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WHO CLASSIFICATION OF TUMOURS

DIGESTIVE SYSTEM TUMOURS

Complete MD Pathology Notes - WHO 6th Edition (2026)

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EDITION STATUS: The WHO Classification of Tumours: Digestive System Tumours, 6th Edition was released as an online beta version in January 2026 via the Tumour Classification Online (TCO) subscription platform. This is the FIRST volume in the new 6th Edition series. The print edition is anticipated to follow. As of June 2026, this is the most current and authoritative classification.

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1. WHO BOOK INFORMATION

Exam Point: The 6th edition is the FIRST volume published in the new WHO Blue Book 6th edition series. The WHO digestive system volume has historically always been Volume 1 in each edition series, reflecting its primacy in oncologic pathology.

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2. EVOLUTION OF CLASSIFICATION

Timeline of WHO Digestive System Tumour Classification

Why the Classification Changed

1. Molecular revolution: Next-generation sequencing (NGS), whole-genome sequencing, and multi-omics have redefined tumour identities at a molecular level rather than purely morphologic.
2. Clinical-pathological correlation: Survival data and treatment response have validated new entities and grading approaches.
3. Harmonization: Alignment across all WHO Blue Book volumes (e.g., NEN grading, mesenchymal tumour chapters) was needed.
4. New entities validated: Years of research since 2019 validated several provisional entities to full entity status.
5. HPV-related terminology update: Alignment with LAST (Lower Anogenital Squamous Terminology) system.
6. International standardization: Global consistency for epidemiological reporting, registries, and clinical trials.

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3. MAJOR UPDATES: 6th EDITION VS. 5th EDITION (2019)

3A. Structural Reorganization

3B. Newly Introduced Entities

3C. Renamed/Reclassified Entities

3D. Key Grading Changes

3E. Concept Changes

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4. COMPLETE CLASSIFICATION HIERARCHY

WHO 6th Edition Digestive System Tumours - Master Classification

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I. OESOPHAGUS

• Squamous cell hyperplasia
• Squamous intraepithelial neoplasia (dysplasia) - Low grade / High grade
• Oesophageal epidermoid metaplasia (NEW 6th Ed.)
• Squamous cell carcinoma (SCC)
  • Conventional SCC
  • Basaloid SCC
  • Spindle cell (sarcomatoid) SCC
  • Verrucous SCC
  • Papillary SCC

• Barrett oesophagus (columnar metaplasia)
• Dysplasia in Barrett oesophagus (Low grade / High grade)
• Oesophageal adenocarcinoma (OAC)

• Adenosquamous carcinoma
• Mucoepidermoid carcinoma
• Undifferentiated carcinoma
• NEC (small cell / large cell)
• NET (rare)

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II. STOMACH

• Gastric intestinal metaplasia
• Gastric dysplasia (Low grade / High grade) (consolidated in 6th Ed.)
• Gastric adenoma (tubular, villous, tubulovillous)
• Fundic gland polyp
• Hyperplastic polyp

• Gastric adenocarcinoma - classified by:
  • Histological type: Tubular, papillary, mucinous, poorly cohesive (signet ring cell), mixed, hepatoid, Paneth cell-rich
  • Molecular subtypes (TCGA 2014):
    • EBV-associated (EBVaGC): ~9%
    • Microsatellite instable (MSI): ~22%
    • Genomically stable (GS): ~20% (enriched for CDH1, RHOA mutations)
    • Chromosomally instable (CIN): ~50%
  • Lauren classification (diffuse/intestinal/mixed) retained for clinical use
• Gastric squamous cell carcinoma (rare)
• Gastric adenosquamous carcinoma
• Gastric undifferentiated/poorly differentiated carcinoma
• Gastric NEC (small cell / large cell)
• Amphicrine-like carcinoma (NEW 6th Ed.)

• Pyloric gland adenoma
• Oxyntic gland adenoma/polyp

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III. SMALL INTESTINE

• Duodenal adenoma (tubular, villous, tubulovillous, including flat/polypoid)
• Duodenal adenocarcinoma
• Duodenal NEC / NET

• Ampullary adenoma
• Ampullary carcinoma
  • Pancreatobiliary type
  • Intestinal type
  • Mixed type
  • Poorly differentiated/undifferentiated

• Small intestinal adenoma
• Small intestinal adenocarcinoma
• Small intestinal NEC / NET (including ileal NET - most common SI NET)

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IV. APPENDIX

• Appendiceal mucinous neoplasm (LAMN - Low grade; HAMN - High grade)
• Appendiceal adenocarcinoma
• Appendiceal NET (well-differentiated; L-cell, EC-cell types)
• Appendiceal NEC
• Goblet cell adenocarcinoma (formerly goblet cell carcinoid) - GCA Grade 1, 2, 3

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V. COLORECTUM

• Tubular adenoma
• Villous adenoma
• Tubulovillous adenoma
• Flat adenoma
• Serrated polyps:
  • Hyperplastic polyp (HP)
  • Sessile serrated lesion (SSL) - without dysplasia / with dysplasia (SSL-D)
  • Traditional serrated adenoma (TSA) (Clearer categorization in 6th Ed.)

• Colorectal intramucosal adenocarcinoma (NEW 6th Ed.)
• Colorectal adenocarcinoma
  • Conventional (tubular, mucinous)
  • Low-grade tubuloglandular adenocarcinoma (LTGA) (NEW)
  • Lymphoglandular complex-like adenocarcinoma (NEW)
  • Signet ring cell carcinoma (>50% signet ring cells)
  • Serrated adenocarcinoma
  • Micropapillary carcinoma
  • Medullary carcinoma
  • Cribriform comedo-type adenocarcinoma
• Squamous cell carcinoma of colorectum (rare)
• Adenosquamous carcinoma
• Undifferentiated carcinoma (now includes carcinoma with mesenchymal differentiation)
• Colorectal NEC (small cell / large cell)

• Low grade: Well-differentiated + Moderately differentiated
• High grade: Poorly differentiated + Undifferentiated

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VI. ANAL CANAL

• Squamous intraepithelial lesion (SIL):
  • Low-grade SIL (LSIL) = AIN 1 (HPV terminology per LAST) (harmonized 6th Ed.)
  • High-grade SIL (HSIL) = AIN 2/3 (harmonized 6th Ed.)
• Squamous cell carcinoma of anal canal
• Adenocarcinoma of anal canal
• NEC of anal canal

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VII. LIVER

• Hepatocellular adenoma (HCA) - subtyped:
  • HNF1A-mutated HCA (H-HCA)
  • Inflammatory HCA (I-HCA)
  • Beta-catenin activated HCA (b-HCA) - exon 3 vs exon 7/8 mutations
  • Unclassified HCA
  • Sonic Hedgehog HCA (SHH-HCA) (NEW 6th Ed.) - GLI1 amplification
• Hepatocellular carcinoma (HCC)
  • Conventional HCC
  • Fibrolamellar HCC (DNAJB1-PRKACA fusion)
  • Combined HCC-cholangiocarcinoma
  • Scirrhous HCC
  • Clear cell HCC
  • Steatohepatitic HCC
  • Macrotrabecular massive HCC
  • Chromophobe HCC
• Hepatoblastoma (primarily paediatric - see Paediatric volume)

• Biliary adenofibroma
• Intrahepatic cholangiocarcinoma:
  • Small-duct intrahepatic cholangiocarcinoma (iCCA) (NOW FORMALLY SEPARATE)
  • Large-duct intrahepatic cholangiocarcinoma (iCCA) (NOW FORMALLY SEPARATE)
  • Combined iCCA and HCC

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VIII. GALLBLADDER AND EXTRAHEPATIC BILE DUCTS

• Biliary intraepithelial neoplasia (BilIN) - Low grade / High grade
• Intracholecystic papillary neoplasm (ICPN) - Low grade / High grade (unified mass-forming precursor terminology)
• Gallbladder adenocarcinoma
  • Conventional adenocarcinoma
  • Adenosquamous carcinoma
  • SCC (rare)
  • Undifferentiated carcinoma

• BilIN - Low grade / High grade
• Intraductal papillary neoplasm (IPN) - bile duct (unified mass-forming precursor terminology)
• Perihilar cholangiocarcinoma (Klatskin tumour)
• Distal cholangiocarcinoma

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IX. PANCREAS

• Pancreatic intraepithelial neoplasia (PanIN) - Low grade / High grade
• Intraductal papillary mucinous neoplasm (IPMN) - Low grade / High grade dysplasia
  • Main duct type
  • Branch duct type
  • Combined type
  • Subtypes: gastric, intestinal, pancreatobiliary, oncocytic (IOPN)
• Mucinous cystic neoplasm (MCN) - Low grade / High grade
• Serous cystadenoma
• Solid pseudopapillary neoplasm (SPN)

• Conventional PDAC (acinar cell)
• Adenosquamous carcinoma
• Colloid (mucinous non-cystic) carcinoma
• Undifferentiated carcinoma ± osteoclast-like giant cells
• Carcinoma with mesenchymal differentiation (NEW inclusion in undifferentiated category)
• Large duct type PDAC
• Invasive carcinoma from IPMN
• Invasive carcinoma from MCN

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X. NEUROENDOCRINE NEOPLASMS (DEDICATED CHAPTER - All GI sites)

• Well-differentiated NEN = NET (Neuroendocrine Tumour):
  • NET G1: Mitotic rate <2/2mm², Ki-67 <3%
  • NET G2: Mitotic rate 2-20/2mm², Ki-67 3-20%
  • NET G3: Mitotic rate >20/2mm², Ki-67 >20% (well-differentiated morphology)
• Poorly differentiated NEN = NEC (Neuroendocrine Carcinoma):
  • Small cell NEC
  • Large cell NEC
• Mixed NEN = MiNEN (Mixed Neuroendocrine-Non-Neuroendocrine Neoplasm): requires ≥30% of each component
• Amphicrine-like Carcinoma (ALC) (NEW - SEPARATED from MiNEN): dual differentiation WITHIN single cells

• Gastric NET Type 1 (ECL-cell; hypergastrinaemia/CAG)
• Gastric NET Type 2 (ECL-cell; MEN1/ZES)
• Gastric NET Type 3 (sporadic; large; aggressive)
• Ileal/jejunal NET (EC-cell, serotonin-producing; most common SI malignancy)
• Appendiceal NET (EC-cell; usually benign <2cm)
• Rectal NET (L-cell, PP/glucagon; generally good prognosis)
• Pancreatic NET (pNET): Functioning and non-functioning

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XI. MESENCHYMAL TUMOURS (DEDICATED CHAPTER)

• GIST (Gastrointestinal Stromal Tumour)
  • KIT-mutant (~70-75%)
  • PDGFRA-mutant (~10%)
  • SDH-deficient (~5-7%)
  • NF1-associated
  • BRAF-mutant (rare)
  • Quadruple wild-type GIST
• Leiomyoma / Leiomyosarcoma
• Schwannoma
• Granular cell tumour
• Inflammatory fibrosarcoma (ALK-rearranged)
• Lipoma / liposarcoma (rare)
• Perivascular epithelioid cell tumour (PEComa) - incl. AML of liver

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XII. HAEMATOLYMPHOID TUMOURS (DEDICATED CHAPTER)

• MALT lymphoma (Extranodal marginal zone lymphoma) - especially stomach (H. pylori-associated)
• Diffuse Large B-Cell Lymphoma (DLBCL) - GI
• Mantle cell lymphoma - GI
• Follicular lymphoma - duodenum
• Burkitt lymphoma - ileocaecal
• EBV-associated T-cell/NK-cell lymphoma
• Enteropathy-associated T-cell lymphoma (EATL)
• Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL)

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XIII. GENETIC TUMOUR SYNDROMES (REORGANIZED BY PATHWAY/GENE)

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XIV. OTHER TUMOURS AND METASTASES (NEW SECTION)

• Metastatic disease to GI tract (comprehensive coverage)
• Carcinoma of Unknown Primary (CUP) - NEW dedicated section

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5. EVERY MAJOR TUMOUR ENTITY - DETAILED DESCRIPTIONS

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OESOPHAGUS

5.1 Squamous Cell Carcinoma of Oesophagus (ESCC)

5.2 Oesophageal Adenocarcinoma (OAC)

5.3 Barrett Oesophagus and Dysplasia

5.4 Oesophageal Epidermoid Metaplasia (NEW - 6th Ed.)

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STOMACH

5.5 Gastric Adenocarcinoma

Normal mucosa
    ↓ H. pylori
Superficial gastritis
    ↓
Chronic atrophic gastritis
    ↓
Intestinal metaplasia (complete → incomplete)
    ↓
Dysplasia (Low grade → High grade)
    ↓
Intestinal-type adenocarcinoma

Normal mucosa
    ↓ CDH1 mutation (germline or somatic)
Loss of E-cadherin
    ↓
Poorly cohesive/signet ring cell carcinoma

• Borrmann classification:
  • Type I: Polypoid/fungating
  • Type II: Ulcerated with raised edges
  • Type III: Ulceroinfiltrative
  • Type IV: Diffusely infiltrating (Linitis plastica)

• Tubular adenocarcinoma: Back-to-back glands, minimal stroma
• Papillary: Finger-like projections with fibrovascular cores
• Mucinous: >50% extracellular mucin pools
• Poorly cohesive: Individual cells infiltrating stroma; signet ring cells (intracytoplasmic mucin displacing nucleus)
• Hepatoid: Large polygonal cells resembling hepatocytes; AFP+
• Lymphoepithelioma-like: Syncytial nests in dense lymphocytic infiltrate; EBER+

5.6 Gastric Dysplasia (Consolidated in 6th Ed.)

6th Ed. change: Intermediate grade dysplasia is no longer used as a separate category. The two-tier system (LGD/HGD) is now standard.

5.7 MALT Lymphoma (Gastric)

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SMALL INTESTINE

5.8 Small Intestinal Adenocarcinoma

5.9 Ileal Neuroendocrine Tumour (Midgut NET)

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APPENDIX

5.10 Low-grade Appendiceal Mucinous Neoplasm (LAMN)

5.11 High-grade Appendiceal Mucinous Neoplasm (HAMN)

5.12 Appendiceal Goblet Cell Adenocarcinoma (GCA)

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COLORECTUM

5.13 Serrated Polyps (Clearer Categorization - 6th Ed.)

6th Ed. update: "Sessile serrated adenoma/polyp" terminology replaced by "Sessile Serrated Lesion (SSL)" uniformly. The term "adenoma" is dropped because SSL lacks the cytological atypia of conventional adenomas. This was introduced in the 5th Ed. but reinforced and clarified in the 6th Ed.

5.14 Colorectal Adenocarcinoma (CRC)

Normal epithelium
    ↓ APC mutation (FAP or sporadic; ~85%)
Aberrant crypt foci → Adenoma (tubular → villous)
    ↓ KRAS mutation
Growing adenoma with LGD
    ↓ SMAD4/TGF-β loss
HGD
    ↓ TP53 mutation
Invasive adenocarcinoma
    ↓ Further alterations (DCC, 18q loss)
Metastatic disease

Exam Point: This is a major change. The 5th edition used G1/G2/G3 (3-tier). The 6th edition uses a 2-tier system (Low grade/High grade). This simplification has been shown to have better reproducibility and prognostic significance.

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ANAL CANAL

5.15 Anal Canal SCC and Precursors

Exam Point: p16 block positivity (diffuse cytoplasmic AND nuclear) is the accepted IHC surrogate for high-risk HPV in anal SCC. Patchy/focal p16 staining should trigger HPV ISH/PCR for confirmation.

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LIVER

5.16 Hepatocellular Carcinoma (HCC)

Macro-regenerative nodule
    ↓
Low-grade dysplastic nodule (LGDN)
    ↓
High-grade dysplastic nodule (HGDN)
    ↓ [Increased arterial supply; CD34 sinusoidal pattern]
Early HCC (well-differentiated; <2cm; vaguely nodular)
    ↓
Progressed HCC (conventional; invasive)
    ↓
Advanced HCC (portal vein invasion; satellite nodules)

5.17 Hepatocellular Adenoma (HCA) - Subtypes (6th Ed.)

Exam Point: SHH-HCA - The 6th edition introduces this as a new, distinct subtype characterized by activation of the Sonic Hedgehog (SHH) pathway. It is identified by GLI1 amplification/fusion. Clinically, it may be associated with a higher risk of hemorrhage. This is a high-yield exam point for 2026 examinations.

5.18 Intrahepatic Cholangiocarcinoma (iCCA) - Now Two Separate Entities

Exam Point: FGFR2 fusions and IDH1/2 mutations are targetable in iCCA - this is why the separation of small-duct from large-duct iCCA has MAJOR clinical implications. IDH and FGFR alterations are predominantly in small-duct iCCA.

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GALLBLADDER AND BILE DUCTS

5.19 Gallbladder Adenocarcinoma

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PANCREAS

5.20 Pancreatic Ductal Adenocarcinoma (PDAC)

PanIN-Low grade (formerly PanIN-1A/1B/2):
- Normal-appearing cells → mucin-lined → mild dysplasia
- KRAS mutation early (~>90%)
    ↓
PanIN-High grade (formerly PanIN-3):
- Severe dysplasia; cribriform; necrotic debris
- SMAD4 loss, TP53 mutation, CDKN2A loss
    ↓
Invasive PDAC

6th Ed. change: PanIN is now graded as Low grade / High grade (not PanIN-1A/1B/2/3 as in older classifications).

• Smear/cell block: Drunken honeycomb arrangement; nuclear enlargement; prominent nucleoli; anisonucleosis; loss of polarity
• "Central meal" pattern (nuclear overlap) characteristic
• EUS-FNA/FNB gold standard for diagnosis (sensitivity 85-95%)
• WHO Pancreaticobiliary Cytology Reporting System: Non-diagnostic, Negative, Atypical, Neoplastic, Suspicious, Positive/Malignant

5.21 Pancreatic Neuroendocrine Tumours (pNET)

Critical Exam Point: G3 NET vs. NEC - Both have Ki-67 >20% but G3 NET has WELL-DIFFERENTIATED morphology (organoid, salt-and-pepper chromatin, low N:C ratio) while NEC is POORLY DIFFERENTIATED. IHC: G3 NET retains DAXX/ATRX expression; NEC often TP53 mutant/p53 aberrant, Rb loss.

• Synaptophysin++, Chromogranin A+ (variable by grade), SSTR2+, CD56+
• Site-specific hormones: Insulin, Glucagon, Somatostatin, Gastrin, VIP (IHC on sections)
• DAXX/ATRX loss: ~40% of pNETs (chromosomal instability; worse prognosis)
• MEN1 mutation: Multiple lesions; MENIN loss by IHC

5.22 Solid Pseudopapillary Neoplasm (SPN)

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6. ESSENTIAL DIAGNOSTIC CRITERIA

Key Examples

Colorectal Adenocarcinoma

• Essential: Malignant epithelial tumour with glandular differentiation infiltrating beyond muscularis mucosae into submucosa or deeper; or intramucosal carcinoma (6th Ed. - invasion into lamina propria)
• Desirable: Morphological subtype classification; MMR/MSI testing (all CRC); KRAS/NRAS/BRAF testing (metastatic CRC); SMAD4 testing (metastatic)
• Exclusion: Intraepithelial neoplasia/dysplasia (no invasion); neuroendocrine neoplasm

HCC

• Essential: Hepatocellular differentiation (morphology or IHC: GPC3/Arginase-1/HepPar1); malignant criteria (nuclear atypia, mitoses, vascular invasion)
• Desirable: Background liver disease; imaging characteristics (LI-RADS); AFP level; HBV/HCV status; BCLC staging
• Exclusion: Hepatocellular adenoma (no malignant features); metastatic carcinoma (negative hepatocellular markers)

GIST

• Essential: Spindle cell and/or epithelioid tumour of GI tract/mesentery; CD117 (KIT)+ or DOG1+ (OR proven KIT/PDGFRA/SDH/NF1 mutation)
• Desirable: Mutation analysis (KIT exon 9/11/13/17; PDGFRA exon 12/14/18; SDH complex in WT); risk stratification (site, size, mitotic rate)
• Exclusion: Leiomyoma (SMA+, CD117-, DOG1-); Schwannoma (S100+, CD117-)

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7. MOLECULAR PATHOLOGY - COMPREHENSIVE TABLE

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8. IMMUNOHISTOCHEMISTRY - COMPREHENSIVE TABLES

Hepatic Tumours IHC

GIST IHC

NEN IHC

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9. DIFFERENTIAL DIAGNOSIS - KEY COMPARISON TABLES

HCC vs. Hepatocellular Adenoma vs. Focal Nodular Hyperplasia (FNH)

Well-differentiated HCC vs. High-grade Dysplastic Nodule

"Barcelona Panel" for early HCC: GPC3 + HSP70 + Glutamine Synthetase (GS) - 2 out of 3 positive = HCC diagnosis (sensitivity 72%, specificity 100%)

PDAC vs. Autoimmune Pancreatitis (AIP) vs. Chronic Pancreatitis

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10. GROSS vs. MICROSCOPIC CORRELATION

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11. CYTOLOGY CORRELATION

EUS-FNA Pancreaticobiliary Cytology (WHO Reporting System)

Gastric Cytology (brush/FNA):

• Signet ring cells: large vacuole with eccentric compressed nucleus - highly specific for poorly cohesive carcinoma
• "Tiger-claw" appearance: tightly cohesive sheets with prominent mucin borders in mucinous carcinoma
• "3D clusters with nuclear overlapping": tubular adenocarcinoma

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12. CLINICAL CORRELATION

TNM Staging (AJCC 8th Edition - relevant to WHO tumours)

Colorectal Cancer TNM Summary

Important: Colorectal intramucosal adenocarcinoma (lamina propria invasion) = Tis in AJCC staging. This is distinct from submucosal invasion (T1) which carries lymph node metastasis risk. Endoscopic management is appropriate for intramucosal adenocarcinoma.

GIST Risk Stratification (Miettinen & Lasota Criteria - WHO adopted)

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13. WHO GRADING

Summary Grading Systems in 6th Edition

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14. TNM CHANGES (AJCC 9th Edition Notes)

The AJCC 9th Edition Cancer Staging Manual is expected/released around 2024-2025. Key anticipated changes relevant to WHO digestive tumours include:

• Colorectal Cancer: Potential refinement of T1 sub-staging (T1a/b based on submucosa depth = Haggitt/Kikuchi criteria for pedunculated/sessile polyps)
• HCC: Microvascular invasion (MVI) and satellite nodules may be incorporated more explicitly
• Pancreatic Ca: No major changes from 8th edition pending data

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15. PRACTICAL REPORTING POINTS

For Colorectal Carcinoma Reports:

1. Histological type with 6th Ed. terminology (including LTGA, lymphoglandular complex-like, intramucosal if applicable)
2. Grade: Low grade or High grade (6th Ed. 2-tier)
3. Depth of invasion (pT stage)
4. Lymphovascular invasion (LVI: small vessel = L; large vessel = V)
5. Perineural invasion (Pn)
6. Tumour budding (ITBCC grading: Bd1/2/3 based on buds per 0.785mm² hotspot)
7. Resection margin status (R0/R1/R2; for rectal cancer: CRM distance in mm)
8. Lymph nodes (pN stage; minimum 12 nodes for adequate staging)
9. MMR/MSI status (mandatory for all CRC - Lynch screening + immunotherapy eligibility)
10. KRAS/NRAS/BRAF (for metastatic cases)
11. Treatment response (for neo-adjuvant treated cases: Mandard TRG 1-5 or CAP TRG 0-3)

For Gastric Carcinoma Reports:

1. Lauren classification (diffuse/intestinal/mixed)
2. WHO histological type
3. HER2 scoring (IHC: 0/1+/2+/3+; FISH if IHC 2+) - Ruschoff/Hofmann scoring
4. EBV (EBER ISH)
5. MMR status (dMMR/pMMR)
6. Tumour budding
7. Resection margins; omentum; lymph nodes

For HCC/Liver Biopsy Reports:

1. Hepatocellular differentiation markers used
2. Background liver disease (cirrhosis, steatosis, viral hepatitis)
3. Microvascular invasion (critical for staging and recurrence)
4. Macrovascular invasion
5. Satellite nodules
6. HCA subtype (molecular subtype: H-HCA, I-HCA, b-HCA, SHH-HCA)

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16. CAP/ICCR RECOMMENDATIONS

ICCR Updates (January 2026 - aligned with WHO 6th Edition)

• Updating 8 existing datasets for GI tumours
• Developing 1 new dataset

Key CAP/ICCR Reporting Requirements:

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17. COMMON DIAGNOSTIC PITFALLS

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18. ANCILLARY TECHNIQUES

Molecular Techniques Used in Digestive Pathology

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19. ARTIFICIAL INTELLIGENCE AND DIGITAL PATHOLOGY UPDATES (2024-2026)

AI in GI Pathology - Current Status

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20. HIGH-YIELD MD PATHOLOGY EXAMINATION POINTS

University Theory Questions (Long Essay Type)

1. Describe the WHO 6th Edition (2026) classification of colorectal carcinoma. Discuss the new entities introduced, the novel two-tier grading system, molecular pathology, and predictive biomarkers in detail.
2. Classify gastric adenocarcinoma according to the TCGA molecular classification. Discuss the pathogenesis, IHC, and clinical implications of each subtype.
3. Write an essay on intrahepatic cholangiocarcinoma with emphasis on the 6th Edition separation into small-duct and large-duct subtypes, their molecular differences, and therapeutic targeting.
4. Describe the classification of pancreatic neuroendocrine neoplasms according to WHO 6th Edition. Distinguish G3 NET from NEC and discuss the diagnostic approach.
5. Write a detailed note on the hepatocellular adenoma subtypes as per the current WHO Blue Book, including the newly introduced SHH-HCA.

Short Notes

• Amphicrine-like carcinoma vs. MiNEN
• Sonic Hedgehog Hepatocellular Adenoma
• Low-grade tubuloglandular adenocarcinoma
• Barcelona panel for early HCC
• LAMN vs. appendiceal mucinous adenocarcinoma
• Colorectal intramucosal adenocarcinoma

Viva Questions

• Q: What is the difference between SSL and TSA?
• Q: How do you diagnose a G3 NET vs. NEC in the pancreas?
• Q: What are the IHC markers for fibrolamellar HCC?
• Q: Name the 5 TCGA molecular subtypes of gastric cancer and their key molecular alterations.
• Q: What is the significance of SMAD4 loss in PDAC?
• Q: Why is FGFR2 fusion clinically important in iCCA?
• Q: What is the "Barcelona panel" and when do you use it?
• Q: How is intramucosal adenocarcinoma of colorectum managed differently from submucosal invasion?
• Q: What molecular alteration is pathognomonic for fibrolamellar HCC?

Spotter Exam Points (Histological Patterns)

Frequently Confused Entities

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21. MNEMONICS

KRAS-SMAD4-TP53 in PDAC:

TCGA Gastric Cancer Subtypes:

HCA Subtypes (6th Edition):

Colorectal Carcinogenesis Pathways:

GIST Mutation Spectrum:

NET Grading (Ki-67):

High-yield HCC panel:

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22. FLOWCHARTS

Colorectal Polyp Management (Simplified)

Colorectal Polyp on Endoscopy
         |
    ┌────┴────┐
Tubular/Villous      Serrated
Adenoma              Polyp
    |                    |
    ↓                ┌───┴───┐
Degree of         Hyperplastic  SSL/TSA
dysplasia?        Polyp         |
    |                |          ↓
  LGD → HGD      Left/Distal  Right/Proximal
    |            Small (<5mm)  Large (>1cm)
Resection        Surveillance  Resect+
                 at 5-10 yrs  Surveillance

HCC Diagnostic Algorithm (Cirrhotic Liver)

Liver nodule in cirrhotic patient (AFP rise or imaging)
                    |
              Size <1 cm?
           ┌────┘    └────┐
          Yes              No (≥1 cm)
           |                    |
     Repeat US 3-6 months   LI-RADS CT/MRI
                                 |
                    ┌────────────┴────────────┐
              LI-RADS 5 (HCC)           LI-RADS 3-4
                    |                        |
              Treat as HCC            Biopsy / Further imaging
                                            |
                                    Histology + IHC
                                    (GPC3/HSP70/GS panel)
                                    2/3 + = HCC

GI NEN Classification Flowchart

GI Neuroendocrine Neoplasm
          |
     Morphology?
   ┌──────┴──────┐
Well-differentiated   Poorly differentiated
(NET)                 (NEC)
     |                    |
Ki-67/Mitotic rate   Small cell vs. Large cell
   ┌──┴──┐
G1   G2   G3
<3%  3-20%  >20%
(Still well-diff morphology in G3)
          |
Compare with: G3 NET vs. NEC
- G3 NET: Well-diff morphology; DAXX/ATRX+; Rb retained; p53 normal pattern
- NEC: Poorly-diff; Rb LOSS; p53 ABERRANT

GIST Diagnostic Approach

GI spindle/epithelioid tumour
              |
       IHC: CD117 (KIT)
     ┌────────┴────────┐
     +                 -
     |                 |
  GIST?           Add DOG1, CD34, SMA, Desmin, S100
  Consider          |
  mutation       DOG1+/KIT+ → GIST
  analysis        SMA+/Desmin+/CD117- → Leiomyoma/LMS
                  S100+ → Schwannoma
     |
GIST confirmed → Mutation analysis:
KIT exon 11/9/13/17 → Imatinib (exon 9: double dose)
PDGFRA D842V → Avapritinib
SDHB loss → SDH-deficient GIST → Sunitinib/surveillance

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23. SUMMARY TABLES

Summary of All New Entities in WHO 6th Edition Digestive System Tumours

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24. COMPARISON TABLES

5th Edition vs. 6th Edition: Key Differences

Old Terminology vs. New Terminology (Selected)

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25. RAPID REVISION SHEET

WHO 6th Edition Digestive System Tumours - RAPID REVISION
==========================================================

PUBLICATION: Online beta January 2026; FIRST volume of 6th edition series

TOP 5 STRUCTURAL CHANGES:
1. Dedicated NEN / Mesenchymal / Haematolymphoid chapters
2. Genetic syndromes reorganized by pathway/gene
3. Duodenum/ampullary SEPARATED from jejuno-ileal
4. Metastatic disease in dedicated chapter
5. CUP included for first time

TOP NEW ENTITIES:
• Oesophageal epidermoid metaplasia
• Colorectal intramucosal adenocarcinoma (Tis; endoscopic Rx)
• LTGA (low-grade tubuloglandular adenocarcinoma) - excellent prognosis
• Lymphoglandular complex-like adenocarcinoma
• ITPN + IOPN of bile ducts
• SHH-HCA (sonic hedgehog hepatocellular adenoma; GLI1 amplification)
• ALC (amphicrine-like carcinoma; dual diff WITHIN same cells; ≠ MiNEN)
• Small-duct iCCA + Large-duct iCCA (formally separated)

KEY GRADING CHANGES:
• CRC: 3-tier (G1/G2/G3) → 2-tier (LOW / HIGH grade)
• Precursor lesions: uniform 2-tier (LG/HG)
• PanIN: 1A/1B/2/3 → Low grade / High grade
• NEN grading: G1/G2/G3 for NET; SC-NEC or LC-NEC for NEC

KEY MOLECULAR POINTS:
• Gastric Ca TCGA: EBV / MSI / GS / CIN
• CRC: KRAS/NRAS (anti-EGFR); BRAF V600E (encorafenib); MSI-H (pembrolizumab)
• PDAC: KRAS >90%; BRCA → olaparib; NTRK → larotrectinib
• iCCA small-duct: FGFR2 fusion (pemigatinib) + IDH1/2 (ivosidenib/enasidenib)
• GIST: KIT/PDGFRA/SDH/NF1/BRAF
• G3 NET vs NEC: morphology + Rb/p53/DAXX/ATRX

KEY IHC PANELS:
• Early HCC Barcelona: GPC3 + HSP70 + GS (2/3 = HCC)
• HCA: LFABP loss (H-HCA); SAA/CRP+ (I-HCA); beta-cat nuclear+ (b-HCA); GLI1/PTCH2 (SHH-HCA)
• GIST: DOG1 + CD117 +/- SDHB (for SDH-deficient)
• NEN: Synaptophysin + CgA + Ki-67 + SSTR2
• CRC MMR: MLH1/PMS2/MSH2/MSH6 (all CRC - mandatory)

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26. TOP 50 MUST-KNOW FACTS

1. WHO 6th Edition Digestive System was the FIRST volume released in the 6th edition series (online beta, January 2026).
2. CRC grading changed from 3-tier to 2-tier: Low grade (G1+G2) and High grade (G3+G4).
3. Colorectal intramucosal adenocarcinoma is a NEW entity - invasion into lamina propria without muscularis mucosae breach = Tis; managed endoscopically.
4. LTGA (Low-grade tubuloglandular adenocarcinoma) is a new CRC entity with excellent prognosis (~100% 5-year survival).
5. Lymphoglandular complex-like adenocarcinoma is a new CRC entity with distinctive morphology.
6. SHH-HCA (Sonic Hedgehog hepatocellular adenoma) is a new HCA subtype with GLI1 amplification.
7. Small-duct and large-duct intrahepatic cholangiocarcinoma are now formally separate entities.
8. Small-duct iCCA is associated with FGFR2 fusions (15-20%) and IDH1/2 mutations (25%) - both targetable.
9. ALC (Amphicrine-like Carcinoma) is separated from MiNEN: ALC = dual differentiation WITHIN single cells; MiNEN = two distinct populations (each ≥30%).
10. Anal canal terminology now aligned with LAST: LSIL (= AIN 1) and HSIL (= AIN 2/3).
11. CUP (Carcinoma of Unknown Primary) is included for the first time in the WHO GI classification.
12. PanIN grading simplified: 1A/1B/2 = Low grade; 3 = High grade.
13. Genetic tumour syndromes reorganized by mechanism/pathway/gene (not anatomical site).
14. Oesophageal epidermoid metaplasia is a new entity in the oesophagus chapter.
15. GIST risk stratification: Site + Size + Mitotic rate + Rupture (all four factors required).
16. PDGFRA D842V (exon 18) mutation in GIST = resistant to imatinib; treat with avapritinib.
17. KRAS mutation in CRC (~45%) = resistant to anti-EGFR (cetuximab/panitumumab) - must test ALL exons 2/3/4 of KRAS AND NRAS.
18. BRAF V600E in CRC (~10%) = poor prognosis; treat with encorafenib + cetuximab (BEACON-CRC).
19. MSI-H/dMMR CRC = eligible for pembrolizumab first-line (KEYNOTE-158/177); Lynch syndrome screening mandatory.
20. DNAJB1-PRKACA fusion = pathognomonic for fibrolamellar HCC; found in virtually all cases.
21. Barcelona panel for early HCC: GPC3 + HSP70 + Glutamine Synthetase - 2/3 positive = HCC.
22. G3 NET ≠ NEC: G3 NET has well-differentiated morphology; NEC has poorly differentiated morphology.
23. NEC diagnosis requires poorly differentiated morphology - Ki-67 >20% alone does NOT make a NEC diagnosis.
24. Goblet cell carcinoid is ABANDONED; renamed Goblet Cell Adenocarcinoma (GCA) with G1/G2/G3 grading.
25. Sessile Serrated Lesion (SSL) = NOT adenoma; lacks cytological atypia; BRAF V600E; CIMP-high pathway.
26. SMAD4 loss in PDAC (~55%) predicts widespread metastatic disease.
27. H. pylori eradication can cure gastric MALT lymphoma in ~75% of cases (without t(11;18) translocation).
28. t(11;18)(q21;q21) = API2-MALT1 = H. pylori eradication RESISTANT gastric MALT lymphoma.
29. LAMN = LOW malignant potential; pushing margins; cause of pseudomyxoma peritonei (PMP).
30. IPMN with main duct involvement ≥5mm = HIGH surgical risk (up to 70% malignancy rate).
31. EBV-associated gastric cancer (EBVaGC): highest PD-L1 expression; best candidate for immunotherapy.
32. Lauren "diffuse" type gastric cancer: CDH1 mutation/loss of E-cadherin; worst prognosis; young patients.
33. HER2 testing is MANDATORY in all gastric/GEJ adenocarcinoma resections (ICCR requirement).
34. Trastuzumab + chemotherapy is standard of care for HER2-positive (IHC 3+ or IHC 2+/FISH+) gastric/GEJ adenocarcinoma.
35. BRCA1/2 germline mutation in PDAC = olaparib maintenance therapy (POLO trial).
36. MEN1 syndrome: multiple gastric NETs (Type 2, ECL-cell) + duodenal gastrinoma (Zollinger-Ellison).
37. Insulinoma is the most common FUNCTIONING pNET (~90% benign).
38. Gastrinoma triangle: (1) head of pancreas/cystic duct junction; (2) second/third duodenum junction; (3) body/neck junction of pancreas.
39. Ileal NET is the most common malignant small intestinal tumour; multicentricity in 30%.
40. Carcinoid syndrome (flushing, diarrhea, bronchospasm) = liver metastases bypassing portal detoxification.
41. 5-HIAA (5-hydroxyindoleacetic acid) in urine = diagnostic for carcinoid syndrome; >25mg/24h = positive.
42. SDH-deficient GIST: Loss of SDHB by IHC; associated with Carney triad and Carney-Stratakis syndrome; imatinib resistant; indolent but recurrent.
43. NF1-associated GIST: Multiple small intestinal GISTs; usually wild-type for KIT/PDGFRA; imatinib less effective.
44. HNF1A-mutated HCA (H-HCA): LFABP loss by IHC; lowest malignant potential; OCP-associated; steatotic.
45. Beta-catenin exon 3 mutated HCA: Highest malignant potential for HCC transformation; GS diffuse+; nuclear beta-catenin.
46. Fibrolamellar HCC: Young patients (15-35 yrs); non-cirrhotic; CK7+, CD68+; DNAJB1-PRKACA fusion; EpCAM may be positive.
47. Gallbladder T staging: T1a (lamina propria) = cholecystectomy only; T1b (muscularis) = cholecystectomy ± re-resection; T2a (peritoneal side) vs T2b (hepatic side) - important in 8th edition AJCC.
48. Cribriform comedo-type colorectal adenocarcinoma: Associated with POLE mutations; ultra-mutated; excellent immunotherapy response.
49. Medullary CRC: No gland formation; syncytial sheets; CD8+ TILs; almost always MSI-H; better prognosis despite poorly differentiated appearance.
50. PD-L1 in gastric/GEJ/oesophageal cancer is scored by CPS (Combined Positive Score) = (stained tumour + immune cells) / total tumour cells × 100; CPS ≥10 required for pembrolizumab in many trials.

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27. RECENT REFERENCES

1. WHO Classification of Tumours: Digestive System Tumours, 6th Edition (2026). WHO Classification of Tumours Editorial Board (Arends MJ, Esposito I, Gill AJ, Hruban RH, Khoury JD, Kojima M et al.). International Agency for Research on Cancer (IARC), Lyon. Online beta release January 2026. Available via Tumour Classification Online (TCO).
2. WHO Classification of Tumours: Digestive System Tumours, 5th Edition, Volume 1 (2019). WHO Classification of Tumours Editorial Board. IARC Press, Lyon. ISBN: 978-92-832-4499-8.
3. Arends MJ, Esposito I, Gill AJ, Hruban RH, Khoury JD, Kojima M, et al. "Changes in the 6th edition of the World Health Organization classification of tumours of the digestive system." Histopathology. 2026 Jun. DOI: 10.1111/his.70116. [PMID: 41724188] - PRIMARY REFERENCE
4. ICCR (International Collaboration on Cancer Reporting). "New WHO Classification for Digestive System Tumours 6th Edition online." ICCR News, January 2026. Available at: iccr-cancer.org.
5. Cancer Genome Atlas Research Network. "Comprehensive molecular characterization of gastric adenocarcinoma." Nature. 2014;513:202-209.
6. Centeno BA, Saieg M, Siddiqui MT. "The World Health Organization Reporting System for Pancreaticobiliary Cytopathology." Cancer Cytopathol. 2024 Jul. [PMID: 38709670]
7. Vocino Trucco G, Volante M. "Changes in categorization or nomenclature within neuroendocrine tumors." Endocr Relat Cancer. 2024 Aug. [PMID: 38776393]
8. AJCC Cancer Staging Manual, 8th Edition (2017). Amin MB et al. Springer International Publishing. (9th Edition anticipated 2024-2025)
9. CAP (College of American Pathologists). Gastrointestinal Cancer Protocols. Available at: cap.org (current protocols, 2024-2026 versions).
10. ENETS Consensus Guidelines for Standard of Care in NEN, 2023-2024.

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STOP - SYSTEM COMPLETE This completes the comprehensive WHO 6th Edition Digestive System Tumours notes. Type "Continue" to proceed to Organ System #2: Breast Tumours.