Lynch syndrome

Disease Description (Causes and Symptoms)

• Definition summary: Lynch syndrome is an autosomal dominant hereditary cancer syndrome caused mainly by pathogenic variants in DNA mismatch repair (MMR) genes such as MLH1, MSH2, MSH6, and PMS2. It greatly increases the risk of cancer in multiple organs, including colorectal, endometrial, and ovarian cancers.
• Causes and pathophysiology: Genetic variants in MMR genes allow errors that occur during DNA replication, such as small insertions and deletions (microsatellite instability, MSI), to accumulate, promoting tumor formation. The distribution of associated cancer risks differs depending on the type of gene variant (for example, the risk of urinary tract cancers is increased with MSH2-associated disease).
• Main symptoms (clinical manifestations):
  • Colorectal cancer: Often occurs in the right colon and at a relatively young age (on average, in the early 40s). Symptoms may include bleeding, abdominal pain, intestinal obstruction, and a palpable mass. Histologically, poorly differentiated and mucinous features and increased lymphocytic infiltration are common.
  • Endometrial and ovarian cancer (especially in female patients): Vaginal bleeding, menstrual abnormalities, and other symptoms.
  • Other associated cancers: Gastric cancer, small-intestinal cancer, biliary tract cancer, cancers of the renal pelvis and ureter and other urinary tract cancers, skin cancer, and nervous system cancers.
• Epidemiology summary: Approximately 2–5% of all colorectal cancers are associated with Lynch syndrome, and the lifetime risk of colorectal cancer in people who carry the gene is considerably high (70–90% in the literature); the risk of endometrial cancer in women is also high (approximately 40–50%).

Treatment Methods

• Confirmatory diagnosis and surveillance strategy: Immunohistochemistry (IHC) testing for MMR proteins and microsatellite instability (MSI) testing of tumor tissue, followed ultimately by genetic testing of genes such as MLH1, MSH2, MSH6, PMS2, and EPCAM in blood (or normal tissue), are standard for genetic diagnosis. Familial criteria (for example, the Amsterdam criteria) are used as an aid to diagnosis.
• Standard treatment when cancer develops:
  • Colorectal cancer: Standard colorectal cancer surgery (segmental resection) is performed depending on the tumor’s location and extent. Because patients with Lynch syndrome have a high risk of multiple primary cancers and recurrence, more extensive surgery, such as subtotal or total colectomy (for example, total colectomy with ileorectal anastomosis), may be considered based on the patient’s preferences, family history, age, and other factors.
  • Rectal cancer: Depending on the lesion, extensive surgery such as total colectomy may be considered.
  • In postmenopausal women or women who no longer plan to become pregnant and who have a high risk of cancer of the uterine adnexa (uterus and ovaries), prophylactic hysterectomy and oophorectomy may be discussed.
  • Cancers of other associated organs: Follow the standard surgical, medical, and radiation treatment guidelines for the relevant cancer.
• Prevention and surveillance (important):
  • Regular colonoscopic surveillance is recommended (the recommended interval varies according to the gene type and family history, but an interval of 1–2 years is generally recommended), with early initiation (the recommended starting age is usually 20–25 years or 2–5 years before the youngest age at diagnosis in the family).
  • Women: Surveillance for endometrial and ovarian cancer (including endometrial examination and ultrasonography) and consultation regarding preventive surgery.
  • Other: In specific cases, such as in people with MSH2 variants, urinary tract surveillance (such as urine cytology) may be considered, and surveillance strategies for the stomach, small intestine, and biliary tract may be discussed.
• Medication and lifestyle management:
  • Based on the CAPP2 study, which demonstrated a colorectal cancer preventive effect with high-dose aspirin, aspirin chemoprevention should be decided after an individual assessment of its benefits and bleeding risk and consultation with a doctor.
  • Healthy lifestyle habits that reduce overall cancer risk, such as not smoking, eating a balanced diet, and exercising regularly, are recommended.
• Genetic counseling and family testing: Genetic testing of blood relatives (cascade testing) is essential to identify variant carriers and establish surveillance plans.

Checklist Before an Outpatient Visit (Including Example Questions)

• Items and information to prepare:
  • List of currently used medications (including over-the-counter medications) and supplements
  • Personal medical history and surgical records (especially cancer-related records)
  • Cancer history of first-degree relatives (type of cancer diagnosed, age at diagnosis, and whether the person is alive or deceased) — if possible, a written list summarizing the medical history
  • Results of previous tests: biopsy, surgical records, endoscopy findings, and genetic test results (if available)
  • Record of symptom changes: bleeding, changes in bowel habits, weight loss, abnormal vaginal bleeding, and other symptoms
• Items to check during the outpatient visit: Drug allergies, possibility of pregnancy (for women), whether any family members have undergone genetic testing, and whether preventive surgery is desired
• Example questions (useful to ask the doctor in advance):
  • Do I currently need genetic testing? If testing has already been performed, how should the results be interpreted?
  • When should the recommended surveillance (endoscopy and gynecologic examinations) begin, and at what intervals should it be performed?

General Example Questions to Ask the Doctor

• What are the expected benefits and risks (complications) of this treatment (surgery or medication)?
• What level of cancer risk is associated with my (or my family member’s) specific MMR gene variant?
• At what intervals should surveillance (endoscopy and gynecologic examinations) be performed, and which tests are needed?
• Should I consider aspirin chemoprevention? What is the risk of side effects (such as bleeding), and how will it be monitored?
• What tests and screening schedule and methods are recommended for family members?

Disease-Specific Example Questions

• In which organs does the specific gene variant that I (or my family member) carry (for example, MSH2, MLH1, MSH6, or PMS2) particularly increase the risk of cancer? How do the recommended surveillance measures differ accordingly?
• As a woman who is postmenopausal (or no longer plans to become pregnant), should I consider prophylactic removal of the uterus and ovaries? Could you explain the appropriate timing and the advantages and disadvantages of the surgery?

(When necessary, it is recommended to request referral to genetic counseling and a multidisciplinary team, including medical oncology, surgery, gynecology, and genetic counseling.)