Mismatch repair markers in preoperative and operative endometrial cancer samples; expression concordance and prognostic value

Berg, Hege Fredriksen; Engerud, Hilde; Myrvold, Madeleine; Lien, Hilde; Hjelmeland, Marta Espevold; Halle, Mari K.; Woie, Kathrine; Høivik, Erling A.; Haldorsen, Ingfrid S.; Vintermyr, Olav Karsten; Trovik, Jone; Krakstad, Camilla

doi:10.1038/s41416-022-02063-3

Cited by 10 publications

(9 citation statements)

References 43 publications

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“…The International Society of Gynecological Pathologists (ISGyP) recommends MMR/MSI status analysis (preferably with curettage or hysterectomy samples) for EC patients of all ages ( Cho et al, 2019 ). Our results were similar to those of previous studies ( Talhouk et al, 2016 ; Berg et al, 2023 ), with 27.5% and 26.7% of dMMR and MSI-H, respectively, for the curettage samples but slightly higher than the 23.8% and 22.3% for the hysterectomy samples.…”

Section: Discussionsupporting

confidence: 92%

A retrospective study of consistency between immunohistochemistry and polymerase chain reaction of microsatellite instability in endometrial cancer

Wang,

Kuang,

Zeng

et al. 2023

PeerJ

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Objectives Identification of endometrial cancers (EC) with mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H) is essential for Lynch syndrome screening and treatment stratification. We aimed to assess the utility of immunohistochemistry (IHC) staining for MMR protein expression and polymerase chain reaction (PCR)-based MSI assays in EC and the correlation between MMR/MSI status and various clinicopathological parameters. Methods We reviewed the clinical and pathological information of 333 patients with EC. MMR protein expression was assessed as retained or lost to determine MMR status by IHC staining, and MSI status was identified by PCR capillary electrophoresis (PCR-CE) testing with a National Cancer Institute (NCI) panel. The correlation of MMR/MSI status with clinicopathological features was determined by statistical analysis. Discrepant results were further analyzed using an alternative PCR-CE MSI (Promega panel) method, MLH1 promoter methylation assays, and next-generation sequencing (NGS). Results Among the EC patients, the overall percentage of dMMR was 25.2%, and the overall percentage of MSI-H was 24%. Among the dMMR patients, 50 (59.5%) showed loss of MLH1 and PMS2 expression, 19 (22.6%) loss of MSH2 and MSH6 expression, and seven (8.3%) and eight (9.5%) loss of PMS2 and MSH6 expression, respectively. The dMMR subgroup was significantly younger than the pMMR subgroup, especially for <60-years-old patients (p = 0.038). In addition, we identified a strong correlation between MMR/MSI status and high-grade endometrioid or nonendometrioid components (p = 0.004 or p = 0.003). IHC staining and PCR-CE assay results showed a high level of overall concordance (98.8%, Cohen’s κ = 0.98). Four patients were found to have dMRR/MSS in both examinations. We reanalyzed them with additional methods. One case showed MLH1 promotor methylation, and the other three cases harbored MSH6 germline pathogenic variations. One of the cases with MSH6 deficiency was reanalyzed as MSI-H by alternative PCR-CE assay or NGS testing. Conclusions This study indicates that the combined use of MMR-IHC and PCR-CE MSI analyses may effectively avoid misdiagnoses of EC patients with dMMR/MSI-H. However, use of PCR-CE alone to evaluate MMR/MSI status may lead to missed diagnosis, especially for EC patients with MSH6 deficiency and presenting MSS.

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Section: Discussionsupporting

confidence: 92%

A retrospective study of consistency between immunohistochemistry and polymerase chain reaction of microsatellite instability in endometrial cancer

Wang,

Kuang,

Zeng

et al. 2023

PeerJ

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“…Factors such as advanced age, higher grade, LVSI, and deeper myometrial invasion are utilized to predict patients at high risk for recurrence despite early stage disease. This study, and others ( 9 , 13 , 22 , 27 , 28 ), confirms that MMR deficient EC is associated negative prognostic indicators. However, we found that patients with probable MMR mutation did not differ from those with MMR proficient EC in terms of stage, grade, LVSI, and myometrial invasion.…”

Section: Discussionsupporting

confidence: 87%

“…However, even with these poor prognostic features, data regarding outcomes in EC with MMR deficiency and epigenetic MMR defects have been inconsistent (9,21). While many groups have reported on reduced recurrence free survival in EC with MMR defects others have reported that there is no effect or even an improvement in OS in these tumors (11,(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33).…”

Section: Introductionmentioning

confidence: 99%

Epigenetic MMR defect identifies a risk group not accounted for through traditional risk stratification algorithms in endometrial cancer

et al. 2023

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PurposeWe sought to evaluate the contribution of mismatch repair (MMR) status to traditional risk stratification algorithms used to predict nodal involvement and recurrence in a large single-institution cohort.MethodsEndometrioid endometrial cancer (EC) cases from 2014-2020 were evaluated. MMR immunohistochemistry (IHC) was performed universally. Uterine factors assessed in the Mayo criteria were used to retrospectively classify patients as low or high risk for lymphatic spread. Patients were classified according to risk for recurrence using GOG 99 and PORTEC criteria. Associations were evaluated using chi-square and t-tests and contributing factors assessed using logistic regression models.Results1,514 endometrioid EC were evaluated; 392 (25.9%) were MMR (MMR) deficient of which 80.4% of MMR defects were associated with epigenetic silencing of MLH1. Epigenetic MMR defects were significantly more likely to be high risk for lymph node (LN) metastasis based on Mayo criteria (74.9% vs 60.6%, p=<0.001) and with the presence of LN metastasis (20.3 vs 10.5%, p=0.003) compared to MMR proficient tumors. Tumors with epigenetic MMR defects were significantly more likely to be classified as high or high intermediate risk using GOG99 and PORTEC criteria. Furthermore, cases with epigenetic MMR defects classified as low or low intermediate risk were significantly more likely to recur (GOG99 p=0.013; PORTEC p=0.008) and independently associated with worse disease-free survival (DFS). MMR status was found to be independently associated with worse DFS (HR 1.90; 95% CI 1.34-2.70; p=0.003) but not overall survival.ConclusionWhile MMR deficient EC has been associated with poor prognostic features in prior reports; we demonstrate that only epigenetic MMR defects have poorer outcomes. Epigenetic MMR defect were independently associated with lymph node metastasis after controlling for risk criteria. Epigenetic MMR deficiency was found to be an independent predictor of recurrence beyond the factors considered in traditional risk stratification algorithms. Traditional uterine-based risk stratification algorithms may not fully reflect the risk for recurrence in MMR deficient tumors. Consideration should be given to implementing MMR status and MLH1 hypermethylation alongside traditional risk stratification algorithms. Performing MMR IHC on preoperative pathologic specimens may aid in risk stratification and patient counseling.

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“…In this study, we constructed classification models using surgical specimens, but it is known that there is substantial agreement regarding MMR status between endometrial curettage and hysterectomy samples. Berg et al [61] mentioned the high concordance rate that can be used not only as a value for MMR status classification in endometrial cancer but also as an independent prognostic marker before resection. Therefore, if the AI classification model could be constructed for curettage specimens, it would enable the consideration of treatment strategies at an earlier phase.…”

Section: Discussionmentioning

confidence: 99%

Prediction of Mismatch Repair Status in Endometrial Cancer from Histological Slide Images Using Various Deep Learning-Based Algorithms

Umemoto,

Mariya,

Nambu

et al. 2024

Cancers

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The application of deep learning algorithms to predict the molecular profiles of various cancers from digital images of hematoxylin and eosin (H&E)-stained slides has been reported in recent years, mainly for gastric and colon cancers. In this study, we investigated the potential use of H&E-stained endometrial cancer slide images to predict the associated mismatch repair (MMR) status. H&E-stained slide images were collected from 127 cases of the primary lesion of endometrial cancer. After digitization using a Nanozoomer virtual slide scanner (Hamamatsu Photonics), we segmented the scanned images into 5397 tiles of 512 × 512 pixels. The MMR proteins (PMS2, MSH6) were immunohistochemically stained, classified into MMR proficient/deficient, and annotated for each case and tile. We trained several neural networks, including convolutional and attention-based networks, using tiles annotated with the MMR status. Among the tested networks, ResNet50 exhibited the highest area under the receiver operating characteristic curve (AUROC) of 0.91 for predicting the MMR status. The constructed prediction algorithm may be applicable to other molecular profiles and useful for pre-screening before implementing other, more costly genetic profiling tests.

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Mismatch repair markers in preoperative and operative endometrial cancer samples; expression concordance and prognostic value

Cited by 10 publications

References 43 publications

A retrospective study of consistency between immunohistochemistry and polymerase chain reaction of microsatellite instability in endometrial cancer

A retrospective study of consistency between immunohistochemistry and polymerase chain reaction of microsatellite instability in endometrial cancer

Epigenetic MMR defect identifies a risk group not accounted for through traditional risk stratification algorithms in endometrial cancer

Prediction of Mismatch Repair Status in Endometrial Cancer from Histological Slide Images Using Various Deep Learning-Based Algorithms

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