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Key Features

  • Hereditary nonpolyposis colorectal cancer (Lynch syndrome) is an autosomal dominant condition

  • Markedly increased risk of other cancers besides colorectal cancer, including those of

    • Endometrium

    • Ovary

    • Kidney or bladder

    • Hepatobiliary

    • Stomach

    • Small intestine

  • Accounts for up to 3% of all colorectal cancers

  • Autosomal dominant

  • Caused by a defect in one of several genes

    • MLH1

    • MSH2

    • MSH6

    • PMS2

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

  • Cancer develops at an earlier age (mean, 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

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

Diagnosis

  • Obtain thorough family history of cancer

  • Offer genetic testing to patients whose families fulfill one or more revised Bethesda criteria; these criteria identify > 90% Lynch syndrome families and include familial

    • Colorectal cancer under age 50 years

    • Synchronous or metachronous Lynch syndrome–associated tumors (endometrial, stomach, ovary, pancreas, ureter and renal pelvis, biliary tract, brain) regardless of age

    • Colorectal cancer with more than one first-degree relative with colorectal or Lynch syndrome–related cancer, with one of the cancers occurring in a family member younger than age 50 years

    • Colorectal cancer with more than two second-degree relatives with colorectal cancer or other Lynch syndrome–related cancer, regardless of age

    • Tumors with infiltrating lymphocytes, mucinous/signet ring differentiation, or medullary growth pattern in patients younger than age 60 years

  • Multisociety guidelines recommend that all colorectal cancers should undergo testing for Lynch syndrome with either immunohistochemistry or microsatellite instability

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

  • Germline testing is warranted in families with a strong history consistent with Lynch syndrome when tumors from affected members are unavailable for assessment

Treatment

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

    • Begin at age 25 years or

    • Begin 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 aspiration or transvaginal ultrasound screening for endometrial cancer in women beginning at age 25–35 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

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