Discordant Staining Patterns and Microsatellite Results in Tumors of MSH6 Pathogenic Variant Carriers

Anne-Sophie van der Werf-'t; Diantha Terlouw; Carli M. Tops; Merel S. van Kan; Liselotte P. van Hest; Hans J. P. Gille; Floor A. M. Duijkers; Anja Wagner; Ellis L. Eikenboom; Tom G. W. Letteboer; Mirjam M. de Jong; Sanne W. Bajwa-ten Broeke; Fonnet E. Bleeker; Encarna B. Gomez Garcia; Niels de Wind; J. Tom van Wezel; Hans Morreau; Manon Suerink; Maartje Nielsen

doi:10.1016/j.modpat.2023.100240

Discordant Staining Patterns and Microsatellite Results in Tumors of MSH6 Pathogenic Variant Carriers

Anne-Sophie van der Werf-'t, Diantha Terlouw, Carli M. Tops, Merel S. van Kan, Liselotte P. van Hest, Hans J. P. Gille, Floor A. M. Duijkers, Anja Wagner, Ellis L. Eikenboom, Tom G. W. Letteboer, Mirjam M. de Jong, Sanne W. Bajwa-ten Broeke, Fonnet E. Bleeker, Encarna B. Gomez Garcia, Niels de Wind, J. Tom van Wezel, Hans Morreau, Manon Suerink, Maartje Nielsen^*

^*Corresponding author for this work

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

Abstract

Diagnosis of Lynch syndrome (LS) caused by a pathogenic germline MSH6 variant may be complicated by discordant immunohistochemistry (IHC) and/or by a microsatellite stable (MSS) phenotype. This study aimed to identify the various causes of the discordant phenotypes of colorectal cancer (CRC) and endometrial cancer (EC) in MSH6-associated LS. Data were collected from Dutch family cancer clinics. Carriers of a (likely) pathogenic MSH6 variant diagnosed with CRC or EC were categorized based on an microsatellite instability (MSI)/IHC test outcome that might fail to result in a diagnosis of LS (eg, retained staining of all 4 mismatch repair proteins, with or without an MSS phenotype, and other staining patterns). When tumor tissue was available, MSI and/or IHC were repeated. Next-generation sequencing (NGS) was performed in cases with discordant staining patterns. Data were obtained from 360 families with 1763 (obligate) carriers. MSH6 variant carriers with CRC or EC (n 1/4 590) were included, consisting of 418 CRCs and 232 ECs. Discordant staining was reported in 77 cases (36% of MSI/IHC results). Twelve patients gave informed consent for further analysis of tumor material. Upon revision, 2 out of 3 MSI/IHC cases were found to be concordant with the MSH6 variant, and NGS showed that 4 discordant IHC results were sporadic rather than LSassociated tumors. In 1 case, somatic events explained the discordant phenotype. The use of reflex IHC mismatch repair testing, the current standard in most Western countries, may lead to the misdiagnosis of germline MSH6 variant carriers. The pathologist should point out that further diagnostics for inheritable colon cancer, including LS, should be considered in case of a strong positive family history. Germline DNA analysis of the mismatch repair genes, preferably as part of a larger gene panel, should therefore be considered in potential LS patients. & COPY; 2023 THE AUTHORS. Published by Elsevier Inc. on behalf of the United States & Canadian Academy of Pathology. This is an open access article under the CC BY license (http://creativecommons.org/ licenses/by/4.0/).

Original language	English
Article number	100240
Number of pages	10
Journal	Modern Pathology
Volume	36
Issue number	9
Early online date	1 Jul 2023
DOIs	https://doi.org/10.1016/j.modpat.2023.100240
Publication status	Published - 1 Sept 2023

Keywords

immunohistochemistry
Lynch Syndrome
microsatellite instability
Mismatch repairdeficiency
NONPOLYPOSIS COLORECTAL-CANCER
MISMATCH REPAIR PROTEINS
LYNCH SYNDROME
ENDOMETRIAL CANCERS
INSTABILITY
IMMUNOHISTOCHEMISTRY
MUTATIONS
EXPRESSION
GERMLINE
COLON

Access to Document

10.1016/j.modpat.2023.100240Licence: CC BY

Cite this

van der Werf-'t, A.-S., Terlouw, D., Tops, C. M., van Kan, M. S., van Hest, L. P., Gille, H. J. P., Duijkers, F. A. M., Wagner, A., Eikenboom, E. L., Letteboer, T. G. W., de Jong, M. M., Broeke, S. W. B., Bleeker, F. E., Garcia, E. B. G., de Wind, N., van Wezel, J. T., Morreau, H., Suerink, M., & Nielsen, M. (2023). Discordant Staining Patterns and Microsatellite Results in Tumors of MSH6 Pathogenic Variant Carriers. Modern Pathology, 36(9), Article 100240. https://doi.org/10.1016/j.modpat.2023.100240

@article{40c0eec61881463486e1ee777432026a,

title = "Discordant Staining Patterns and Microsatellite Results in Tumors of MSH6 Pathogenic Variant Carriers",

abstract = "Diagnosis of Lynch syndrome (LS) caused by a pathogenic germline MSH6 variant may be complicated by discordant immunohistochemistry (IHC) and/or by a microsatellite stable (MSS) phenotype. This study aimed to identify the various causes of the discordant phenotypes of colorectal cancer (CRC) and endometrial cancer (EC) in MSH6-associated LS. Data were collected from Dutch family cancer clinics. Carriers of a (likely) pathogenic MSH6 variant diagnosed with CRC or EC were categorized based on an microsatellite instability (MSI)/IHC test outcome that might fail to result in a diagnosis of LS (eg, retained staining of all 4 mismatch repair proteins, with or without an MSS phenotype, and other staining patterns). When tumor tissue was available, MSI and/or IHC were repeated. Next-generation sequencing (NGS) was performed in cases with discordant staining patterns. Data were obtained from 360 families with 1763 (obligate) carriers. MSH6 variant carriers with CRC or EC (n 1/4 590) were included, consisting of 418 CRCs and 232 ECs. Discordant staining was reported in 77 cases (36% of MSI/IHC results). Twelve patients gave informed consent for further analysis of tumor material. Upon revision, 2 out of 3 MSI/IHC cases were found to be concordant with the MSH6 variant, and NGS showed that 4 discordant IHC results were sporadic rather than LSassociated tumors. In 1 case, somatic events explained the discordant phenotype. The use of reflex IHC mismatch repair testing, the current standard in most Western countries, may lead to the misdiagnosis of germline MSH6 variant carriers. The pathologist should point out that further diagnostics for inheritable colon cancer, including LS, should be considered in case of a strong positive family history. Germline DNA analysis of the mismatch repair genes, preferably as part of a larger gene panel, should therefore be considered in potential LS patients. & COPY; 2023 THE AUTHORS. Published by Elsevier Inc. on behalf of the United States & Canadian Academy of Pathology. This is an open access article under the CC BY license (http://creativecommons.org/ licenses/by/4.0/).",

keywords = "immunohistochemistry, Lynch Syndrome, microsatellite instability, Mismatch repairdeficiency, NONPOLYPOSIS COLORECTAL-CANCER, MISMATCH REPAIR PROTEINS, LYNCH SYNDROME, ENDOMETRIAL CANCERS, INSTABILITY, IMMUNOHISTOCHEMISTRY, MUTATIONS, EXPRESSION, GERMLINE, COLON",

author = "{van der Werf-'t}, Anne-Sophie and Diantha Terlouw and Tops, {Carli M.} and {van Kan}, {Merel S.} and {van Hest}, {Liselotte P.} and Gille, {Hans J. P.} and Duijkers, {Floor A. M.} and Anja Wagner and Eikenboom, {Ellis L.} and Letteboer, {Tom G. W.} and {de Jong}, {Mirjam M.} and Broeke, {Sanne W. Bajwa-ten} and Bleeker, {Fonnet E.} and Garcia, {Encarna B. Gomez} and {de Wind}, Niels and {van Wezel}, {J. Tom} and Hans Morreau and Manon Suerink and Maartje Nielsen",

year = "2023",

month = sep,

day = "1",

doi = "10.1016/j.modpat.2023.100240",

language = "English",

volume = "36",

journal = "Modern Pathology",

issn = "0893-3952",

publisher = "Nature Publishing Group",

number = "9",

}

van der Werf-'t, A-S, Terlouw, D, Tops, CM, van Kan, MS, van Hest, LP, Gille, HJP, Duijkers, FAM, Wagner, A, Eikenboom, EL, Letteboer, TGW, de Jong, MM, Broeke, SWB, Bleeker, FE, Garcia, EBG, de Wind, N, van Wezel, JT, Morreau, H, Suerink, M & Nielsen, M 2023, 'Discordant Staining Patterns and Microsatellite Results in Tumors of MSH6 Pathogenic Variant Carriers', Modern Pathology, vol. 36, no. 9, 100240. https://doi.org/10.1016/j.modpat.2023.100240

TY - JOUR

T1 - Discordant Staining Patterns and Microsatellite Results in Tumors of MSH6 Pathogenic Variant Carriers

AU - van der Werf-'t, Anne-Sophie

AU - Terlouw, Diantha

AU - Tops, Carli M.

AU - van Kan, Merel S.

AU - van Hest, Liselotte P.

AU - Gille, Hans J. P.

AU - Duijkers, Floor A. M.

AU - Wagner, Anja

AU - Eikenboom, Ellis L.

AU - Letteboer, Tom G. W.

AU - de Jong, Mirjam M.

AU - Broeke, Sanne W. Bajwa-ten

AU - Bleeker, Fonnet E.

AU - Garcia, Encarna B. Gomez

AU - de Wind, Niels

AU - van Wezel, J. Tom

AU - Morreau, Hans

AU - Suerink, Manon

AU - Nielsen, Maartje

PY - 2023/9/1

Y1 - 2023/9/1

N2 - Diagnosis of Lynch syndrome (LS) caused by a pathogenic germline MSH6 variant may be complicated by discordant immunohistochemistry (IHC) and/or by a microsatellite stable (MSS) phenotype. This study aimed to identify the various causes of the discordant phenotypes of colorectal cancer (CRC) and endometrial cancer (EC) in MSH6-associated LS. Data were collected from Dutch family cancer clinics. Carriers of a (likely) pathogenic MSH6 variant diagnosed with CRC or EC were categorized based on an microsatellite instability (MSI)/IHC test outcome that might fail to result in a diagnosis of LS (eg, retained staining of all 4 mismatch repair proteins, with or without an MSS phenotype, and other staining patterns). When tumor tissue was available, MSI and/or IHC were repeated. Next-generation sequencing (NGS) was performed in cases with discordant staining patterns. Data were obtained from 360 families with 1763 (obligate) carriers. MSH6 variant carriers with CRC or EC (n 1/4 590) were included, consisting of 418 CRCs and 232 ECs. Discordant staining was reported in 77 cases (36% of MSI/IHC results). Twelve patients gave informed consent for further analysis of tumor material. Upon revision, 2 out of 3 MSI/IHC cases were found to be concordant with the MSH6 variant, and NGS showed that 4 discordant IHC results were sporadic rather than LSassociated tumors. In 1 case, somatic events explained the discordant phenotype. The use of reflex IHC mismatch repair testing, the current standard in most Western countries, may lead to the misdiagnosis of germline MSH6 variant carriers. The pathologist should point out that further diagnostics for inheritable colon cancer, including LS, should be considered in case of a strong positive family history. Germline DNA analysis of the mismatch repair genes, preferably as part of a larger gene panel, should therefore be considered in potential LS patients. & COPY; 2023 THE AUTHORS. Published by Elsevier Inc. on behalf of the United States & Canadian Academy of Pathology. This is an open access article under the CC BY license (http://creativecommons.org/ licenses/by/4.0/).

AB - Diagnosis of Lynch syndrome (LS) caused by a pathogenic germline MSH6 variant may be complicated by discordant immunohistochemistry (IHC) and/or by a microsatellite stable (MSS) phenotype. This study aimed to identify the various causes of the discordant phenotypes of colorectal cancer (CRC) and endometrial cancer (EC) in MSH6-associated LS. Data were collected from Dutch family cancer clinics. Carriers of a (likely) pathogenic MSH6 variant diagnosed with CRC or EC were categorized based on an microsatellite instability (MSI)/IHC test outcome that might fail to result in a diagnosis of LS (eg, retained staining of all 4 mismatch repair proteins, with or without an MSS phenotype, and other staining patterns). When tumor tissue was available, MSI and/or IHC were repeated. Next-generation sequencing (NGS) was performed in cases with discordant staining patterns. Data were obtained from 360 families with 1763 (obligate) carriers. MSH6 variant carriers with CRC or EC (n 1/4 590) were included, consisting of 418 CRCs and 232 ECs. Discordant staining was reported in 77 cases (36% of MSI/IHC results). Twelve patients gave informed consent for further analysis of tumor material. Upon revision, 2 out of 3 MSI/IHC cases were found to be concordant with the MSH6 variant, and NGS showed that 4 discordant IHC results were sporadic rather than LSassociated tumors. In 1 case, somatic events explained the discordant phenotype. The use of reflex IHC mismatch repair testing, the current standard in most Western countries, may lead to the misdiagnosis of germline MSH6 variant carriers. The pathologist should point out that further diagnostics for inheritable colon cancer, including LS, should be considered in case of a strong positive family history. Germline DNA analysis of the mismatch repair genes, preferably as part of a larger gene panel, should therefore be considered in potential LS patients. & COPY; 2023 THE AUTHORS. Published by Elsevier Inc. on behalf of the United States & Canadian Academy of Pathology. This is an open access article under the CC BY license (http://creativecommons.org/ licenses/by/4.0/).

KW - immunohistochemistry

KW - Lynch Syndrome

KW - microsatellite instability

KW - Mismatch repairdeficiency

KW - NONPOLYPOSIS COLORECTAL-CANCER

KW - MISMATCH REPAIR PROTEINS

KW - LYNCH SYNDROME

KW - ENDOMETRIAL CANCERS

KW - INSTABILITY

KW - IMMUNOHISTOCHEMISTRY

KW - MUTATIONS

KW - EXPRESSION

KW - GERMLINE

KW - COLON

U2 - 10.1016/j.modpat.2023.100240

DO - 10.1016/j.modpat.2023.100240

M3 - Article

C2 - 37307877

SN - 0893-3952

VL - 36

JO - Modern Pathology

JF - Modern Pathology

IS - 9

M1 - 100240

ER -

Discordant Staining Patterns and Microsatellite Results in Tumors of MSH6 Pathogenic Variant Carriers

Abstract

Keywords

Access to Document

Fingerprint

Cite this