What are the screening and management recommendations for a patient with a family history of cancer and suspected Lynch syndrome?

Lynch Syndrome: Screening and Management

Universal Tumor Screening for All Colorectal Cancer Patients

All patients diagnosed with colorectal cancer should undergo tumor testing with either immunohistochemistry (IHC) or microsatellite instability (MSI) testing to identify Lynch syndrome, regardless of age or family history. 1 This universal screening approach is strongly recommended because Lynch syndrome accounts for 2-4% of all colorectal cancer cases and can present even in elderly patients, with significant implications for both the patient and their family members. 1

Tumor Testing Algorithm

• Initial tumor testing should use IHC to detect absence of MLH1, MSH2, MSH6, or PMS2 proteins, or MSI testing to identify high microsatellite instability. 1
• If MLH1 protein is absent, proceed with BRAF mutation testing or MLH1 promoter methylation analysis to distinguish Lynch syndrome from sporadic colorectal cancer. 1
• If BRAF is negative or MLH1 promoter is not hypermethylated, or if MSH2, MSH6, or PMS2 are absent, proceed directly to germline genetic testing. 1
• Colorectal cancer patients aged ≤70 years should all undergo Lynch syndrome screening after excluding familial adenomatous polyposis and Peutz-Jeghers syndrome. 1

Clinical Criteria for Suspected Lynch Syndrome

High-Risk Family History Patterns

Families meeting the following criteria should be highly suspected for Lynch syndrome and offered genetic testing: 1

• At least two cases of histologically confirmed colorectal cancer in first-degree relatives (parent-child or siblings), AND any of:
  • At least one case with multiple colorectal cancers including adenomas 1
  • At least one case of colorectal cancer occurring before age 50 1
  • At least one case of Lynch syndrome-related extracolonic malignancy (gastric, endometrial, small intestine, ureteral/renal pelvis, ovarian, hepatobiliary, pancreatic, brain, or sebaceous gland tumors) 1

Amsterdam II Criteria

These stringent criteria identify families with approximately 50% probability of having a mismatch repair gene mutation, but miss up to 68% of Lynch syndrome patients: 1

• Three relatives with Lynch syndrome-associated cancer 1
• One relative is a first-degree relative of the other two 1
• At least two successive generations affected 1
• At least one cancer diagnosed before age 50 1

Bethesda Guidelines (Broader Screening)

• Colorectal cancer diagnosed younger than age 50 1
• Synchronous or metachronous colorectal or Lynch syndrome-associated tumors 1
• Colorectal cancer with MSI-high histology (tumor-infiltrating lymphocytes, Crohn's-like reaction, mucinous/signet-ring differentiation, medullary growth pattern) in patients younger than age 60 1
• Colorectal cancer with family history of Lynch syndrome-associated cancer diagnosed before age 50 1

Risk Prediction Models for Unaffected Individuals

For individuals without personal cancer history but with suggestive family history, risk prediction models (such as PREMM1,2,6) should be offered before proceeding to germline genetic testing. 1 This approach helps avoid unnecessary testing in low-risk individuals, though patients meeting Amsterdam criteria can proceed directly to germline testing. 1

• The PREMM1,2,6 model can be self-administered by patients and quantifies likelihood of carrying germline mutations in MLH1, MSH2, or MSH6. 2
• Individuals with PREMM1,2,6 scores ≥5% should be offered genetic counseling and germline testing. 2
• In community practice implementation, 2.1-10.7% of individuals with scores ≥5% were found to have Lynch syndrome mutations. 2

Surveillance for Confirmed Lynch Syndrome Carriers

Colorectal Surveillance

MLH1 or MSH2 mutation carriers should undergo colonoscopy every 1-2 years starting at age 20-25 years, which reduces colorectal cancer incidence by 62% and mortality. 1, 3

• MSH6 or PMS2 mutation carriers can begin colonoscopy every 1-2 years at age 25-30 years. 1
• Chromoendoscopy should be considered to improve detection of subtle lesions. 3
• When colorectal cancer is diagnosed in Lynch syndrome patients, subtotal colectomy should be considered due to high risk of metachronous cancers. 3

Extracolonic Cancer Surveillance

Women with Lynch syndrome require gynecologic surveillance starting at age 30-35 years: 3

• Annual endometrial sampling and transvaginal ultrasound beginning at age 30-35 years, which detects cancers at earlier stages 3
• Prophylactic hysterectomy and bilateral salpingo-oophorectomy after childbearing shows efficacy in reducing gynecologic cancer risk 3

Additional surveillance recommendations: 3

• Annual urinalysis with cytology beginning at age 25-35 years for urinary tract cancers 3
• Upper endoscopy (esophagogastroduodenoscopy) every 1-2 years for gastric and small intestinal cancer screening, particularly in families with these cancers or those of Asian descent 1, 3
• Annual comprehensive physical examination with review of systems beginning at age 21 years 3

Genetic Testing Strategy

When a Known Family Mutation Exists

If a known MMR or EPCAM mutation exists in the family, test the individual for that specific familial mutation. 1

• Individuals testing positive or those who decline testing should follow full Lynch syndrome surveillance protocols. 1
• Individuals testing negative for the familial mutation are at average risk (not zero risk) and should follow average-risk screening guidelines. 1

Testing Affected Family Members First

When possible, genetic testing should begin with an affected family member, as a negative test is only informative if a mutation has been previously identified in the family. 3

Critical Pitfalls to Avoid

Do not rely solely on family history criteria, as some Lynch syndrome families may not meet Amsterdam or Bethesda criteria due to small family size, early deaths from other causes, or incomplete penetrance. 3

Do not assume a negative genetic test excludes Lynch syndrome if clinical suspicion remains high, as current testing may not detect all mutations or variants of uncertain significance. 3

Do not overlook the possibility of Familial Colorectal Cancer Type X, where approximately 45% of families meeting Amsterdam criteria do not have mismatch repair gene mutations but still have increased colorectal cancer risk (though lower than Lynch syndrome and with fewer extracolonic cancers). 3

Verify family history information whenever possible, as this information is often incomplete or inaccurate and critically determines screening intensity. 4

Do not forget that Lynch syndrome predisposes to multiple cancer types beyond colorectal cancer, including endometrial (most common in women), gastric, ovarian, pancreatic, urethral, brain (glioblastoma), small intestinal, hepatobiliary, and sebaceous gland tumors. 1, 5

Genetic Counseling Requirements

Genetic counseling is essential before and after testing to ensure proper interpretation of results, discuss surveillance and prevention options, and address reproductive considerations to reduce transmission of pathogenic variants to offspring. 6, 7