Regarding the Clinical Practice Guidelines for the Surgical Treatment of Patients With Lynch Syndrome
The error relates to the definition of familial colorectal cancer type X (FCC type X). This is mentioned at the end of the paragraph titled “Statement of the Problem.” The article defines FCC type X as patients (the term really applies to the families of patients) meeting Amsterdam criteria with no germline mutation in a DNA mismatch repair gene. The original article by Lindor et al2 defined FCC type X as patients affected with colorectal cancer in Amsterdam I–compliant families whose tumors were either microsatellite stable (MSS) or microsatellite instability (MSI) low. The intent of the article was to differentiate patients with a family history that suggested dominant inheritance but had no evidence of hereditary mismatch repair deficiency in the tumor from those who did have evidence of hereditary mismatch repair deficiency (ie, Lynch syndrome). Of 161 Amsterdam I–compliant pedigrees, 90 had MSI-high colorectal cancer, and 71 (44%) had MSS (n = 60) or MSI-low (n = 11) colorectal cancer. Analysis of phenotype strongly suggested that most of the group A patients (Amsterdam I compliant, MSI high) actually had Lynch syndrome but that the group B patients (Amsterdam I compliant, MSI low or MSS) did not (no increased risk of extracolonic cancers, one third the increased risk of colorectal cancers, ≥50-year age at onset). There was no testing of the germline in any of these patients. To state that patients in Amsterdam I families with a colon cancer but no germline mutation in a mismatch repair gene have FCC type X is wrong. Quite a high proportion may actually have Lynch syndrome, because mutation detection in the germline is never 100%. The complicated relationships of family history, tumor testing, and germline genetic testing have been discussed recently in detail, and a reading of this article will help to clarify definitions and clinical implications.3 It is important to get these definitions correct, because it is central to an understanding of biology and of how to approach these complicated cases. It is also important to realize that only Amsterdam I criteria were used in the study by Lindor et al,2 excluding those where an extracolonic Lynch cancer is used to qualify the family.
A diagnosis of FCC type X opens the door to a variety of possible genotypes. These patients have a strong family history suggestive of dominant inheritance, do not have classical polyposis (one of the Amsterdam criteria), and do not have Lynch syndrome. Subsequent work has shown that some of the cases represent very mild versions of polyposis because of a variety of uncommon germline mutations that were not suspected at the time that Lindor et al2 wrote their article. These include familial adenomatous polyposis, polymerase proofreading-associated polyposis,4 MYH-associated polyposis5 and NTHL1-associated polyposis.6 FCC type X is therefore not a syndrome, per se, but likely represents a number of different genotypes with overlapping phenotypes. This sort of clinical overlap is precisely why panel testing is so helpful in providing a precise diagnosis.7
The discussion of colorectal surgical options in the article is helpful as far as it goes, but does not provide a full coverage of the decision making that caring for patients and families with Lynch syndrome involves. Recently this has been described under 3 headings, as described below.