TY - JOUR
T1 - Discordant Staining Patterns and Microsatellite Results in Tumors of MSH6 Pathogenic Variant Carriers
AU - van der Werf-'t Lam, 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 - Bajwa-Ten Broeke, Sanne W
AU - Bleeker, Fonnet E
AU - Gomez Garcia, Encarna B
AU - de Wind, Niels
AU - van Wezel, J Tom
AU - Morreau, Hans
AU - Suerink, Manon
AU - Nielsen, Maartje
N1 - Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
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 = 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 LS-associated 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.
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 = 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 LS-associated 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.
KW - Colonic Neoplasms/genetics
KW - Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis
KW - Colorectal Neoplasms/pathology
KW - DNA Mismatch Repair/genetics
KW - DNA-Binding Proteins/genetics
KW - Endometrial Neoplasms/genetics
KW - Female
KW - Humans
KW - Lynch Syndrome
KW - Microsatellite Instability
KW - Microsatellite Repeats
KW - immunohistochemistry
KW - mismatch repair deficiency
UR - http://www.scopus.com/inward/record.url?scp=85172424189&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.modpat.2023.100240
DO - https://doi.org/10.1016/j.modpat.2023.100240
M3 - Article
C2 - 37307877
SN - 0893-3952
VL - 36
SP - 100240
JO - Modern Pathology
JF - Modern Pathology
IS - 9
M1 - 100240
ER -