What are the recommended genetic testing and lifelong cancer surveillance strategies for a patient suspected of having Lynch syndrome, including colonoscopy, endometrial, upper gastrointestinal, dermatologic, and urinary screening?

Lynch Syndrome: Genetic Testing and Lifelong Cancer Surveillance

All patients with suspected Lynch syndrome should undergo tumor testing with microsatellite instability (MSI) or immunohistochemistry (IHC) followed by germline genetic testing for mismatch repair gene mutations, with confirmed carriers requiring colonoscopy every 1-2 years starting at age 20-25, annual gynecologic surveillance from age 30-35, and consideration of aspirin chemoprevention and risk-reducing surgery. 1

Genetic Testing Strategy

Initial Tumor Testing

• Begin with tumor tissue analysis using either MSI testing or IHC staining for MLH1, MSH2, MSH6, and PMS2 proteins in all patients with colorectal cancer diagnosed under age 50, or those meeting revised Bethesda guidelines 2
• IHC testing demonstrates 83% sensitivity with 89% specificity for identifying Lynch syndrome regardless of the MMR gene involved 2
• MSI testing shows 80-91% sensitivity for MLH1/MSH2 mutations but only 55-77% sensitivity for MSH6/PMS2 mutations, with 90% specificity 2

Second-Step Testing for MLH1 Loss

• When IHC shows absent MLH1 staining, perform BRAF V600E mutation testing or MLH1 promoter hypermethylation analysis before proceeding to germline testing 2
• BRAF mutations occur in 68% of sporadic colorectal cancers but are virtually absent in Lynch syndrome, making this an efficient triage strategy 2
• This approach reduces unnecessary germline testing costs and patient anxiety, though it may miss up to 10% of Lynch syndrome cases 2

Germline Genetic Testing

• Full germline testing must include both DNA sequencing and large deletion/rearrangement analysis of MLH1, MSH2, MSH6, PMS2, and EPCAM 2
• Approximately 80% of mutations occur in MLH1 and MSH2, 10-12% in MSH6, and 2-3% in PMS2 2
• EPCAM deletions affecting the 3' end can cause MSH2 deficiency and should be included in screening protocols 3, 4
• Current detection methods identify approximately 84% of Lynch syndrome cases, with PMS2 mutations being the most challenging to detect 2

Colorectal Cancer Surveillance

Colonoscopy Protocol

• Start colonoscopy at age 20-25 years (or 5 years before the youngest family member's diagnosis, whichever is earlier) and repeat every 1-2 years throughout life 2, 1
• The 1-2 year interval is non-negotiable, as surveillance colonoscopy reduces colorectal cancer burden by 77% and decreases mortality by 94% 1
• Complete colonoscopy to the cecum is mandatory because approximately 70% of Lynch syndrome colorectal cancers occur proximal to the splenic flexure 1
• No specific upper age limit exists; continue surveillance based on individual health status 2

Gene-Specific Considerations

• MLH1 mutation carriers face higher risk of young-onset colorectal cancer 2
• MSH2 carriers have elevated risk of extracolonic cancers 2
• MSH6 carriers typically develop cancers at later ages 1
• PMS2 carriers show lower lifetime colorectal cancer risk (15-20%) compared to other mutation carriers 2

Gynecologic Cancer Surveillance

Endometrial and Ovarian Screening

• Begin annual surveillance at age 30-35 years with gynecologic examination, transvaginal pelvic ultrasound, CA-125 analysis, and endometrial aspiration biopsy 2
• Women with Lynch syndrome face 30-60% lifetime risk of endometrial cancer and 4-24% lifetime risk of ovarian cancer 5, 1
• If endometrial biopsy yields insufficient tissue, repeat the procedure immediately as insufficient samples cannot fulfill surveillance requirements for detecting early malignancy 5
• Consider hysteroscopy with directed biopsy if multiple insufficient samples occur, as this provides highest diagnostic accuracy 5

Prophylactic Surgery

• Strongly recommend prophylactic hysterectomy and bilateral salpingo-oophorectomy after age 35 and completion of childbearing 2, 1
• Retrospective data show 0% gynecologic cancer incidence in women who underwent prophylactic surgery versus 33% endometrial cancer and 5% ovarian cancer in those who did not 2
• This eliminates the need for ongoing endometrial surveillance and significantly reduces cancer risk 5, 1

Upper Gastrointestinal Surveillance

EGD Screening Indications

• Consider EGD starting at age 30-35 years and repeated every 2-3 years for MLH1, MSH2, or EPCAM mutation carriers, particularly those of Asian descent or with family history of gastric cancer 1, 6
• Gastric cancer risk varies dramatically by geography: 2-4% in Western populations versus 30% in Korean populations 6
• Extend EGD to the distal duodenum or jejunum given elevated risk of small intestinal cancers (lifetime risk 5-15%) 2, 6

H. pylori Management

• Test for H. pylori during initial EGD and treat if positive, as eradication reduces gastric cancer risk by 32% and mortality by 33% 6
• Confirm eradication after treatment due to high failure rates, particularly in Asian populations with higher prevalence of CYP2C19 poor metabolizer genotypes 6

Urinary Tract Surveillance

Screening Approach

• Perform abdominal ultrasound with urine cytology every 1-2 years starting at age 30-35 years, particularly for MSH2 mutation carriers 2
• Lifetime risk of upper urinary tract cancers ranges from 2.9-28%, with MSH2 carriers at highest risk 1
• Base surveillance intensity on family history rather than routine universal screening 1
• Maintain high clinical suspicion for hematuria or urinary symptoms, as these warrant immediate evaluation beyond scheduled surveillance 1

Dermatologic Surveillance

Sebaceous Neoplasm Screening

• Examine for sebaceous gland adenomas and keratoacanthomas annually, particularly in MSH2 and MLH1 mutation carriers 2
• These lesions characterize Muir-Torre syndrome, a variant of Lynch syndrome 2
• Refer suspicious lesions for biopsy and histopathologic confirmation 2

Aspirin Chemoprevention

Evidence-Based Recommendation

• Offer aspirin 600 mg daily for cancer prevention after individualized discussion of bleeding risks and cardiovascular benefits 2, 1
• High-quality randomized controlled trial demonstrates aspirin reduces colorectal cancer incidence by 44% beyond colonoscopy surveillance alone 1
• This represents the only evidence-based chemoprevention strategy; resistant starch showed no benefit 2

Critical Pitfalls to Avoid

Common Errors

• Do not rely solely on Amsterdam II criteria or family history to exclude patients from genetic testing, as these criteria demonstrate poor sensitivity for identifying Lynch syndrome 2
• Never dismiss new gastrointestinal or genitourinary symptoms as age-related without thorough evaluation in confirmed Lynch syndrome patients 1
• Do not perform prophylactic colectomy in healthy mutation carriers, as no data support this approach 2
• Avoid using transvaginal ultrasound alone for endometrial surveillance, as it has limited sensitivity for detecting early endometrial cancer and should not replace biopsy 5

Surgical Considerations for Diagnosed Cancer

• When colorectal cancer is diagnosed, discuss subtotal colectomy versus segmental resection given 16% risk of metachronous colorectal cancer within 10 years, especially in young patients 2, 1

Family Management

Cascade Testing

• Offer genetic counseling and testing to all first-degree relatives of confirmed Lynch syndrome patients, as they have 50% chance of carrying the same mutation due to autosomal dominant inheritance 2, 1
• Provide educational materials explaining potential benefits and harms of genetic testing to facilitate informed decision-making 2
• Establish protocols for contacting, educating, testing, and following relatives with Lynch syndrome 2