What is Lynch syndrome and how is it managed?

From the Guidelines

Lynch syndrome is a genetic disorder that significantly increases the risk of various cancers, particularly colorectal cancer, and its management should focus on early detection and prevention through intensive cancer screening, as recommended by the American Gastroenterological Association Institute guideline 1.

Key Points in Management

• Individuals with Lynch syndrome should begin colonoscopy screening every 1-2 years starting at age 20-25 or 2-5 years before the earliest colon cancer diagnosis in the family.
• Women should undergo endometrial sampling and transvaginal ultrasound annually beginning at age 30-35 to screen for endometrial and ovarian cancers.
• Upper endoscopy every 3-5 years starting at age 30-35 is recommended to detect gastric and small bowel cancers.
• Prophylactic surgery, such as total colectomy or hysterectomy with bilateral salpingo-oophorectomy, may be considered for high-risk individuals.
• Daily aspirin (600mg) may reduce colorectal cancer risk, though optimal dosing is still being studied, as indicated by a high-quality randomized controlled trial 1.

Importance of Early Detection and Genetic Counseling

• Regular screening is crucial because Lynch syndrome cancers often develop at younger ages and can progress more rapidly than sporadic cancers, but when detected early, they can be treated effectively.
• Genetic counseling is essential for patients and their families, as first-degree relatives have a 50% chance of carrying the mutation.

Recent Guidelines and Recommendations

• The NCCN guidelines insights: genetic/familial high-risk assessment: colorectal, version 2.2019, provide revised clinical/pathologic criteria to identify Lynch syndrome, including the Amsterdam II criteria and the revised Bethesda criteria 1.
• Urologists should consider routine tissue testing of de novo upper tract urothelial carcinoma tissue in individuals at risk, as Lynch syndrome is a common genetic disease that is an underappreciated cause of upper tract urothelial carcinoma 1.

From the Research

Definition and Prevalence of Lynch Syndrome

• Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is the most common form of hereditary colorectal cancer, accounting for 2% to 7% of all colorectal cancer cases 2.
• It is an autosomal dominant inherited disease caused by germline pathogenic variants in mismatch repair genes, including MLH1, MSH2, MSH6, and PMS2 3.
• The syndrome is associated with a high risk of colorectal, endometrial, ovarian, and urinary tract cancers, as well as other types of cancer, such as stomach, small bowel, hepatobiliary tract, upper uroepithelial tract, and brain cancers 2, 4.

Diagnosis and Screening

• A diagnosis of Lynch syndrome is almost certain when a mutation in a mismatch repair gene is identified 2.
• Universal screening for Lynch syndrome in endometrial cancer patients has yielded positive results for identification of patients at risk for this inherited syndrome 5.
• Screening methods include mismatch repair immunohistochemistry (IHC), microsatellite instability (MSI) testing, MLH1 promoter methylation testing, and gene sequencing 5, 3.
• The effectiveness of endometrial biopsy and transvaginal ultrasound for clinical monitoring of asymptomatic women with Lynch syndrome is uncertain 3.

Management and Prevention

• Once diagnosed, the potential for significant reduction in cancer-related morbidity and mortality through highly targeted surveillance may be profound 2.
• Colonoscopy initiated at an early age (e.g., 25 years) and repeated annually is recommended due to accelerated carcinogenesis 2.
• In women, endometrial aspiration biopsy and transvaginal ultrasound are important given the extraordinarily high risk for endometrial and ovarian carcinoma 2, 6.
• Preventive strategies include hysterectomy and bilateral salpingo-oophorectomy (BSO) as well as chemoprophylaxis using exogenous progestin or aspirin 3.
• Recent research has revealed the benefits of immunotherapy for Lynch syndrome-associated endometrial cancer, with the NCCN guidelines recommending pembrolizumab and nivolumab for treating patients with advanced or recurrent microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) endometrial cancer 3.