Lynch syndrome

Lynch syndrome, or hereditary nonpolyposis colon cancer (HNPCC), is a familial cancer syndrome caused by an autosomal dominant mutation in DNA mismatch repair (MMR) genes. Affected individuals develop a small number of adenomas that can rapidly progress to colorectal cancer (CRC), resulting in a considerably earlier symptom onset compared to sporadic colorectal cancer. Individuals with Lynch syndrome are also at increased risk of developing other forms of cancer, especially endometrial, gastric, and ovarian cancer. Individuals are asymptomatic until they present with symptoms of advanced cancer. To identify those at high risk for Lynch syndrome, individuals are assessed according to the Amsterdam II criteria. Subsequent genetic analysis with detection of MMR mutations confirms the diagnosis. Treatment of CRC consists of surgical colectomy and immunotherapy. Preventative screening for colorectal cancer and associated tumors is recommended in individuals with family members known to have a Lynch syndrome gene mutation; it should occur every 1–2 years, starting at 20–25 years of age, or 2–5 years before the earliest recorded case of a tumor in the family.

• Prevalence
  • Most common cause of inherited CRC
  • Accounts for approx. 3–8% of all new cases of CRC
  • Individuals with Lynch syndrome have a 70–80% lifetime risk of developing CRC
• Sex: ♂ = ♀
• Average age of onset: 44 years
• Increased lifetime risk of associated cancers (by age 70)
  • Endometrial cancer: up to 40%
  • Gastric cancer: ∼ 10%
  • Ovarian tumors: ∼ 10%
  • Urothelial cancer: up to 10%
  • Skin: ∼ 4%
  • Small bowel cancer: ∼ 2%
  • Brain tumor: ∼ 2%
  • Biliary tract cancer: ∼ 2%

References:^[1]

Epidemiological data refers to the US, unless otherwise specified.

• Hereditary disease: autosomal dominant with varying penetrance
• Mutations in various DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2) cause microsatellite instability.
  • Increased occurrence of adenomas with ∼ 80% risk of progression to carcinomas

References:^[2]

• Patients are usually asymptomatic until CRC develops (see colorectal cancer).
• Lynch syndrome-associated CRC usually affects the right (proximal) colon.
• Possibly extracolonic symptoms of associated cancers (see “Epidemiology” section above)

References:^[2]

• Muir-Torre syndrome
  • A variant of Lynch syndrome caused by mutations also occurring in MLH1, MSH2, or MSH6
  • Characterized by sebaceous gland tumors and keratoacanthomas in addition to Lynch syndrome-associated cancers
• Turcot syndrome: presence of Lynch syndrome-related CRC and brain tumors (especially gliomas)

References:^[3]

Lynch syndrome should be suspected if there is a positive family history based on the Amsterdam II criteria. Genetic testing confirms the diagnosis.

Family history

The Amsterdam II criteria are used to identify individuals who are likely to be mutation carriers for Lynch syndrome.

3-2-1 rule: (3 affected family members, 2 generations, 1 relative under 50 years of age).

The Revised Bethesda guidelines are used to identify individuals with colorectal cancer who should undergo tumor testing for microsatellite instability.

Genetic testing

• First test: tumor microsatellite instability (MSI) and/or immunohistochemical staining (IHC)
  • Low MSI/stable microsatellite and normal IHC: rules out Lynch syndrome
  • High MSI and/or abnormal IHC: requires further evaluation
• Confirmatory test: germline testing via DNA sequencing
  • Detection of mutations in DNA repair genes (MLH1, MSH2, MSH6, and PMS2)

Colorectal cancer

• For diagnosis of CRC, see colorectal cancer.

Lynch syndrome typically manifests with colorectal cancer of the proximal colon, with only a few adenomatous polyps, in contrast to familial adenomatous polyposis, in which hundreds of adenomatous polyps are present.

References:^[2][4]

• Surgery
  • Subtotal colectomy with ileorectal anastomosis
  • Total colectomy with ileostomy
  • Total colectomy with ileorectal anastomosis
• Immunotherapy with an immune checkpoint inhibitor (pembrolizumab or nivolumab) may be used for high MSI or mismatch repair deficient (dMMR) metastatic colorectal cancer. ^[5][6]
• For more specific guidelines regarding management, see colorectal cancer.
• For women with Lynch syndrome, prophylactic hysterectomy and bilateral salpingo-oophorectomy should be offered when they are no longer of child-bearing age.

References:^[7]

• Genetic counseling
  • Genetic testing is generally not recommended for at-risk individuals < 18 years of age.
  • Genetic screening should be initiated 10 years before the earliest manifestation of the condition in the family.
• Cancer screening: for Lynch syndrome patients with a confirmed mutation or who meet Amsterdam criteria
  • Colonoscopy: every 1–2 years, starting at 20–25 years of age, or 2–5 years before the earliest recorded case of a tumor in the family (only if it occurred before 25 years of age), whichever comes first ^[8]
  • Annual pelvic examination with transvaginal sonography and endometrial biopsy starting at 30–35 years of age or 3–5 years before the earliest reported case of a tumor in the family
  • Annual upper endoscopy with biopsy of the gastric antrum starting at 30–35 years of age
  • Annual physical exam and urinalysis
• Total colectomy: not generally recommended in patients with normal endoscopy

References:^[2][7]