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

Patients with one of several known mutations have a 70 to 80% lifetime risk of developing 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―see Tumors of the GI Tract: Familial Adenomatous Polyposis), the other main hereditary form of CRC.

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

Symptoms and Signs

Symptoms and signs are similar to other forms of CRC, 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.

Diagnosis

• Clinical criteria followed by testing for microsatellite instability (MSI)
• Genetic testing for confirmation

To meet the Amsterdam II criteria for HNPCC, all three of the following historical elements must be present:

• Three or more relatives with CRC or an HNPCC-associated cancer
• CRC involving at least two generations
• At least one case of CRC before age 50

Patients meeting these criteria should have their tumor tissue tested for MSI, a DNA abnormality. 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 an appropriate center.

Patients with confirmed HNPCC require ongoing screening for other cancers. 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 options. 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.

Treatment

• Surgical resection

The most common treatment is resection of the index lesion with frequent surveillance for another colon cancer and any associated tumors in other organs. Because most HNPCC tumors occur proximal to the splenic flexure, subtotal colectomy, leaving the rectosigmoid intact, has been suggested as an alternative. In either case, close follow-up is needed.

Key Points

• Certain autosomal dominant mutations confer a 70 to 80% lifetime risk of developing colorectal cancer (CRC).
• Patients also have an increased risk of other cancers, particularly of the endometrium and ovary.
• Symptoms, initial diagnosis, and treatment are similar to other forms of CRC.
• Patients with certain familial risk factors should have their tumor tissue tested for microsatellite instability (MSI), a DNA abnormality; if MSI is present, genetic testing is done.
• First-degree relatives should have colonoscopy every 1 to 2 yr beginning in their 20s, and annually after age 40; women should also be tested annually for endometrial and ovarian cancer.
• More distant relatives should have genetic testing.

Last full review/revision October 2012 by Elliot M. Livstone, MD