Lynch syndrome is an autosomal dominant disorder responsible for 2 to 3% of cases of colorectal cancer (1). Symptoms, initial diagnosis, and treatment are similar to other forms of colorectal cancer. Lynch syndrome is suspected by history and is confirmed by genetic testing. Patients also require surveillance for other cancers, particularly endometrial and ovarian cancer. Treatment is surgical resection.
Lynch syndrome is an autosomal dominant disorder in which patients have one of several known genetic mutations that impair DNA mismatch repair. Lynch syndrome confers a 70 to 80% lifetime risk of developing colorectal cancer (CRC) (1).
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, the other main hereditary form of CRC.
However, similar to familial adenomatous polyposis, 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, gallbladder, small bowel, and brain.
General reference
1. Rubenstein JH, Enns R, Heidelbaugh J, et al: American Gastroenterological Association Institute Guideline on the Diagnosis and Management of Lynch Syndrome. Gastroenterology 149(3):777-782, 2015. doi: 10.1053/j.gastro.2015.07.036
Symptoms and Signs of Lynch Syndrome
Symptoms and signs of Lynch syndrome are similar to other forms of colorectal cancer, and diagnosis and management of the tumor itself are generally the same.
Diagnosis of Lynch Syndrome
Detailed family history
Clinical criteria followed by testing for microsatellite instability (MSI) or with immunohistochemistry (IHC)
Genetic testing for confirmation
The specific diagnosis of Lynch syndrome is confirmed by genetic testing. However, deciding who to test is difficult because, unlike familial adenomatous polyposis, there is no typical phenotypic appearance. Thus, suspicion of Lynch syndrome requires a detailed family history, which should be obtained in all younger patients identified with colorectal cancer (CRC).
To meet the Amsterdam II criteria for Lynch syndrome, all three of the following historical elements must be present (1):
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 PREMM5 model) and other criteria (eg, the Bethesda criteria [2]) are used by some health care professionals.
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 American Gastroenterological Association guidelines recommend that tumors of all patients with CRC should be tested either with IHC or for MSI. If MSI or IHC is positive, genetic testing (germline testing) for specific Lynch syndrome mutations is indicated.
Patients with Lynch syndrome should have surveillance colonoscopy every 1 to 2 years. 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 genetic testing. If no genetic testing has been done, they should have colonoscopy every 1 to 2 years beginning in their 20s, and annually after age 40. Female first-degree relatives should be tested annually for endometrial and ovarian cancer.
Diagnosis references
1. Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 116(6):1453–1456, 1999. doi: 10.1016/s0016-5085(99)70510-x
2. 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. doi: 10.1093/jnci/djh034
Treatment of Lynch Syndrome
Surgical resection
The surgical management of Lynch syndrome is based on the predicted lifetime risk of a second colon cancer arising in the same patient at a later date (metachronous disease).
In younger adults, total abdominal colectomy with an ileorectal anastomosis and surveillance of the rectum is often offered. A reasonable alternative is removal of only the part of the colon with the primary tumor (segmental colectomy) with close endoscopic surveillance of the remainder. Often this alternative is used in older adults or in patients with comorbidities that make surgery high risk (1).
Treatment reference
1. Giardiello FM, Allen JI, Axilbund JE, et al: Guidelines on genetic evaluation and management of Lynch syndrome: A consensus statement by the US Multi-society Task Force on colorectal cancer. Am J Gastroenterol 109(8):1159–1179, 2014. doi: 10.1038/ajg.2014.186
Key Points
Certain autosomal dominant mutations confer a 70 to 80% lifetime risk of developing colorectal cancer.
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 colorectal cancer.
Patients with colorectal cancer, particularly those with certain familial risk factors, should have their tumor tissue tested for microsatellite instability or with immunohistochemistry; if positive, genetic testing is done.
Treatment is surgical resection with close endoscopic surveillance of any remaining colorectal mucosa.
First-degree relatives who have not undergone genetic testing should have colonoscopy every 1 to 2 years beginning in their 20s, and annually after age 40; women should also be tested annually for endometrial and ovarian cancer.
More Information
The following English-language resources may be useful. Please note that THE MANUAL is not responsible for the content of these resources.
American Gastroenterological Association: Guidelines for the diagnosis and management of Lynch syndrome (2015)
American College of Gastroenterology: Guidelines for genetic testing and management of hereditary gastrointestinal cancer syndromes (2015)
PREMM5: Prediction model for MLH1, MSH2, MSH6, PMS2, and EPCAM gene mutations
