What is the management and treatment approach for Lynch syndrome?

Management and Treatment of Lynch Syndrome

Colorectal Cancer Surveillance

Patients with Lynch syndrome must undergo colonoscopy every 1-2 years starting at age 20-25 years, which reduces colorectal cancer incidence by 62% and mortality by 94%. 1

• Begin surveillance at age 20-25 years, or 2-5 years younger than the youngest family member diagnosed with colorectal cancer, whichever comes first. 1
• For MSH6 mutation carriers specifically, initiate screening at age 30 years due to later onset of cancer risk. 1
• Continue regular surveillance indefinitely with no established upper age limit, though decisions should consider overall health status and life expectancy. 1
• Never extend colonoscopy intervals beyond 2 years, even in older patients, as accelerated carcinogenesis occurs in Lynch syndrome. 1
• Surveillance colonoscopy extends life expectancy by approximately 7 years compared to no surveillance. 1

Aspirin Chemoprevention

Offer aspirin 600 mg daily for at least 2 years for cancer prevention, as this reduces colorectal cancer incidence by 44-60% beyond surveillance alone. 1

• A high-quality randomized controlled trial demonstrated that aspirin 600 mg daily for up to 4 years reduced colorectal cancer incidence with a hazard ratio of 0.65 for all Lynch syndrome-associated cancers. 1
• The protective effect extends beyond colorectal cancer to other Lynch syndrome-associated malignancies. 1
• This intervention should be offered to all Lynch syndrome patients as an adjunct to surveillance. 2

Gynecological Cancer Management

Women with Lynch syndrome should be offered risk-reducing hysterectomy and bilateral salpingo-oophorectomy after childbearing is complete, due to up to 60% lifetime risk of endometrial cancer. 1, 2

Timing of Risk-Reducing Surgery by Gene Type:

• MSH2 or MLH1 carriers: Consider surgery around age 35 years. 2
• MSH6 carriers: Consider surgery after age 40 years. 2
• PMS2 carriers: Lower risk but should still be offered risk-reducing surgery. 2

Pre-Surgical Evaluation:

• Perform preoperative endometrial biopsy and pelvic ultrasound to identify occult cancer, particularly if symptomatic. 2
• Coordinate risk-reducing gynecological surgery with colorectal surveillance (colonoscopy at time of surgery if not up-to-date). 2
• Laparoscopic approach is preferred when possible due to less postoperative pain, quicker recovery, and improved short-term quality of life. 2

Post-Surgical Management:

• Estrogen-only hormone replacement therapy (preferably transdermal) is strongly recommended until natural menopause age (51 years) for women undergoing risk-reducing oophorectomy. 2
• HRT prevents surgical menopause sequelae including vasomotor symptoms, urogenital dryness, sexual dysfunction, cognitive decline, osteoporosis, and cardiovascular disease. 2

Surveillance for Women Not Undergoing Surgery:

• Annual gynecologic examination with endometrial sampling and transvaginal ultrasound starting at age 30-35 years. 1, 2
• Combined oral contraceptive pill recommended for women requiring contraception as it reduces endometrial and ovarian cancer risk. 2

Surgical Management of Colorectal Cancer

Subtotal colectomy should be favored over segmental resection for Lynch syndrome patients who develop colorectal cancer, due to the high risk (16-40%) of metachronous colorectal cancers. 1

• Prophylactic colectomy is not routinely recommended for unaffected Lynch syndrome carriers. 1

Extracolonic Cancer Surveillance

Surveillance for extracolonic cancers should be gene-specific and risk-stratified, with particular attention to gastric and urinary tract cancers in high-risk mutations. 1

• Consider initial screening upper endoscopy with biopsy, particularly in families with gastric cancer history, as lifetime gastric cancer risk ranges from 0.2% to 13% depending on the specific gene mutation. 1
• Annual urinalysis with cytology is a noninvasive means of evaluating the urinary tract, though no data on efficacy is available in this population. 3
• Perform a general examination on a regular basis from the young adult years onward, with focus on careful review of systems and physical examination to elicit any unexplained signs or symptoms (abdominal pain, unexpected vaginal bleeding, skin lesions, adenopathy) that merit further evaluation. 3

Genetic Counseling and Family Testing

First-degree relatives of Lynch syndrome patients should be offered genetic counseling and testing, as they have a 50% chance of carrying the mutation. 1

• Approximately 95% of relatives who receive genetic counseling choose to undergo testing. 1
• Cascade testing of family members is critical for identifying at-risk individuals who can benefit from surveillance. 1

Gene-Specific Cancer Risks

Endometrial Cancer Risk by Gene:

• MSH2 carriers: 57% lifetime risk, 2% cumulative risk at age 40. 2
• MLH1 carriers: 43% lifetime risk, 3% cumulative risk at age 40. 2
• MSH6 carriers: 46% lifetime risk, 0% cumulative risk at age 40. 2

Ovarian Cancer Risk by Gene:

• MSH2 carriers: 17% lifetime risk. 2
• MLH1 carriers: 10% lifetime risk. 2
• MSH6 carriers: 13% lifetime risk. 2

Additional Prevention Strategies

• Maintain healthy body mass index. 2
• Eat a healthy diet and exercise regularly. 2
• Avoid smoking and limit alcohol consumption. 2
• Avoid known carcinogens (e.g., tamoxifen). 2

Critical Pitfalls to Avoid

• Never dismiss new gastrointestinal or genitourinary symptoms as age-related without thorough evaluation given the patient's cancer predisposition. 1
• Delaying risk-reducing surgery beyond recommended age increases cancer risk. 2
• Failure to provide estrogen-only HRT after oophorectomy in premenopausal women can lead to significant quality of life issues and health risks. 2
• Overlooking the need for coordinated care between gynecologic and colorectal specialists. 2
• Underestimating the importance of aspirin chemoprevention as an adjunct to surgical prevention. 2