumors.[11] The WHO framework separates well-differentiated neuroendocrine tumors (NETs) from poorly differentiated neuroendocrine carcinoma (NEC), a distinction with major molecular, prognostic, and therapeutic consequences.[12][4] Neuroendocrine differentiation is confirmed by two of three markers: synaptophysin, chromogranin A, and INSM1.[4]
Differentiation and Grade (WHO)
NETs are graded by whichever of Ki-67 index or mitotic rate places the tumor in the higher category.[4]
| Category | Differentiation | Mitotic rate (per 2 mm²) | Ki-67 index |
|---|---|---|---|
| NET G1 | Well differentiated | <2 | <3% |
| NET G2 | Well differentiated | 2–20 | 3–20% |
| NET G3 | Well differentiated | >20 | >20% |
| NEC (small-cell or large-cell type) | Poorly differentiated | >20 | >20% |
- NET G3 vs NEC: Recognition of well-differentiated NET G3 (Ki-67 >20% with retained neuroendocrine morphology) as distinct from poorly differentiated NEC is the pivotal change of the 2017 endocrine and 2019 digestive WHO classifications. NEC is high grade by definition and not formally graded.[13][14][4] In difficult cases, an immunohistochemical panel including Rb, p53, p16, ATRX, and DAXX helps separate the two.[4]
- Proposed G2 subdivision: G2a (Ki-67 3–10%) and G2b (>10–20%) improves prognostic stratification but has not been adopted in formal WHO grading.[15][16]
Functional Classification
Functioning PanNETs are defined by a clinical hormonal syndrome. Hormone immunohistochemistry does not establish functional status.[4] Most PanNETs are sporadic, but syndromic associations (MEN1, von Hippel-Lindau disease, and less commonly neurofibromatosis type 1 and tuberous sclerosis) should be considered.[11]
| Tumor / syndrome | Hormone / biomarker | Typical location | Key features |
|---|---|---|---|
| Insulinoma | Insulin, proinsulin, C-peptide | Evenly distributed | Whipple triad (fasting hypoglycemia, neuroglycopenia, relief with glucose); usually small and benign[11][13] |
| Gastrinoma (Zollinger–Ellison syndrome) | Gastrin | Gastrinoma triangle; often duodenal/extrapancreatic | Refractory peptic ulcers, diarrhea, GERD; associated with MEN1[11] |
| Glucagonoma | Glucagon | Body/tail; often large | Necrolytic migratory erythema, diabetes, weight loss, stomatitis[11] |
| VIPoma (Verner–Morrison/WDHA) | VIP | Body/tail | Watery diarrhea, hypokalemia, achlorhydria[11] |
| Somatostatinoma | Somatostatin | Head/periampullary | Gallstones, diabetes, steatorrhea[11] |
| Nonfunctioning PanNET (includes former "PPoma") | Chromogranin A ± pancreatic polypeptide | Often head | No hormonal syndrome; most common PanNET; larger at diagnosis with higher metastatic rate; PP elevation is not a clinical syndrome[11][4] |
Anatomic Staging
Pancreatic Ductal Adenocarcinoma (AJCC 8th Edition, 2017)
AJCC 8 made the T category size-based for T1–T3, dropped the ambiguous "extension beyond the pancreas" criterion, subdivided N by number of positive nodes, and removed the MX designation.[17][18][3]
| Category | Definition |
|---|---|
| Primary tumor (T) | |
| TX | Primary tumor cannot be assessed |
| T0 | No evidence of primary tumor |
| Tis | Carcinoma in situ, including high-grade PanIN and IPMN, ITPN, or MCN with high-grade dysplasia |
| T1 | ≤2 cm (T1a ≤0.5 cm; T1b >0.5 to <1 cm; T1c 1–2 cm) |
| T2 | >2 to ≤4 cm |
| T3 | >4 cm |
| T4 | Involves the celiac axis, superior mesenteric artery, and/or common hepatic artery, regardless of size |
| Regional lymph nodes (N) | |
| NX | Regional lymph nodes cannot be assessed |
| N0 | No regional lymph node metastasis |
| N1 | Metastasis in 1–3 regional lymph nodes |
| N2 | Metastasis in ≥4 regional lymph nodes |
| Distant metastasis (M) | |
| M0 | No distant metastasis |
| M1 | Distant metastasis |
| Stage | T | N | M |
|---|---|---|---|
| IA | T1 | N0 | M0 |
| IB | T2 | N0 | M0 |
| IIA | T3 | N0 | M0 |
| IIB | T1–T3 | N1 | M0 |
| III | T1–T3 Any T4 |
N2 Any N |
M0 |
| IV | Any T | Any N | M1 |
Validation:
- In a multi-institutional validation, AJCC 8 distributed patients more evenly across stages and improved T-stage reproducibility compared with AJCC 7, which placed ~68% of resected patients in stage IIB.[19]
- International validation confirmed modestly better overall stratification. The improvement came mainly from the node-count N category. The size-based T category discriminated poorly among node-negative patients.[20][19]
Pancreatic Neuroendocrine Tumors (AJCC 8th Edition)
AJCC 8 uses a separate staging system for well-differentiated PanNETs, distinct from PDAC and aligned with ENETS. PDAC size cutoffs and the PDAC celiac/SMA-based T4 definition should not be applied to NETs.[11][12]
| Category | Definition |
|---|---|
| T1 | <2 cm, confined to pancreas |
| T2 | 2–4 cm |
| T3 | >4 cm, or invading duodenum or common bile duct |
| T4 | Invading adjacent organs or vessels |
| M1a | Hepatic metastasis only |
| M1b | Extrahepatic metastasis only |
| M1c | Both hepatic and extrahepatic metastases |
Pathology Reporting Essentials
- PDAC (CAP synoptic protocol, NCCN-endorsed): Report WHO histologic type, histologic grade, full TNM, margin clearance in mm ("close" = within 1.0 cm), lymphovascular and perineural invasion, number of involved and examined nodes, and a tumor regression score after neoadjuvant therapy.[3]
- High-grade PanIN at a margin: Document its presence at the neck/duct margin; on frozen section it may prompt more extensive resection.[8]
- PanNET: Report the specific Ki-67 percentage (not a range) from hot-spot counting of ≥500 cells, the actual mitotic rate, and the classification system used. A diagnosis of "neuroendocrine tumor" without a grade is inadequate for management. When Ki-67 and mitotic rate are discordant, assign the higher grade.[4] Ki-67 is more reproducible and prognostic than mitotic count.[4][21]
Areas of Uncertainty
- The size-based AJCC 8 T category underperforms as an independent prognostic discriminator in node-negative resected PDAC. Validation studies disagree on whether the 8th or 7th edition better predicts overall survival.[20][19][22]
- Tumor regression grading after neoadjuvant therapy is not standardized. CAP and MD Anderson systems coexist, with limited reliability, especially in partial responders.[6]
- Distinguishing NET G3 from NEC can be difficult because proliferation overlaps. The diagnosis depends on morphology plus ancillary markers and has different treatment implications.[13][4]
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Nagtegaal ID, Odze RD, Klimstra D, Paradis V, Rugge M, Schirmacher P, Washington KM, Carneiro F, Cree IA; WHO Classification of Tumours Editorial Board (2020). "The 2019 WHO classification of tumours of the digestive system". Histopathology. 76 (2): 182–188. doi:10.1111/his.13975. PMID 31433515.
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 Verbeke C, Webster F, Brosens L, Campbell F, Del Chiaro M, Esposito I; et al. (2021). "Dataset for the reporting of carcinoma of the exocrine pancreas: recommendations from the International Collaboration on Cancer Reporting (ICCR)". Histopathology. 79 (6): 902–912. doi:10.1111/his.14540. PMID 34379823 Check
|pmid=value (help). - ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Pancreatic Adenocarcinoma. Version 4.2026. Updated September 11, 2026. https://www.nccn.org
- ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine and Adrenal Tumors. Version 1.2026. Updated April 21, 2026. https://www.nccn.org
- ↑ 5.0 5.1 5.2 5.3 Wood LD, Canto MI, Jaffee EM, Simeone DM (2022). "Pancreatic cancer: pathogenesis, screening, diagnosis, and treatment". Gastroenterology. 163 (2): 386–402.e1. doi:10.1053/j.gastro.2022.03.056.
- ↑ 6.0 6.1 Luchini C (2026). "Pancreatic ductal adenocarcinoma and its subtypes: clinical relevance of histopathology and molecular characterization, integrating the key updates of the 2026 WHO classification". Virchows Arch. doi:10.1007/s00428-026-04681-1.
- ↑ 7.0 7.1 Xue Y, Basturk O (2023). "Intraductal neoplasms of the pancreatobiliary tract: navigating the alphabet". Histopathology. 83 (4): 499–508. doi:10.1111/his.15003. PMID 37455382 Check
|pmid=value (help). - ↑ 8.0 8.1 Kim MC, Kim JH, Jeon SK, Kang HJ (2024). "CT findings and clinical effects of high grade pancreatic intraepithelial neoplasia in patients with intraductal papillary mucinous neoplasms". PLoS One. 19 (4): e0298278. doi:10.1371/journal.pone.0298278.
- ↑ 9.0 9.1 9.2 9.3 Pedro BA, Wood LD (2025). "Early neoplastic lesions of the pancreas: initiation, progression, and opportunities for precancer interception". J Clin Invest. 135 (14): e191937. doi:10.1172/JCI191937.
- ↑ Makohon-Moore A, Iacobuzio-Donahue CA (2016). "Pancreatic cancer biology and genetics from an evolutionary perspective". Nat Rev Cancer. 16 (9): 553–565. doi:10.1038/nrc.2016.66.
- ↑ 11.00 11.01 11.02 11.03 11.04 11.05 11.06 11.07 11.08 11.09 Expert Panel on Gastrointestinal Imaging; Yacoub JH, Yano M, Chang KJ, Bergsland E, Bhosale PR; et al. (2026). "ACR Appropriateness Criteria® Staging and Follow-Up of Pancreatic Neuroendocrine Tumors". J Am Coll Radiol. 23 (7): 1445–1461. doi:10.1016/j.jacr.2026.02.012. PMID 41823937 Check
|pmid=value (help). - ↑ 12.0 12.1 12.2 Couvelard A, Cros J (2022). "An update on the development of concepts, diagnostic criteria, and challenging issues for neuroendocrine neoplasms across different digestive organs". Virchows Arch. 480 (6): 1129–1148. doi:10.1007/s00428-022-03306-7.
- ↑ 13.0 13.1 13.2 Baughman AW, Wei NJ, Hahn PF, Casey BW, Zhang ML (2022). "Case 23-2022: A 49-year-old man with hypoglycemia". N Engl J Med. 387 (4): 356–365. doi:10.1056/NEJMcpc2115858.
- ↑ Mukherjee JJ, Lee KO, Kaltsas G. Epidemiology and classification of neuroendocrine tumors of the pancreas. In: The Pancreas. 2023.
- ↑ Kasajima A, Perren A, Klöppel G (2026). "Concept of neuroendocrine neoplasms of all organs with a focus on grading, subtyping". Virchows Arch. 488 (1): 3–20. doi:10.1007/s00428-025-04296-y.
- ↑ Kageyama Y, Ashida R, Ohike N; et al. (2025). "Stratification of G2 pancreatic neuroendocrine tumors using a ten percent Ki-67 index cut-off based on clinicopathological and molecular analyses". Sci Rep. 15 (1): 18919. doi:10.1038/s41598-025-04356-y.
- ↑ 17.0 17.1 17.2 Kulkarni NM, Soloff EV, Tolat PP, Sangster GP, Fleming JB, Brook OR; et al. (2020). "White paper on pancreatic ductal adenocarcinoma from Society of Abdominal Radiology's disease-focused panel for pancreatic ductal adenocarcinoma: Part I, AJCC staging system, NCCN guidelines, and borderline resectable disease". Abdom Radiol (NY). 45 (3): 716–728. doi:10.1007/s00261-019-02289-5. PMID 31748823.
- ↑ 18.0 18.1 Cong L, Liu Q, Zhang R; et al. (2018). "Tumor size classification of the 8th edition of TNM staging system is superior to that of the 7th edition in predicting the survival outcome of pancreatic cancer patients after radical resection and adjuvant chemotherapy". Sci Rep. 8 (1): 10383. doi:10.1038/s41598-018-28193-4.
- ↑ 19.0 19.1 19.2 Allen PJ, Kuk D, Castillo CF, Basturk O, Wolfgang CL, Cameron JL; et al. (2017). "Multi-institutional validation study of the American Joint Commission on Cancer (8th edition) changes for T and N staging in patients with pancreatic adenocarcinoma". Ann Surg. 265 (1): 185–191. doi:10.1097/SLA.0000000000001763. PMID 27163957.
- ↑ 20.0 20.1 van Roessel S, Kasumova GG, Verheij J; et al. (2018). "International validation of the eighth edition of the American Joint Committee on Cancer (AJCC) TNM staging system in patients with resected pancreatic cancer". JAMA Surg. 153 (12): e183617. doi:10.1001/jamasurg.2018.3617. PMID 30285076.
- ↑ Tihy M, Hercent A, Cros J, Couvelard A (2026). "Differential diagnosis and predictive markers of pancreatic neuroendocrine tumours (PanNET)". Virchows Arch. 488 (1): 65–77. doi:10.1007/s00428-025-04320-1.
- ↑ Colino-Gallardo AM, Fernández-Aceñero MJ, de la Torre-Serrano M; et al. (2025). "Prognostic validity of the eighth edition of the U.S. Joint Committee on Cancer TNM staging system for pancreatic adenocarcinomas: an analysis of 214 patients at a Spanish center". Cancers (Basel). 17 (11): 1890. doi:10.3390/cancers17111890.