Central Pathology Review of Endometrial Hyperplasia and Adenocarcinoma Before and After Treatment With the Levonorgestrel Intrauterine Device–Results From the feMMe Phase 2 Randomized Clinical Trial

Distinguishing endometrial hyperplasia from endometrial adenocarcinoma remains a histopathologic challenge. Several retrospective studies have reported high interobserver variability when assessing the progestin-naive endometrium, while only one study has assessed interobserver variability of postprogestin endometrial biopsies. This study quantified the interobserver variability between trial site pathologists and central pathology review of endometrial specimens taken before treatment with the levonorgestrel intrauterine device (LNG-IUD), 3 months and 6 months post-treatment as part of the feMMe phase 2 randomized clinical trial (NCT01686126). Interobserver agreement was 73% (105/143, κ=0.50) at baseline, 80% (107/134, κ=0.72) at 3 months and 77% (98/127, κ=0.64) at 6 months post-LNG-IUD treatment. Overall, 42% (45/107) site-reported diagnoses of endometrial hyperplasia and 13% (21/161) site-reported diagnoses of endometrial adenocarcinoma were discordant. Site-reported diagnoses were upgraded to higher risk pathology on central review for 77% (72/94) discordant cases. This study confirms the high rate of interobserver variability when diagnosing endometrial hyperplasia or endometrial adenocarcinoma both before and after progestin treatment in specimens collected as part of a clinical trial. It emphasizes the value of confirming diagnosis by a gynecologic pathologist and comparing specimens from the progestin-treated endometrium with the pretreatment biopsy. This study highlights the importance of central pathology review for clinical trial reporting and when deciding on treatment options and assessing response, particularly in the context of progestin treatment.