What is the management and prevention of Lynch syndrome?

Management and Prevention of Lynch Syndrome

The management of Lynch syndrome requires a comprehensive surveillance program including colonoscopy every 1-2 years starting at age 20-25, annual gynecologic examination with endometrial sampling for women, and consideration of prophylactic surgery for those at high risk. 1

Genetic Basis and Cancer Risk

• Lynch syndrome is an autosomal dominant disorder caused by pathogenic variants in DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) or deletions in the EPCAM gene, which significantly increases cancer risk 1, 2
• MLH1 and MSH2 mutations account for approximately 90% of detected mutations in affected families 3
• MSH2 mutation carriers have the highest cancer risks across the spectrum, especially for urinary tract cancers 1, 3
• MSH6 mutation carriers have increased risk of endometrial cancer and gastrointestinal cancers 3
• PMS2 mutation carriers show lower lifetime risk of colorectal and endometrial cancer (15-20%) compared to other mutation carriers 3

Cancer Risk Profile

• Colorectal cancer: 25-70% lifetime risk (varies by specific gene mutation) 1, 2
• Endometrial cancer: 30-60% lifetime risk in women 1, 2
• Ovarian cancer: up to 24% lifetime risk in women 4
• Other increased risks include gastric, small intestinal, pancreatic, urinary tract, biliary tract, and brain cancers 1, 2

Colorectal Cancer Surveillance and Prevention

• Colonoscopy every 1-2 years beginning at age 20-25 or 2-5 years younger than the youngest diagnosis in the family, whichever comes first 1
  • For MSH6 mutation carriers, colonoscopy can begin at age 30 1
• Colonoscopic surveillance reduces colorectal cancer incidence by 62% and mortality in Lynch syndrome 1, 2
• Daily aspirin may reduce cancer risk, though optimal dosing remains under investigation 1, 2
• For individuals who develop colorectal cancer, subtotal colectomy should be considered due to the high risk of metachronous colorectal cancers 1

Gynecological Cancer Surveillance and Prevention

• Annual gynecologic examination with endometrial sampling and transvaginal ultrasound starting at age 30-35 years 1
• Risk-reducing total abdominal hysterectomy and bilateral salpingo-oophorectomy should be offered to women who have completed childbearing 1
• Prophylactic gynecologic surgery has been shown to be highly effective, with no endometrial or ovarian cancers developing in women who underwent the procedure 1, 4

Surveillance for Other Lynch-Associated Cancers

• Annual urinalysis with cytology beginning at age 25-35 years for urinary tract cancer screening 1, 2
• Consider upper endoscopy with extended duodenoscopy every 3-5 years beginning at age 30-35 years for gastric and small bowel cancer screening 1
• Annual physical examination, review of systems, and education about Lynch syndrome-associated cancer symptoms beginning at age 21 years 1

Diagnostic Testing Strategy

• Universal screening of all colorectal cancers for Lynch syndrome is recommended using immunohistochemistry (IHC) or microsatellite instability (MSI) testing 1
• BRAF V600E mutation testing is recommended, as BRAF mutations are rare or absent in Lynch syndrome tumors 3
• Germline genetic testing should be performed to identify pathogenic variants in MMR genes 2
• Cascade testing should be offered to at-risk relatives of individuals with confirmed Lynch syndrome 2

Special Clinical Considerations

• Lynch syndrome colorectal cancers have more rapid adenoma-to-carcinoma progression (approximately 35 months vs. 10-15 years in sporadic cases) 2
• Lynch syndrome colorectal cancers have better stage-for-stage survival compared to sporadic colorectal cancer 2
• Turcot syndrome refers to patients with MMR gene mutations and brain tumors 3
• Muir-Torre syndrome refers to patients with cutaneous gland tumors, including keratoacanthomas and sebaceous adenomas 3

Genetic Counseling

• Genetic counseling is essential for understanding inheritance patterns, risk assessment, and management options 2
• Despite guidelines recommending universal screening, genetic testing remains underutilized among those with colorectal or endometrial cancer 5
• Early identification of Lynch syndrome allows for implementation of appropriate surveillance strategies that can significantly reduce morbidity and mortality 3