• Clinical science

Lynch syndrome (Hereditary nonpolyposis colorectal cancer)

Summary

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.

Epidemiology

References:[1][2]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

References:[3]

Clinical features

  • Patients are usually asymptomatic until CRC develops (see colorectal cancer).
  • Signs of right CRC are more likely than signs of left CRC.
  • Possibly extracolonic symptoms of associated cancers (see “Epidemiology” section above)

References:[3]

Subtypes and variants

References:[4]

Diagnostics

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.

Amsterdam II criteria

Presence of at least three relatives with a Lynch syndrome-associated cancer; all the following criteria should be present:

  • One should be a first-degree relative of the other two
  • At least two consecutive generations affected
  • At least one relative with a diagnosis before 50 years of age
  • Exclude cases of familial adenomatous polyposis.
  • Verify tumors with pathological examination.

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

Genetic testing

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:[1][3]

Treatment

  • 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]

Prevention

  • 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:[1][3][7]