Clinical Guidance

EPCAM. The risk for extracolonic cancers is dependent on the size of the deletion. 3' EPCAM deletions have been shown to confer a lower risk for extracolonic cancers, whereas deletions that extend into MSH2 confer extracolonic cancer risks similar to intragenic MSH2 pathogenic variants .

Source: GeneReviews — "Lynch Syndrome"

Penetrance

Penetrance of CRCs and extracolonic cancers associated with pathogenic variants in an MMR gene or EPCAM is less than 100% . Therefore, some individuals with a cancer-predisposing pathogenic variant in an MMR gene or EPCAM may never develop cancer.

Source: GeneReviews — "Lynch Syndrome"

Diagnostic Criteria

No consensus clinical diagnostic criteria for Lynch syndrome have been published.

Suggestive Findings

A diagnosis of Lynch syndrome should be suspected in a proband with:

• A diagnosis of a tumor of the Lynch syndrome spectrum (e.g., colorectal, endometrial, ovarian, stomach, small bowel, urinary tract [urothelial], biliary tract, prostate, brain [usually glioblastoma], skin [sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas], and pancreas) with one of the following on tumor tissue

testing:

Source: GeneReviews — "Lynch Syndrome"

Differential Diagnosis

Hereditary Cancer Syndromes Table 4. Hereditary Cancer Syndromes with Increased Risk of Colorectal Cancer in the Differential Diagnosis of Lynch Syndrome

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Lynch syndrome, the evaluations summarized in are recommended.

Table 6.

Recommended Evaluations Following Initial Diagnosis in Individuals with Lynch Syndrome

System/Concern | Evaluation | Comment

Colorectal cancer

| Colonoscopy w/removal of precancerous polyps1 | Beginning between ages 20 25 yrs or 2-5 yrs before earliest CRC diagnosis in family, whichever is earlier

Endometrial cancer

| Educate females re symptoms of endometrial cancers (e.g., abnormal uterine bleeding, postmenopausal bleeding). | Eval of symptoms should incl endometrial biopsy every 1-2 yrs2

Screening by endometrial biopsy2 | Beginning between ages 30 35 yrs

Ovarian cancer

| Educate females re symptoms assoc w/ovarian cancer (e.g., pelvic or abdominal pain, bloating, abdominal girth, difficulty eating, early satiety, urinary frequency or urgency). | Symptoms that persist for several wks are a change from baseline should prompt eval by physician.

Gastric duodenal

cancers | • Consider upper endoscopy exam esp for those w/family history of gastric cancer those of Asian ancestry.

• Biopsies should be evaluated for H pylori infections so that appropriate treatment can be given as needed.3

| Beginning at age 40 yrs

Distal small bowel

| Consider capsule endoscopy small bowel enterography. | In symptomatic persons

Urinary tract cancers

(renal pelvis, ureter,

Source: GeneReviews — "Lynch Syndrome"

Clinical Guidance

There is accumulating evidence that a high body mass, cigarette smoking, type 2 diabetes, and high cholesterol increase the risk of CRC in Lynch syndrome. The direction and strength of observed associations are similar to those for the general population .

Source: GeneReviews — "Lynch Syndrome"

Therapies Under Investigation

Chromoendoscopy vs narrow band imaging (NBI) vs high-definition white-light colonoscopy for Lynch syndrome surveillance. Two studies compared different colonoscopy imaging modalities against chromoendoscopy. In a study of 138 individuals with Lynch syndrome undergoing back-to-back colonoscopies (first with NBI followed by indigo carmine chromoendoscopy), the adenoma detection rate (ADR) for NBI alone was 20.3% while the ADR for both was 30.4%. A 10.1% difference in detection failed to reach the prespecified noninferiority assumption margin of 5% . In another study of 256 individuals with Lynch syndrome randomized to indigo carmine chromoendoscopy versus high-definition white-light colonoscopy, no significant difference in ADR was detected by pancolonic chromoendoscpy (34.4%; 95% CI 26.

Source: GeneReviews — "Lynch Syndrome"

Surveillance Guidelines

Table 8. Recommended Surveillance for Individuals with Lynch Syndrome

Source: GeneReviews — "Lynch Syndrome"