Lynch Syndrome

Key Features

• Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, is an autosomal dominant condition

• Besides colorectal cancer, there is a markedly increased risk of other cancers, including cancers of

  • Endometrium

  • Ovary

  • Kidney or bladder

  • Liver and biliary tree

  • Stomach

  • Small intestine

• Accounts for up to 3% of all colorectal cancers

• Caused by a defect in one of several genes

  • MLH1

  • MSH2

  • MSH6

  • PMS2

  • EPCAM, a promoter for MSH2

• Associated with a 22–75% lifetime risk of colorectal carcinoma and a 30–60% lifetime risk of endometrial cancer

• Cancer develops at an earlier age (mean age 45–50 years) than sporadic nonhereditary cancers

• Associated with markedly improved survival compared with sporadic colorectal cancers

Clinical Findings

• Few colonic adenomas; adenomas flat, and more often contain villous features or high-grade dysplasia

• Polyps undergo rapid transformation from normal tissue into cancer (1–2 years instead of over 10 years)

• Synchronous or metachronous cancers within 10 years occur in up to 45% of patients

Diagnosis

• Genetic evaluation is recommended for those with a personal or family history of colorectal cancer under age 50, a history of multiple family members with cancer, or a > 5% PREMM5 model-predicted chance of Lynch syndrome

• Because personal and family history alone are insufficient to identify a significant proportion of patients with Lynch syndrome, the National Comprehensive Cancer Network recommends that all colorectal cancers should undergo testing for Lynch syndrome

• Universal testing has the greatest sensitivity for the diagnosis of Lynch syndrome and is cost-effective

• Individuals whose tumors have normal immunohistochemical staining or do not have microsatellite instability

  • Are unlikely to have germline mutations in mismatch repair genes

  • Do not require further genetic testing

  • Do not require intensive cancer surveillance

• Germline testing for gene mutations is positive in > 90% of individuals whose cancers show absent histochemical staining of one of the mismatch repair genes or high level of microsatellite instability without a BRAF mutation

Treatment

• If genetic testing documents a Lynch syndrome gene mutation, then affected relatives should be screened with colonoscopy every 1–2 years

  • Beginning at age 25 years or

  • Beginning at 5 years younger than the age of the family member in whom cancer was first diagnosed

• Subtotal colectomy with ileorectal anastomosis if cancer is found (followed by annual surveillance of the rectal stump)

• Endometrial and ovarian cancer screening with pelvic examination, transvaginal ultrasound, and endometrial sampling in women beginning at age 30–35 years

• Consider prophylactic hysterectomy and oophorectomy in women at age 40 or once they have finished childbearing

• Consider screening for gastric cancer with upper endoscopy every 2–3 years beginning at age 30–35 years