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Test ID: MSIHC Microsatellite Instability (MSI)/Mismatch Repair (MMR) Protein Immunohistochemistry Profile

Useful For

Assessment for defective mismatch repair (dMMR) to identify solid tumors that may respond to anti-PD-L1/PD-1 immunotherapy

 

Evaluation of colon tumor tissue for evidence of microsatellite instability to stratify prognosis

 

Identification of individuals at high risk for having hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome

Additional Tests

Test ID Reporting Name Available Separately Always Performed
MLH1I MLH-1, Immunostain No, (Bill Only) Yes
MSH2I MSH-2, Immunostain No, (Bill Only) Yes
MSH6I MSH-6, Immunostain No, (Bill Only) Yes
PMS2I PMS-2, Immunostain No, (Bill Only) Yes
SLIRV Slide Review in MG No, (Bill Only) Yes

Testing Algorithm

When this test is ordered, slide review, MLH1, MSH2, MSH6, and PMS2 stains will always be performed at an additional charge.

 

See Hereditary Nonpolyposis Colorectal Cancer Testing Algorithm.

Method Name

Microsatellite Instability (MSI): Polymerase Chain Reaction (PCR)/Immunohistochemistry

Reporting Name

MSI/MMR IHC Profile

Specimen Type

Varies


Shipping Instructions


Ambient specimen preferred to arrive within 96 hours of draw.

Necessary Information


Pathology report must accompany specimen in order for testing to be performed.



Specimen Required


Tumor and normal tissue are required. If normal tissue in a formalin-fixed, paraffin-embedded tissue block is not available, whole blood may be submitted.

Specimen Type:
Tissue block and slides

Specimen Volume: Approximately 1 cm(2) of tumor and normal tissue are required. This can be 1 cm(2) in aggregate (eg, 5 unstained slides each with 0.2 cm[2] of tumor and normal tissue).

Collection Instructions:

1. Submit formalin-fixed, paraffin-embedded tissue block with corresponding hematoxylin and eosin (H and E)-stained slides (preferred) or 1 slide stained with H and E and 10 unstained, nonbaked slides (5-micrometer thick sections) of the tumor/normal tissue.

2. If sending in multiple blocks,  identify individual blocks as containing normal or tumor tissue.

3. Paraffin-embedded tissue blocks that have been decalcified are generally unsuccessful and not validated for testing. If a decalcified specimen is submitted, testing will be canceled.

Specimen Stability Information: Ambient (preferred)/Frozen/Refrigerated

 

Specimen Type: Whole blood

Container/Tube: lavender-top (EDTA) or yellow-top (ACD)

Acceptable: Any anticoagulant

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send specimen in original tube.

Specimen Stability Information: Ambient (preferred)/Refrigerated


Specimen Stability Information

Specimen Type Temperature Time
Varies Ambient (preferred)
  Frozen 
  Refrigerated 

Clinical Information

Assessment for defective mismatch repair (dMMR) through microsatellite instability (MSI) and immunohistochemistry (IHC) analysis is a predictor of therapeutic response in solid tumors. Current data suggest that unresectable or metastatic solid tumors with microsatellite instability-high (MSI-H) or defective mismatch repair (dMMR) may respond to anti-PD-L1/PD-1 immunotherapy (eg, pembrolizumab).

 

Colon cancers that demonstrate defective DNA mismatch repair (MSI-H) have a significantly better prognosis compared to those with intact mismatch repair (MSS/MSI-L). Additionally, current data indicate that stage II patients with colon cancers characterized by the presence of defective MMR (MSI-H) may not benefit from treatment with fluorouracil (5-FU) alone or in combination with leucovorin (LV).

 

Additionally, assessment for dMMR in tumors has utility in evaluating patients for Lynch syndrome. Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal dominant hereditary cancer syndrome associated with germline mutations in the mismatch repair genes, MLH1, MSH2, MSH6, and PMS2. Deletions within the 3-prime end of the EPCAM gene have also been associated with HNPCC/Lynch syndrome, as this leads to inactivation of the MSH2 promoter.

 

Lynch syndrome 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 Lynch syndrome-related genes and the lifetime risk for endometrial cancer (approximately 25%-60%) is also highly variable. Other malignancies within the tumor spectrum include 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 Lynch syndrome spectrum.

 

Several clinical variants of Lynch syndrome 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 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/Lynch syndrome. Testing tumors from individuals at risk for HNPCC/Lynch syndrome for microsatellite instability (MSI) indicates the presence or absence of defective DNA mismatch repair within the tumor. Individuals whose tumors demonstrate the presence of defective DNA mismatch repair in the form of microsatellite instability are more likely to have a germline mutation in 1 of the mismatch repair genes, MLH1, MSH2, MSH6, and PMS2. Tumors from affected individuals usually demonstrate an MSI-H phenotype (MSI >30% of microsatellites examined), whereas tumors from individuals who do not have HNPCC/Lynch syndrome usually have an MSS/MSI-L phenotype (MSI at <30% of microsatellites examined). 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/Lynch syndrome-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/Lynch syndrome 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 Analysis, Tumor or ML1HM / MLH1 Hypermethylation Analysis, Tumor may also help to distinguish between a sporadic and germline etiology.

 

It should be noted that this test 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.

 

See Hereditary Nonpolyposis Colorectal Cancer Testing Algorithm in Special Instructions for additional information.

Reference Values

An interpretive report will be provided.

Interpretation

The report will include specimen information, assay information, and interpretation of test results. Microsatellite stable (MSS) is reported as MSS/MSI-L (0 or 1 of 5 markers demonstrating instability) or MSI-H (2 or more of 5 markers demonstrating instability).

Clinical Reference

1. Baudhuin LM, Burgart LJ, Leontovich O, Thibodeau SN: Use of microsatellite instability and immunohistochemistry testing for the identification of individuals at risk for Lynch syndrome. Fam Cancer 2005;4(3):255-265

2. Terdiman JP, Gum JR, Conrad PG, et al: Efficient detection of hereditary nonpolyposis colorectal cancer gene carriers by screening for tumor microsatellite instability before germline genetic testing. Gastroenterology 2001 January;120(1):21-30

3. Vasen HF, Moslein G, Alonso A, et al: Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet 2007;44:353-362

4. Kohlmann W, Gruber SB: Lynch Syndrome. In GeneReviews 2004 Feb 5 (Updated 2014 May 22) edited by RA Pagon, MP Adam, HH Ardinger, et al: Seattle WA. University of Washington, Seattle; 1993-2014. Available at www.ncbi.nlm.nih.gov/books/NBK1211/

5. Popat S, Hubner R, Houlston RS: Systematic review of microsatellite instability and colorectal cancer prognosis. JCO 2005 23(3):609-618

6. Ribic CM, Sargent DJ, Moore MJ, et al: Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 2003 349:247-257

7. Le DT, Uram JN, Wang H, et al: PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med 2015 25;372(26):2509-2520

Day(s) and Time(s) Performed

Monday, Wednesday; 2 p.m.

Analytic Time

14 days

Test Classification

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the U.S. Food and Drug Administration.

CPT Code Information

81301-Microsatellite instability analysis (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) of markers for mismatch repair deficiency (eg, BAT25, BAT26), includes comparison of neoplastic and normal tissue, if performed

MLH-1, Immunostain

88341 (if appropriate)

 

MSH-2, Immunostain

88341 (if appropriate)

 

MSH-6, Immunostain

88341 (if appropriate)

 

PMS-2, Immunostain

88342 (if appropriate)

 

88381-Microdissection, manual

LOINC Code Information

Test ID Test Order Name Order LOINC Value
MSIHC MSI/MMR IHC Profile In Process

 

Result ID Test Result Name Result LOINC Value
53312 Result Summary 50397-9
53313 Result No LOINC Needed
53314 Interpretation 50595-8
53315 Specimen 31208-2
53316 Source 31208-2
54449 Tissue ID No LOINC Needed
53317 MLH1 IHC 50322-7
53318 MSH2 IHC 50323-5
53319 MSH6 IHC 50324-3
53320 PMS2 IHC 50328-4
53321 Released By No LOINC Needed

Forms

1. Molecular Genetics: Inherited Cancer Syndromes Patient Information (T519) in Special Instructions

2. If not ordering electronically, complete, print, and send an Oncology Test Request Form (T729) with the specimen

(http://www.mayomedicallaboratories.com/it-mmfiles/oncology-request-form.pdf)

Mayo Medical Laboratories | Genetics and Pharmacogenomics Catalog Additional Information:

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