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Multiplexed Fluorescent Immunohistochemical Staining of Four Endometrial Immune Cell Types in Recurrent Miscarriage
Published on: August 4, 2021
Subclonal loss of DNA mismatch repair proteins in endometrial carcinomas: an unusual pattern with distinct molecular
Graziele Bovolim1, Sara Oliveira Silva2, Bruna Tirapelli Gonçalves2
1A.C.Camargo Cancer Center, Department of Anatomic Pathology, São Paulo, Brazil.
Objective:
Subclonal loss of mismatch repair (MMR) proteins in endometrial carcinoma has recently been identified through immunohistochemistry (IHC) evaluations, characterized by discrete areas of tumors with complete loss of nuclear expression adjacent to tumor cells with retaining expression. Controversies persist regarding reporting findings and managing such cases. Therefore, we conducted a detailed clinicopathological and molecular analysis on a large cohort of endometrial carcinoma cases with subclonal loss of MMR proteins to explore potential reclassification into different molecular categories that could influence diagnostic and treatment strategies.
Methods:
Eligible endometrial carcinoma cases underwent IHC evaluation for PMS2/MLH1/MSH2/MSH6. Cases showing subclonal loss of MMR proteins underwent macrodissection of both proficient and deficient MMR expression areas, followed by testing for microsatellite instability (Idylla), MLH1 promoter methylation (next-generation sequencing), POLE mutations (next-generation sequencing), and p53 expression (IHC). The proposed molecular evaluation was performed in both proficient and deficient areas. Clinical and pathological data for patients with subclonal loss were also analyzed.
Results:
We evaluated 356 cases of endometrial carcinoma, identifying subclonal loss in 16 patients (4.4%), predominantly endometrioid (15 cases, 93.75%) and International Federation of Gynecology and Obstetrics stage I (13 cases, 81.25%). Subclonal loss of MSH6 occurred independently in 6 cases (37.5%), and concurrently with subclonal loss of MLH1 in 2 cases (12.5%). Complete loss of MLH1/PMS2 was observed in 2 cases (12.5%). MLH1 promoter methylation was detected in 6 cases (37.5%), with 4 cases showing methylation in both areas analyzed. POLE mutations were found in 3 cases (18.75%), occurring in both deficient and proficient areas. The correlation between IHC findings and molecular results varied, providing valuable predictive and prognostic insights that could guide treatment decisions in some patients.
Conclusions:
Molecular evaluation should be standard practice in all endometrial carcinoma cases exhibiting subclonal loss of MMR proteins to accurately delineate tumor characteristics. Subclonal loss should be reported distinctly, warranting a more comprehensive diagnostic approach to enhance tumor classification.
Insights
Subclonal loss of mismatch repair (MMR) proteins in endometrial cancer requires molecular analysis for accurate classification. Reporting distinct subclonal loss is crucial for improved diagnosis and treatment strategies.
Area of Science:
- Oncology
- Molecular Pathology
- Cancer Genomics
Background:
- Subclonal loss of mismatch repair (MMR) proteins in endometrial carcinoma presents diagnostic challenges.
- Immunohistochemistry (IHC) reveals discrete tumor areas with MMR protein loss, leading to management controversies.
Purpose of the Study:
- To conduct a clinicopathological and molecular analysis of endometrial carcinoma cases with subclonal MMR protein loss.
- To explore reclassification into molecular categories influencing diagnostic and treatment strategies.
Main Methods:
- IHC for MMR proteins (PMS2/MLH1/MSH2/MSH6) on 356 endometrial carcinoma cases.
- Macrodissection of proficient and deficient MMR areas for microsatellite instability, MLH1 promoter methylation, POLE mutations, and p53 expression analysis.
- Correlation of IHC findings with molecular results and clinical data.
Main Results:
- Subclonal MMR loss identified in 16 cases (4.4%), primarily endometrioid and early-stage tumors.
- MSH6 loss occurred independently or with MLH1 loss; MLH1/PMS2 complete loss seen in 2 cases.
- MLH1 promoter methylation and POLE mutations were detected in subsets of cases, with varied distribution in proficient/deficient areas.
Conclusions:
- Molecular evaluation is essential for endometrial carcinoma cases with subclonal MMR loss.
- Distinct reporting of subclonal loss is necessary for comprehensive tumor classification and improved patient management.
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