TY - JOUR
T1 - Heterogenous MSH6 loss is a result of microsatellite instability within MSH6 and occurs in sporadic and hereditary colorectal and endometrial carcinomas
AU - Graham, Rondell P.
AU - Kerr, Sarah E.
AU - Butz, Malinda L.
AU - Thibodeau, Stephen N.
AU - Halling, Kevin C.
AU - Smyrk, Thomas C.
AU - Dina, Michelle A.
AU - Waugh, Victoria M.
AU - Rumilla, Kandelaria M.
N1 - Publisher Copyright:
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
PY - 2015/10/1
Y1 - 2015/10/1
N2 - Mismatch-repair (MMR) immunohistochemistry is used to detect tumor MMR deficiency associated with high-level microsatellite instability (MSI). Rare tumors show heterogenous loss of mutS homolog 6 (MSH6) with immunohistochemistry, defined by areas of retained staining and separate areas of complete loss of staining. To investigate the clinical interpretation of this phenomenon, we identified 22 cases of heterogenous MSH6 loss interpreted at Mayo Clinic from January 2001 through December 2012 and reviewed histologic features, MSH6 and other MMR immunohistochemistry, and accompanying MSI testing results (n=20). Heterogenous MSH6 loss was seen in colorectal carcinoma (n=18), endometrial carcinoma (n=3), and sebaceous neoplasm (n=1). In the 18 colorectal carcinoma cases, it accompanied complete loss of mutL homolog 1 (MLH1) or PMS2, or both. HeterogenousMSH6 loss was characterized byMSI and MSH6 C8 tract instability in treatment-naive cases and showed mucinous or signet-ring zones in one quarter of cases. Two cases status post neoadjuvant chemoradiation showed heterogenous MSH6 loss but were microsatellite and C8 tract stable. C8 tracts were unstable in 2 of 4 MSH6-associated Lynch syndrome (LS) tumors, but all 4 showed complete MSH6 loss on immunohistochemistry. Further, 12 such MSH6-associated LS cases showed complete MSH6 loss. In conclusion, heterogenous MSH6 loss is uncommon, usually caused by instability in MSH6 exon 5 polycytosine tract, and not associated with germline MSH6 mutation. Although heterogenous MSH6 loss provides evidence against germline MSH6 mutation, patients whose tumors exhibit this immunolabeling pattern may have LS due to a defect in a different MMR gene.
AB - Mismatch-repair (MMR) immunohistochemistry is used to detect tumor MMR deficiency associated with high-level microsatellite instability (MSI). Rare tumors show heterogenous loss of mutS homolog 6 (MSH6) with immunohistochemistry, defined by areas of retained staining and separate areas of complete loss of staining. To investigate the clinical interpretation of this phenomenon, we identified 22 cases of heterogenous MSH6 loss interpreted at Mayo Clinic from January 2001 through December 2012 and reviewed histologic features, MSH6 and other MMR immunohistochemistry, and accompanying MSI testing results (n=20). Heterogenous MSH6 loss was seen in colorectal carcinoma (n=18), endometrial carcinoma (n=3), and sebaceous neoplasm (n=1). In the 18 colorectal carcinoma cases, it accompanied complete loss of mutL homolog 1 (MLH1) or PMS2, or both. HeterogenousMSH6 loss was characterized byMSI and MSH6 C8 tract instability in treatment-naive cases and showed mucinous or signet-ring zones in one quarter of cases. Two cases status post neoadjuvant chemoradiation showed heterogenous MSH6 loss but were microsatellite and C8 tract stable. C8 tracts were unstable in 2 of 4 MSH6-associated Lynch syndrome (LS) tumors, but all 4 showed complete MSH6 loss on immunohistochemistry. Further, 12 such MSH6-associated LS cases showed complete MSH6 loss. In conclusion, heterogenous MSH6 loss is uncommon, usually caused by instability in MSH6 exon 5 polycytosine tract, and not associated with germline MSH6 mutation. Although heterogenous MSH6 loss provides evidence against germline MSH6 mutation, patients whose tumors exhibit this immunolabeling pattern may have LS due to a defect in a different MMR gene.
KW - Heterogenous mismatch-repair immunohistochemistry
KW - Lynch syndrome
KW - MSH6
KW - Microsatellite instability
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U2 - 10.1097/PAS.0000000000000459
DO - 10.1097/PAS.0000000000000459
M3 - Article
C2 - 26099011
AN - SCOPUS:84941756350
SN - 0147-5185
VL - 39
SP - 1370
EP - 1376
JO - American Journal of Surgical Pathology
JF - American Journal of Surgical Pathology
IS - 10
ER -