How is Lynch syndrome diagnosed?

Diagnosis of Lynch Syndrome

Lynch syndrome is diagnosed through a combination of clinical criteria, tumor testing, and genetic testing, with universal screening of all colorectal and endometrial cancers now recommended as the primary strategy for identifying affected individuals.

Clinical Criteria for Suspecting Lynch Syndrome

• Amsterdam II criteria include: 3 relatives with Lynch syndrome-associated cancers (colorectal, endometrial, small bowel, ureter, renal pelvis), with one being a first-degree relative of the other two, at least 2 successive generations affected, at least 1 cancer diagnosed before age 50, and familial adenomatous polyposis excluded 1

• Revised Bethesda criteria include: colorectal cancer diagnosed before age 50, synchronous or metachronous Lynch syndrome-associated tumors, colorectal cancer with microsatellite instability-high histology diagnosed before age 60, colorectal cancer in a patient with family history of Lynch syndrome-associated cancer diagnosed before age 50, or colorectal cancer in multiple relatives with Lynch syndrome-associated cancer regardless of age 1

• Consider Lynch syndrome when upper tract urothelial carcinoma presents before age 60 1

• Consider Lynch syndrome when patient meets the "3-2-1 rule": 3 affected relatives, across 2 generations, with 1 diagnosed before age 50 2

Diagnostic Testing Algorithm

For Patients with Colorectal or Endometrial Cancer:

1. Universal tumor screening of all colorectal and endometrial cancers regardless of age 1:

   • Immunohistochemistry (IHC) testing for mismatch repair proteins (MLH1, MSH2, MSH6, PMS2)
   • AND/OR microsatellite instability (MSI) testing

2. For tumors with abnormal screening results:

   • If MLH1/PMS2 proteins are absent: Test for BRAF mutation or MLH1 promoter hypermethylation 1

     • If BRAF mutation present or MLH1 promoter hypermethylated: Likely sporadic cancer
     • If BRAF negative or MLH1 promoter not hypermethylated: Proceed to germline genetic testing

   • If MSH2/MSH6 or PMS2 proteins are absent (with MLH1 present), or isolated loss of MSH6: Proceed directly to germline genetic testing 1

3. Germline genetic testing for mutations in MLH1, MSH2, MSH6, PMS2, or EPCAM genes confirms the diagnosis 1, 2

For Patients Without Cancer but with Family History Suggestive of Lynch Syndrome:

1. If a first-degree relative has a known Lynch syndrome mutation:

   • Offer germline genetic testing for that specific mutation 1

2. If no known mutation in the family:

   • Use risk prediction models (PREMM1,2,6 or MMRpro) to estimate probability of Lynch syndrome 1
   • If probability >5%: Offer germline genetic testing 1
   • If tumor tissue from an affected relative is available: Begin with tumor testing as described above 1

Key Features of Lynch Syndrome

• Autosomal dominant inheritance pattern caused by germline mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2) or deletions in EPCAM 2, 3

• Associated with high lifetime risk of multiple cancers:

  • Colorectal cancer (22-80%)
  • Endometrial cancer (up to 60% in women)
  • Upper tract urothelial carcinoma (2.9-28%)
  • Gastric, small intestinal, pancreatic, biliary tract, ovarian, and brain tumors 1, 2

• Lynch syndrome colorectal cancers have distinct features:

  • Earlier age of onset than sporadic cases
  • More rapid adenoma-to-carcinoma progression (approximately 35 months vs. 10-15 years)
  • Often poorly differentiated with lymphoid host response
  • Better stage-for-stage survival compared to sporadic colorectal cancer 2

Common Pitfalls in Lynch Syndrome Diagnosis

• Relying solely on family history criteria (Amsterdam or Bethesda) misses many Lynch syndrome cases, as these criteria have limited sensitivity 1

• Approximately 10-15% of sporadic colorectal cancers demonstrate microsatellite instability, so additional testing (BRAF mutation or MLH1 promoter methylation) is needed to distinguish these from Lynch syndrome 1

• Normal tumor studies in non-colorectal or non-Lynch syndrome-associated cancers do not necessarily exclude Lynch syndrome; colorectal or endometrial tumor tissue is preferred for evaluation 1

• Most Lynch syndrome kindreds remain undiagnosed, with estimates suggesting only 5% of affected individuals are aware of their diagnosis 3

• Approximately 10% of Lynch syndrome colorectal cancers show intact mismatch repair protein staining on IHC, so clinical judgment should be used when interpreting results 1

Implications of Diagnosis

• Once diagnosed, surveillance colonoscopy should begin at age 20-25 and continue every 1-2 years, reducing colorectal cancer risk by 77% 1, 2

• Women with Lynch syndrome should undergo endometrial sampling and transvaginal ultrasound annually beginning at age 30-35 4

• Daily aspirin (600mg) may decrease colorectal cancer risk by 44%, though optimal dosage is not established 1, 2

• Genetic counseling is essential for affected individuals and their families, as first-degree relatives have a 50% risk of carrying the mutation 1, 3