biomarker ihc reporting - mmr
LAST UPDATE: 09/27/2024
GENERAL
Microsatellites = Repetitive DNA sequences (2-10 nucleotides).
Mismatch Repair (MMR) = Defective MMR genes (MLH1, PMS2, MSH2, MSH6) causes microsatellite instability (MSI).
MSI-High (MSI-H) phenotype indicates MMR defective (dMMR).
10-15% of colorectal cancers (CRC) are MSI-H/MMR-deficient.
80% of dMMR CRCs are sporadic and 20% familial (Lynch syndrome).
RELEVANCE
dMMR CRCs have better stage-adjusted survival than microsatellite stable tumors.
dMMR CRCs are eligible for immunotherapy with pembrolizumab or nivolumab.
TESTING
All CRCs should be tested for MSI with IHC for MLH1, MSH2, MSH6 and PMS2.
MLH1 hypermethylation or BRAF mutation if MMR proteins are absent on IHC.
MICROSCOPY
POSITIVE STAIN (MMR preserved/stable): Diffuse nuclear immunoreactivity is present in neoplastic cells, similar or higher than internal control (normal epithelium, lymphocytes, fibroblasts, endothelium).
NEGATIVE STAIN (MMR loss/unstable): Complete absence of nuclear immunoreactivity in neoplastic cells with positive internal control
INTERPRETATION
Positive for all MMR proteins = low probability of dMMR CRC/MSI-H phenotype
No furher testing required
Negative for MLH1 and PMS2 = High probability of sporadic CRC
Testing for methylation of the MLH1 promoter and / or mutation of BRAF is indicated
Negative for MSH2 and MSH6: High probability of familial CRC
Sequencing and / or large deletion / duplication testing of germline MSH2 may be indicated
Negative for MSH6 only = High probability of familial CRC
Sequencing and / or large deletion / duplication testing of germline MSH6 may be indicated
Negative for PMS2 only = High probability of familial CRC
Sequencing and / or large deletion / duplication testing of germline PMS2 may be indicated
ADDITIONAL COMMENTS
IHC MMR markers are fixation-dependent. Poor fixation can lead to false negatives
IHC is better performed on biopsies than resection specimens.
images
REFERENCES
NATIONAL COMPREHENSIVE CANCER NETWORK (NCCN). Clinical practice guidelines in oncology: colon cancer. Version 2.2021. Disponível em: https://www.nccn.org. Acesso em: 27 set. 2024.
LIU, D.; XU, X.; DU, Y.; SUN, P.; CHEN, H. Microsatellite Instability and its Association with Clinicopathological Features in Colorectal Cancer: A Systematic Review and Meta-Analysis. Scientific Reports, v. 11, n. 1, p. 1-10, 2021.
KANZAKI, T. R.; ITOH, F. Microsatellite instability and Mismatch Repair Deficiency in Colorectal Cancer. Journal
of Gastroenterology and Hepatology, v. 34, n. 5, p. 832-839, 2020.
VOGELSTEIN, B.; KINZLER, K. W. The genetic basis of human cancer. 3. ed. New York: McGraw-Hill, 2013.
PATTYN, N.; SCHREURS, S.; ALEXANDERS, C. Immunohistochemistry in the diagnosis of Lynch Syndrome-related
colorectal cancer. Journal of Pathology and Translational Medicine, v. 54, n. 1, p. 25-34, 2022.
LINDE, M. et al. Immunotherapy for Mismatch Repair Deficient Colorectal Cancer. Oncogene, v. 39, n. 17, p. 3776-3785, 2020.
BENSON, A. B. et al. NCCN Guidelines Insights: Colon Cancer, Version 2.2018. Journal of the National Comprehensive Cancer Network, v. 16, n. 4, p. 359-369, 2018.
ARNOLD, M. et al. Global patterns and trends in colorectal cancer incidence and mortality. Gut, v. 66, n. 4, p. 683-691, 2017.
YAMAMOTO, H.; IMAI, K. Microsatellite instability: an update. Archives of Toxicology, v. 89, n. 6, p. 899-921, 2015.
SINHA, R.; ALLEN, B. G.; MALEK, J. A. Detection and clinical significance of microsatellite instability in colorectal cancer. Journal of Clinical Oncology, v. 31, n. 15, p. 1572-1580, 2013.
COLLEGE OF AMERICAN PATHOLOGISTS (CAP). Protocol for the examination of specimens from patients with primary carcinoma of the colon and rectum. Version 4.0.0. 2020. Disponível em: https://www.cap.org/protocols-and-guidelines/cancer-reporting-tools/cancer-protocol-templates. Acesso em: 27 set. 2024.
PATHOLOGY OUTLINES. Microsatellite instability. Disponível em: https://www.pathologyoutlines.com/topic/colonmicrosatelliteinstability.html. Acesso em: 27 set. 2024.