Prognostic impact of hysteroscopic resection of endometrial atypical hyperplasia/endometrioid intraepithelial neoplasia and early-stage cancer in combination with megestrol acetate

Objective: In 5-30% of cases, endometrial cancer occurs in women age 45 or younger. A valid option for women desiring fertility is primary hormonal treatment, such as oral megestrol acetate (MA) alone or combined with hysteroscopic resection1, or levonorgestrel-releasing intrauterine system (LNG-IUS); however, 20-30% and 41% patients undergoing progestin-based treatments alone failed to achieve complete response (CR) and recur2. The current knowledge is drawn from observational cohort studies on small series of patients for which long follow-up is rare3. Moreover, the worldwide data on hysteroscopic treatment are still limited4. Here, we evaluated the prognostic outcome of a large, single-institution series of young women diagnosed with endometrial atypical hyperplasia (EAH)/endometrioid intraepithelial neoplasia (EIN) and early stage endometrial cancer (EEC) who were selected for fertility preservation and treated with oral MA combined with hysteroscopic resection in the subgroup of patients carrying a single lesion. Study design: Patients with EAH/EIN (n= 49) or well differentiated EEC (n= 36), FIGO stage IA (no myometrial invasion at MRI) were prospectively included from June 2007 to December 2019. The inclusion criteria for conservative treatment followed NCCN guidelines 20185. All patients received MA 160 mg daily for a minimum of 6 months and were evaluated by hysteroscopy-guided biopsy and ultrasounds every three months until achieving CR. Next, follow-up was performed every 3 months until pregnancy was obtained. Only suspected single lesion (cancerous polyp or neoformation) were hysteroscopically removed before progestin treatment with the NEMos (Neoplasia Endometrium Myometrium organized sections) technique1,6. Multifocal lesions were treated with MA alone. Results: The median follow-up time was 36 months (range 6-150). A total of 82 patients (96.5%) achieved CR. The mean treatment duration for achieving CR was 4.51 months (range 3-18 months). Hysteroscopic removal of EAH/EIN or EEC prior to therapy was the only factor significantly associated with shorter treatment duration to achieve CR (p=0.001). Patients who underwent hysteroscopic resection plus MA (n=15) or MA therapy alone (n=67) achieved CR in 3.4 months (range 3-18) and 4.75 months (range 3-18), respectively. The cumulative relapse rate was 62% (51/82) and the median time to relapse was 21 months (28 months for EAH/EIN and 21 months for EEC). Patients with lesion removed by hysteroscopy plus MA relapsed later (average 38, median 33, range 6-150 months) compared to patients who were treated with MA alone (average 27, median 18, range 6-108 months) (p=0.043) (Fig. 1). Among the 82 patients who achieved CR, 52 patients planned for parenthood; and 26 patients (50%) achieved at least one pregnancy. Only 4 patients received in vitro fertilization. Spontaneous miscarriage rate was 17% (9 out of 52 cases) and live birth rate was 32.7% (17 out of 52 cases), respectively. Conclusion: In this study, we report our institutional experience with a large series of EAH/EIN (n=49) and EEC (n=36) patients eligible for fertility-sparing treatment with MA alone or combined with NEMo's hysteroscopic resection1,5. We found that hysteroscopic resection of EAH/EIN or EEC in combination with oral progestin therapy was significantly associated with shorter treatment duration to achieve CR and longer time to relapse, compared to patients treated with progestin therapy alone. This large, single-institution study provides convincing data on the efficacy of MA plus hysteroscopic resection in conservative treatment of both EAH/EIN and EC patients, which will have to be confirmed in a prospective multi-institutional trial