Specific Biomarker Expression Patterns in the Diagnosis of Residual and Recurrent Endometrial Precancers After Progestin Treatment

Abstract

Background: Conservative management with progestin is a treatment option for atypical hyperplasia (AH). However, pathologic diagnosis of residual/recurrent lesions is often problematic because of the profound morphologic changes induced by progestin and the lack of established diagnostic criteria for progestin-treated residual AH. Methods: We conducted a longitudinal study of 265 endometrial biopsies from 54 patients with a history of AH on progestin therapy. Patient outcomes were divided into 3 categories after morphologic review and immunohistochemical staining with phosphatase and tensin homolog (PTEN) and paired box 2 (PAX2): (1) persistent or residual disease; (2) recurrent disease; (3) complete response. All specimens were classified into 3 categories based on morphology: (1) persistent/recurrent disease (nonresponse), (2) morphologically uncertain response, (3) optimally treated (complete response). The staining patterns of PTEN/PAX2 were tracked over time in individual patients and correlated with morphologic findings before and after progestin therapy. Results: Our data showed that aberrant expression patterns of PTEN and/or PAX2 were identified in 48 (88.9%) of the 54 primary biopsies and persisted in persistent/recurrent AH across serial endometrial biopsies (n=99, P<0.00001), while normal PTEN and PAX2 expressions were consistently observed in optimally treated cases (n=84, P<0.00001). More importantly, follow-up biopsies that showed a morphologically uncertain response but a PTEN/PAX2 expression pattern identical to the initial biopsy were significantly correlated with persistent or recurrent disease (n=18, P=0.000182), as evidenced by areas with morphologic features diagnostic of AH on subsequent biopsy. Conclusions: Biomarker PTEN/PAX2 signatures offer a valuable diagnostic aid to identify residual AH in progestin-treated endometrial samples for which the biomarker status from preprogestin treated AH is known. The findings of this study are promising for a possible future change of diagnostic practice.

Use of clinicopathological factors to predict prognosis of fertility‑sparing treatment for endometrial endometrioid carcinoma and atypical hyperplasia

“…Similarly, an association between PTEN protein expression and prognosis was not demonstrated in the EEC and AH groups before treatment. This was not consistent with the data previously reported by Chen et al ( 14 ). In a previous meta-analysis or systematic review of fertility-sparing treatment of EEC or AH in young women, no clear predictive biomarkers which were associated with remission, recurrence or progression could be identified following multivariate analysis ( 30 ).…”

“…The patients underwent follow-up using endometrial sampling by hysteroscopy or curettage to assess endometrial changes every 3 months. According to Wheeler et al ( 13 ) and Chen et al ( 14 ), response to treatment based on the latest biopsy can be classified as follows: i) Complete response (CR), defined as a proliferative, secretory, inactive or atrophic endometrium without hyperplasia or atypia; ii) partial response (PR), defined as histological regression with decidual endometrial change; iii) stable disease (SD), defined as the persistence of EEC or AH/EIN in both the original and final specimens; iv) progressive disease (PD), defined as progression to lesions if the pre-treatment specimen showed AH whereas the latest specimen showed EEC, or if the original specimen showed grade 1 EEC whereas the latest specimen showed EEC grade 2 or 3; and v) recurrent disease (RD), defined as a CR to progestin treatment once or more according to a follow-up biopsy, but in which EEC/AH recurrence was subsequently identified. All pre-treatment and post-treatment evaluations were independently performed by two experienced gynecological pathologists.…”

Reliable Identification of Endometrial Precancers Through Combined Pax2, β-Catenin, and Pten Immunohistochemistry

“… 7 , 52 A large recent longitudinal investigation of Pax2 and Pten expression patterns in serial biopsies from women treated with progestin found that expression patterns in pretreatment AH/EIN were consistently recapitulated by AH/EIN present following treatment. 53 β-Catenin patterns are also likely to be recapitulated following treatment. 37 Thus, in addition to facilitating the initial diagnosis of AH/EIN, establishment of baseline expression patterns should be useful diagnostically in follow-up biopsies in the setting of progestin treatment.…”

β-catenin, Pax2, and Pten Panel Identifies Precancers Among Histologically Subdiagnostic Endometrial Lesions

“…Interpretation is across an entire biopsy, not limited to the most worrisome foci (making it useful even with limited samples), and it is able to detect aberrancy across a wide range of morphologic alterations as documented in this and prior studies. 27,54 At the same time, the 3-marker panel has some shortcomings. In addition to the time and cost associated with 3 immunostains, it too has nuances in interpretation.…”

“…Interpretation is across an entire biopsy, not limited to the most worrisome foci (making it useful even with limited samples), and it is able to detect aberrancy across a wide range of morphologic alterations as documented in this and prior studies. 27 , 54 …”