Pregnancy and obstetric outcomes after fertility-sparing management of endometrial cancer and atypical hyperplasia: a multicentre cohort study.

STUDY QUESTION: What are the pregnancy and obstetric outcomes in women with atypical hyperplasia (AH) or early-stage endometrial cancer (EC) managed conservatively for fertility preservation? SUMMARY ANSWER: The study found a live birth rate of 62% in patients with AH or EC after conservative treatment, with higher level of labour induction, caesarean section, and post-partum haemorrhage. WHAT IS KNOWN ALREADY: Fertility-sparing treatment is a viable option for women with AH or EC during childbearing years, but the outcomes of such treatments, especially regarding pregnancy and obstetrics, need further exploration. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study analysed data from January 2010 to October 2022, involving 269 patients from the French national register of patients with fertility-sparing management of AH/EC. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women above 18 years of age, previously diagnosed with AH/EC, and approved for fertility preservation were included. Patients were excluded if they were registered before 2010, if their treatment began <6 months before the study, or if no medical record on the pregnancy was available. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 95 pregnancies in 67 women were observed. Pregnancy was achieved using ART in 63 cases (66%) and the live birth rate was 62%, with early and late pregnancy loss at 26% and 5%, respectively. In the 59 cases resulting in a live birth, a full-term delivery occurred in 90% of cases; 36% of cases required labour induction and 39% of cases required a caesarean section. The most common maternal complications included gestational diabetes (17%) and post-partum haemorrhaging (20%). The average (±SD) birthweight was 3110 ± 736 g; there were no significant foetal malformations in the sample. No significant difference was found in pregnancy or obstetric outcomes between ART-obtained and spontaneous pregnancies. However, the incidence of induction of labour, caesarean section, and post-partum haemorrhage appears higher than in the general population. LIMITATIONS, REASONS FOR CAUTION: The retrospective nature of the study may introduce bias, and the sample size might be insufficient for assessing rare obstetric complications. WIDER IMPLICATIONS OF THE FINDINGS: This study offers valuable insights for healthcare providers to guide patients who received fertility-sparing treatments for AH/EC. These pregnancies can be successful and with an acceptable live birth rate, but they seem to be managed with caution, leading to possible tendency for more caesarean sections and labour inductions. No increase in adverse obstetric outcomes was observed, with the exception of suspicion of a higher risk of post-partum haemorrhaging, to be confirmed. STUDY FUNDING/COMPETING INTEREST(S): No funding was received for this study. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

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.

ARID1A Regulates Progesterone Receptor Expression in Early Endometrial Endometrioid Carcinoma Pathogenesis.

Loss of progesterone receptor (PR) expression is an established risk factor for unresponsiveness to progesterone therapy in patients with endometrial atypical hyperplasia and endometrioid carcinoma. ARID1A is one of the most commonly mutated genes in endometrioid carcinomas, and the loss of its expression is associated with tumor progression. In this study, we investigated the roles of ARID1A deficiency in PR expression in human and murine endometrial epithelial neoplasia. An analysis of genome-wide chromatin immunoprecipitation sequencing in isogenic ARID1A-/- and ARID1A+/+ human endometrial epithelial cells revealed that ARID1A-/- cells showed significantly reduced chromatin immunoprecipitation sequencing signals for ARID1A, BRG1, and H3K27AC in the PgR enhancer region. We then performed immunohistochemistry to correlate the protein expression levels of ARID1A, estrogen receptor, and PR in 50 human samples of endometrial atypical hyperplasia and 75 human samples of endometrial carcinomas. The expression levels of PR but not were significantly lower in ARID1A-deficient low-grade endometrial carcinomas and atypical hyperplasia (P = .0002). When Pten and Pten/Arid1a conditional knockout murine models were used, Pten-/-;Arid1a-/- mice exhibited significantly decreased epithelial PR expression in endometrial carcinomas (P = .003) and atypical hyperplasia (P < .0001) compared with that in the same tissues from Pten-/-;Arid1a+/+ mice. Our data suggest that the loss of ARID1A expression, as occurs in ARID1A-mutated endometrioid carcinomas, decreases PgR transcription by modulating the PgR enhancer region during early tumor development.

The impact of previous conservative treatment of atypical hyperplasia on pregnancy outcomes after IVF/ICSI-embryo transfer: a propensity score-matched retrospective cohort study.

STUDY QUESTION: Do women have worse pregnancy and neonatal outcomes of IVF/ICSI-fresh embryo transfer (ET) after conservative treatment of atypical hyperplasia (AH)? SUMMARY ANSWER: AH has no impact on live birth but is associated with increased risks of pregnancy loss and preterm delivery (PTD). WHAT IS KNOWN ALREADY: AH is a precancerous lesion of endometrial cancer. Several recognized AH risk factors include nulliparity, increased body mass index, ovulation disorders, diabetes mellitus, and others. As such, patients are suggested to attempt conception upon achieving AH regression. Recently, successful pregnancies with IVF/ICSI have been increasingly reported. STUDY DESIGN, SIZE, DURATION: Forty-two patients with AH regression and 18 700 women with no evidence of endometrial abnormality, who underwent their first autologous oocytes' retrieval and fresh ET cycles of IVF/ICSI in the Center for Reproductive Medicine, Shandong University, from May 2008 to July 2021, were retrospectively enrolled. PARTICIPANTS/MATERIALS, SETTING, METHODS: First, 42 AH patients were propensity score matched with control women (n = 168) at a 1:4 ratio. Reproductive outcomes and maternal/neonatal complications were compared between the matched pairs. Binary logistic regression analyses were conducted to assess odds ratios (ORs) of AH for live birth, pregnancy loss, and PTD from AH women and all 18 700 eligible controls. MAIN RESULT AND THE ROLE OF CHANCE: Patients with AH achieved a numerically lower live birth rate (LBR) as compared to the matched controls, but without significant difference (26% versus 37%, P = 0.192). However, compared with the matched controls, AH patients showed significantly higher rates of pregnancy loss (52% versus 21%, P = 0.003) and PTD (45% versus 16%, P = 0.041). Further analyses revealed a statistically significantly increased rate of late pregnancy loss (17% versus 3%, P = 0.023), but not early miscarriage (35% versus 18%, P = 0.086), in the AH group. Furthermore, after correcting for potential confounders, the likelihood of a live birth in AH patients narrowly failed to be statistically significantly different from controls (adjusted OR [aOR]: 0.51, 95% CI: 0.25-1.04, P = 0.064). Nonetheless, the logistic regression reconfirmed that AH was an independent risk factor for pregnancy loss (aOR: 3.62, 95% CI: 1.55-8.46, P = 0.003), late pregnancy loss (aOR: 9.33, 95% CI: 3.00-29.02, P < 0.001), and PTD (aOR: 5.70, 95% CI: 1.45-22.38, P = 0.013). LIMITATIONS, REASONS FOR CAUTION: Selection bias was an inherent drawback of this study. First, because of the low AH prevalence among women receiving IVF/ICSI treatment, and consequently, limited sample size, the relationship between AH with LBR and adverse complications might be concealed and underestimated. Hence, the results should be interpreted cautiously. Similarly, the impacts of diverse clinical features of AH patients on the pregnancy outcomes need further studies in a larger population. Second, although most data used in this study were obtained by reviewing the medical records, missing data did exist and so did the recall bias. Third, although the propensity score matching and multivariable logistic models were performed collectively in order to minimize potential confounders between AH and controls, the intrinsic disadvantages of the retrospective nature of this study could not be avoided completely, and additional confirmation bias might be induced with reduplication of statistical analyses. WIDER IMPLICATION OF THE FINDINGS: Our results highlight the necessity of adequate counseling and intensive pregnancy monitoring for AH individuals and their families. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants from the National Key Research & Developmental Program of China (2022YFC2703800), the Natural Science Foundation of Shandong Province (ZR2022MH009), and Projects of Medical and Health Technology Development Program in Shandong Province (202005010520, 202005010523). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Mesonephric-like adenocarcinoma of the female genital tract: novel observations and detailed molecular characterisation of mixed tumours and mesonephric-like carcinosarcomas.

AIMS: To report novel observations in five mesonephric-like adenocarcinomas (MLAs) of the female genital tract. METHODS AND RESULTS: We report two endometrial MLAs in association with endometrioid carcinoma and atypical hyperplasia and three (one endometrial, two ovarian) cases with a sarcomatoid component (mesonephric-like carcinosarcoma). Pathogenic KRAS mutations, which are characteristic of MLA, were identified in all cases although interestingly, in one of the mixed carcinomas, this was confined to the endometrioid component. The concurrent MLA, endometrioid carcinoma and atypical hyperplasia components in one case harboured identical EGFR, PTEN and CCNE1 mutations, suggesting that the atypical hyperplasia gave rise to a Müllerian carcinoma with both endometrioid and mesonephric-like components. The carcinosarcomas all contained a component of MLA and a sarcomatous component with chondroid elements. In the ovarian carcinosarcomas, the coexisting epithelial and sarcomatous components shared some mutations including KRAS and CREBBP, suggesting that they are clonally related. Furthermore, in one case CREBBP and KRAS mutations detected in the MLA and sarcomatous components were also detected in an associated undifferentiated carcinoma component, suggesting that it was clonally related to the MLA and sarcomatous components. CONCLUSIONS: Our observations provide additional evidence that MLAs have a Müllerian origin and characterise mesonephric-like carcinosarcomas in which chondroid elements appear to be characteristic. In reporting these findings, we provide recommendations for distinction between a mesonephric-like carcinosarcoma and a MLA with a spindle cell component.

Acceptability of bariatric surgery in people with endometrial cancer and atypical hyperplasia: A qualitative study.

OBJECTIVE: In young individuals with obesity, infertility, and endometrial cancer, significant, sustained weight loss through bariatric surgery may result in a durable oncologic and reproductive response. However, it is not known whether bariatric surgery is acceptable to this patient population. We performed a qualitative study to understand the acceptability of bariatric surgery in young individuals with obesity and endometrial cancer or atypical hyperplasia. STUDY DESIGN: All participants were of reproductive age with body mass index [BMI] ≥ 35 and grade 1 endometrial cancer or atypical hyperplasia. Semi-structured interviews were used to explore participant perception of their weight, fertility, and the possibility of bariatric surgery as part of the treatment strategy for their endometrial cancer/atypical hyperplasia. Thematic saturation was reached after 14 interviews. RESULTS: Fourteen participants with a median age of 34 years (range 27-38) and BMI of 42 (33-64) were interviewed. Participants were reluctant to accept bariatric surgery as a treatment option due to 1) lack of knowledge about the procedure, 2) stigma attached to bariatric surgery, and 3) fear of the risks associated with bariatric surgery. Their perception towards their weight, fertility, and cancer diagnosis was characterized by concepts of 'helplessness', 'isolation', 'frustration', and 'guilt'. We observed a significant gap in participant understanding of the complex interplay between their cancer, infertility, and obesity. CONCLUSIONS: More support and resources are required, with patient-oriented counseling focused on the implication of their weight on their cancer diagnosis and fertility, before presenting bariatric surgery as a treatment option.

Is sentinel lymph node assessment useful in patients with a preoperative diagnosis of endometrial intraepithelial neoplasia?

OBJECTIVE: To determine the prevalence of underlying high-intermediate (high-IM) and high-risk endometrial cancer (EC) in patients with preoperative diagnosis of Endometrial intraepithelial neoplasia (EIN) and to assess the impact of the information retrieved from the sentinel lymph node (SLN) on adjuvant therapy. METHODS: Retrospective cohort study of women undergoing hysterectomy, optional bilateral salpingo-oophorectomy (BSO) and lymph nodes assessment for EIN between December 2007 and August 2021. RESULTS: One hundred and sixty two (162) eligible patients were included, of whom 101 (62.3%) had a final diagnosis of EIN, while 61 (37.7%) were ultimately diagnosed with carcinoma. Out of 15 patients with high-IM to high-risk disease (9.25% of all EIN), 12 had grade 2-3 EC including 8 with >50% myometrial invasion, 2 with serous subtype, 1 with cervical invasion and 2 with pelvic lymph nodes involvement. Of the 3 patients with grade 1 EC, one patient had disease involving the adnexa and 2 patients had tumor invading >50% of the myometrium and with lymphovascular space invasion (LVSI). Ten patients received vaginal brachytherapy after surgery, 3 patients with extrauterine spread were treated with systemic chemotherapy followed by vaginal brachytherapy and pelvic external-beam radiotherapy and 2 patients with early-stage serous carcinoma received chemotherapy followed by vaginal brachytherapy. CONCLUSIONS: Information from SLN, even when negative, can be helpful in the management of patients with EC after preoperative EIN, as some patients are found to have high-IM to high-risk disease on final pathology. These patients would require either re-staging surgery or adjuvant external beam radiotherapy, both could be avoided by proper staging.

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.

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.

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.

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.

Endometrial carcinoma: molecular subtypes, precursors and the role of pathology in early diagnosis.

Endometrial carcinoma (EC) is classified into a wide range of morphological variants; this list has expanded over the past decade with the inclusion of mesonephric-like and dedifferentiated carcinoma as EC variants in the fifth edition of the WHO Classification of Female Genital Tumours, and recognition that carcinosarcoma is a biphasic carcinoma rather than a sarcoma. Each EC variant has distinct molecular abnormalities, including TCGA-based molecular subtypes, allowing further subclassification and adding complexity. In contrast to this rapid progress in understanding EC, there are only two recognized EC precursor lesions: endometrial atypical hyperplasia/endometrioid intraepithelial neoplasia (EAH/EIN) and serous intraepithelial carcinoma, a situation that has not changed for many years. Diagnosis of EC precursors is a cornerstone of surgical pathology practice, with early diagnosis contributing to the relatively favorable prognosis of EC. In this review we relate the precursor lesions to each of the EC morphological variants and molecular subtypes, discuss how successful early diagnosis is for each variant/molecular subtype and how it might be improved, and identify knowledge gaps where there is insufficient understanding of EC histogenesis. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Genome-wide mutation analysis in precancerous lesions of endometrial carcinoma.

Clinicopathological evidence supports endometrial atypical hyperplasia (AH) or endometrial intraepithelial neoplasia as the precursor of uterine endometrioid carcinoma (EC), the most common gynecologic malignancy. However, the pathogenic progression from AH to EC remains unclear. Here, we employed whole-exome sequencing to identify somatic mutations and copy number changes in micro-dissected lesions from 30 pairs of newly diagnosed AH and EC. We found that all but one pair of AHs shared the same DNA mismatch repair status as their corresponding ECs. The percentage of common mutations between AH lesions and corresponding ECs varied significantly, ranging from 0.1% to 82%. Microsatellite stable AHs had fewer cancer driver mutations than ECs (5 versus 7, p = 0.017), but among microsatellite unstable AHs and ECs there was no difference in mutational numbers (36 versus 38, p = 0.65). As compared to AH specimens, 19 (79%) of 24 microsatellite stable EC tumors gained new cancer driver mutations, most of which involved PTEN, ARID1A, PIK3CA, CTNNB1, or CHD4. Our results suggest that some AH lesions are the immediate precursor of ECs, and progression depends on acquisition of additional cancer driver mutations. However, a complex clonal relationship between AH and EC can also be appreciated, as in some cases both lesions diverge very early or arise independently, thus co-developing with distinct genetic trajectories. Our genome-wide profile of mutations in AH and EC shines new light on the molecular landscape of tumor progression. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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.

Nodal Assessment in Endometrial Atypical Hyperplasia.

OBJECTIVE: Atypical endometrial hyperplasia (AH) is the neoplastic precursor more often associated with endometrial cancer (EC). Nowadays, 25-50% of patients subjected to hysterectomy for preoperative AH are diagnosed with EC at the final pathological analysis. Furthermore, there is no consensus on which preoperative AH patients would benefit from sentinel lymph node mapping. This study aimed to evaluate nodal assessment and preoperative cancer risk factors in preoperative AH patients undergoing nodal surgical staging. METHODS: Patients undergoing surgical treatment for AH were retrospectively included in the analysis. Patients were divided into two groups (AH and EC groups) based on the final surgical pathology. The ESGO/ESTRO/ESP risk classification was used for EC cases. DESIGN: This was a retrospective study. RESULTS: Of the 207 AH patients treated, 152 cases met the inclusion criteria. Among preoperative AH patients with final EC diagnosis, 39 patients were in the low-risk group (25.7%), 8 in the intermediate-risk group (5.3%), 4 in high-intermediate (2.6%), and 3 patients were allocated in the high-risk group (2.0%). Fifty-four total patients underwent nodal surgical staging. Only one nodal micrometastasis (0.7%) was found at ultrastaging. Multivariate analysis showed abnormal uterine bleeding (AUB) (p = 0.01), hypertension (p < 0.01), and endometrial thickness ≥20 mm (p = 0.02) statistically more represented in patients with EC at final surgical analysis. EC risk was 2.9 (95% CI: 1.29-6.48) in AUB, 2.7 (95% CI: 1.06-6.92) in hypertension, and 3.1 (95% CI: 1.19-7.97) in endometrial thickness ≥20 mm cases. LIMITATIONS: The present study has limitations inherent in its retrospective nature. CONCLUSION: The overall risk of nodal metastases in preoperative AH patients was low. Conversely, 9.9% of the preoperative AH patients belonged to the intermediate or high-risk group for EC at the final histological examination. Preoperative cancer risk factors would identify AH patients for whom nodal staging could be suggested.

Prognostic factors in the treatment of gastric mucosal atypical hyperplasia by endoscopic submucosal dissection.

BACKGROUND: Endoscopic submucosal dissection (ESD) is becoming increasingly popular as a treatment for precancerous lesions and early cancers of the stomach. However, there have been few studies on the factors associated with the recurrence of precancerous lesions after ESD. METHODS: To investigate the prognostic factors of gastric intraepithelial neoplasia, we retrospectively analyzed 115 patients who were treated with ESD between February 2018 and January 2020. Chi-square test and Fisher's extract test were used to select factors for further investigation, and prognostic analysis was carried out with the Kaplan-Meier method and a Cox regression model. RESULTS: Platelet counts (P = 0.027) and albumin levels (P = 0.011) were both lower in patients with recurrence than in patients without recurrence of gastric mucosal atypical hyperplasia after ESD. CONCLUSIONS: This study reveals that low platelet counts and albumin levels were probably unfavorable prognostic factors in mucosal atypical hyperplasia of the stomach.

The utilisation of sentinel lymph node biopsy for endometrial cancer in Australia and New Zealand.

AIMS: The aim of this study was to identify to what extent the sentinel lymph node (SLN) technique is utilised by gynaecological oncologists in Australia and New Zealand, identifying the techniques used, any barriers to uptake, and management of isolated tumour cells (ITCs) and micrometastases. MATERIALS AND METHODS: We conducted an online survey of all practising gynaecological oncologists in Australia and New Zealand. They were asked whether they utilised SLN biopsy and in what circumstances, how they managed non-mapping and how their multidisciplinary team managed small volume disease. Those who did not were asked to identify their concerns with the procedure, reasons for non-uptake and their alternate technique. RESULTS: We surveyed 63 gynaecological oncologists of whom 59 were practising, and 48 (81%) responded. Six members (11%) do not utilise SLN biopsy, and 42 (89%) do. Areas where clinicians differ in practice are those areas that are most controversial and include the use of SLN biopsy in complex atypical hyperplasia, the management of ITCs and micrometastases and procedures on unilateral or bilateral non-mapping. Those who do not utilise the technique cite concerns about the false-negative rate, equipment and training issues. CONCLUSIONS: The utilisation of SLN biopsy in endometrial cancer is well established in Australia and New Zealand, with similar practices and concerns to those of other international groups.

[Clinical analysis of fertility-sparing therapy of patients with complex atypical hyperplasia and endometrial cancer].

OBJECTIVE: To analyze the efficacy and prognosis of fertility-sparing therapy of the patient with complex atypical hyperplasia (CAH) and endometrial cancer (EC). METHODS: Clinical data of 191 EC and CAH patients who received fertility-sparing therapy in Peking University People's Hospital between January 2009 and September 2021 were recruited retrospectively. Outcomes of remission, recurrence and pregnancy were analyzed. RESULTS: (1) Efficacy and efficacy-related factors: The complete response (CR) rate was 86.1% (161/187) for all the patients, and the CR rate of the CAH patients were higher than that of the EC patients (92.7% vs. 79.1%, P=0.007), the CR rate was significant higher in the CAH patients (OR=2.786, P=0.035). (2) The recurrence rate was 19.3% (31/161), and the recurrence rate of the EC patients were much higher than that of the CAH patients (26.4% vs. 13.5%, P=0.039). The median recurrence time was 22.5 (9.0, 50.0) months. (3) The high risk factors of recurrence were pathological type of EC (χ2=4.880, P=0.027), without the use of metfor-min (χ2=7.075, P=0.008), longer time to complete remission (>7 months) (χ2=6.204, P=0.013), and no pregnancy (χ2=6.765, P=0.009). (4) Results of pregnancy and related factors: Among the patients who achieved CR, 108 patients had fertility willing with the pregnancy rate of 41.7% (45/108), and the live birth rate was 34.3% (37/108). The live birth rate was lower in EC than that in the CAH patients (28.6% vs. 42.4%, P=0.045). The median time to achieve pregnancy was 10.50 (5.75, 33.25) months. The pregnancy rate was significant higher in the patients with pregnancy history (OR=9.468, P < 0.001) and in those who received assisted reproductive therapy (OR=7.809, P < 0.001). CONCLUSION: Fertility-sparing therapy of CAH and EC patients is effective resulting in high disease remission and certain pregnancy. However, the high recurrence rate and low pregnancy rate are still key problems for EC and CAH patients, therefore close monitoring and follow-up are indicated.