Affiliations of authors: Colorectal Medicine and Genetics (FW), Familial Cancer Clinic (MH), The Royal Melbourne Hospital, 3050, Victoria, Australia
Correspondence to: Finlay Macrae, MBBS (Hons1), MD, FRACP, FRCP, Head, Colorectal Medicine and Genetics, PO Box 2010, The Royal Melbourne Hospital, 3050, Victoria, Australia (e-mail: finlay.macrae{at}mh.org.au).
The revised Bethesda Guidelines were long awaited by practitioners in the field. The commentary on the new guidelines (1), however, raises concerns. Two versions of the revised Bethesda Guidelines that were determined at the 2002 National Cancer Institute hereditary nonpolyposis colorectal cancer (HNPCC) workshop were published in February 2004. One version was published in the Journal (1) and the other in Nature Reviews Cancer (2); both were written by nearly the same group of authors. The suggested five guidelines are not the same in each publication, so it is not clear which set of guidelines reflects the true consensus. We have issues with both publications. Parts of the commentary published in the Journal are poorly worded and hence confusing. In particular, Guidelines 4 and 5 in the JNCI presentation should have been introduced with a reference to a presenting patient with colorectal cancer, as was done in the Nature Reviews Cancer presentation Thus, the guidelines should read as follows:
In Guideline 4, the Nature Reviews Cancer report includes an alternative to one of the cancers diagnosed before 50 years of age"(this includes adenoma, which must have been diagnosed before the age of 40 years)." This qualification is not mentioned in the version of the Guideline 4 published in the Journal. It is important for practitioners to know whether the consensus was for adenomas to be "in" or "out" of the revised guidelines. Emerging data suggest that adenomas in young patients have a low rate of microsatellite instability and may be best removed from this classification (3).
We also have concerns about the evidence supporting revised Guideline 5. The existing Bethesda Guidelines already have high sensitivity and low specificity. The new Guideline 5 will certainly further reduce specificity. For example, this guideline could be used to justify microsatellite instability (MSI) testing in an 80-year-old person with bowel cancer who has both a maternal uncle who was diagnosed with bowel cancer at age 95 years and a grandfather (either maternal or paternal) who was diagnosed at age 98 years. The Nature Reviews Cancer report included no restriction on the degree of relatedness. Indeed, everybody with bowel cancer is likely to have at least two relatives with colorectal cancer if the pedigree is pursued extensively enough. Revised Guideline 5 should be restricted to the same side of the family among first- and second-degree relatives.
Further detail is also required to determine how many of the described pathologic features are required to meet Guideline 3. The criterion shorthands this as "MSI-H histology." The discussion in the text is diffuse on the details of this, without clear direction as to which and/or how many of the features need to be present to qualify for this criterion. Mention is made of mucinous and signet-ring cell carcinoma, poor differentiation, and tumorinfiltrating lymphocytes.
The evidence to support the removal of patients with endometrial cancer diagnosed before age 50 years (with no family history) from the original Bethesda Guidelines is not clear.
If the revised Bethesda Guidelines are to be taken and applied internationally as the "gold standard" for immunohistochemistry/MSI testing, the issues outlined above need to be addressed. Failing this, we suggest that the original 1997 Bethesda Guidelines (4) remain the standard for deciding which patients and families should have immunohistochemistry/MSI testing performed as a screening test for HNPCC.
REFERENCES
(1) Umar A, Boland R, Terdiman JP, Syngal S, de la Chapelle A, Ruschoff J, et al. Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch Syndrome) and microsatellite instability. J Natl Cancer Inst 2004;96:2618.
(2) Umar A, Risinger JI, Hawk ET, Barret JC. Testing guidelines for hereditary non-polyposis colorectal cancer. Nat Rev Cancer 2004; 4:1538.[ISI][Medline]
(3) Velayos F, Allen BA, Gum JR, Kim YS, Sleisenger MH, Terdiman J. Low rate of microsatellite instability in your patients with adenomas: assessment of the Bethesda Guidelines to detect hereditary non-polyposis colorectal cancer. Gastroenterology 2004; 125:A117.[CrossRef]
(4) Rodriguez-Bigas MA, Boland CR, Hamilton SR, Henson DE, Jass JR, Khan PM, et al. A National Cancer Institute workshop on hereditary non-polyposis colorectal cancer syndrome: meeting highlights and Bethesda Guidelines. J Natl Cancer Inst 1997;89:175862.
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