Nomogram using human epididymis protein 4 predicted concurrent endometrial cancer from endometrial atypical hyperplasia before surgery.

Objective: To establish a nomogram based on presurgical predictors of concurrent endometrial cancer (EC) for patients diagnosed with endometrial atypical hyperplasia before definitive surgery (preoperative-EAH) to improve the risk stratification and clinical application. Methods: Preoperative-EAH patients who underwent hysterectomy in a tertiary hospital from January 2020 to December 2022 were retrospectively analyzed. Independent predictors from the multivariate logistic regression model were used to establish a nomogram, and bootstrap resampling was used for internal validation. Results: Of 370 preoperative-EAH patients, 23.4% were diagnosed with EC after definitive surgery (final-EC). Multivariate analyses found three independent predictors of final EC: human epididymis protein 4 (HE4) ≥43.50 pmol/L [odds ratio (OR) = 3.70; 95% confidence intervals (CI) = 2.06-6.67], body mass index (BMI) ≥ 28 kg/m2 (OR = 2.05; 95% CI = 1.14-3.69), and postmenopausal status, particularly at postmenopausal time ≥5 years (OR = 5.84, 95% CI = 2.51-13.55), which were used to establish a nomogram model. The bootstrap-corrected C-index of the nomogram was 0.733 (95% CI = 0.68-0.79), which was significantly higher than that of each individual factor. The calibration curve and decision curve showed good consistency and clinical net benefit of the model. At the maximum Youden index, 49.4% (43/87) of women in the high-risk group defined by nomogram had concurrent EC, versus 16.6% in the low-risk group (P< 0.001). Conclusion: The nomogram based on HE4, menopausal status, and BMI was found with an improved predictive value to stratify preoperative-EAH patients at high risk of concurrent EC for better clinical management.

Fertility-sparing treatment in MSI-H/MMRd endometrial carcinoma or atypical endometrial hyperplasia: A systematic review and meta-analysis.

INTRODUCTION: This systematic review and meta-analysis aimed to describe the oncological and reproductive outcomes of patients with MSI-H/MMRd endometrial carcinoma (EC) or atypical endometrial hyperplasia (AEH) undergoing fertility-sparing treatment. METHODS: The study protocol was registered with the PROSPERO database (No: CRD42024530406). A systematic literature search in major electronic databases (PubMed, Embase, and Cochrane Library) was conducted from January 1, 2013 to August 10, 2024. The primary outcomes were complete remission (CR) rate and recurrence rate. Other outcomes included oncological outcomes in patients with Lynch syndrome and overall patient fertility status. RESULTS: The study included ten retrospective studies summarizing 66 patients with MSI-H/MMRd undergoing fertility-sparing treatment. The publication bias analysis was low. The length of follow-up varied from 3 to 164 months according to the different studies analyzed. After fertility-sparing treatment, 61.8 % of patients achieved CR, and 41.2 % of patients relapsed. Twelve patients were identified with germline mutations in Lynch syndrome, nine (75 %) achieved CR, and seven (77.8 %) relapsed. Only one study with active use of assisted reproductive technology reported a 1-year cumulative pregnancy rate of more than 60 % and more than half live births, while the remaining five studies assessed fertility outcomes and reported only one live birth. CONCLUSION: EC and AEH patients with the MSI-H/MMRd subtype had a low remission rate and high recurrence rate compared to conservative treatment. Caution is recommended when evaluating fertility-sparing therapy for patients with the MSI-H/MMRd subtype.

Clinicopathological characteristics and fertility preserving treatment of atypical polypoid adenomyoma.

Objective: Atypical polypoid adenomyoma (APA) is a rare benign tumor frequently diagnosed in young women that may coexist with or progress to atypical endometrial hyperplasia (EAH) or endometrioid endometrial carcinoma (EEC). This study aimed to investigate which subset of patients with APA are prone to concurrent or subsequent EAH or EEC, evaluate the necessity of progestin treatment in patients with APA only after achieving a complete response (CR) through hysteroscopic lesion resection, and assess the impact of concurrent APA on the fertility-preserving treatment of EAH or EEC. Methods: This retrospective single-center study analyzed 86 patients with APA treated at the Obstetrics and Gynecology Hospital of Fudan University between January 2010 and October 2021. Patients with EAH or EEC only who underwent fertility-preserving treatment during the same period were matched in a 2:1 ratio with patients with concurrent APA and EAH or EEC. The clinicopathological characteristics, treatments, and prognosis were analyzed. Results: The median patient age was 31 years (range 21-47 years). Among the 86 included patients, nine underwent total hysterectomy, 62 received conservative treatment, and the remaining 15 were lost to follow-up. A comparison of the 16 patients with APA only versus the 58 patients with APA and concurrent or subsequent EAH or EEC revealed that a homeostasis model assessment of insulin resistance (HOMA-IR) of > 2.2 (P = 0.047) and high-density lipoprotein (HDL) concentration of < 1.2 mmol/L (P = 0.028) were independent risk factors for EAH or EEC in patients with APA. Among the 17 patients with APA only who received conservative treatment and achieved a CR after hysteroscopic lesion resection, 13 received hormone treatment for a median duration of 6.3 months. The median follow-up time for these 17 patients was 49.0 months, during which no recurrence of APA was observed, but six patients developed endometrial hyperplastic diseases. Regarding the impact of concurrent APA on fertility-preserving treatment for EAH or EEC, the median time to achieve a CR was 24.0 weeks (95% confidence interval [CI]: 23.0-40.4) in the APA group and 26.0 weeks (95% CI: 24.3-32.3) in the non-APA group (P = 0.424). There were no significant differences between the two groups in the outcomes of fertility-preserving treatment. Conclusion: Patients with APA only may still develop endometrial hyperplastic diseases after complete resection of the lesion under hysteroscopy to achieve a CR, particularly those with a HOMA-IR of > 2.2 or HDL concentration of < 1.2 mmol/L. Concurrent APA did not affect the efficacy of fertility-preserving treatment in patients with EAH or EEC.

Mismatch repair deficiency and abnormal p53 expression has significant predictive value for progesterone resistance and endometrial tumorigenesis in patients with endometrial atypical hyperplasia receiving fertility-preserving treatment.

OBJECTIVE: This study aimed to evaluate the prognostic ability of mismatch repair deficiency (MMR-d) and abnormal p53 expression (p53abn) in patients with endometrial atypical hyperplasia (EAH) who underwent fertility-preserving treatment. METHODS: This retrospective study evaluated 51 patients with EAH who underwent fertility-sparing treatment. Endometrial biopsy specimens obtained before hormone therapy were collected and used for immunohistochemical staining for MMR and p53 proteins. Response, relapse, and progression rates were assessed based on age, body mass index, diabetes, polycystic ovary syndrome, reproductive history, MMR status, and p53 status. RESULTS: Overall, 11/51 (21.6%) patients had loss of MMR proteins and 6/51 (11.8%) had p53abn. Patients with MMR-d had lower complete response (CR) rates than those with normal staining patients at 12 months after initial treatment (p = 0.049). Patients with MMR-d had significantly higher relapse rates than those with MMR-p at the 1-year follow-ups after achieving CR (p = 0.035). Moreover, patients with MMR-d had a higher incidence of disease progression at 2, 3, and 4 years after fertility-sparing treatment (p = 0.001, p = 0.01 and p = 0.035, respectively). Patients with p53abn had higher relapse rates than those with p53wt at the 1- and 2-year follow-ups after achieving CR (p = 0.047 and p = 0.036, respectively). Moreover, patients with p53abn had a higher incidence of disease progression at 3 and 4 years after fertility-sparing treatment (p = 0.02 and p = 0.049, respectively). CONCLUSIONS: EAH patients with MMR-d and p53abn have a significantly higher risk of disease relapse and progression. Thus, MMR-d and p53abn may be used as predictive biomarkers of progestin resistance and endometrial tumorigenesis in EAH.

Oncological and reproductive outcomes of endometrial atypical hyperplasia and endometrial cancer patients undergoing conservative therapy with hysteroscopic resection: A systematic review and meta-analysis.

INTRODUCTION: Our objective was to conduct a systematic review and meta-analysis of studies evaluating the oncological and reproductive outcomes of patients with endometrial atypical hyperplasia (AH) and endometrioid endometrial cancer (EEC) undergoing conservative therapy with hysteroscopic resection (HR). MATERIAL AND METHODS: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for systematic reviews and meta-analyses. The study strictly followed the methodological framework proposed by the Cochrane Handbook and was retrospectively registered in PROSPERO (CRD42023469986). Searches were conducted in PubMed, Embase, and the Cochrane Library, from inception to October 10, 2023. A checklist based on items of the Newcastle-Ottawa Scale and the Methodological Index for Non-randomized Studies was used for quality assessment. The primary end points for this meta-analysis were complete response (CR), pregnancy, and live birth rates following HR-based therapy in patients with EEC or AH. The secondary end point was the recurrence rate (RR). RESULTS: Twenty-one articles involving 407 patients with clinical stage IA, low or intermediate grade, EEC, and 444 patients with AH managed with HR-based conservative treatment were included for this systematic review. CR to HR-based conservative therapy was achieved in 88.6% of patients with EEC and 97.0% of patients with AH. Of these, 30.6% and 24.2%, respectively, had live births. The overall pooled disease RR was 18.3% and 10.8% in patients with EEC and AH, respectively. Further subset analyses revealed that EEC patients with body mass index (BMI) ≤28 kg/m2 had higher CR rates as well as higher chances of pregnancy and live birth (91.6% CR, 32.9% pregnancy, 31.1% live birth) compared with patients with BMI >28 kg/m2 (86.4% CR, 28.4% pregnancy, 23.0% live birth). The HR followed by oral progestogen subgroup had higher CR rates and higher chances of pregnancy and live birth (91.8% CR, 36.3% pregnancy, 28.2% live birth) than the HR followed by the levonorgestrel intrauterine system subgroup (82.5% CR, 25.3% pregnancy, 16.3% live birth). CONCLUSIONS: Hysteroscopic resection followed by progestins appears to be a promising choice for fertility-sparing treatment in young patients with AH and EEC, with effective and safe responses. The live birth rate remains to be improved by providing medical guidance and encouragement.

Triglyceride-glucose index (TyG index) and endometrial carcinoma risk: A retrospective cohort study.

OBJECTIVE: We analyzed the association between the triglyceride-glucose index (TyG index) and incident endometrial carcinogenesis, aiming to determine whether the TyG index is a promising predictive biomarker for endometrial carcinoma (EC). METHODS: In this retrospective cohort study, multiple logistic regression analysis was performed to evaluate the relationship between TyG index and EC incidence and progression. The receiver operating characteristic (ROC) curve was used to calculate the area under the curve (AUC), as well as the cut-off value of the TyG index for EC incidence. RESULTS: The TyG index was significantly higher in patients with EC or endometrial atypical hyperplasia (EAH) than in those with normal endometrium (P < 0.001). A continuous rise was observed in the incidence of EC and EAH among the tertiles of the TyG index (P < 0.001). The multiple logistic regression analysis revealed that the TyG index was associated with EC and EAH risk after adjusting for potential confounding factors (EAH: odds ratio [OR] 2.54, 95% confidence interval [CI] 1.33-4.85, P = 0.005; EC: OR 2.65, 95% CI 1.60-4.41, P < 0.001). Moreover, high TyG index was positively associated with advanced pathological stage (OR 2.14, 95% CI 1.32-3.47, P = 0.002) and poorer differentiation (OR 2.53, 95% CI 1.36-4.72, P = 0.004). CONCLUSION: The TyG index might be a promising biomarker for endometrial carcinogenesis. Subjects with a higher TyG index should be aware of the risk of EC incidence and progression.

Recurrent endometrial atypical hyperplasia diagnosed by pathological examination of the placenta from a live birth: a case report.

BACKGROUND: Pregnancy complicated with endometrial atypical hyperplasia, which is often observed during early pregnancy, is extremely rare. CASE PRESENTATION: The patient was a 30-year-old woman who had premature delivery at 30+ 1 weeks gestation, and endometrial atypical hyperplasia was discovered by placental examination. CONCLUSIONS: For patients who undergo fertility-sparing treatment for endometrial atypical hyperplasia, the evaluation of the decidua via the placental pathological examination is particularly important. These examinations make a great clinical contribution to the early detection and diagnosis of endometrial atypical hyperplasia.

A study evaluating liquid-based endometrial cytology test and transvaginal ultrasonography as a screening tool for endometrial cancer in 570 postmenopausal women.

OBJECTIVE: To evaluate the combination of transvaginal ultrasonography (TVS) and endometrial cytology test (ECT) as a potential diagnostic strategy for endometrial cancer and endometrial precancerous lesions in postmenopausal patients. METHODS: 570 postmenopausal patients admitted in our hospital due to abnormal bleeding or other symptoms and/or with endometrium thickness over 5 mm on ultrasound. The endometrial thickness was evaluated by TVS. Following obtainment with written consent, all patients underwent ECT, hysteroscopy and then dilatation and curettage (D&C). Cytological sampling was conducted by scratching the uterus cavity using SAP-1 and the samples were prepared as liquid-based smear using SurePath technology. The samples were stained using Papanicolaou method. The correlation between cytological diagnosis and TVS results with the D&C histological diagnosis was analyzed. The WHO classification was used for diagnosis. RESULTS: Sensitivity of ECT, TVS, ECT or TVS positive, ECT and TVS positive to diagnose atypical hyperplasia or worse were estimated at 80.7%, 86.8%, 97.4%, 70.2%, specificity at 94.7%, 20.4%, 17.5%, 88.4%, positive predictive value at 58.2%, 21.1%, 22.8%, 60.2%, negative predictive value at 94.4%, 86.1%, 96.4%, 92.2%, and accuracy at 84.6%, 33.7%, 33.5%, 84.7%, respectively. CONCLUSIONS: Transvaginal ultrasonography and Endometrial cytology test may be regarded as a effective first-line method in endometrial pathology detection in postmenopausal women.

PTEN mutation predicts unfavorable fertility preserving treatment outcome in the young patients with endometrioid endometrial cancer and atypical hyperplasia.

OBJECTIVE: This study aimed to investigate the impact of molecular classification and PTEN, KRAS and PIK3CA gene mutation on the outcome of fertility-preserving treatment in the patients with endometrioid endometrial cancer (EEC) and endometrial atypical hyperplasia (EAH). METHODS: This is a single-center retrospective study. A total of 135 patients with EEC and EAH receiving fertility-preserving treatment and molecular classification were reviewed. The distribution of the four types of molecular classification was described. The impact of non-specific molecular profile (NSMP), mismatch repair-deficiency (MMRd), and PTEN, KRAS and PIK3CA gene mutation on the outcome of fertility-preserving treatment was analyzed. RESULTS: Of the patients analyzed, 86.7% (117/136) were classified as having NSMP; 14 (10.4%), MMRd; 1 (0.7%), POLEmut EAH; and 3 (2.2%), p53abn EEC. The patients having NSMP and MMRd achieved similar 16-, 32-, and 48-week complete response rates. The patients harboring tier I and tier II PTEN mutations (PTENmut-Clin) achieved lower cumulative 32-week CR rates than those with PTEN-others (without PTENmut-Clin) (22/47, 46.8% vs. 50/74, 67.6%; p=0.023; odds ratio=0.422; 95% confidence interval [CI]=0.199-0.896). Insulin-resistance (hazard ratio [HR]=0.435; 95% CI=0.269-0.702; p=0.001) and PTENmut-Clin (HR=0.535; 95% CI=0.324-0.885; p=0.015) were independent negative predictors for lower 32-week CR rates. CONCLUSION: PTENmut-Clin is an independent risk factor for unfavorable fertility-preserving treatment outcomes in the patients with EEC and EAH. The patients with MMRd receiving fertility-preserving treatment achieved outcomes similar to those of the patients with NSMP. The molecular profiles might guide fertility-preserving treatment in the prognosis and clinical decisions.

Obstetric and perinatal outcomes following frozen and fresh embryo transfer in patients with endometrial hyperplasia and carcinoma: a retrospective study in a high-volume reproductive center.

BACKGROUND: There is ongoing debate regarding which embryo transfer procedure can achieve a higher live birth rate. Research has suggested that frozen ET might be beneficial for certain populations, such as hyper-responders. This study aimed to compare outcomes of pregnancies between frozen and fresh embryo transfer cycles in patients with endometrial hyperplasia and carcinoma. METHODS: This retrospective cohort study was conducted at a high-volume reproductive center from January 2010 to January 2022. Patients who were diagnosed with endometrial hyperplasia with atypia and endometrial carcinoma were included. They all underwent in vitro fertilization after conservative treatment. The primary outcome was live birth after frozen and fresh embryo transfer cycles, and secondary outcomes included perinatal complications and other pregnancy outcomes. RESULTS: Overall, 259 ET cycles (130 fresh and 129 frozen) were included. The rate of live births per embryo transfer cycle of the whole cohort was 20.8% (54/259), and no significant between-group difference was found after adjusting for potential confounding factors (23.8% vs. 17.8%; adjusted OR, 0.47; 95% CI, 0.21-1.06; p=0.068). Compared to fresh embryo transfer group, the incidence of total maternal complications in the frozen embryo transfer group was significantly higher (30.4% vs. 6.5%, p=0.019). Analyzing each complication as a separate entity, patients in the frozen embryo transfer group had a higher incidence of hypertensive disorders of pregnancy (p=0.028). Multiple logistic regression analysis showed that frozen embryo transfer was related with an increased occurrence of maternal complications (OR, 6.68, 95% CI, 1.01-44.19, p=0.040). CONCLUSIONS: Among patients with endometrial hyperplasia and carcinoma, the rate of live births was comparable between both embryo transfer procedures, while frozen embryo transfer might be associated with a higher risk of maternal complications compared to that with fresh embryo transfer.

Correlation of plasma adipokines with endometrial atypical hyperplasia and type I/II endometrial cancer.

The aim of the study was to systematically explore the relationships between various adipokines and risks of endometrial atypical hyperplasia (EAH), type I endometrial cancer (EC), and type II EC. We enrolled 219 patients in this study, including 39 EAH, 87 type I EC, 38 type II EC and 55 control individuals. We subsequently explored the association of adipokine levels and the leptin-to-adiponectin (L/A) ratio with EAH, type I EC, and type II EC. The plasma leptin level and L/A ratio were significantly higher in the EAH group than in the control group (p = 0.012). Leptin, resistin, vaspin, and visfatin levels were significantly higher in the type I EC group; however, the adiponectin level was lower in the type I EC, which resulted in a higher L/A ratio. Notably, the L/A ratio and visfatin level in the type II EC group were significantly higher. Multiple logistic regression analysis revealed that a higher leptin level was significantly associated with a higher EAH risk (p = 0.012). Higher leptin level (p = 0.042) and L/A ratio (p = 0.027) were significantly associated with an increased type I EC risk. By contrast, higher leptin (p = 0.059) and visfatin (p = 0.003) levels, higher L/A ratio (p = 0.033), and lower adiponectin level (p = 0.042) were associated with an increased type II EC risk. We suggested that adipokines are potentially correlated with EAH and EC risks.

What is already known on this subject? EAH and EC are considered significantly correlated with obesity and the related insulin resistance. Studies reported that some of the adipokines mediate obesity-related EC risk.What do the results of this study add? We systematically explored whether the adipokines produced from adipose tissue, including leptin, adiponectin, resistin, vaspin, and visfatin as well as the L/A ratio were associated with increased EAH, type I EC, and type II EC risks; whether they are independent risk factors for EAH and EC. Moreover, we analysed the underlying roles of these adipokines in EC tumorigenesis and development.What are the implications of these findings for clinical practice and/or further research? This study aimed to systematically explore the relationships between various adipokines and risks of EAH, type I EC, and type II EC, to suggest that adipokine levels correlated with EAH and EC risks, and to analyse the underlying molecular mechanisms linking adipokines with endometrial carcinogenesis. It is helpful to improve our understanding of EC tumorigenesis and development.

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

The incidence of endometrial endometrioid carcinoma (EEC) has been gradually increasing over the past decade. Fertility-sparing therapy with progestin is a treatment option for EEC or endometrial atypical hyperplasia (AH). The present study evaluated the role of numerous prognostic factors following fertility-sparing therapy for EEC or AH. Furthermore, the present study assessed the strength of various clinicopathological indicators for the prediction of treatment efficacy. A retrospective analysis was performed of patients with EEC and AH who received fertility-sparing therapy between August 2013 and September 2021 at Peking University People's Hospital (Beijing, China). Endometrial specimens were obtained from each patient after 3 months of treatment and at the end of the fertility-sparing therapy, before treatment efficacy and prognosis were evaluated using the χ2 test. Furthermore, the protein expression levels of EEC biomarkers, such as estrogen receptor (ER), progesterone receptor (PR), paired box 2 (PAX2), PTEN and p53 were assessed using immunohistochemistry. The overall complete response (CR) rate of fertility-sparing treatment in the EEC group was 67.39% (31/46), whereas that in the AH group was 86.49% (32/37). The difference between the CR rates in the EEC and AH groups was statistically significant (P<0.05). There was no association between prognosis after treatment and ER, PAX2, PTEN or Ki-67 expression in the initially untreated AH or EEC groups. However, tissues with >50% positive PR expression were demonstrated to have a higher CR rate compared with those with ≤50% positive PR expression in both the EEC and AH groups. Furthermore, the PAX2-positive group tended to demonstrate higher CR rates compared with the PAX2-negative group in the patients with EEC. In conclusion, these data suggested that fertility-sparing therapy is effective for patients with EEC and AH who wish to remain fertile after treatment. Specifically, in the AH group, a higher proportion of patients achieved a CR whilst also achieving this more rapidly. Furthermore, PR was demonstrated to be a useful marker for the evaluation of EEC and AH.

Application of molecular classification to guiding fertility-sparing therapy for patients with endometrial cancer or endometrial intraepithelial neoplasia.

BACKGROUND: The aim of this study was to evaluate whether molecular classification was associated with treatment response in women with endometrial endometrioid carcinoma (EEC) or Endometrial atypical hyperplasia/endometrial intraepithelial neoplasia (EAH/EIN) treated with progestin. METHODS: A retrospective analysis of 59 patients with EEC or EAH/EIN who received fertility-sparing therapy between 2013 and 2021 was performed. For each patient, medical records and pathological reports were reviewed. The treatment efficacy and tumor prognosis were evaluated. Immunohistochemistry analysis for p53 and MSH2, MSH6, PSM2, MLH1 were performed. Molecular classification was analyzed using a 11-gene panel based on next generation sequencing technology. RESULTS: 23 of 39 patients with EEC received complete response (CR) after fertility-sparing treatment which was significantly lower than the EAH/EIN group (58.97 % vs 80.0 %, P < 0.05). Molecular classification via the Cancer Genome Atlas (TCGA) algorithm was successfully applied to 59 cases. The distribution of specimens into the four molecular classes was as follows: 83.05 % (49/59) CNL(copy number-low)，6.78 % (4/59) MSI-H (microsatellite instability -high), 5.08 %(3/59) POLE-mutated and 5.08 % (3/59) CNH(copy number-high). MSI and TP53 sequencing results were concordant with immunohistochemistry analyses of MMR and p53 protein. The patients with CNH and MSI-H subtypes showed worse prognosis than those with POLE-mutated and CNL subtypes. CONCLUSIONS: Molecular classification of EAH/EIN prior to management with progestin treatment was feasible and may predict patients at risk of progression.

Analysis of immunohistochemical characteristics and recurrence after complete remission with fertility preservation treatment in patients with endometrial carcinoma and endometrial atypical hyperplasia.

OBJECTIVE: To investigate the relationship between immunohistochemical characteristics and recurrence after complete remission (CR) with fertility preservation treatment in patients with endometrial cancer (EC) and endometrial atypical hyperplasia (AH). METHODS: The clinical data and immunohistochemical results of 53 patients with EC and 68 patients with AH admitted to Peking University People's Hospital from January 2010 to January 2021 were retrospectively analyzed. Patients were divided into two groups according to whether recurrence after complete remission (CR): group 1: recurrence after CR; group 2: no recurrence after CR, for statistical analysis. RESULTS: (1) The expression rate of ER in group 1 was lower than that in group 2, (P < 0.05). The expression rate of Ki-67 in group 1 was significantly higher than that in group 2, (P < 0.01). The expression rates of PR, P16, P53, and PTEN were not significantly different between the two groups (P > 0.05); (2) combination index ER/ Ki-67 row ROC curve analysis, there was a significant difference (P < 0.01), the best cut-off value was 3.55, sensitivity 0.730, specificity 1.000, Youden index 0.730. The 3-year RFS of high rate patients was 100%, and that of low rate patients was 42.3%, P < 0.01. CONCLUSIONS: The expression rate of Ki-67 is of great significance in predicting the recurrence of EC after fertility preservation therapy. The best cut-off value of combination index ER/ Ki-67 (3.55) was better than a single immunohistochemical marker in predicting recurrence of EC after fertility preservation treatment.

Efficacy and pregnancy outcomes of hysteroscopic surgery combined with progestin as fertility-sparing therapy in patients with early stage endometrial cancer and atypical hyperplasia.

PURPOSE: This study aims to evaluate the efficacy of hysteroscopic curettage combined with progestin therapy in young patients with early-stage endometrial cancer (EC) and endometrial atypical hyperplasia (EAH) who wished to preserve their fertility. METHODS: This prospective cohort study included 16 patients with early-stage EC and 25 patients with EAH in Dalian Maternal and Child Health Hospital from August 2014 to October 2018. All patients received fertility-sparing therapy with hysteroscopic evaluation every 3 months until achieving complete response (CR). Demographic, clinical, and pathological data follow-up information as well as fertility outcomes was analyzed. RESULTS: There were 92.6% (37/41) patients who achieved CR. The mean treatment duration to CR was 7.47 ± 2.91 months. BMI ≤ 30 kg/m2 was associated with shorter treatment duration to achieve CR (P = 0.003). Among the patients who attempted to conceive, 30.3% (10/33) had successful pregnancy, and 18.2% (6/33) delivered live births. The implementation of assisted reproductive technology (ART) is closely associated with pregnancy (P = 0.001). CONCLUSION: The fertility-sparing therapy, hysteroscopic curettage combined with progestin therapy, of early young EC and EAH patients is safe and effective. BMI is the main factor affecting the duration of CR. After achieving CR, ART can significantly improve the pregnancy rate of these patients.

Effects of Weight Status and Related Metabolic Disorders on Fertility-Sparing Treatment Outcomes in Endometrial Atypical Hyperplasia and Endometrial Cancer: A Retrospective Study.

BACKGROUND: Although obesity was an independent risk factor for fertility-sparing treatment in endometrial atypical hyperplasia (EAH) and endometrioid endometrial cancer (EEC), the roles of other weight statuses and related metabolism were unclear. This study aimed to investigate the body mass index (BMI) interval that produced optimal treatment efficacy and the effects of related metabolic disorders in EAH/EEC patients. METHODS: A total of 286 patients (including 209 EAH and 77 well-differentiated EEC) under progestin therapy were retrospectively analyzed. The cumulative complete response (CR) rate, relapse rate, and fertility outcomes were compared among different weight or metabolic statuses. RESULTS: Underweight and overweight/obese status significantly decreased the cumulative 16-week and 32-week CR rate (p = 0.004, p = 0.022, respectively). The highest 16-week CR rate was observed at a BMI of 21-22 kg/m2 in the overall population (p = 0.033). Obesity (HR 0.37, 95%CI 0.15-0.90, p = 0.029) and PCOS (HR 0.55, 95%CI 0.31-0.99, p = 0.047) were associated with lower 16-week CR rate. Hyperuricemia (HR 0.66, 95%CI 0.45-0.99, p = 0.043) was associated with lower 32-week CR rate. The 16-week and 32-week CR rate (p = 0.036, p = 0.008, respectively) were significantly lower in patients exhibiting both obesity and hyperuricemia. CONCLUSIONS: The optimal fertility-sparing treatment efficacy was observed at a BMI of 21-22 kg/m2 in EAH/EEC. Hyperuricemia was an independent risk factor for long-term treatment outcomes.

Identification of potential models for predicting progestin insensitivity in patients with endometrial atypical hyperplasia and endometrioid endometrial cancer based on ATAC-Seq and RNA-Seq integrated analysis.

Objective: The aim of this study was to establish predictive models based on the molecular profiles of endometrial lesions, which might help identify progestin-insensitive endometrial atypical hyperplasia (EAH) or endometrioid endometrial cancer (EEC) patients before progestin-based fertility-preserving treatment initiation. Methods: Endometrial lesions from progestin-sensitive (PS, n = 7) and progestin-insensitive (PIS, n = 7) patients were prospectively collected before progestin treatment and then analyzed by ATAC-Seq and RNA-Seq. Potential chromatin accessibility and expression profiles were compared between the PS and PIS groups. Candidate genes were identified by bioinformatics analyses and literature review. Then expanded samples (n = 35) were used for validating bioinformatics data and conducting model establishment. Results: ATAC-Seq and RNA-Seq data were separately analyzed and then integrated for the subsequent research. A total of 230 overlapping differentially expressed genes were acquired from ATAC-Seq and RNA-Seq integrated analysis. Further, based on GO analysis, REACTOME pathways, transcription factor prediction, motif enrichment, Cytoscape analysis and literature review, 25 candidate genes potentially associated with progestin insensitivity were identified. Finally, expanded samples were used for data verification, and based on these data, three predictive models comprising 9 genes (FOXO1, IRS2, PDGFC, DIO2, SOX9, BCL11A, APOE, FYN, and KLF4) were established with an overall predictive accuracy above 90%. Conclusion: This study provided potential predictive models that might help identify progestin-insensitive EAH and EEC patients before fertility-preserving treatment.

Conservative Management of Atypical Endometrial Hyperplasia and Early Endometrial Cancer in Childbearing Age Women.

Total hysterectomy and bilateral adnexectomy is the standard treatment for atypical endometrial hyperplasia and early-stage endometrial cancer. However, the recommended surgical treatment precludes future pregnancy when these conditions are diagnosed in women in their fertile age. In these patients, fertility-sparing treatment may be feasible if the desire for childbearing is consistent and specific conditions are present. This review summarizes the available evidence on fertility-sparing management for atypical endometrial hyperplasia and early-stage endometrial cancer. Historically, oral progestins have been the mainstay of conservative management for atypical endometrial hyperplasia and stage IA endometrioid endometrial cancer with no myometrial invasion, although there is no consensus on dosage and treatment length. Intrauterine progestin therapy has proved a valid alternative option when oral progestins are not tolerated. GnRH analogs, metformin, and hysteroscopic resection in combination with progestins appear to increase the overall efficacy of the treatment. After a complete response, conception is recommended; alternatively, maintenance therapy with strict follow-up has been proposed to decrease recurrence. The risk of disease progression is not negligible, and clinicians should not overlook the risk of hereditary forms of the disease in young patients, in particular, Lynch syndrome. Hysterectomy is performed once the desire for childbearing desire has been established. The conservative management of atypical endometrial hyperplasia and early-stage endometrial cancer is feasible, provided a strong desire for childbearing and permitting clinical-pathological conditions. However, patients must be aware of the need for a strict follow-up and the risk of progression with a possible consequent worsening of the prognosis. More homogenous and well-designed studies are necessary to standardize and identify the best treatment and follow-up protocols.

YTHDF2 is a novel diagnostic marker of endometrial adenocarcinoma and endometrial atypical hyperplasia/ intraepithelial neoplasia.

Numerous studies show that some biomarkers are aberrantly expressed in endometrial endometrioid adenocarcinoma (EMAC) and endometrial atypical hyperplasia/endometrioid intraepithelial neoplasia (EAH/EIN) compared to endometrial benign lesions. Because of low sensitivity and/or specificity, the utility of these markers to distinguish EMAC and EAH/EIN from benign endometrial lesions is limited. YTH domain family 2 (YTHDF2) is a functional N6-methyladenosine (m6A)-specific reader protein that mainly regulates mRNA stability. Aberrant YTHDF2 expression has been reported in many cancers and plays important functions in tumorigenesis and cancer progression. However, its expression in endometrial benign and malignant lesions has not been investigated. We evaluated YTHDF2 mRNA and protein expression in EMAC and normal endometrium using the UALCAN database and validated the bioinformatic results in EMAC cells using qRT-PCR, Western blot, and immunohistochemical (IHC) staining. We found that YTHDF2 was weakly expressed in normal endometrium, benign endometrial lesions, endometrial hyperplasia without atypia, and adenomyosis. In contrast, YTHDF2 was upregulated in EAH/EIN and EMAC. These results indicate that YTHDF2 immunostaining may be a useful tool to distinguish EAH/EIN from EHWA. Finally, YTHDF2 expression can accurately assess the depth of myometrial invasion (DMI) in EMAC when EMAC coexists with adenomyosis.

Histopathologic diagnosis of endometrial precancers: Updates and future directions.

Early detection of endometrial cancer, especially its precancers, remains a critical and evolving issue in patient management and the quest to decrease mortality due to endometrial cancer. Due to many factors such as specimen fragmentation, the confounding influence of endogenous or exogenous hormones, and variable or overlapping histologic features, identification of bona fide endometrial precancers and their reliable discrimination from benign mimics remains one of the most challenging areas in diagnostic pathology. At the same time, the diagnosis of endometrial precancer, or the presence of suspicious but subdiagnostic features in an endometrial biopsy, can lead to long clinical follow-up with multiple patient visits and serial endometrial sampling, emphasizing the need for accurate diagnosis. Our understanding of endometrial precancers and their diagnosis has improved due to systematic investigations into morphologic criteria, the molecular genetics of endometrial cancer and their precursors, the validation of novel biomarkers and their use in panels, and more recent methods such digital image analysis. Although precancers for both endometrioid and non-endometrioid carcinomas will be reviewed, emphasis will be placed on the former. We review these advances and their relevance to the histopathologic diagnosis of endometrial precancers, and the recently updated 2020 World Health Organization (WHO) Classification of Female Genital Tumors.