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Genetics of Colorectal Cancer (PDQ®): Genetics - Health Professional Information [NCI] - Major Genetic Syndromes

Table 8. Clinical Practice Guidelines for Diagnosis and Colon Surveillance of Familial Adenomatous Polyposis (FAP) continued...

These criteria provide a general approach to identifying LS families, but they are not considered comprehensive; a number of families who do not meet these criteria, but have germline MMR gene mutations, have been reported.[236,237]

To address these issues and to improve the diagnosis of LS clinically, the ICG developed revised criteria in 1999; these are known as Amsterdam criteria II.[238]

Amsterdam criteria II:

  1. There should be at least three relatives with a LS-associated cancer (CRC or cancer of the endometrium, small bowel, ureter, or renal pelvis).
  2. One should be a first-degree relative of the other two.
  3. At least two successive generations should be affected.
  4. At least one should be diagnosed before age 50 years.
  5. FAP should be excluded in the CRC cases.
  6. Tumors should be verified by pathological examination.

Although these criteria are among the most stringent used to identify potential candidates for microsatellite and germline testing, it must be cautioned that by definition, familial CRC type X includes families meeting Amsterdam criteria but in whom there is no evidence of MSI. (Refer to the Familial CRC type X section in the Major Genetic Syndromes section of this summary for more information.)

A third set of clinical criteria that can be used to identify LS families is the revised Bethesda guidelines.[239] The criteria was expanded to improve sensitivity in identifying families. The Bethesda guidelines are the least stringent for identifying families with germline mutations in one of the MMR genes. Because of lack of specificity for LS, the Bethesda guidelines are utilized to identify individuals whose colorectal tumors should be tested for MSI and/or IHC, rather than to identify families that meet clinical criteria for LS. (Refer to the Genetic/Molecular Testing for LS section in the Major Genetic Syndromes section of this summary for more information about testing for MSI and IHC.)

Revised Bethesda Guidelines for Testing of Colorectal Tumors for MSI:

  1. CRC diagnosed in an individual younger than 50 years.
  2. Presence of synchronous, metachronous colorectal, or other LS-associated tumors.*
  3. CRC with MSI-high (MSI-H) pathologic associated features diagnosed in an individual younger than 60 years. Presence of tumor-infiltrating lymphocytes, Crohn-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern.
  4. CRC or LS-associated tumor* diagnosed in at least one first-degree relative younger than 50 years.
  5. CRC or LS-associated tumor* diagnosed at any age in two first-degree or second-degree relatives.

*LS-associated tumors include colorectal, endometrial, stomach, ovarian, pancreatic, ureter and renal pelvis, biliary tract, and brain tumors; sebaceous gland adenomas and keratoacanthomas in Muir-Torre syndrome; and carcinoma of the small bowel.[239,240]

Research has included CRC families who do not meet Amsterdam criteria for LS and/or in whom the colorectal tumors are microsatellite stable (MSS). A number of these families have been found to have mutations in MSH6.[241,242,243,244,245] While the clinical significance and implications of these findings are not clear, these observations suggest that germline mutations in MSH6 may predispose to late-onset familial CRCs that do not meet Amsterdam criteria for LS and tumors that might not necessarily display MSI.


WebMD Public Information from the National Cancer Institute

Last Updated: February 25, 2014
This information is not intended to replace the advice of a doctor. Healthwise disclaims any liability for the decisions you make based on this information.
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