🔁 GI Cancer Pathway Diagrams (Progression Pathways)

🔹 1. Colorectal Cancer (Adenoma-Carcinoma Sequence)

📈 Vogelstein Model / Chromosomal Instability Pathway
(Accounts for ~80% of sporadic CRC)

NORMAL MUCOSA
   │
   ▼
APC mutation (tumor suppressor gene)
   │
   ▼
Hyperproliferative epithelium (early adenoma)
   │
   ▼
KRAS mutation (oncogene)
   │
   ▼
Intermediate adenoma
   │
   ▼
p53 mutation + DCC loss (tumor suppressor genes)
   │
   ▼
Carcinoma

🧠 Mnemonic: "AK-53" = APC → KRAS → p53

🔹 2. Lynch Syndrome (Mismatch Repair Pathway)

📈 Microsatellite Instability (MSI) Pathway
(~15% of CRC; autosomal dominant)

Germline mutation in DNA mismatch repair genes:
→ MLH1, MSH2, MSH6, PMS2
   │
   ▼
Microsatellite instability → Accumulation of mutations
   │
   ▼
Sessile serrated polyp → Adenocarcinoma

🧠 Associated with: Endometrial, Ovarian, Gastric, Urothelial, Pancreatic cancers

🔹 3. H. pylori → Gastric Cancer Pathway

📈 Correa Cascade (Intestinal-Type Gastric Adenocarcinoma)

H. pylori infection
   │
   ▼
Chronic gastritis
   │
   ▼
Atrophic gastritis (loss of parietal cells)
   │
   ▼
Intestinal metaplasia
   │
   ▼
Dysplasia
   │
   ▼
Gastric adenocarcinoma

🧠 Also associated: Smoking, salt-preserved foods, blood type A

🔹 4. Barrett’s Esophagus → Esophageal Adenocarcinoma

📈 GERD-Induced Metaplasia Progression

Chronic GERD
   │
   ▼
Barrett’s esophagus (non-ciliated columnar metaplasia)
   │
   ▼
Low-grade dysplasia
   │
   ▼
High-grade dysplasia
   │
   ▼
Esophageal adenocarcinoma (distal)

🧠 Surveillance: EGD every 3–5 years for non-dysplastic Barrett’s

🔹 5. Pancreatic Cancer Pathway

📈 Multistep Genetic Mutations

KRAS activation (oncogene)

│

▼

CDKN2A (p16) inactivation

│

▼

TP53, SMAD4/DPC4 inactivation (tumor suppressors)

│

▼

Pancreatic ductal adenocarcinoma

🧠 Genetic syndromes:

• Peutz-Jeghers (STK11/LKB1)

• Lynch

• BRCA1/2

🔹 6. PSC → Cholangiocarcinoma

📈 Chronic Inflammatory → Neoplastic Sequence

Primary Sclerosing Cholangitis (PSC)
   │
   ▼
Chronic biliary inflammation & fibrosis
   │
   ▼
Bile duct dysplasia
   │
   ▼
Cholangiocarcinoma (intrahepatic or hilar)

🧠 High-yield: Associated with Ulcerative colitis
🧠 Screening: MRCP annually + CA 19-9 trend (controversial)

🔹 7. Peutz-Jeghers Syndrome → GI & Extra-GI Cancers

📈 Hamartoma–Carcinoma Sequence (rare)

STK11 (LKB1) mutation
   │
   ▼
Hamartomatous polyps (non-malignant but numerous)
   │
   ▼
↑ Risk of epithelial cancers:
   - Pancreas
   - GI (stomach, small bowel, colon)
   - Breast, Ovary, Cervix

🧠 Buzzword: Mucocutaneous pigmentation (lips, oral mucosa)

🔹 8. Chronic Hepatitis/Cirrhosis → Hepatocellular Carcinoma

📈 Inflammation → Regeneration → Dysplasia → Neoplasia

Chronic liver injury (Hep B/C, Alcohol, NASH)
   │
   ▼
Cirrhosis (fibrosis + regenerative nodules)
   │
   ▼
Dysplastic nodules
   │
   ▼
Hepatocellular carcinoma (HCC)

🧠 HCC in Hep B may arise without cirrhosis

🔹 9. IBD (Ulcerative Colitis) → CRC

📈 Chronic Inflammation → Dysplasia → Carcinoma

Ulcerative colitis >8 years
   │
   ▼
Continuous colonic inflammation
   │
   ▼
Multifocal low/high-grade dysplasia
   │
   ▼
Colorectal cancer

🧠 Start colonoscopy screening 8 years after diagnosis
🧠 Then every 1–2 years

✳️ Optional: Summary Mnemonics

• "AK-53": Adenoma-Carcinoma = APC → KRAS → p53

• “VILLous is VILLainous”: Villous adenomas more likely to become cancer

• “Peutz = Pigmentation + Pancreas”: GI polyps + dark spots + ↑ pancreatic risk

• “PSC + UC = Cholangiocarcinoma”: Chronic inflammation → bile duct cancer

Q1: What are the steps in the adenoma-carcinoma sequence for colorectal cancer?
A1: The progression involves APC mutation → KRAS mutation → p53 mutation leading to transformation of normal mucosa into invasive carcinoma.

Q2: How does chronic H. pylori infection lead to gastric cancer?
A2: Chronic infection causes atrophic gastritis, leading to intestinal metaplasia, dysplasia, and eventually gastric adenocarcinoma.

Q3: What genetic syndromes increase the risk for pancreatic cancer?
A3: Peutz-Jeghers syndrome, Lynch syndrome, BRCA1/2 mutations, and MEN1 all elevate pancreatic cancer risk.

Q4: How often should patients with PSC be screened for cholangiocarcinoma?
A4: Screening with MRCP and CA 19-9 is recommended annually, especially if concurrent ulcerative colitis is present.

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