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Abstract
Introduction/Background Endometrial cancer has been shown to be the sentinel cancer in over half the female patients with heritable mismatch repair (MMR) mutations as part of Lynch syndrome. Immunohistochemical testing for MMR protein expression in endometrial cancer is the first screening test identifying cases that potentially harbour familial cancer syndrome-related mutations. MMR has also become a biomarker to predict response to targeted therapeutics such as in immune-checkpoint blockade. This is the first study to describe the prevalence of MMR protein expression defects in Maltese endometrial carcinoma patients and the correlation with patient age at diagnosis.
Methodology 200 endometrioid endometrial cancer cases were retrospectively identified from the Mater Dei Hospital laboratory information system and categorized into three arms: the first consisting of 151 cases over the age of 50 at diagnosis, the second consisting of 49 cases at or under the age of 50 at diagnosis and a control group consisting of 30 patients who underwent endometrial tissue sampling for benign conditions. H&E slides for these cases were re-examined by an independent pathologist to confirm the diagnosis as well as to identify the block best representing the tumour. Four new slides per case were recut and immunohistochemistry performed for MLH1, PMS2, MSH2, and MSH6 MMR proteins. Protein expression was analysed semiquantitatively using Allred score.
Results In the overall cohort 69% of cases were MMR proficient while 31% of cases were deficient for one or more MMR proteins. Dual loss of the MLH1 and PMS2 heterodimer protein expression was the most common deficiency and occurred in 24.5% of the EEC population. Loss of MSH2-MSH6 heterodimer protein expression was less common and represented 3.2% of MMR-deficient cases. Well differentiated tumours had a 76.5% proficiency rate as opposed to grade 2/3 disease with 53.2% and 52.9% proficiency rate respectively. There was no statistically significant difference in overall MMR status when age 50 was used as a hypothetical testing threshold. After correcting for tumour grade as a confounding variable it was shown that MLH1 and PMS2 expression were negatively correlated with increasing age while MSH6 expression was positively correlated with increasing age at diagnosis (figures 1 and 2).
Conclusion There is no statistically significant difference in overall immunohistochemical MMR status when using the age of 50 as a threshold for tumour analysis. Such a threshold would have missed 82.3% of cases with tumoral MMR deficiency and should not be included in lab protocols for EEC IHC analysis. Reflex testing of all EEC cases is highly advised as IHC testing is no longer solely about diagnosis of Lynch syndrome. Prospective evidence is required to clarify the role IHC scoring and semi-quantitative analysis should play in MMR status interpretation and patient management especially in the ever-evolving field of targeted therapeutics.
Disclosures This study was self-financed. Authors declare they have no conflict of interest, financial or otherwise.