What are the indications for genetic testing and the recommended surveillance protocol for a patient with suspected Lynch syndrome (hereditary non‑polyposis colorectal cancer)?

Lynch Syndrome: Indications for Genetic Testing and Surveillance Protocol

All patients with newly diagnosed colorectal cancer should undergo universal tumor screening for Lynch syndrome using microsatellite instability (MSI) testing or immunohistochemistry (IHC) for mismatch repair proteins, followed by germline genetic testing when tumor screening is abnormal, and mutation carriers require colonoscopy every 1-2 years starting at age 20-25 with additional surveillance for extracolonic cancers. 1, 2

Indications for Genetic Testing

Universal Tumor Screening Approach (Preferred Strategy)

The NCCN recommends screening all patients with colorectal cancer for Lynch syndrome as of 2016, representing a shift from selective criteria-based testing. 1

• Tumor tissue testing should be performed first using either MSI testing or IHC for MLH1, MSH2, MSH6, and PMS2 proteins 1
• MSI testing has 80-91% sensitivity for MLH1/MSH2 mutations and 55-77% sensitivity for MSH6/PMS2 mutations, with 90% specificity 1
• IHC testing has 83% sensitivity regardless of gene involved, with 89% specificity 1
• Either test may be used initially; if results are normal but Lynch syndrome is strongly suspected, the other test should be performed 1

Follow-up Testing Algorithm

When tumor screening is abnormal, the next steps depend on the specific pattern:

• If MLH1 is absent by IHC: Perform BRAF V600E mutation testing and/or MLH1 promoter hypermethylation testing on tumor tissue 1

  • BRAF mutation or MLH1 hypermethylation indicates sporadic cancer (not Lynch syndrome) 1
  • If both are negative, proceed to germline MLH1 testing 1

• If MSH2 is absent by IHC: Proceed directly to germline testing for MSH2 and EPCAM deletions 1

• If MSH6 or PMS2 is absent: Proceed to germline testing for the corresponding gene 1

Clinical Criteria-Based Testing (Alternative When Universal Screening Unavailable)

Bethesda Guidelines (broader criteria than Amsterdam II): 1

• Colorectal cancer diagnosed before age 50 years
• Synchronous or metachronous colorectal or Lynch syndrome-associated cancers
• Colorectal cancer with MSI-high histology (tumor-infiltrating lymphocytes, Crohn's-like reaction, mucinous differentiation) before age 60 years
• Colorectal cancer with family history of Lynch syndrome-associated cancer

Amsterdam II Criteria (more stringent, misses 68% of Lynch syndrome cases): 1

• Three relatives with Lynch syndrome-associated cancer (colorectal, endometrial, small bowel, ureter, renal pelvis)
• One relative is first-degree relative of the other two
• At least two successive generations affected
• At least one cancer diagnosed before age 50 years

Germline Genetic Testing

• Test for mutations in MLH1, MSH2, MSH6, PMS2, and EPCAM genes 1
• Multigene panels that include additional hereditary cancer genes may be used 1
• Confirm that testing includes large rearrangements and deletions, not just point mutations 1
• If a known familial mutation exists, test directly for that specific mutation 1

Surveillance Protocol for Confirmed Lynch Syndrome

Colorectal Cancer Surveillance

Colonoscopy every 1-2 years starting at age 20-25 years (or 10 years younger than earliest family diagnosis, whichever comes first) and continued throughout life. 1, 2, 3

• The 1-2 year interval is critical due to accelerated adenoma-to-carcinoma progression (approximately 35 months vs. 10-15 years in sporadic cases) 3, 4
• Colonoscopic surveillance reduces colorectal cancer incidence by 62-77% and mortality by 72-94% 1, 3
• Complete colonoscopy is mandatory as approximately 70% of Lynch syndrome colorectal cancers occur proximal to the splenic flexure 3, 4
• Consider chromoendoscopy with indigo carmine or methylene blue to improve detection of subtle lesions 2

Gynecological Cancer Surveillance (Women)

Annual gynecological examination with endometrial sampling and transvaginal ultrasound starting at age 30-35 years. 2, 3

• Endometrial biopsy is the primary screening method (transvaginal ultrasound alone has limited sensitivity) 2
• Lifetime endometrial cancer risk is 25-60% in women with Lynch syndrome 3, 4
• If endometrial biopsy yields insufficient samples, repeat promptly 2
• Educate patients to report any abnormal uterine bleeding or postmenopausal bleeding immediately 2

Risk-Reducing Surgery

Prophylactic hysterectomy with bilateral salpingo-oophorectomy should be discussed after childbearing is complete. 2, 3

• This effectively prevents endometrial and ovarian cancers in Lynch syndrome carriers 2
• Timing varies by gene mutation: 2
  • MLH1 carriers: Consider at age 40 years due to higher early cancer risk
  • MSH2 and MSH6 carriers: Similar timing to MLH1
  • PMS2 carriers: May defer until age 50 years due to more modest risk elevation
• Estrogen-only hormone replacement therapy until natural menopause age (~51 years) is strongly recommended following prophylactic oophorectomy 2
• Hysterectomy without oophorectomy is inadequate due to elevated ovarian cancer risk 2

Extracolonic Cancer Surveillance

Upper gastrointestinal surveillance (esophagogastroduodenoscopy with gastric biopsy): 2, 3

• Consider starting at age 30-35 years at 1-2 year intervals
• Particularly important for MSH2 mutation carriers or those with family history of gastric cancer

Urinary tract surveillance: 2, 3, 4

• At minimum, routine urinalysis using ≥3 red blood cells per high-power field as trigger for further evaluation
• Lifetime risk for upper tract urothelial carcinoma is 2.9-28% 3, 4
• Consider annual urinalysis with cytology and renal ultrasound starting at age 30-35 years

Chemoprevention

Aspirin 600 mg daily is strongly recommended for cancer prevention. 3

• Reduces colorectal cancer incidence by 44% beyond colonoscopy surveillance alone 3
• Discuss individualized bleeding risks and cardiovascular benefits 3
• Consider enrollment in clinical trials such as CaPP3 2

Combined oral contraceptives or progestin-only methods may provide protection against endometrial cancer in women, though evidence is limited 2

Gene-Specific Risk Stratification

Cancer risks vary by specific mismatch repair gene mutation: 3

• MLH1 and MSH2: Highest penetrance for both colorectal (up to 80%) and endometrial cancer (up to 60%) 3, 5
• MSH2: Higher risk for extracolonic cancers, particularly urinary tract cancers 3, 4
• MSH6: Later onset of cancers, accounts for 7-10% of Lynch syndrome families 3, 5
• PMS2: Lower lifetime colorectal cancer risk, accounts for <5% of Lynch syndrome families 3, 5
• EPCAM deletions: Lead to MSH2 silencing 1, 5

Family Management

Genetic counseling and testing should be offered to all first-degree relatives of confirmed Lynch syndrome patients. 3

• First-degree relatives have 50% chance of carrying the same mutation due to autosomal dominant inheritance 3
• Approximately 95% of relatives who receive counseling choose to undergo genetic testing 2
• Relatives who test negative for the familial mutation are at average risk for colorectal cancer 1

Critical Pitfalls to Avoid

• Do not rely solely on family history criteria (Amsterdam II or Bethesda) as they miss many Lynch syndrome cases; universal tumor screening is superior 1, 3
• Do not dismiss new gastrointestinal or genitourinary symptoms as age-related without thorough evaluation in Lynch syndrome patients 3
• Do not perform hysterectomy without bilateral salpingo-oophorectomy in Lynch syndrome carriers due to ovarian cancer risk 2
• Do not recommend prophylactic surgery based solely on family history without genetic testing confirmation 2
• Ensure genetic testing includes large rearrangements and deletions, not just sequencing for point mutations 1
• Do not use transvaginal ultrasound alone for endometrial cancer screening; endometrial biopsy is required 2