Validity of a two-antibody testing algorithm for mismatch repair deficiency testing in cancer; a systematic literature review and meta-analysis
Modern Pathology, vol. 35, pp. 1775–1783
Abstract
Reflex mismatch repair immunohistochemistry (MMR IHC) testing for MLH1, PMS2, MSH2 and MSH6 is used to screen for Lynch syndrome. Recently MMR-deficiency (MMRd) has been approved as a pan-cancer predictive biomarker for checkpoint inhibitor therapy, leading to a vast increase in the use of MMR IHC in clinical practice. We explored whether immunohistochemical staining with PMS2 and MSH6 can be used as a reliable substitute. This two-antibody testing algorithm has the benefit of saving tissue, cutting costs and saving time. PubMed, Embase and Cochrane library were systematically searched for articles reporting on MMR IHC. The weighed percentage of cases with isolated MLH1 or MSH2 loss or combined MLH1/MSH2 loss alone was analyzed using a random effects model meta-analysis in R. The search yielded 1704 unique citations, of which 131 studies were included, describing 9014 patients. A weighed percentage of 1.1% (95% CI 0.53-18.87, I = 87%) of cases with isolated MLH1 or MSH2 loss or combined MLH1/MSH2 loss alone was observed. In the six articles with the main aim of investigating the two-antibody testing algorithm all MMRd cases were detected with the two-antibody testing algorithm, there were no cases with isolated MLH1 or MSH2 loss or combined MLH1/MSH2 loss alone. This high detection rate of MMRd of the two-antibody testing algorithm supports its use in clinical practice by specialized pathologists. Staining of all four antibodies should remain the standard in cases with equivocal results of the two-antibody testing algorithm. Finally, educational sessions in which staining pattern pitfalls are discussed will continue to be important.
Authors 9
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Leiden University Medical Center
Affiliation as printed
Department of Pathology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, Leiden, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Pathology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, Leiden, The Netherlands
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University of Manchester · University of Bristol · St Mary's Hospital
Affiliation as printed
Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St Mary's Hospital, Manchester, UK
The Academic Women's Health Unit, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
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Leiden University Medical Center
Affiliation as printed
Department of Clinical Genetics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, Leiden, The Netherlands
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Manchester Academic Health Science Centre · University of Manchester · St Mary's Hospital · Manchester University NHS Foundation Trust
Affiliation as printed
Department of Obstetrics and Gynecology, Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, UK
Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St Mary's Hospital, Manchester, UK
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Leiden University Medical Center
Affiliation as printed
Department of Pathology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, Leiden, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Pathology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, Leiden, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Biomedical Data Sciences, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, Leiden, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Pathology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, Leiden, The Netherlands. t.bosse@lumc.nl
Department of Pathology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, Leiden, The Netherlands
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