Table 8. Clinical Practice Guidelines for Diagnosis and Colon Surveillance of Familial Adenomatous Polyposis (FAP) continued...
A complementary and perhaps even alternative approach to MSI is to test the tumor by IHC for protein expression using monoclonal antibodies of the MSH2, MLH1, MSH6, and PMS2 proteins. Loss of expression of these proteins appears to correlate with the presence of MSI and may suggest which specific MMR gene is altered in a particular patient.[276,277,278,279]
(Refer to the Issues With Informed Consent for MSI and IHC Tumor Testing section in the Psychosocial Issues in Hereditary Colon Cancer Syndromes section of this summary for information about educational strategies and issues related to informed consent for MSI and IHC testing.)
Tumor testing for suspected LS
It appears that clinical practice has shifted from reliance on MSI in the early days of tumor testing to increasing, and in many cases exclusive, reliance on IHC currently. Using both of these tests increases the sensitivity of the initial screen and improves quality assurance; therefore, many laboratories assess both MSI and IHC initially. However, because these tests are so commonly regarded as simple alternatives, cost-effectiveness considerations seem to support IHC and account for its preferential use. Part of this rationale is that the information provided by IHC may direct testing toward a specific MMR gene (the one with loss of protein expression) as opposed to comprehensive testing that would be necessitated by the use of MSI alone.[206,207,280,281,282,283] Arguments for a sequential approach to increase efficiency have been made. A German consortium has proposed an algorithm suggesting a sequential approach; this is likely to depend on the different costs of MSI and IHC and the prior probability of a mutation. Data from a large U.S. study support IHC analysis as the primary screening method, emphasizing its ease of performance in routine pathology laboratories. To identify a more efficient screening approach, the strategy of performing IHC staining only for PMS2 and MSH6 has been considered, on the assumption that negative staining of either of these would, in most instances, detect the majority of cases of LS. This approach may be more appropriate when all tumors are being screened (universal testing). Although this strategy appears attractive from the standpoint of efficiency, staining for all four MMR proteins remains the current standard of care. Further studies are necessary to validate the utility of the two-protein approach. (Refer to the Diagnostic Strategies for all individuals diagnosed with CRC (universal testing) section of this summary for more information.)
Even in centers that rely exclusively on IHC testing, there may be a role for subsequent MSI testing in cases where the clinical picture suggests LS, notwithstanding the results of IHC.
If greatest weight is given to clinical selection considerations (i.e., Bethesda guidelines being met), then IHC combined with MSI may be appropriate. In fact, in a truly high-risk population (Amsterdam criteria being met), any strategy may be acceptable, including germline testing without the benefit of tumor testing first. (Refer to the Genetic/Molecular Testing for LS section of this summary for information about models.) However, as more institutions are adopting universal testing using MSI or IHC, perhaps in part based on some of the outlier (older, family history-negative) cases reported [206,280,284] or in part based on prognostic considerations (MSI-H having better prognosis), concerns about cost effectiveness of screening commonly dictate a more truncated approach. Thus, in a relatively low-risk population of patients with CRC, a screen with IHC or MSI alone may be adequate in cases of normal staining or MSS tumor.