Universal Immunohistochemistry for Lynch Syndrome: A Systematic Review and Meta-analysis of 58,580 Colorectal Carcinomas

Ellis L Eikenboom; Anne-Sophie van der Werf-'t Lam; Mar Rodríguez-Girondo; Christi J Van Asperen; Winand N M Dinjens; Robert M W Hofstra; Monique E Van Leerdam; Hans Morreau; Manon C W Spaander; Anja Wagner; Maartje Nielsen

doi:10.1016/j.cgh.2021.04.021

Universal Immunohistochemistry for Lynch Syndrome: A Systematic Review and Meta-analysis of 58,580 Colorectal Carcinomas

Clin Gastroenterol Hepatol. 2022 Mar;20(3):e496-e507. doi: 10.1016/j.cgh.2021.04.021. Epub 2021 Apr 19.

Affiliations

¹ Department of Clinical Genetics, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
² Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
³ Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands.
⁴ Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁵ Department of Clinical Genetics, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁶ Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands; Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
⁷ Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
⁸ Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁹ Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: m.nielsen@lumc.nl.

PMID: 33887476
DOI: 10.1016/j.cgh.2021.04.021

Abstract

Background & aims: Lynch syndrome is a form of hereditary colorectal cancer (CRC) caused by pathogenic germline variants (PV) in DNA mismatch repair (MMR) genes. Currently, many Western countries perform universal immunohistochemistry testing on CRC to increase the identification of Lynch syndrome patients and their relatives. For a clear understanding of health benefits and costs, data on its outcomes are required: proportions of Lynch syndrome, sporadic MMR-deficient (MMRd) cases, and unexplained MMRd cases.

Methods: Ovid Medline, Embase, and Cochrane CENTRAL were searched for studies reporting on universal MMR immunohistochemistry, followed by MMR germline analysis, until March 20, 2020. Proportions were calculated, subgroup analyses were performed based on age and diagnostics used, and random effects meta-analyses were conducted. Quality was assessed using the Joanna Briggs Critical Appraisal Tool for Prevalence Studies.

Results: Of 2723 identified articles, 56 studies covering 58,580 CRCs were included. In 6.22% (95% CI, 5.08%-7.61%; I² = 96%) MMRd was identified. MMR germline PV was present in 2.00% (95% CI, 1.59%-2.50%; I² = 92%), ranging from 1.80% to 7.27% based on completeness of diagnostics and age restriction. Immunohistochemistry outcomes were missing in 11.81%, and germline testing was performed in 76.30% of eligible patients. In 7 studies, including 6848 CRCs completing all diagnostic stages, germline PV and biallelic somatic MMR inactivation were found in 3.01% and 1.75%, respectively; 0.61% remained unexplained MMRd.

Conclusions: Age, completeness, and type of diagnostics affect the percentage of MMR PV and unexplained MMRd percentages. Complete diagnostics explain almost all MMRd CRCs, reducing the amount of subsequent multigene panel testing. This contributes to optimizing testing and surveillance in MMRd CRC patients and relatives.

Keywords: Colorectal Cancer; Immunohistochemistry; Lynch Syndrome; Mismatch Repair Deficiency; Universal Tumor Screening.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't
Systematic Review

MeSH terms

Colorectal Neoplasms* / diagnosis
Colorectal Neoplasms* / genetics
Colorectal Neoplasms, Hereditary Nonpolyposis* / diagnosis
Colorectal Neoplasms, Hereditary Nonpolyposis* / genetics
Colorectal Neoplasms, Hereditary Nonpolyposis* / pathology
DNA Mismatch Repair
Humans
Immunohistochemistry