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

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

22 Citations (Scopus)

206 Downloads (Pure)

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.

Original language	English
Pages (from-to)	e496-e507
Journal	Clinical Gastroenterology and Hepatology
Volume	20
Issue number	3
Early online date	18 Apr 2021
DOIs	https://doi.org/10.1016/j.cgh.2021.04.021
Publication status	Published - 1 Mar 2022

Bibliographical note

Funding Information:
The authors wish to thank José Plevier, librarian from the Walaeus library (Leiden University Medical Center), for her help during the literature search. The authors also wish to thank Anne Steutel and Olga van der Hel from The Netherlands Comprehensive Cancer Organisation for their helpful advice. Writing assistence was provided by Medactie, The Netherlands. This work is supported by MLDS (Maag Lever Darm Stichting, FP16-06). Ellis Eikenboom, Drs (Data curation: Lead; Formal analysis: Supporting; Investigation: Equal; Methodology: Equal; Visualization: Lead; Writing – original draft: Lead; Writing – review & editing: Lead), Anne-Sophie van der Werf - 't Lam, MD (Data curation: Lead; Formal analysis: Equal; Investigation: Equal; Methodology: Equal; Visualization: Lead; Writing – original draft: Lead; Writing – review & editing: Lead), Mar Rodriguez Girondo, PhD (Formal analysis: Lead; Methodology: Lead; Writing – review & editing: Supporting), Christi van Asperen, Prof, MD (Supervision: Supporting; Writing – original draft: Supporting; Writing – review & editing: Equal), Winand Dinjens, Prof (Writing – original draft: Supporting; Writing – review & editing: Equal), Robert Hofstra, Prof. (Supervision: Supporting; Writing – review & editing: Equal), Monique van Leerdam, Prof. MD (Supervision: Supporting; Writing – original draft: Equal; Writing – review & editing: Equal), Hans Morreau, Prof, MD (Writing – original draft: Equal; Writing – review & editing: Supporting), Manon Spaander, Prof, MD (Writing – original draft: Supporting; Writing – review & editing: Equal), Anja Wagner, PhD MD (Conceptualization: Equal; Supervision: Lead; Writing – original draft: Supporting; Writing – review & editing: Supporting), Maartje Nielsen, PhD MD (Conceptualization: Lead; Funding acquisition: Lead; Supervision: Lead; Writing – original draft: Supporting; Writing – review & editing: Supporting)

Funding Information:
The authors wish to thank José Plevier, librarian from the Walaeus library (Leiden University Medical Center), for her help during the literature search. The authors also wish to thank Anne Steutel and Olga van der Hel from The Netherlands Comprehensive Cancer Organisation for their helpful advice. Writing assistence was provided by Medactie, The Netherlands. This work is supported by MLDS (Maag Lever Darm Stichting, FP16-06).

Publisher Copyright:
© 2022 The Authors

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Eikenboom, E. L., van der Werf–‘t Lam, A. S., Rodríguez-Girondo, M., Van Asperen, C. J., Dinjens, W. N. M., Hofstra, R. M. W., Van Leerdam, M. E., Morreau, H., Spaander, M. C. W., Wagner, A., & Nielsen, M. (2022). Universal Immunohistochemistry for Lynch Syndrome: A Systematic Review and Meta-analysis of 58,580 Colorectal Carcinomas. Clinical Gastroenterology and Hepatology, 20(3), e496-e507. https://doi.org/10.1016/j.cgh.2021.04.021

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

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.",

author = "Eikenboom, {Ellis L.} and {van der Werf–{\textquoteleft}t Lam}, {Anne Sophie} and Mar Rodr{\'i}guez-Girondo and {Van Asperen}, {Christi J.} and Dinjens, {Winand N.M.} and Hofstra, {Robert M.W.} and {Van Leerdam}, {Monique E.} and Hans Morreau and Spaander, {Manon C.W.} and Anja Wagner and Maartje Nielsen",

note = "Funding Information: The authors wish to thank Jos{\'e} Plevier, librarian from the Walaeus library (Leiden University Medical Center), for her help during the literature search. The authors also wish to thank Anne Steutel and Olga van der Hel from The Netherlands Comprehensive Cancer Organisation for their helpful advice. Writing assistence was provided by Medactie, The Netherlands. This work is supported by MLDS (Maag Lever Darm Stichting, FP16-06). Ellis Eikenboom, Drs (Data curation: Lead; Formal analysis: Supporting; Investigation: Equal; Methodology: Equal; Visualization: Lead; Writing – original draft: Lead; Writing – review & editing: Lead), Anne-Sophie van der Werf - 't Lam, MD (Data curation: Lead; Formal analysis: Equal; Investigation: Equal; Methodology: Equal; Visualization: Lead; Writing – original draft: Lead; Writing – review & editing: Lead), Mar Rodriguez Girondo, PhD (Formal analysis: Lead; Methodology: Lead; Writing – review & editing: Supporting), Christi van Asperen, Prof, MD (Supervision: Supporting; Writing – original draft: Supporting; Writing – review & editing: Equal), Winand Dinjens, Prof (Writing – original draft: Supporting; Writing – review & editing: Equal), Robert Hofstra, Prof. (Supervision: Supporting; Writing – review & editing: Equal), Monique van Leerdam, Prof. MD (Supervision: Supporting; Writing – original draft: Equal; Writing – review & editing: Equal), Hans Morreau, Prof, MD (Writing – original draft: Equal; Writing – review & editing: Supporting), Manon Spaander, Prof, MD (Writing – original draft: Supporting; Writing – review & editing: Equal), Anja Wagner, PhD MD (Conceptualization: Equal; Supervision: Lead; Writing – original draft: Supporting; Writing – review & editing: Supporting), Maartje Nielsen, PhD MD (Conceptualization: Lead; Funding acquisition: Lead; Supervision: Lead; Writing – original draft: Supporting; Writing – review & editing: Supporting) Funding Information: The authors wish to thank Jos{\'e} Plevier, librarian from the Walaeus library (Leiden University Medical Center), for her help during the literature search. The authors also wish to thank Anne Steutel and Olga van der Hel from The Netherlands Comprehensive Cancer Organisation for their helpful advice. Writing assistence was provided by Medactie, The Netherlands. This work is supported by MLDS (Maag Lever Darm Stichting, FP16-06). Publisher Copyright: {\textcopyright} 2022 The Authors",

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month = mar,

day = "1",

doi = "10.1016/j.cgh.2021.04.021",

language = "English",

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Eikenboom, EL, van der Werf–‘t Lam, AS, Rodríguez-Girondo, M, Van Asperen, CJ, Dinjens, WNM, Hofstra, RMW, Van Leerdam, ME, Morreau, H, Spaander, MCW , Wagner, A & Nielsen, M 2022, 'Universal Immunohistochemistry for Lynch Syndrome: A Systematic Review and Meta-analysis of 58,580 Colorectal Carcinomas', Clinical Gastroenterology and Hepatology, vol. 20, no. 3, pp. e496-e507. https://doi.org/10.1016/j.cgh.2021.04.021

Universal Immunohistochemistry for Lynch Syndrome: A Systematic Review and Meta-analysis of 58,580 Colorectal Carcinomas. / Eikenboom, Ellis L.; van der Werf–‘t Lam, Anne Sophie; Rodríguez-Girondo, Mar et al.
In: Clinical Gastroenterology and Hepatology, Vol. 20, No. 3, 01.03.2022, p. e496-e507.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Universal Immunohistochemistry for Lynch Syndrome

T2 - A Systematic Review and Meta-analysis of 58,580 Colorectal Carcinomas

AU - Eikenboom, Ellis L.

AU - van der Werf–‘t Lam, Anne Sophie

AU - Rodríguez-Girondo, Mar

AU - Van Asperen, Christi J.

AU - Dinjens, Winand N.M.

AU - Hofstra, Robert M.W.

AU - Van Leerdam, Monique E.

AU - Morreau, Hans

AU - Spaander, Manon C.W.

AU - Wagner, Anja

AU - Nielsen, Maartje

N1 - Funding Information: The authors wish to thank José Plevier, librarian from the Walaeus library (Leiden University Medical Center), for her help during the literature search. The authors also wish to thank Anne Steutel and Olga van der Hel from The Netherlands Comprehensive Cancer Organisation for their helpful advice. Writing assistence was provided by Medactie, The Netherlands. This work is supported by MLDS (Maag Lever Darm Stichting, FP16-06). Ellis Eikenboom, Drs (Data curation: Lead; Formal analysis: Supporting; Investigation: Equal; Methodology: Equal; Visualization: Lead; Writing – original draft: Lead; Writing – review & editing: Lead), Anne-Sophie van der Werf - 't Lam, MD (Data curation: Lead; Formal analysis: Equal; Investigation: Equal; Methodology: Equal; Visualization: Lead; Writing – original draft: Lead; Writing – review & editing: Lead), Mar Rodriguez Girondo, PhD (Formal analysis: Lead; Methodology: Lead; Writing – review & editing: Supporting), Christi van Asperen, Prof, MD (Supervision: Supporting; Writing – original draft: Supporting; Writing – review & editing: Equal), Winand Dinjens, Prof (Writing – original draft: Supporting; Writing – review & editing: Equal), Robert Hofstra, Prof. (Supervision: Supporting; Writing – review & editing: Equal), Monique van Leerdam, Prof. MD (Supervision: Supporting; Writing – original draft: Equal; Writing – review & editing: Equal), Hans Morreau, Prof, MD (Writing – original draft: Equal; Writing – review & editing: Supporting), Manon Spaander, Prof, MD (Writing – original draft: Supporting; Writing – review & editing: Equal), Anja Wagner, PhD MD (Conceptualization: Equal; Supervision: Lead; Writing – original draft: Supporting; Writing – review & editing: Supporting), Maartje Nielsen, PhD MD (Conceptualization: Lead; Funding acquisition: Lead; Supervision: Lead; Writing – original draft: Supporting; Writing – review & editing: Supporting) Funding Information: The authors wish to thank José Plevier, librarian from the Walaeus library (Leiden University Medical Center), for her help during the literature search. The authors also wish to thank Anne Steutel and Olga van der Hel from The Netherlands Comprehensive Cancer Organisation for their helpful advice. Writing assistence was provided by Medactie, The Netherlands. This work is supported by MLDS (Maag Lever Darm Stichting, FP16-06). Publisher Copyright: © 2022 The Authors

PY - 2022/3/1

Y1 - 2022/3/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85107055917&partnerID=8YFLogxK

U2 - 10.1016/j.cgh.2021.04.021

DO - 10.1016/j.cgh.2021.04.021

M3 - Article

C2 - 33887476

AN - SCOPUS:85107055917

SN - 1542-3565

VL - 20

SP - e496-e507

JO - Clinical Gastroenterology and Hepatology

JF - Clinical Gastroenterology and Hepatology

IS - 3

ER -

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

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