Colorectal Cancer, Hereditary Nonpolyposis (HNPCC)

• • Perhaps 6% of patients with cancer of the colon or rectum have HNPCC

  • Most common form of hereditary colorectal cancer

  • Gene responsible for this syndrome has been localized to chromosome 2p

  • Lynch syndrome II:

  • -Early onset (average age 44)

    -Proximal dominance

    -Synchronous and metachronous cancers and other associated extracolonic adenocarcinomas, especially endometrial carcinoma

  • Lynch syndrome I: Hereditary site-specific colon cancer shows the same characteristics except that there are no extracolonic cancers

  • Autosomal dominant inheritance

  • Cancers arise in discrete adenomas but polyposis (ie, hundreds of polyps) does not occur

  • Diagnostic criteria (Amsterdam criteria)

  • -Families must have at least 3 relatives with colorectal cancer, 1 of whom is a first-degree relative of the other 2

    -Colorectal cancer must involve at least 2 generations, and at least 1 cancer case must occur before age of 50

  • Adenomas and carcinomas in HNPCC arise at an early age

  • -Adenomas may occur in patients in their 20s and 30s, with a mean age for carcinoma development of 40 to 45 years

    -Are often proximal in location and multiple

  • Alterations in DNA mismatch repair genes that help maintain DNA fidelity during replication are characteristic of patients with HNPCC: (hMLH1, hPMS1 and hPMS2, and hMSH2, hMSH3, and hMSH6) may lead to the inability to repair base pair mismatches and result in DNA replication errors or microsatellite instability

  • Accelerated carcinogenesis occurs in hereditary nonpolyposiscolorectal cancer compared with sporadic cases

Epidemiology

• • The frequency of HNPCC in the general population is yet to be determined, but HNPCC may account for as many as 6% of colorectal cancer cases

  • Multiple generations are affected with colorectal cancer at an early age (mean, approximately 45 years) with a predominance of right-sided colorectal cancer (approximately 70% proximal to the splenic flexure)

  • Excess of synchronous colorectal cancer and metachronous colorectal cancer

  • Excess of extracolonic cancers—namely, carcinoma of the endometrium (second only to colorectal cancer in frequency), ovary, stomach (particularly in Asian countries such as Japan and Korea), small bowel, pancreas, hepatobiliary tract, brain, and upper uroepithelial tract

  • As compared with sporadic colorectal cancer, tumors in HNPCC are more often poorly differentiated, with an excess of mucoid and signet-cell features

Symptoms and Signs

• • Most patients are asymptomatic

  • Lower GI bleeding, although most bleeding is occult

  • Vague abdominal pain

• • Must always evaluate for synchronous colon carcinoma

• • History and physical exam

  • Digital rectal exam

  • Colonoscopy

  • Mainstay of the diagnosis of Lynch syndromes is a detailed family history

  • -A nuclear pedigree should be obtained from any patient with suspected cancer, as well as a history of colonic polyps

    -When a pedigree is identified, genetic counseling should be provided to decide about testing for genetic markers

When to Refer

• • Suspicion of familial component of colorectal malignancy

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