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Familial Adenomatous Polyposis (Lynch syndrome)

Familial Adenomatous Polyposis (Lynch syndrome) and Gastric Cancer Risk: Surveillance and Management

Familial Adenomatous Polyposis (Lynch syndrome), caused by pathogenic variants in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2, or EPCAM), increases the risk of gastric cancer alongside colorectal and endometrial cancers. Below is a synthesis of gastric cancer risk, surveillance strategies, and evidence-based management in LS.

Gastric Cancer Risk in Lynch Syndrome

1. Lifetime Risk:
   • 5–13% for gastric cancer, with higher risks in MLH1 and MSH2 carriers15.
   • Duodenal cancer risk: Up to 7% in MLH1 carriers1.
2. Tumor Characteristics:
   • Intestinal type: 62–79% of LS-associated gastric cancers2.
   • Early-stage detection: ~33% of cases identified via surveillance1.

Risk Stratification

High-Risk Factors	Low-Risk Factors
MLH1 or MSH2 mutations13	MSH6 or PMS2 mutations23
Male sex3	Female sex
First-degree relative with gastric cancer3	No family history of gastric cancer
Age >50 years1	Age <50 years

Surveillance Recommendations

1. Esophagogastroduodenoscopy (EGD):
   • Guideline Variability:
     • European (ESGE): Advises against routine EGD1.
     • German/U.S.: Recommends starting at age 30–35 for high-risk subgroups (MLH1/MSH2 carriers)12.
   • Effectiveness:
     • Early detection: 83% of surveillance-detected cancers are stage Ia-Ib vs. 25% in symptomatic cases2.
     • Resectability: >60% of tumors are resectable at diagnosis1.
2. Frequency:
   • Every 1–3 years if high-risk features are present2.

Management and Outcomes

1. Early Detection:
   • Surgical resection: Standard for localized tumors.
   • Chemotherapy: For advanced/metastatic cases (e.g., cisplatin, 5-FU)1.
2. Prognosis:
   • Survival: Improved with early-stage diagnosis (5-year survival >90% for stage I)1.
   • Competing risks: Mortality from other LS-related cancers (e.g., colorectal) may offset gastric cancer risk1.

Challenges and Future Directions

• Cost-effectiveness: High number of negative EGDs (0.93% yield)2.
• Personalized Surveillance: Focus on MLH1/MSH2 carriers with family history3.

Conclusion
Familial Adenomatous Polyposis (Lynch syndrome) significantly elevates gastric cancer risk, particularly in MLH1/MSH2 carriers. While surveillance guidelines conflict, early EGD in high-risk subgroups improves detection and outcomes.

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References

1. Lancet: Gastric/Duodenal Cancer in LS
2. PMC: Gastric Cancer Risk in LS
3. PMC: Clinical Factors in LS Gastric Cancer
4. AACR: Upper Endoscopic Surveillance
5. Lancet: LS Gastric Cancer Risk