Assessing the prognostic value of PAX2 and PTEN in endometrial carcinogenesis

in Endocrine-Related Cancer
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In order to avoid the consequences of over- and under-treatment of endometrial hyperplasia, diagnostic accuracy and progression risk assessment must be improved. The aim of this study was to assess whether PAX2 or PTEN expression could predict progression-free survival in endometrial intraepithelial neoplasia (EIN) and endometrial endometrioid carcinoma (EEC). Immunohistochemistry for detection of PAX2 and PTEN was performed on 348 endometrial samples; 75 proliferative endometrium (PE), 36 EIN and 237 EEC. Cases classified as PTEN null (1 or more glands negatively stained) were more prevalent in EEC than in PE and EIN (64% EEC vs 11% PE/EIN). A progressive decrease in PAX2 expression was observed from PE to EIN to EEC. Long-term clinical follow-up (6–310 months, median: 126) was available for 62 PE cases, all 36 EIN cases and 178 EEC cases. No patients with PE demonstrated progression to EIN or EEC. Progression of disease was observed in 10 (28%) EIN patients. These patients had significantly lower PAX2 expression than those that regressed (P = 0.005). Progression-free survival analysis revealed that EIN patients with a high-risk PAX2 expression score (H-score ≤75) had a higher probability of progression of disease in comparison to those with a low-risk score (H-score >75). PAX2 expression was not prognostic in EEC nor was PTEN status of prognostic value in either EIN or EEC. PAX2 expression analysis by means of H-score has prognostic potential for the identification of high-risk progression cases in EIN but needs to be validated in a larger cohort.

 

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    Example of an EIN lesion immunostained for the detection of (A and B) PAX2 or (C and D) PTEN protein. The D-score was −0.5. (A) Intensity of PAX2 staining was observed to vary across the lesion. Of note, glands with weak expression and glands with strong expression tended to group within the lesion. (B) A close-up of glands indicated by the box in (A) compares a gland with low expression (top) with a gland with high PAX2 expression (bottom). PAX2 expression could also vary within a single gland with some nuclei strongly expressing PAX2 neighbouring nuclei that did not. (C) This lesion was defined as PTEN-null due to the presence of one or more PTEN-null glands (null glands indicated by absence of PTEN staining). PTEN-negative staining was very distinct from PTEN-positive staining with neighbouring glands showing contrasting expression in some areas. (D) A close-up of the glands indicated by the box in (C) emphasising that PTEN staining was very distinct readily distinguishing PTEN-positive (bottom) glands from PTEN-negative glands (top). Scale bar represents 100 µm. A full colour version of this figure is available at https://doi.org/10.1530/ERC-18-0106.

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    PAX2 expression according to diagnosis. All diagnostic categories had significantly different PAX2 expression scores (one-way ANOVA, P < 0.05).

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    PAX2 expression of EIN patients that demonstrated either progression (n = 10) or regression (n = 26) in the follow-up. Patients with an initial EIN diagnosis where progression was observed in the follow-up had a significantly lower PAX2 expression score than those that regressed (independent samples t-test, P = 0.005).

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    Long-term progression-free survival curve of patients initially diagnosed with EIN according to risk status determined by PAX2 expression score. For EIN samples that were defined as high-risk, where PAX2 ≤75 (n = 11, red) patients had a significantly lower progression-free survival than low-risk patients, where PAX >75 (n = 25, blue) (Kaplan–Meier log rank, P = 0.001). A full colour version of this figure is available at https://doi.org/10.1530/ERC-18-0106.

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