Stomach 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] Omer Kamal, M.D.[3], Parminder Dhingra, M.D. [4], Mohammed Abdelwahed M.D[5]
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Overview
No single scheme captures all clinically relevant information about gastric cancer. In current practice, a gastric adenocarcinoma is described along several complementary axes:[1][2]
- Anatomic site: non-cardia (true gastric) versus gastroesophageal junction (GEJ) tumors, with Siewert subtyping for junctional tumors
- Extent of disease: the AJCC/UICC 8th-edition TNM system, with separate clinical (cTNM), pathologic (pTNM), and post-neoadjuvant (ypTNM) stage groups
- Histology: the Laurén types and the WHO histologic subtypes
- Macroscopic pattern: the Borrmann classification for advanced tumors and the Paris/superficial classification for early tumors
- Molecular subtype: the TCGA and ACRG genomic classifications, plus the predictive biomarkers HER2, PD-L1, mismatch repair/microsatellite instability (MMR/MSI), and claudin 18.2 (CLDN18.2)
- Precursor lesions: gastric dysplasia graded by the WHO two-tier system and the Vienna classification
Only TNM stage and the predictive biomarkers currently change management. Histologic and molecular subtypes remain mainly descriptive and prognostic.[3][4]
Classification
Anatomic classification and Siewert subtyping
Non-cardia and cardia/GEJ cancers differ in epidemiology, etiology, and treatment. Location should therefore be assigned first.[1] Adenocarcinomas involving the GEJ are subtyped by the Siewert classification, which uses the position of the tumor epicenter relative to the anatomic junction.[5][3]
| Siewert type | Epicenter location | Description | Staging and treatment pathway (AJCC 8th / NCCN) |
|---|---|---|---|
| Type I | 1–5 cm above the EGJ | Distal esophageal adenocarcinoma, often Barrett-associated | Esophageal |
| Type II | 1 cm above to 2 cm below the EGJ | True cardia carcinoma | Esophageal/EGJ |
| Type III | 2–5 cm below the EGJ | Subcardial carcinoma infiltrating the junction from below | Gastric |
- Under the AJCC 8th edition, a tumor that involves the EGJ and has its epicenter no more than 2 cm into the proximal stomach is staged as esophageal. A tumor with its epicenter more than 2 cm distal to the EGJ is staged as gastric, even if the EGJ is involved.[6][7]
- Genomically, Siewert type I and II tumors resemble lower esophageal adenocarcinoma: they are predominantly chromosomal-instability (CIN) tumors with Barrett metaplasia and p53 pathway dysregulation. Siewert type III tumors share features with gastric cancer, which supports staging them as gastric.[7]
TNM staging (AJCC/UICC 8th edition)
The AJCC/UICC 8th edition, implemented in 2018, is the main classification used for prognosis and treatment selection. It defines separate stage groups for clinical (cTNM), pathologic (pTNM), and post-neoadjuvant (ypTNM) settings. Using the stage group that matches the clinical setting avoids misclassification.[8][6][3]
| Primary tumor (T) | |
|---|---|
| Tis | Carcinoma in situ: intraepithelial tumor or high-grade dysplasia without invasion of the lamina propria |
| T1a | Invades the lamina propria or muscularis mucosae |
| T1b | Invades the submucosa |
| T2 | Invades the muscularis propria |
| T3 | Penetrates the subserosal connective tissue without invading the visceral peritoneum or adjacent structures |
| T4a | Invades the serosa (visceral peritoneum) |
| T4b | Invades adjacent structures or organs |
| Regional lymph nodes (N) | |
| N0 | No regional lymph node metastasis |
| N1 | 1–2 regional nodes |
| N2 | 3–6 regional nodes |
| N3a | 7–15 regional nodes |
| N3b | ≥16 regional nodes |
| Distant metastasis (M) | |
| M0 | No distant metastasis |
| M1 | Distant metastasis, including positive peritoneal cytology without visible implants |
Key changes from the 7th edition:[6][9]
- N3 was formally split into N3a and N3b for stage grouping. As a result, T1N3b, T2N3b, and T3N3b were upstaged, and several T4 combinations were downstaged.
- Separate clinical and post-neoadjuvant (ypTNM) stage groupings were introduced.
- Siewert type III tumors were reassigned from esophageal to gastric staging.
- In Korean and SEER validation cohorts, the 8th edition predicted survival more accurately than the 7th edition and produced more homogeneous stage IIB–IIIC subgroups.[9]
Histologic classification
Laurén classification
The Laurén classification (1965) remains the scheme most widely used for subgroup analysis in clinical trials, although its independent predictive value is limited.[10][1][2]
| Type | Morphology | Clinical and biologic associations |
|---|---|---|
| Intestinal | Gland-forming, well to moderately differentiated | Arises on chronic gastritis and intestinal metaplasia, usually associated with Helicobacter pylori; older patients; often distal/antral; environmental etiology |
| Diffuse | Poorly cohesive single cells or signet-ring cells without gland formation | Younger patients; worse prognosis; associated with CDH1 (E-cadherin) alterations and hereditary diffuse gastric cancer; prone to peritoneal spread; signet-ring morphology often chemoresistant |
| Mixed / indeterminate | Mixed components, or features not classifiable | About 20% of cases; mixed tumors behave aggressively, with worse overall survival |
WHO classification
Morphology remains the basis of diagnosis, and the predominant histologic pattern defines the subtype. The WHO 6th edition (2026) moves toward an integrated histomolecular framework. It incorporates genotype–phenotype correlation and requires predictive-biomarker assessment.[11][12]
| WHO subtype | Key features | Approximate Laurén correlate |
|---|---|---|
| Tubular adenocarcinoma | Most common subtype (about 45% in Europe, up to 64% in Japan); includes the newly recognized crawling-type variant | Intestinal |
| Papillary adenocarcinoma | Rare; associated with liver metastasis | Intestinal |
| Poorly cohesive carcinoma (PCC) | Subclassified in the 6th edition into signet-ring cell type and non-signet-ring cell type; includes the concept of pure signet-ring cell carcinoma | Diffuse |
| Mucinous adenocarcinoma | Extracellular mucin-predominant | Intestinal |
| Mixed adenocarcinoma | Glandular and poorly cohesive components; formally recognized since the 5th edition | Mixed |
| Rare variants | Carcinoma with lymphoid stroma (medullary; often EBV- or MSI-associated), AFP-producing/hepatoid adenocarcinoma, micropapillary adenocarcinoma, adenocarcinoma of fundic-gland type, sarcomatoid carcinoma; gastroblastoma and other GLI1-altered neoplasms newly delineated | — |
- A European consensus defines signet-ring cell carcinoma within the PCC category as a tumor made up of more than 90% signet-ring cells. The consensus also recommends classifying tumors according to the current WHO edition.[13]
- WHO terminology has changed over successive editions. Signet-ring cell carcinoma was folded into poorly cohesive carcinoma in the 4th edition, mixed adenocarcinoma was recognized in the 5th edition, and PCC was subclassified in the 6th edition.[11]
Macroscopic classification
Borrmann classification (advanced gastric cancer)
The Borrmann classification (1926) describes the gross growth pattern of advanced gastric cancer and is associated with molecular features, disease extent, and survival.[14][15]
| Borrmann type | Gross appearance | Clinical associations |
|---|---|---|
| Type I | Polypoid, well-demarcated mass | Earlier stage; intestinal histology; best prognosis |
| Type II | Ulcerated, with elevated, sharply defined margins | — |
| Type III | Ulcerated, with infiltrative, poorly defined margins | Most common type in some series; relative frequency of types II and III varies by cohort |
| Type IV | Diffusely infiltrative (linitis plastica) | Diffuse histology; younger patients; peritoneal dissemination; worst prognosis |
Paris / superficial classification (early gastric cancer)
Early gastric cancer is described with the superficial (type 0) classification rather than the Borrmann system.[16][14][2]
- 0-I: protruded
- 0-II: superficial, subdivided into 0-IIa (elevated), 0-IIb (flat), and 0-IIc (depressed)
- 0-III: excavated
Molecular classification
TCGA classification (2014)
| Subtype | Approximate frequency | Defining and associated features |
|---|---|---|
| EBV-positive | ~9% | Proximal stomach; extreme DNA hypermethylation (CIMP); recurrent PIK3CA, ARID1A, and BCOR mutations; PD-L1/PD-L2 overexpression; immunotherapy-sensitive |
| Microsatellite unstable (MSI) | ~22% | Older patients; high tumor mutational burden; MLH1 promoter silencing; highly immunogenic; best prognosis |
| Genomically stable (GS) | ~20% | Diffuse histology; CDH1 and RHOA mutations; CLDN18–ARHGAP fusions |
| Chromosomal instability (CIN) | ~50% | Intestinal histology; GEJ/cardia predominance; TP53 mutation; receptor tyrosine kinase amplifications (including ERBB2/HER2, VEGFA, FGFR2) |
ACRG classification (2015)
The ACRG classification is expression-based. It was developed and validated in East Asian cohorts and stratifies prognosis more strongly than TCGA.[18]
| ACRG subtype | Features | Prognosis |
|---|---|---|
| MSI | Hypermutated | Best |
| MSS/TP53-active | Intact p53 activity | Intermediate |
| MSS/TP53-inactive | Loss of p53 activity | Intermediate |
| MSS/EMT | Mesenchymal phenotype; CDH1 loss; diffuse histology; youngest patients; peritoneal metastasis | Worst |
- TCGA and ACRG overlap with Laurén/WHO histology: GS corresponds broadly to diffuse histology, and CIN and MSI to intestinal histology. However, the two genomic systems do not map cleanly onto each other. In addition, TCGA subtypes stratify survival only weakly in Asian (ACRG) cohorts.[18][2]
- Neither system is used for routine treatment selection. Prognostic and predictive validity is robust mainly for the MSI and EBV subtypes.[4]
Clinically actionable biomarkers
These biomarkers are the molecular classifiers that currently change management.[3][19]
| Biomarker | Testing and positivity definition | Clinical relevance |
|---|---|---|
| HER2 (ERBB2) | IHC first, with reflex ISH for IHC 2+ (equivocal). Positive = IHC 3+, or IHC 2+ with ISH-positive result (HER2:CEP17 ratio ≥2.0; NCCN also accepts average HER2 copy number ≥6)[20] | Overexpressed or amplified in ~15–25%, more often in intestinal-type and proximal/GEJ tumors; directs HER2-targeted therapy (trastuzumab; zanidatamab). Marked intratumoral heterogeneity: obtain multiple biopsies (≥5) and consider testing primary and metastatic sites.[2][21] |
| PD-L1 (CPS) | Combined positive score | CPS ≥1 determines addition of an immune checkpoint inhibitor (pembrolizumab, nivolumab, tislelizumab) to first-line chemotherapy |
| MMR / MSI | IHC for MMR proteins or MSI testing; universal in newly diagnosed patients | dMMR/MSI-H is prognostically favorable and strongly predictive of checkpoint-inhibitor benefit |
| CLDN18.2 | IHC positive = moderate-to-strong membranous staining in ≥75% of tumor cells | Directs zolbetuximab in HER2-negative advanced disease[22] |
| Other | BRAF V600E, NTRK/RET fusions, tumor mutational burden; next-generation sequencing or ctDNA when tissue is limited or at progression | Tumor-agnostic targeted therapy options |
- NCCN recommends universal MMR/MSI and PD-L1 testing at diagnosis, and HER2 and CLDN18.2 testing in documented or suspected advanced or metastatic adenocarcinoma.[3]
Precursor lesions and gastric dysplasia
Gastric dysplasia (non-invasive epithelial neoplasia) is the recognized precursor of intestinal-type adenocarcinoma. It is graded with the WHO two-tier system:[23][12]
- Low-grade dysplasia (LGD)
- High-grade dysplasia (HGD)
- "Indefinite for dysplasia" is used when inflammation or regenerative change obscures interpretation.
This two-tier system replaced the older three-tier (mild/moderate/severe) grading. Earlier schemes such as the Padova international classification and the Japanese Group I–V biopsy categories have been largely superseded by the Vienna and WHO systems.[24][23]
Vienna classification of gastrointestinal epithelial neoplasia (revised)
| Category | Diagnosis |
|---|---|
| 1 | Negative for neoplasia/dysplasia |
| 2 | Indefinite for neoplasia/dysplasia |
| 3 | Mucosal low-grade neoplasia (low-grade adenoma/dysplasia) |
| 4 | Mucosal high-grade neoplasia: 4.1 high-grade adenoma/dysplasia; 4.2 non-invasive carcinoma (carcinoma in situ); 4.3 suspicious for invasive carcinoma; 4.4 intramucosal carcinoma |
| 5 | Submucosal invasion by carcinoma |
- The Vienna scheme was created to reconcile a long-standing East–West discrepancy. Japanese pathologists diagnose "adenocarcinoma" on cytoarchitectural atypia alone, whereas Western/WHO pathologists reserve "carcinoma" for invasive lesions.[23][26]
WHO 6th edition (2026) refinements
- Gastric dysplasia, intestinal-type adenomas, and gastric-type adenomas are consolidated into a single "gastric dysplasia" section, mirroring the MAPS III management framework.[27][12]
- Surface epithelium–derived lesions are divided into:[27]
- Intestinal-type
- Foveolar-type, including indolent flat-elevated and "raspberry-type" lesions in H. pylori-naïve stomachs
- Serrated dysplasia/adenoma
- Subsurface lesions are classified separately: pyloric gland adenoma, oxyntic gland adenoma, and pit/crypt dysplasia.[27]
- Serrated dysplasia is rare but high-risk and warrants complete resection.[27]
- Interobserver variability is substantial, especially for indefinite and low-grade lesions. Dysplasia should be confirmed by an experienced GI pathologist, and active H. pylori should be eradicated before definitive grading.[28]
Correlation across classification systems
| Phenotype | Laurén / WHO | Macroscopic | Molecular | Typical features |
|---|---|---|---|---|
| Diffuse/infiltrative | Diffuse / poorly cohesive (signet-ring) | Borrmann IV (linitis plastica) | TCGA GS; ACRG MSS/EMT | Younger patients, CDH1 loss, peritoneal spread, worst prognosis |
| Intestinal/proximal | Intestinal / tubular, papillary | Borrmann I–III | TCGA CIN | GEJ/cardia predominance, TP53 mutation, enriched HER2 amplification |
| Immunogenic | Intestinal; carcinoma with lymphoid stroma | — | TCGA MSI or EBV; ACRG MSI | Favorable prognosis (MSI); checkpoint-inhibitor sensitivity |
Areas of uncertainty
- The prognostic value of histologic subtype varies across studies, partly because classification is applied inconsistently. This is particularly true for signet-ring cell tumors.[2]
- Genomic classifications derive largely from resected primary tumors. Data on metastases and premalignant lesions are limited.[4]
- Whether Siewert type II tumors should be managed with an esophageal or a gastric approach remains debated, and molecular profiling may eventually supplement purely anatomic GEJ classification.[7]
- East–West diagnostic criteria for dysplasia and early cancer still diverge despite the Vienna consensus. Management of low-grade non-invasive neoplasia (surveillance versus endoscopic resection) is not uniformly defined.[26]
- HER2 heterogeneity limits the reproducibility of HER2 classification in gastric cancer compared with breast cancer.[21]
References
- ↑ 1.0 1.1 1.2 Van Cutsem E, Sagaert X, Topal B, Haustermans K, Prenen H (2016). "Gastric cancer". Lancet. 388 (10060): 2654–2664. doi:10.1016/S0140-6736(16)30354-3. PMID 27156933.
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 Smyth EC, Nilsson M, Grabsch HI, van Grieken NC, Lordick F (2020). "Gastric cancer". Lancet. 396 (10251): 635–648. doi:10.1016/S0140-6736(20)31288-5. PMID 32861308 Check
|pmid=value (help). - ↑ 3.0 3.1 3.2 3.3 3.4 National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Gastric Cancer. Version 4.2026. 2026. NCCN
- ↑ 4.0 4.1 4.2 Sundar R, Nakayama I, Markar SR, Shitara K, van Laarhoven HWM; et al. (2025). "Gastric cancer". Lancet. doi:10.1016/S0140-6736(25)00052-2.
- ↑ Siewert JR, Stein HJ (1998). "Classification of adenocarcinoma of the oesophagogastric junction". Br J Surg. 85 (11): 1457–1459. doi:10.1046/j.1365-2168.1998.00940.x. PMID 9823902.
- ↑ 6.0 6.1 6.2 Kumagai K, Sano T (2021). "Revised points and disputed matters in the eighth edition of the TNM staging system for gastric cancer". Jpn J Clin Oncol. 51 (7): 1024–1027. doi:10.1093/jjco/hyab069. PMID 33987661 Check
|pmid=value (help). - ↑ 7.0 7.1 7.2 Nakauchi M, Walch HS, Nussenzweig S, Carr R, Vos E, Berger MF; et al. (2024). "Genomic landscape of adenocarcinomas across the gastroesophageal junction: moving on from the Siewert classification". Ann Surg. PMID 38841851 Check
|pmid=value (help). - ↑ Amin MB, Greene FL, Edge SB, Compton CC, Gershenwald JE, Brookland RK; et al. (2017). "The Eighth Edition AJCC Cancer Staging Manual: continuing to build a bridge from a population-based to a more "personalized" approach to cancer staging". CA Cancer J Clin. 67 (2): 93–99. doi:10.3322/caac.21388. PMID 28094848.
- ↑ 9.0 9.1 Son T, Sun J, Choi S, Cho M, Kwon IG, Kim HI; et al. (2019). "Multi-institutional validation of the 8th AJCC TNM staging system for gastric cancer: analysis of survival data from high-volume Eastern centers and the SEER database". J Surg Oncol. 120 (4): 676–684. PMID 31338834.
- ↑ Laurén P (1965). "The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification". Acta Pathol Microbiol Scand. 64: 31–49. PMID 14320675.
- ↑ 11.0 11.1 11.2 Kushima R. Gastric carcinoma classification in the WHO 6th edition (2026): updated framework and emerging entities. Virchows Arch. 2026.
- ↑ 12.0 12.1 12.2 Arends MJ, Esposito I, Gill AJ, Hruban RH, Khoury JD, Kojima M; et al. (2026). "Changes in the 6th edition of the World Health Organization classification of tumours of the digestive system". Histopathology. doi:10.1111/his.70116.
- ↑ Mariette C, Carneiro F, Grabsch HI; et al. (2019). "Consensus on the pathological definition and classification of poorly cohesive gastric carcinoma". Gastric Cancer. 22 (1): 1–9. doi:10.1007/s10120-018-0868-0. PMID 30167905.
- ↑ 14.0 14.1 Japanese Gastric Cancer Association (2011). "Japanese classification of gastric carcinoma: 3rd English edition". Gastric Cancer. 14 (2): 101–112. doi:10.1007/s10120-011-0041-5. PMID 21573743.
- ↑ Issin G, Demir F, Cagatay DV, Bakkaloglu I. Macroscopic growth patterns and their molecular implications in gastric carcinoma: toward risk stratification via Borrmann classification. BMC Gastroenterol. 2026;26(1).
- ↑ Participants in the Paris Workshop (2003). "The Paris endoscopic classification of superficial neoplastic lesions: esophagus, stomach, and colon". Gastrointest Endosc. 58 (6 Suppl): S3–43. doi:10.1016/s0016-5107(03)02159-x. PMID 14652541.
- ↑ 17.0 17.1 Cancer Genome Atlas Research Network (2014). "Comprehensive molecular characterization of gastric adenocarcinoma". Nature. 513 (7517): 202–209. doi:10.1038/nature13480. PMID 25079317.
- ↑ 18.0 18.1 18.2 Cristescu R, Lee J, Nebozhyn M, Kim KM, Ting JC, Wong SS; et al. (2015). "Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes". Nat Med. 21 (5): 449–456. doi:10.1038/nm.3850. PMID 25894828.
- ↑ Patel AK, Sethi NS, Park H (2026). "Gastric cancer: a review". JAMA. doi:10.1001/jama.2025.20034.
- ↑ Bartley AN, Washington MK, Colasacco C, Ventura CB, Ismaila N, Benson AB; et al. (2017). "HER2 testing and clinical decision making in gastroesophageal adenocarcinoma: guideline from the College of American Pathologists, American Society for Clinical Pathology, and the American Society of Clinical Oncology". J Clin Oncol. 35 (4): 446–464. doi:10.1200/JCO.2016.69.4836. PMID 28129523.
- ↑ 21.0 21.1 Robbins CJ, Bates KM, Rimm DL. HER2 testing: evolution and update for a companion diagnostic assay. Nat Rev Clin Oncol. 2025.
- ↑ Shitara K, Lordick F, Bang YJ, Enzinger P, Ilson D, Shah MA; et al. (2023). "Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial". Lancet. 401 (10389): 1655–1668. doi:10.1016/S0140-6736(23)00620-7. PMID 37068504 Check
|pmid=value (help). - ↑ 23.0 23.1 23.2 23.3 Schlemper RJ, Riddell RH, Kato Y, Borchard F, Cooper HS, Dawsey SM; et al. (2000). "The Vienna classification of gastrointestinal epithelial neoplasia". Gut. 47 (2): 251–255. doi:10.1136/gut.47.2.251. PMID 10896917.
- ↑ Rugge M, Correa P, Dixon MF, Hattori T, Leandro G, Lewin K; et al. (2000). "Gastric dysplasia: the Padova international classification". Am J Surg Pathol. 24 (2): 167–76. PMID 10680883.
- ↑ Dixon MF (2002). "Gastrointestinal epithelial neoplasia: Vienna revisited". Gut. 51 (1): 130–131. doi:10.1136/gut.51.1.130. PMID 12077106.
- ↑ 26.0 26.1 Kato M (2015). "Diagnosis and therapies for gastric non-invasive neoplasia". World J Gastroenterol. PMID 26640329.
- ↑ 27.0 27.1 27.2 27.3 Ushiku T (2026). "Gastric dysplasia: an integrated classification of surface epithelium-derived precursor lesions". Virchows Arch. PMID 42841970 Check
|pmid=value (help). - ↑ Shah SC, Wang AY, Wallace MB, Hwang JH. AGA Clinical Practice Update on screening and surveillance in individuals at increased risk for gastric cancer in the United States: expert review. Gastroenterology. 2025.