Mutational testing for germline alterations has been somewhat disappointing, as no more than half of suspected HNPCC cases have detectable pathologic mutations. Because of this, and the lack of sufficiently specific clinical features, various genetic screening strategies have emerged to improve the yield of genetic testing. A sufficiently compelling family history, ideally complemented by the presence of MSI, warrants mutational testing, and most clinical practice guidelines provide for such an approach. The Bethesda guidelines are a combination of clinical, pathologic, and family history features that are sufficiently predictive to warrant MSI/IHC screening. Computer risk-assessment profiles have been developed to do this same work more quantifiably and can estimate mutation risk likelihood with or without the intermediate step of using MSI/IHC.
Against this background of potential clinical selection criteria for mutation testing, population studies have emerged that can estimate HNPCC frequency (1%-3%) and determine the performance characteristics of these same selection tools when implemented in otherwise unselected cases.
The combination of genetic counseling/testing strategies with clinical screening/treatment measures has led to the development of consensus clinical practice guidelines. These guidelines can be used by providers and patients alike to better understand the available options and key decision-points that exist. Refer to Table 9 for more information about practice guidelines for diagnosis and colon surveillance in LS.
Terminology related to familial CRC has certainly evolved. Most in the field use the term Lynch syndrome (LS) as a preferred synonym over HNPCC, since HNPCC is both excessively wordy and misleading-many patients do have polyps and many others have tumors other than CRC. In addition, entities such as Muir-Torre syndrome are now recognized as phenotypic variants of LS. Even Turcot syndrome, which was initially thought to only be an FAP variant, is now known to be a LS variant when it presents with glioblastomas and an FAP variant when it presents with medulloblastomas. It has been suggested that the term Lynch syndrome be applied to cases in which the genetic basis can be confidently linked to a germline mutation in a DNA MMR gene (either a germline mutation is present or can be confidently inferred based on the clinical presentation combined with MSI/IHC).
The term familial colorectal cancer type X was coined to refer to families who meet Amsterdam criteria but lack MSI/IHC abnormalities. Maybe a better term will emerge-there are many conditions with "X" in them-but it survives for now since workers in the field at least agree to use it to describe these cases.
In LS,[200,201,202] unlike FAP, most patients do not have an unusual number of polyps. LS accounts for about 3% to 5% of all CRCs. LS is an autosomal dominant syndrome characterized by early age onset of CRC, excess synchronous and metachronous colorectal neoplasms, right-sided predominance, and extracolonic tumors. LS is caused by mutations in the DNA MMR genes, namely MLH1, MSH2, MSH6, and PMS2. Mutations of the EPCAM gene that result in hypermethylation and silencing of MSH2 have also been described. (Refer to the MSI section in the Major Genetic Syndromes section of this summary for more information.) The average age of CRC diagnosis in LS mutation carriers is 44 to 52 years,[203,204,205] compared with 71 years in sporadic CRC. Even though LS is characterized by an early age onset of CRC, in mutation-positive families when probands were excluded and both affected and non-affected relatives were ascertained, the average age at diagnosis of CRC was reported to be 61 years.