Hereditary nonpolyposis colorectal carcinoma (HNPCC) is an autosomal dominant disorder responsible for 3 to 5% of cases of colorectal cancer. Symptoms, initial diagnosis, and treatment are similar to other forms of colorectal cancer. HNPCC is suspected by history and confirmed by genetic testing. Patients also require surveillance for other malignancies, particularly endometrial and ovarian cancer.

Patients with one of several known mutations have a 70 to 80% lifetime risk of developing colorectal cancer (CRC). Compared to sporadic forms of colon cancer, HNPCC occurs at a younger age (mid 40s), and the lesion is more likely to be proximal to the splenic flexure. The precursor lesion is usually a single colonic adenoma, unlike the multiple adenomas present in patients with familial adenomatous polyposis (FAP), the other main hereditary form of CRC.

However, similar to FAP, numerous extracolonic manifestations occur. Nonmalignant disorders include cafe au lait spots, sebaceous gland tumors, and keratoacanthomas. Common associated malignancies include endometrial and ovarian tumors (39% and 9% risk, respectively, by age 70). Patients also have an elevated risk of cancer of the ureter, renal pelvis, stomach, biliary tree, and small bowel.

Symptoms, Signs, and Diagnosis

Symptoms and signs are similar to other forms of colorectal cancer, and diagnosis and management of the tumor itself are the same. The specific diagnosis of HNPCC is confirmed by genetic testing. However, deciding who to test is difficult because (unlike FAP) there is no typical clinical appearance. Thus, suspicion of HNPCC requires a detailed family history, which should be obtained in all younger patients identified with CRC.

To meet the Amsterdam II criteria for HNPCC, all three of the following historical elements must be present: (1) three or more relatives with CRC or an HNPCC-associated malignancy, (2) colorectal cancer involving at least two generations, and (3) at least one case of CRC before age 50.

Patients meeting these criteria should have their tumor tissue tested for a DNA abnormality termed microsatellite instability (MSI). If MSI is present, genetic testing for specific HNPCC mutations is indicated. Other authorities use additional criteria (eg, Bethesda criteria) to initiate MSI testing. If MSI testing is not available locally, the patient should be referred to a center where it is.

Patients with confirmed HNPCC require ongoing screening for other malignancies. For endometrial cancer, annual endometrial aspiration or transvaginal ultrasound is recommended. For ovarian cancer, options include annual transvaginal ultrasound and serum CA 125 levels. Prophylactic hysterectomy and oophorectomy are also an option. Urinalysis may be used to screen for renal tumors.

First-degree relatives of patients with HNPCC should have colonoscopy every 1 to 2 yr beginning in their 20s, and annually after age 40. Female 1st-degree relatives should be tested annually for endometrial and ovarian cancer. More distant blood relatives should have genetic testing; if results are negative, they should have colonoscopy at the frequency for average-risk patients.

Eric J. Szilagy, MD and Asim Farid, MD, FRCS(Edin)
Current Treatment Options in Gastroenterology 2001, 4:275-279
Current Medicine Group LLC ISSN 1092-8472

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