• Clinical science

Lynch syndrome (Hereditary nonpolyposis colon cancer)

Abstract

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. Patients develop a small number of adenomas that can rapidly progress to colorectal cancer (CRC), resulting in a considerably earlier presentation compared to that of sporadic colorectal cancer. Individuals with Lynch syndrome are also at an increased risk of developing other forms of cancer, especially endometrial, gastric, and ovarian cancer. The patients are asymptomatic until presenting with symptoms of advanced cancer. To identify individuals at high risk for Lynch syndrome, patients are assessed according to the Amsterdam II criteria. Subsequent genetic analysis with detection of MMR mutations confirms the diagnosis. Treatment consists of surgical colectomy and chemotherapy. Surgery may also be preventative and is recommended in addition to routine screenings for colorectal cancer and the associated tumors.

Epidemiology

References:[1][2]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

References:[3]

Clinical features

  • Patients usually asymptomatic until CRC develops (see colorectal cancer)
  • More likely signs of right CRC
  • Symptoms of associated cancers (see “Epidemiology” section above)

References:[3]

Subtypes and variants

  • Muir-Torre syndrome
    • Variant of Lynch syndrome caused by mutations in MLH1, MSH2, or MSH6
    • Characterized by sebaceous gland tumors and keratoacanthomas in addition to Lynch syndrome-associated cancers
  • Turcot syndrome: increased association between Lynch syndrome-related CRC and gliomas

References:[4]

Diagnostics

A suspected diagnosisis is based on a positive family history according to 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).

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

Revised Bethesda guidelines

Individuals should be tested for MSI in the following situations:

  • Colorectal cancer diagnosed in patients > 50 years
  • Presence of synchronous, metachronous colorectal, or other Lynch syndrome-associated tumors, regardless of age
  • Colorectal cancer with MSI-H-like histology diagnosed in patients > 60 years
  • Colorectal cancer in ≥ 1 first-degree relative(s) with a Lynch syndrome-related tumor, with one of the cancers being diagnosed under age 50
  • Colorectal cancer in ≥ 2 first-degree or second-degree relatives with Lynch syndrome-related tumors, regardless of age

Genetic testing

Colorectal cancer

References:[1][3]

Treatment

  • Surgery (most commonly one of the following procedures)
    • Subtotal colectomy with ileorectal anastomosis
    • Total colectomy with ileostomy
    • Total colectomy with ileorectal anastomosis
  • For more specific guidelines regarding management, see colorectal cancer
  • For women with Lynch syndrome, prophylactic hysterectomy and bilateral salpingo-oophorectomy should be offered at the end of child-bearing age.

References:[5]

Prevention

  • Genetic counseling
    • Genetic testing is generally not recommended for at-risk individuals < 18 years of age
    • It is recommended to start genetic screening 10 years before the earliest manifestation of the condition in the family
  • Cancer screening: for Lynch syndrome patients with a confirmed mutation or that meet Amsterdam or Bethesda criteria
    • Annual colonoscopy: starting 2–5 years before the earliest case of a tumor in the family
    • Annual pelvic examination with transvaginal sonography and endometrial biopsy starting at 30–35 years of age or 3–5 years before the earliest 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: considered the only method of preventing CRC; not generally recommended

References:[1][3][5]