TEST CATALOG ORDERING & RESULTS SPECIMEN HANDLING CUSTOMER SERVICE EDUCATION & INSIGHTS
Test Catalog

Test ID: MSH6    
MSH6 Immunostain, Technical Component Only

Useful For Suggests clinical disorders or settings where the test may be helpful

Evaluation of tumor tissue to identify patients at high risk for having hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome

 

Evaluation of tumor tissue to identify patients at risk for having hereditary endometrial carcinoma

Testing Algorithm Delineates situations when tests are added to the initial order. This includes reflex and additional tests.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is an autosomal dominant hereditary cancer syndrome associated with germline mutations in the mismatch repair genes: MLH1, MSH2, MSH6, and PMS2.

 

HNPCC is predominantly characterized by significantly increased risks for colorectal and endometrial cancer. The lifetime risk for colorectal cancer is highly variable and dependent on the gene involved. The risk for colorectal cancer associated MLH1 and MSH2 mutations (approximately 50%-80%) is generally higher than the risks associated with mutations in the other HNPCC-related genes and the lifetime risk for endometrial cancer (approximately 25%-60%) is also highly variable. Other malignancies within the tumor spectrum include sebaceous neoplasms, gastric cancer, ovarian cancer, hepatobiliary and urinary tract carcinomas, and small bowel cancer. The lifetime risks for these cancers are less than 15%. Of the 4 mismatch repair genes, mutations within the PMS2 gene confer the lowest risk for any of the tumors within the HNPCC spectrum.

 

Several clinical variants of HNPCC have been defined. These include Turcot syndrome, Muir-Torre syndrome, and homozygous mismatch repair mutations (also called constitutional mismatch repair deficiency syndrome). Turcot syndrome and Muir-Torre syndrome are associated with increased risks for cancers within the tumor spectrum described but also include brain and central nervous system malignancies and sebaceous carcinomas, respectively. Homozygous or compound heterozygous mismatch repair mutations, characterized by the presence of biallelic deleterious mutations within a mismatch repair gene, are associated with a different clinical phenotype defined by hematologic and brain cancers, cafe au lait macules, and childhood colon or small bowel cancer.

 

There are several strategies for evaluating individuals whose personal or family history of cancer is suggestive of HNPCC. Testing tumors from individuals at risk for HNPCC for microsatellite instability (MSI) indicates the presence or absence of defective DNA mismatch repair phenotype within the tumor, but does not suggest in which gene the abnormality rests. Tumors from individuals affected by HNPCC usually demonstrate an MSI-H phenotype (MSI >30% of microsatellites examined). The MSI-H phenotype can also be seen in individuals whose tumors have somatic MLH1 promoter hypermethylation. Tumors from individuals that show the MSS/MSI-L phenotype (MSI at <30% of microsatellites examined), are not likely to have HNPCC or somatic hypermethylation of MLH1. Immunohistochemistry (IHC) is a complementary testing strategy to MSI testing. In addition to identifying tumors with defective DNA mismatch repair, IHC analysis is helpful for identifying the gene responsible for the defective DNA mismatch repair within the tumor, because the majority of MSI-H tumors show a loss of expression of at least 1 of the 4 mismatch repair genes described above.

 

Testing is typically first performed on the tumor of an affected individual and in the context of other risk factors, such as young age at diagnosis or a strong family history of HNPCC-related cancers. If defective DNA mismatch repair is identified within the tumor, mutation analysis of the associated gene can be performed to identify the causative germline mutation and allow for predictive testing of at-risk individuals.

 

Of note, MSI-H phenotypes and loss of protein expression by IHC have also been demonstrated in various sporadic cancers, including those of the colon and endometrium. Absence of MLH1 and PMS2 protein expression within a tumor, for instance, is most often associated with a somatic alteration in individuals with an older age of onset of cancer than typical HNPCC families. Therefore, an MSI-H phenotype or loss of protein expression by IHC within a tumor does not distinguish between somatic and germline mutations. Genetic testing of the gene indicated by IHC analysis can help to distinguish between these 2 possibilities. In addition, when absence of MLH1/PMS2 is observed, BRMLH / MLH1 Hypermethylation and BRAF Mutation Analyses, Tumor or ML1HM / MLH1 Hypermethylation Analysis, Tumor may also help to distinguish between a sporadic and germline etiology.

 

It should be noted that this HNPCC screen is not a genetic test, but rather stratifies the risk of having an inherited cancer predisposition syndrome, and identifies patients who might benefit from subsequent genetic testing.

Interpretation Provides information to assist in interpretation of the test results

This test includes only technical performance of the stain (no pathologist interpretation is performed). Mayo Clinic cannot provide an interpretation of tech only stains outside the context of a pathology consultation. If an interpretation is needed, refer to PATHC / Pathology Consultation for a full diagnostic evaluation or second opinion of the case. All material associated with the case is required. Additional specific stains may be requested as part of the pathology consultation, and will be performed as necessary at the discretion of the Mayo pathologist.

 

The positive and negative controls are verified as showing appropriate immunoreactivity and documentation is retained at Mayo Clinic Rochester. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request; contact 855-516-8404.

 

Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Age of a cut paraffin section can affect immunoreactivity. Stability thresholds vary widely among published literature and are antigen-dependent. Best practice is for paraffin sections to be cut fresh.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Burgart LJ: Testing for defective DNA mismatch repair in colorectal carcinoma: a practical guide. Arch Pathol Lab Med 2005;129:1385-1389

2. Klarskov L, Ladelund S, Holck S, et al: Interobserver variability in the evaluation of mismatch repair protein immunostaining. Hum Pathol 2010;41:1387-1396

3. Modica I, Soslow RA, Black D, et al: Utility of immunohistochemistry in predicting microsatellite instability in endometrial carcinoma. Am J Surg Pathol 2007;31(5):744-751

4. Mojtahed A, Schrijver I, Ford JM, et al: A two-antibody mismatch repair protein immunohistochemistry screening approach for colorectal carcinomas, skin sebaceous tumors, and gynecologic tract carcinomas. Mod Pathol 2011;24:1004-1014

5. Rigau V, Sebbagh N, Olschwang S, et al: Microsatellite instability in colorectal carcinoma. The comparison of immunohistochemistry and molecular biology suggests a role for hMLH6 (correction of hMLH6) immunostaining. Arch Pathol Lab Med 2003;127:694-700

6. Shia J: Immunohistochemistry versus microsatellite instability testing for screening colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome. Part I. The utility of immunohistochemistry. J Mol Diagn 2008;10(4):293-300