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Lynch Syndrome

(Hereditary Nonpolyposis Colorectal Carcinoma [HNPCC]))

By Elliot M. Livstone, MD, Emeritus Staff, Sarasota Memorial Hospital, Sarasota, FL

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Lynch syndrome is an autosomal dominant disorder responsible for 2 to 3% of cases of colorectal cancer (CRC). Symptoms, initial diagnosis, and treatment are similar to other forms of CRC. Lynch syndrome is suspected by history and is confirmed by genetic testing. Patients also require surveillance for other cancer, particularly endometrial and ovarian cancer.

Lynch syndrome is an autosomal dominant disorder in which patients with one of several known genetic mutations that impair DNA mismatch repair have a 70 to 80% lifetime risk of developing CRC. Compared to sporadic forms of colon cancer, Lynch syndrome 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 café-au-lait spots and sebaceous gland tumors. The low-grade skin cancer, keratoacanthoma, can occur. Other common associated cancers include endometrial tumors and ovarian tumors (39% risk of endometrial and 9% risk of ovarian by age 70). Patients also have an elevated risk of other cancers, including of the stomach, urinary tract, pancreas, biliary tree, small bowel, and brain.

Symptoms and Signs

Symptoms and signs of Lynch syndrome are similar to other forms of CRC, and diagnosis and management of the tumor itself are the same.

Diagnosis

  • Detailed family history

  • Clinical criteria followed by testing for microsatellite instability (MSI) or with immunohistochemistry (IHC)

  • Genetic testing for confirmation

(See also the 2016 American Gastroenterological Association's guideline regarding diagnosis and management of Lynch syndrome.)

The specific diagnosis of Lynch syndrome is confirmed by genetic testing. However, deciding who to test is difficult because, unlike FAP, there is no typical clinical appearance. Thus, suspicion of Lynch syndrome requires a detailed family history, which should be obtained in all younger patients identified with CRC.

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

  • Three or more relatives with CRC or a Lynch syndrome–associated cancer

  • CRC involving at least two generations

  • At least one case of CRC before age 50

Other prediction models (eg, the PREMM model) and other criteria (eg, the Bethesda criteria [1]) are used by some health care practitioners.

Patients meeting these criteria should have their tumor tissue tested either for MSI or with IHC to detect proteins responsible for DNA mismatch repair; however, most commercial and hospital pathology laboratories now routinely do this test on all colorectal adenocarcinoma specimens. The 2015 AGA guidelines recommend that tumors of all patients with CRC should be tested either with IHC or for MSI (2). If MSI or IHC is positive, genetic testing for specific Lynch syndrome mutations is indicated.

Patients with Lynch syndrome should have a surveillance colonoscopy every 1 to 2 yr (2). Patients with confirmed Lynch syndrome 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 Lynch syndrome 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.

Diagnosis references

  • 1. Umar A, Boland CR, Terdiman JP, et al: Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96(4): 261–268, 2004.

  • 2. Rubenstein JH, Enns R, Heidelbaugh J, et al: American Gastroenterological Association Institute guideline on the diagnosis and management of Lynch syndrome. Gastroenterology 149:777-782, 2015. doi: 10.1053/j.gastro.2015.07.036.

Treatment

  • Surgical resection

The most common Lynch syndrome treatment is resection of the index lesion with frequent surveillance for another colon cancer and any associated tumors in other organs. Because most Lynch syndrome 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) or with immunohistochemistry (IHC); if positive, 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.

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