Metformin as an adjunct to progestin therapy in endometrial hyperplasia and early-stage endometrial cancer: A systematic review and meta-analysis of randomized controlled trials

Background@#Metformin has been studied for its anti-proliferative effects on endometrial cells, and it is hypothesized to have a synergistic effect with progestin therapy in suppressing endometrial cell proliferation. This systematic review and meta-analysis aimed to determine the efficacy of adjunctive metformin in the clinical regression of endometrial hyperplasia and early-stage endometrial carcinoma.@*Methodology@#This meta-analysis followed the Cochrane methodology and adhered to the PRISMA 2020 guidelines. Randomized controlled trials (RCTs) were included if they enrolled reproductive-aged women with endometrial hyperplasia (with and without atypia) and endometrial carcinoma who were treated with progestin and metformin. The primary outcome was the complete response rate at 12-16 weeks, and secondary outcomes included relapse rate, clinical pregnancy rate, and live birth rate. Odds ratios (ORs) and 95% confidence intervals (CIs) were used for dichotomous data.@*Results@#Six RCTs were included. The addition of metformin to progestin therapy may increase the complete response rate of endometrial hyperplasia without atypia (OR 5.12, 95% CI 1.17 to 22.41; n=102) and live birth rates (OR 2.51, 95% CI 1.34 to 4.69; n=188) compared to progestin therapy alone, but the certainty of the evidence is low. Metformin did not have a significant effect on the clinical response of endometrial hyperplasia with atypia and endometrial carcinoma, relapse rates, and clinical pregnancy rates.@*Conclusion@#Current evidence is uncertain on the potential benefit of metformin with progestin in endometrial hyperplasia and carcinoma. Future high-quality randomized controlled trials with larger sample sizes and longer follow-up periods are needed to support practice recommendations.

Global and regional trends in the incidence and mortality burden of endometrial cancer, 1990-2019: Updated results from the Global Burden of Disease Study, 2019 / 中华医学杂志(英文版)

BACKGROUND@#The disease burdens for endometrial cancer (EC) vary across different countries and geographical regions and change every year. Herein, we reported the updated results of the Global Burden of Disease Study 2019 on EC with respect to age-standardized incidence and mortality from 1990 to 2019.@*METHODS@#The annual percentage change (APC) of incidence and mortality was evaluated using joinpoint regression analysis to examine the temporal trends during the same timeframe in terms of the global landscape, different sociodemographic indices (SDI), and geographic regions. The relationship between Human Development Index (HDI) and incidence and mortality was additionally explored.@*RESULTS@#The age-standardized incidence rates (ASIRs) revealed a significant average global elevation by 0.5% per year (95% confidence interval [CI], 0.3-0.7; P <0.001). The age-standardized mortality rates (ASMRs), in contrast, fell by an average of 0.8% per year (95% CI, -1.0 to -0.7; P <0.001) worldwide. The ASIRs and ASMRs for EC varied across different SDIs and geographical regions. We noted four temporal trends and a significant reduction by 0.5% per year since 2010 in the ASIR, whereas we detected six consecutively decreasing temporal trends in ASMR during the entire period. Notably, the estimated APCs were significantly positively correlated with HDIs (ρ = 0.22; 95% CI, 0.07-0.35; P = 0.003) with regard to incident cases in 2019.@*CONCLUSIONS@#Incidence rates for EC reflected a significant increase overall (although we observed a decline since 2010), and the death rates declined consecutively from 1990 to 2019. We posit that more precise strategies can be tailored and then implemented based on the distinct age-standardized incidence and mortality burden in different geographical areas.

Validación de técnica de ganglio centinela en cáncer de endometrio en el Hospital de Talca / Validation of sentinel lymph node technique in endometrial cancer at the Hospital de Talca

Objetivo: Validar la técnica de ganglio centinela utilizando verde de indocianina en la estadificación del cáncer de endometrio. Método: Realizamos un estudio prospectivo entre enero y diciembre de 2021. Se incluyeron todas las pacientes portadoras de cáncer de endometrio clínicamente en etapa 1, de todos los grados de diferenciación e histologías. Todas las pacientes fueron sometidas a una estadificación laparoscópica. Se inició el procedimiento con identificación de ganglio centinela utilizando verde de indocianina. Posteriormente, se completó la cirugía de estadiaje estándar en todas las pacientes. Los ganglios centinelas fueron procesados con técnica de ultraestadiaje. Resultados: Se incluyeron 33 pacientes. El 81% presentaron histología endometrioide. El 100% fueron sometida además a una linfadenectomía pelviana estándar y el 20% a una linfadenectomía paraaórtica simultáneamente. Se detectó al menos un ganglio centinela en el 100% de los casos. La detección bilateral ocurrió en el 90,9%. La localización más frecuente fue la fosa obturatriz y la arteria hipogástrica. Obtuvimos una sensibilidad del 90% para detectar enfermedad ganglionar y un valor predictivo negativo del 95,8%. Conclusiones: La técnica de ganglio centinela utilizando verde de indocianina es replicable. Los resultados de nuestra serie nos permiten realizar procedimientos menos agresivos al estadificar el cáncer de endometrio.

Objective: To validate sentinel node mapping using indocyanine green in endometrial cancer staging. Method: A prospective study was conducted between January and December 2021. All patients with clinically stage 1 endometrial cancer, of all grades and histologies were included. All patients underwent laparoscopic staging. The procedure began with identification of the sentinel node using indocyanine green. Subsequently, standard staging surgery was completed in all patients. Sentinel nodes were processed using ultrastaging technique. Results: Thirty-three patients were enrolled. 81% of cases had endometrioid histology. All patients also underwent a standard pelvic lymphadenectomy and in 20% of cases a para-aortic lymphadenectomy. At least one sentinel node was detected in 100% of the cases. Bilateral detection occurred in 90.9%. The most frequent location was obturator fossa and hypogastric artery. Sensitivity to detect lymph node disease was 90% and negative predictive value 95.8%. Conclusions: Sentinel lymph node mapping using indocyanine green is a replicable technique. Our results allows us to perform less aggressive procedures in endometrial cancer staging.

Clinical Characteristics and Outcomes of a High-grade Endometrial Cancer Cohort Treated at Instituto Nacional de Câncer, Brazil / Características clínicas e desfechos de uma coorte de câncer endometrial de alto grau tratada no Instituto Nacional de Câncer, Brasil

Abstract Objective To analyze the outcomes of a cohort of patients with high-risk histologies of endometrial cancer (EC) treated at Instituto Nacional de Câncer (National Cancer Institute, INCA, in Portuguese), in Brazil. Materials and Methods We reviewed the medical records of patients with high-risk histologies of EC in any stage registered at INCA between 2010 and 2016 to perform a clinical and demographic descriptive analysis and to evaluate the outcomes in terms of recurrence and survival. Results From 2010 to 2016, 2,145 EC patients were registered and treated at INCA, and 466 had high-grade histologies that met the inclusion criteria. The mean age of the patients was 65 years, 44.6% were Caucasian, and 90% had a performance status of 0 or 1. The most common histology was high-grade endometrioid (31.1%), followed by serous carcinoma (25.3%), mixed (20.0%), carcinosarcoma (13.5%), and clear cell carcinoma (9.4%). Considering the 2018 Fédération Internationale de Gynécologie et d'Obstétrique (International Federation of Gynecology and Obstetrics, FIGO, in French) staging system, 44.8%, 12.4%, 29.8%, and 12.9% of the patient were in stages I, II, III or IV respectively. Age (> 60 years), more than 50% of myoinvasion, higher stage, poor performance status, serous and carcinosarcoma histologies, and adjuvant treatment were independent factors associated with recurrence-free survival (RFS) and overall survival (OS) in the multivariate analysis. Conclusion The current findings reinforced the international data showing poor outcomes of these tumors, especially for serous and carcinosarcomas and tumors with advanced stages, with shorter survival and high recurrence rates in distant sites, independently of the FIGO stage. Adjuvant therapy was associated with better survival.

Resumo Objetivo Analisar os desfechos de uma coorte de pacientes com câncer de endométrio (CE) e histologias de alto risco atendida no Instituto Nacional do Câncer (INCA) entre 2010 e 2016. Materiais e Métodos Foram revisados prontuários de pacientes com histologias de alto risco de CE em qualquer estágio cadastradas no INCA entre 2010 e 2016 para realizar uma análise descritiva clínica e demográfica e avaliar os resultados em termos de recorrência e sobrevida. Resultados De 2010 a 2016, 2.145 pacientes com CE foram cadastradas e atendidas no INCA, e 466 tinham histologias de alto grau e atendiam aos critérios de inclusão. A média de idade das pacientes foi de 65 anos, 44,6% eram brancas, e 90% tinham performance status de 0 ou 1. A histologia mais comum foi endometrioide de alto grau (31,1%), seguida de carcinoma seroso (25,3%), misto (20,0%), carcinossarcoma (13,5%) e carcinoma de células claras (9,4%). Considerando o estadiamento da Fédération Internationale de Gynécologie et d'Obstétrique (Federação Internacional de Ginecologia e Obstetrícia, FIGO, em francês) de 2018, 44,8%, 12,4%, 29,8% e 12,9% apresentaram estágios I, II, III ou IV, respectivamente. Idade (> 60 anos), mais de 50% de mioinvasão, estágio avançado, performance status ruim, histologias serosas e carcinossarcoma, e tratamento adjuvante foram fatores independentes associados à sobrevida livre de recorrência e sobrevida global na análise multivariada. Conclusão Os achados atuais reforçam os dados internacionais que demonstram o prognóstico ruim desses tumores, principalmente para as histologias serosas e carcinossarcomas e para estágios avançados, com menor sobrevida e altas taxas de recorrência à distância, independentemente do estágio da FIGO. A terapia adjuvante foi associada a melhor sobrevida.

Germline Mutations Landscape in a Cohort of the State of Minas Gerais, Brazil, in Patients Who Underwent Genetic Counseling for Gynecological and Breast Cancer / Cenário de mutações germinativas em uma coorte do estado de Minas Gerais, Brasil, em pacientes submetidas ao aconselhamento genético para câncer ginecológico e de mama

Abstract Objective The present study evaluated the profile of germline mutations present in patients who underwent genetic counseling for risk assessment for breast cancer (BC), ovarian cancer (OC), and endometrial cancer (EC) with a possible hereditary pattern. Methods Medical records of 382 patients who underwent genetic counseling after signing an informed consent form were analyzed. A total of 55.76% of patients (213/382) were symptomatic (personal history of cancer), and 44.24% (169/382) were asymptomatic (absence of the disease). The variables analyzed were age, sex, place of birth, personal or family history of BC, OC, EC, as well as other types of cancer associated with hereditary syndromes. The Human Genome Variation Society (HGVS) nomenclature guidelines were used to name the variants, and their biological significance was determined by comparing 11 databases. Results We identified 53 distinct mutations: 29 pathogenic variants, 13 variants of undetermined significance (VUS), and 11 benign. The most frequent mutations were BRCA1 c.470_471delCT, BRCA1 c.4675 + 1G > T, and BRCA2 c.2T> G. Furthermore, 21 variants appear to have been described for the first time in Brazil. In addition to BRCA1/2 mutations, variants in other genes related to hereditary syndromes that predispose to gynecological cancers were found. Conclusion This study allowed a deeper understanding of the main mutations identified in families in the state of Minas Gerais and demonstrates the need to assess the family history of non-gynecological cancer for risk assessment of BC, OC, and EC. Moreover, it is an effort that contributes to population studies to evaluate the cancer risk mutation profile in Brazil.

Resumo Objetivo O presente estudo avaliou o perfil de mutações germinativas presentes em pacientes submetidas a aconselhamento genético para avaliação de risco para câncer de mama (CM), câncer de ovário (OC) e câncer de endométrio (CE) com possível padrão hereditário. Métodos Foram analisados os prontuários de 382 pacientes que realizaram aconselhamento genético após consentimento informado. Um total de 55,76% dos pacientes (213/382) eram sintomáticos (história pessoal de câncer), e 44,24% (169/382) eram assintomáticos (ausência da doença). As variáveis analisadas foram idade, sexo, naturalidade, história pessoal ou familiar de CM, OC, CE bem como outros tipos de câncer associados a síndromes hereditárias. As diretrizes de nomenclatura da Human Genome Variation Society (HGVS) foram usadas para nomear as variantes e seu significado biológico foi determinado pela comparação de 11 bancos de dados. Resultados Identificamos 53 mutações distintas: 29 variantes patogênicas, 13 variantes de significado indeterminado e 11 benignas. As mutações mais frequentes foram BRCA1 c.470_471delCT, BRCA1 c.4675 + 1G > T e BRCA2 c.2T > G. Além disso, 21 variantes parecem ter sido descritas pela primeira vez no Brasil. Além das mutações BRCA1/2, foram encontradas variantes em outros genes relacionados a síndromes hereditárias que predispõem a cânceres ginecológicos. Conclusão Este estudo permitiu conhecer melhor as principais mutações identificadas nas famílias do estado de Minas Gerais e demonstra a necessidade de avaliar a história familiar de câncer não ginecológico para avaliação do risco de CM, OC e CE. Além disso, é um esforço que contribui com estudos populacionais para avaliar o perfil de mutações de risco para câncer no Brasil.

Epidemiological and clinicopathological profile of endometrial cancer in Gabon

Introduction: L'objectif général de notre travail était d'apporter une description épidémiologique et clinicopathologique du cancer de l'endomètre au Gabon. Patients et méthode: Cette étude descriptive et rétrospective a été réalisée à l'Institut de Cancérologie de Libreville chez les patientes atteintes du cancer de l'endomètre sur une période de 7 années (de janvier 2012 à octobre 2018). Résultats: Cette étude a inclus 32 patientes et les résultats obtenus ontmontré que ce cancer au Gabon est plus fréquent chez la femme multipare, que histologiquement le type 1 est le plus souvent rencontré et que ce cancer est de haut grade de malignité. De ce travail ressort également la difficulté du suivi des patientes. Conclusion: Le cancer de l'endomètre étant un cancer souvent d'emblée de mauvais pronostic, il est d'intérêt de mettre en place une stratégie de prévention et de management adapté.Mots clés: cancer, endomètre, étude clinicopathologique, suivi, Gabon Abstract:Introduction:The general objective of our work was to provide an epidemiological and clinicopathological description of endometrial cancer in Gabon.

Introduction: The general objective of our work was to provide an epidemiological and clinicopathological description of endometrial cancer in Gabon. Epidemiological and clinicopathological profile of... Patients and method: This descriptive and retrospective study was carried out at Cancer Institute of Libreville in patients with endometrial cancer over a period of 7 years (from January 2012 to October 2018) . Results: This study included 32 patients and the results obtained showed that this cancer in Gabon is more frequent in multiparous women, that histologically type 1 is most often encountered and that this cancer is of high grade malignancy. This work also shows the difficulty of following up patients. Conclusion: As endometrial cancer is often a cancer with a poor prognosis , it is interest to put in place an appropriate prevention and management strategy.

Profile of gynecological cancers in a tertiary hospital, Eastern Nigeria

Introduction: there is a great diversity in the profile of cancers in the world. This study set out to analyze the profile of gynecological cancer in Federal University Teaching Hospital, Owerri, [FUTHO] (former Federal Medical Centre, Owerri, Imo state, Nigeria). Methods: this was a retrospective cross sectional descriptive study of the records of women admitted in the gynecological ward in FUTHO from January 2020 to November 2022. It was analyzed using SPSS version 23.0 and reported in simple percentages for categorical variables and measures of central tendency for quantitative variables. Results: a total of 1,378 gynecological patients were admitted into the Gynaecological ward of the hospital, out of which 242 (17.6%) were cancer cases. The most common cancer over the three years in review, was ovarian, 81(33.5%), followed by cervical, 66 (27.3 %), endometrial, 65 (26.8 %), choriocarcinoma, 22 (9.1%), vulvar, 6 (2.5%) and vagina, 2(0.8%). The most common gynecological cancers in this study is very different from previous reports from Nigeria and other African countries. The pattern looks like that seen in the developed countries where endometrial and ovarian cancers top the list. Conclusion: this report shows a possible change in lifestyle and improved access to cervical cancer prevention strategies. It is also assumed that all the facilities who have recorded cervical cancer as the most common cancer can actually have a similar result as ours if a more current review is done.

A comparative study of subjective and objective techniques using two‑dimensional ultrasound in the preoperative assessment of cervical and myometrial invasion in patients with endometrial cancer / Philippine Journal of Obstetrics and Gynecology

Context@#Endometrial cancer is the third most common malignancy of the female genital tract in the Philippines, following cervical and ovarian cancer. Ultrasound as the first line in imaging has a major role in preoperative treatment and planning.@*Aims@#To compare the diagnostic accuracy of subjective versus objective ultrasound measurement techniques in detecting cervical stromal invasion (CSI) and deep myometrial invasion (MI).@*Materials and Methods@#Fifty‑seven patients were enrolled in this cross‑sectional study. Deep MI and CSI were evaluated both subjectively and objectively by measuring tumor‑free distance (TFD), distance from the outer cervical os to lowest edge of the tumor border (Dist‑OCO), and distance from the internal cervical os to caudal tumor border (Dist‑ICO). Histopathological result used as the gold standard.@*Results@#Subjective assessment for deep (MI) had 79.3% sensitivity, 82.1% specificity, 82.1% positive predictive value (PPV), 82.1% negative predictive value (NPV), and 80.7%. Subjective assessment for CSI had a sensitivity, specificity, PPV, NPV, and overall accuracy of 80%, 90.4%, 44.4%, 97.9%, and 89.5%. Objective measurement (TFD ≤0.8 cm) to detect deep MI had 86.2% sensitivity, 57.1% specificity, 67.4% PPV, 80% NPV, and 71.9% overall accuracy. Adjusting TFD cutoff to 0.65 increased to 71.4% specificity, making it comparable with subjective assessment. Dist‑OCO (≤2.1 cm) yielded 100% sensitivity, 86.3% specificity, 30% PPV, 100% NPV, and 87% overall accuracy. Dist‑ICO was first used in this study, hence no cutoff yet. By using receiver operating characteristics, cutoff was 0.45 cm, which yielded a 60% sensitivity and 92% specificity (area under the curve 0.731, P = 0.09).@*Conclusions@#Subjective assessment of CSI and deep MI performs better than objective measurement techniques. TFD and Dist‑OCO as the objective measurements showed clinically comparable accuracy to subjective assessment by an expert. Dist‑ICO needs to be validated to a larger population to determine its clinical value in predicting CSI.

Prognosis analysis of radical or modified radical hysterectomy and simple hysterectomy in patients with stage Ⅱ endometrial cancer / 中华妇产科杂志

Objective: To compare the prognosis and perioperative situation of patients with stage Ⅱ endometrial cancer (EC) between radical hysterectomy/modified radical hysterectomy (RH/mRH) and simple hysterectomy (SH). Methods: A total of 47 patients diagnosed EC with stage Ⅱ [International Federation of Gynecology and Obstetrics (FIGO) 2009] by postoperative pathology, from January 2006 to January 2021 in Peking University People's Hospital, were analyzed retrospectively. The patients were (54.4±10.7) years old, and the median follow-up time was 65 months (ranged 9-138 months). They were divided into RH/mRH group (n=14) and SH group (n=33) according to the scope of operation. Then the prognosis of patients between the groups were compared, and the independent prognostic factors of stage Ⅱ EC were explored. Results: (1) The proportions of patients with hypertension in RH/mRH group and SH group were 2/14 and 45% (15/33), the amounts of intraoperative blood loss were (702±392) and (438±298) ml, and the incidence of postoperative complications were 7/14 and 15% (5/33), respectively. There were significant differences (all P<0.05). (2) The median follow-up time of RH/mRH group and SH group were 72 vs 62 months, respectively (P=0.515). According to Kaplan-Meier analysis and log-rank method, the results showed that there were no significant difference in 5-year progression-free survival (PFS) rate (94.3% vs 84.0%; P=0.501), and 5-year overall survival rate (92.3% vs 92.9%; P=0.957) between the two groups. Cox survival analysis indicated that age, pathological type, serum cancer antigen 125 (CA125), and estrogen receptor (ER) status were associated with 5-year PFS rate (all P<0.05). But the scope of hysterectomy (RH/mRH and SH) did not affect the 5-year PFS rate of stage Ⅱ EC patients (P=0.508). And level of serum CA125 and ER status were independent prognostic factors for 5-year PFS rate (all P<0.05). Conclusions: This study could not find any survival benefit from RH/mRH for stage Ⅱ EC, but increases the incidence of postoperative complications. Therefore, the necessity of extending the scope of hysterectomy is questionable.

Comparative study of next generation sequencing and immunohistochemistry on molecular classification of endometrial carcinoma / 中华病理学杂志

Objective: To investigate the differences in molecular classification of endometrial carcinoma (EC) between various technical methods and to explore molecular classification schemes suitable for Chinese population. Methods: The study used a comprehensive scheme of next generation sequencing (NGS) and immunohistochemistry for molecular classification of 254 EC cases that were obtained at Department of Pathology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China from April 2021 to March 2022. According to the recommended threshold of Sanger sequencing which was approximate-20% variant allele fraction (VAF), NGS data were extracted to simulate the results of Sanger sequencing. Results: The 254 EC patients had a mean age of 51 years (range, 24 to 89 years). Combination of POLE (9-14 exons), TP53 total exons and microsatellite instability (MSI) detection was a better single scheme than NGS alone, while combination of MSI fragment analysis and conventional immunohistochemistry was the best solution and seemed best aligned with TCGA data and recent studies. POLE ultramuted type, mismatch repair defect type, TP53 mutant type and non-specific molecular characteristic type accounted for 11.4% (29/254), 31.5% (80/254), 22.4% (57/254) and 34.6% (88/254) of the cases, respectively. If Sanger sequencing was adopted for POLE and TP53 detection, the frequencies of these EC types were 9.1% (23/254), 31.5% (80/254), 12.9% (33/254) and 46.6% (118/254), respectively, with greatly increasing non-specific molecular characteristics cases. If POLE was detected by Sanger sequencing and others by immunohistochemistry, they were 9.1% (23/254), 42.2% (92/218), 13.8% (35/254) and 40.9% (105/254), respectively, with increasing the false positive rates of the mismatch repair defect group. Conclusions: Small and medium-sized NGS panels with MSI detection is a better solution than NGS alone. Sanger sequencing is currently available for POLE mutation detection, which is not sensitive enough for TP53 mutation detection, and seems equivalent to the efficiency of TP53 by immunohistochemistry. Further optimization of small and medium-sized NGS panels covering MSI detection and POLE and TP53 full exons may be the best choice for the future to meet national conditions.

Analysis of microsatellite instability in endometrial cancer: The significance of minimal microsatellite shift / 北京大学学报(医学版)

OBJECTIVE@#To analyze the differences and characteristics of microsatellite instability (MSI) in endometrial cancer (EMC), by using colorectal cancer (CRC) as control.@*METHODS@#In the study, 228 cases of EMC were collected. For comparative analysis, 770 cases of CRC were collected. Mismatch repair (MMR) expression was detected by immunohistochemistry (IHC), and microsatellite instability (MSI) was analyzed by PCR and capillary electrophoresis fragment analysis (MSI-PCR). MSI-PCR was detected using five mononucleotide repeat markers: BAT-25, BAT-26, NR-21, NR-24, and MONO-27.@*RESULTS@#In EMC, we found 27.19% (62/228) of deficient mismatch repair (dMMR) using IHC, significantly higher than CRC (7.79%, 60/770). Meanwhile, subclonal expression of MMR protein was found in 4 cases of dMMR-EMC and 2 cases of dMMR-CRC. According to the criteria of major micro-satellite shift, we found 16.23% (37/228) of MSI-high (MSI-H), 2.63% (6/228) of MSI-low (MSI-L), and 81.14% (185/228) of microsatellite stability (MSS) in EMC using MSI-PCR. The discor-dance rate between MMR-IHC and MSI-PCR in EMC was 11.84% (27/228). In CRC, we found 8.05% (62/770) of MSI-H, 0.13% (1/770) of MSI-L, and 91.82% (707/770) of MSS. The discordance rate between MMR-IHC and MSI-PCR in CRC was only 0.52% (4/770). However, according to the criteria of minimal microsatellite shift, 12 cases of EMC showed minimal microsatellite shift including 8 cases of dMMR/MSS and 4 cases of dMMR/MSI-L and these cases were ultimately evaluated as dMMR/MSI-H. Then, 21.49% (49/228) of EMC showed MSI-H and the discordance rate MMR-IHC and MSI-PCR in EMC decreased to 6.58% (15/228). No minimal microsatellite shift was found in CRC. Compared with EMC group with major microsatellite shift, cases with minimal microsatellite shift showed younger age, better tumor differentiation, and earlier International Federation of Gynecology and Obstetrics (FIGO) stage. There were significant differences in histological variant and FIGO stage between the two groups (P < 0.001, P=0.006).@*CONCLUSION@#EMC was more prone to minimal microsatellite shift, which should not be ignored in the interpretation of MSI-PCR results. The combined detection of MMR-IHC and MSI-PCR is the most sensitive and specific method to capture MSI tumors.

Endometrioid adenocarcinoma with proliferated stromal cells, hyalinization and cord-like formations: A case report / 北京大学学报(医学版)

Corded and hyalinized endometrioid carcinoma (CHEC) is a morphologic variant of endo-metrioid adenocarcinoma. The tumor exhibits a biphasic appearance with areas of traditional low-grade adenocarcinoma merging directly with areas of diffuse growth composed of epithelioid or spindled tumor cells forming cords, small clusters, or dispersed single cells. It is crucial to distinguish CHEC from its morphological mimics, such as malignant mixed mullerian tumor (MMMT), because CHECs are usually low stage, and are associated with a good post-hysterectomy prognosis in most cases while the latter portends a poor prognosis. The patient reported in this article was a 54-year-old woman who presented with postmenopausal vaginal bleeding for 2 months. The ultrasound image showed a thickened uneven echo endometrium of approximately 12.2 mm and a detectable blood flow signal. Magnetic resonance imaging revealed an abnormal endometrial signal, considered endometrial carcinoma (Stage Ⅰ B). On hysterectomy specimen, there was an exophytic mass in the uterine cavity with myometrium infiltrating. Microscopically, most component of the tumor was well to moderately differentiated endometrioid carcinoma. Some oval and spindle stromal cells proliferated on the superficial surface of the tumor with a bundle or sheet like growth pattern. In the endometrial curettage specimen, the proliferation of these stromal cells was more obvious, and some of the surrounding stroma was hyalinized and chondromyxoid, which made the stromal cells form a cord-like arrangement. Immunostains were done and both the endometrioid carcinoma and the proliferating stroma cells showed loss of expression of DNA mismatch repair protein MLH1/PMS2 and wild-type p53 protein. Molecular testing demonstrated that this patient had a microsatellite unstable (MSI) endometrial carcinoma. The patient was followed up for 6 months, and there was no recurrence. We diagnosed this case as CHEC, a variant of endometrioid carcinoma, although this case did not show specific β-catenin nuclear expression that was reported in previous researches. The striking low-grade biphasic appearance without TP53 mutation confirmed by immunohistochemistry and molecular testing supported the diagnosis of CHEC. This special morphology, which is usually distributed in the superficial part of the tumor, may result in differences between curettage and surgical specimens. Recent studies have documented an aggressive clinical course in a significant proportion of cases. More cases are needed to establish the clinical behaviors, pathologic features, and molecular profiles of CHECs. Recognition of the relevant characteristics is the prerequisite for pathologists to make correct diagnoses and acquire comprehensive interpretation.

The value of T2 mapping for evaluating the pathological type, grade and depth of myometrial invasion in endometrial carcinoma / 中华肿瘤杂志

Objective: To investigate the value of T2 map and synthetic T2WI generated by T2 mapping in evaluating the histological type, pathological classification and depth of myometrial invasion of endometrial carcinoma (EC). Methods: Seventy-three patients with pathologically proven EC diagnosed at the First Affiliated Hospital of Zhengzhou University from December 2019 to December 2021 and 42 healthy volunteers were enrolled in the study. All subjects underwent conventional MRI, diffusion weighted imaging (DWI) and T2 mapping sequence for the pelvic cavity to test the T2 values and the apparent diffusion coefficient (ADC) of the focus nidus of the patients and the normal endometrium of the volunteers. The T2 and ADC values of EC vs normal endometrium, and those of different histological types and pathological grades were compared. The receiver operating characteristic (ROC) curves were constructed to evaluate the diagnostic performance of T2 and ADC values in determining the pathological type and classification of EC. In addition, two radiologists used synthetic T2WI combined with T2 map and conventional T2WI combined with DWI, respectively, to evaluate the depth of myometrial invasion, and compared the imaging results with the results of pathological diagnosis to evaluate the diagnostic efficacy of the two methods in determining the depth of myometrial invasion. Results: The T2 and ADC values of endometrial carcinoma were 85.0 (80.8, 92.5) ms and 0.71 (0.64, 0.77) ×10(-3) mm(2)/s, respectively, which were significantly lower than those of normal endometrium [147.4 (123.4, 176.7) ms and 1.46 (1.26, 1.76)×10(-3) mm(2)/s, respectively; both P<0.05]. The T2 values of endometrioid carcinoma (EA) [84.1 (79.5, 88.7) ms] were significantly lower than those of non-EA [98.8 (92.1, 102.8) ms; P<0.05]. There was no significant difference in ADC values between EA and non-EA (P=0.075). The T2 values of G1, G2 and G3 groups in EA were 89.1 (84.4, 94.4) ms, 83.6 (80.9, 86.2) ms, and 76.5 (71.4, 80.3) ms, respectively. There were significant differences in the T2 values between G1 vs G2, G1 vs G3, and G2 vs G3 groups, respectively (all P<0.017). Significant difference was also found in the ADC values between the G1 and G3 groups (P<0.017). The area under the ROC curve (AUC) of T2 values in distinguishing EA from non-EA was 0.867. The AUC of T2 values, ADC values and their combination in predicting high-grade EA was 0.888, 0.730 and 0.895, respectively. The accuracy of synthetic T2WI+ T2 map and conventional T2WI+ DWI in the diagnosis of deep myometrial invasion was 78.1% and 79.5%, respectively, with no significant difference (P>0.05). Conclusions: T2 mapping has great potential in preoperative evaluation of EC. The quantitative T2 value can be used in the diagnosis, pathological classification and grading of EC. The combination of synthetic T2WI and T2 map may be helpful to determine the depth of myometrial invasion.

Significado do uso da prótese peniana de silicone no seguimento da braquiterapia pélvica / Significado do uso da prótese peniana de silicone no seguimento da braquiterapia pélvica / Meaning of the use of silicone penile prosthesis in the follow-up of pelvic brachytherapy

Objetivo: descrever o significado do uso da prótese peniana de silicone para dilatação vaginal no seguimento da braquiterapia em mulheres com câncer ginecológico. Método: pesquisa narrativa, realizada no Centro de Pesquisas Oncológicas, Brasil, com 34 mulheres, após braquiterapia pélvica, em seguimento no serviço de fisioterapia. Coleta de dados por entrevistas semiestruturadas, incluindo dados sociodemográficos, clínicos e o significado do uso da prótese peniana na dilatação vaginal, submetidas à análise de conteúdo e discutidas à luz do estudo From 'sex toy' to intrusive imposition. Resultados: o significado perpassa o exercício de dilatação vaginal; as dificuldades relacionadas às condições vaginais, doença, tratamento, dor, sexo, constrangimentos, preconceitos, falhas na educação em saúde; as motivações relacionam-se à busca por qualidade de vida, apoio dos companheiros e profissionais. Conclusão: a abordagem de possíveis barreiras emocionais, psicológicas, sociais e físicas deve ser planejada e executada para prevenção da estenose vaginal e melhor acolhimento.

Objective: to describe the meaning of the use of silicone penile prosthesis for vaginal dilation in the follow-up of brachytherapy in women with gynecological cancer. Method: narrative research conducted at the Centro de Pesquisas Oncológicas, Brazil, with 34 women after pelvic brachytherapy, under follow-up at the physical therapy service. Data collection through semi-structured interviews, including sociodemographic and clinical data and the significance of the use of penile prosthesis in vaginal dilation, submitted to content analysis and discussed in the light of the study From 'sex toy' to intrusive imposition. Results: the meaning permeates the vaginal dilation exercise; difficulties related to vaginal conditions, disease, treatment, pain, sex, constraints, prejudices, failures in health education; motivations are related to the search for quality of life, support of partners and professionals. Conclusion: the approach of possible emotional, psychological, social and physical barriers should be planned and executed for prevention of vaginal stenosis and better reception.

Objetivo: describir el significado del uso de una prótesis peneana de silicona para la dilatación vaginal posterior a la braquiterapia en mujeres con cáncer ginecológico. Método: investigación narrativa, realizada en el Centro de Pesquisas Oncológicas, Brasil, con 34 mujeres, después de braquiterapia pélvica, en seguimiento en el servicio de fisioterapia. Recopilación de datos a través de entrevistas semiestructuradas, incluyendo datos sociodemográficos y clínicos y el significado del uso de prótesis peneana en la dilatación vaginal, sometidos a análisis de contenido y discutidos a la luz del estudio From 'sex toy' to intrusive imposition. Resultados: el significado impregna el ejercicio de dilatación vaginal; dificultades relacionadas con condiciones vaginales, enfermedad, tratamiento, dolor, sexo, vergüenza, prejuicios, fallas en la educación para la salud; las motivaciones están relacionadas con la búsqueda de calidad de vida, apoyo de la pareja y profesionales. Conclusión: se debe planificar y ejecutar el abordaje de las posibles barreras emocionales, psicológicas, sociales y físicas para prevenir la estenosis vaginal y una mejor recepción.

Qualidade de vida e mapeamento de complicações: avaliação do linfonodo sentinela no câncer de endométrio / Quality of life and complications: evaluation of the sentinel lymph node in endometrial cancer

Objetivo: Avaliar a incidência das complicações pós-operatórias do estadiamento cirúrgico e qualidade de vida relacionada ao protocolo do linfonodo sentinela associado ou não à linfadenectomia sistemática no tratamento do câncer do endométrio. Métodos: Foi conduzida uma coorte prospectiva entre dezembro de 2017 e abril de 2022, incluindo mulheres com carcinoma de endométrio em estágio inicial presumido (doença restrita ao útero) e com estadiamento linfonodal, agrupadas em: Grupo LNS (somente pesquisa do linfonodo sentinela) e Grupo LNS+LND (linfonodo sentinela com adição de linfadenectomia sistemática). Foram incluídas pacientes com baixo e alto risco para metástase linfonodal. As pacientes de alto risco fazem parte do estudo ALICE (NCT03366051), um estudo prospectivo randomizado de não inferioridade. As pacientes foram avaliadas no pré-operatório, 1 mês, 6 e 12 meses, com aplicação de questionário de qualidade de vida (QQV) pelo EORTC QLQ-C30 e Cx24, avaliação clínica e perimetria para avaliar linfedema. Resultados: Foram incluídas 152 mulheres, sendo 113 (74,3%) no grupo LNS e 39 (25,7%) no grupo LNS+LND. Complicações cirúrgicas intraoperatórias ocorreram em 2 (1,3%) casos todas pertencentes ao grupo LNS+LND. Complicações cirúrgicas até 30 dias foram encontradas em 29 (19,1%) casos. As pacientes submetidas a LNS+LND apresentaram taxas gerais de complicações cirúrgicas mais altas em comparação com aquelas submetidas apenas a LNS (33,3% vs. 14,2%; p=0,011). O grupo LNS+LND apresentou maior tempo de cirurgia (p=0,001) e necessidade de UTI (p=0,001). A incidência de linfocele foi encontrada em 8 casos, apenas no grupo LNS+LND (0 vs. 20,5%; p<0,001). Para o linfedema de membros inferiores, não foi encontrada diferença entre os grupos pela avaliação perimétrica do grupo LNS comparado ao LNS+LND (23,2% vs. 13,3%; p= 0,25). O mesmo ocorreu para a avaliação clínica do linfedema, encontrado em 21,2% do grupo LNS e 33,3% do grupo LNS+LND (p=0,14). Entretanto, na avaliação de presença de linfedema pelo score de sintomas do EORTC, houve maior relato de linfedema no grupo LNS+LND (score 23,52) comparado ao grupo LNS (score 12,45) na avaliação de 12 meses (p=0,02). Além disso, encontramos associação entre avaliação clínica e linfedema relatado pelo paciente. O score médio de linfedema foi maior quando este foi detectado por exame clínico em 6 meses (30,10 vs. 7,8; p<0,001) e 12 meses (36,4 vs. 6,0; p<0,001), no entanto sem associação entre perimetria e avaliações clínicas (p=0,76). Em relação à avaliação global de qualidade de vida, não houve diferença entre os grupos aos 12 meses (p=0,21). Conclusões: Houve maior taxa geral de complicações para o grupo submetido a linfadenectomia sistemática, assim como maiores taxas de linfocele e linfedema pelo score de sintomas. Nenhuma diferença foi encontrada em relação à qualidade de vida entre os grupos LNS e LNS+LND

Objectives: To evaluate the incidence of postoperative complications of surgical lymph node staging procedures and quality of life related to the sentinel lymph node protocol associated or not with systemic lymphadenectomy in the treatment of endometrial cancer. Methods: A prospective cohort was conducted between December 2017 and April 2022. Women with presumed early-stage endometrial carcinoma (disease restricted to the uterus) and with lymph node staging were included, grouped as follows: SLN group (sentinel lymph node only) and SLN+LND Group (sentinel lymph node with addition of systematic lymphadenectomy). Patients with low and high risk for lymph node metastasis were included, and high-risk patients were part of the ALICE study (NCT03366051), a prospective randomized non-inferiority study. The patients were assessed preoperatively, 1 month, 6 and 12 months with the application of a quality-of-life questionnaire (QQL) using the EORTC QLQ-C30 and Cx24, clinical evaluation and perimetry to assess lymphedema. Results: 152 women were included, 113 (74.3%) women in the SLN group and 39 (25.7%) in the SLN+LND group. Intraoperative surgical complications occurred in 2 (1.3%) cases, all of them in the SLN+LND group. Surgical complications within 30 days were found in 29 (19.1%) cases. Patients undergoing SLN+LND had higher overall rates of surgical complications compared to women undergoing SLN alone (33.3% vs. 14.2%; p=0.011). The SLN+LND group had longer surgery time (p=0.001) and need for ICU (p=0.001). The incidence of lymphocele was found in 8 cases and only in the SLN+LND group (0 vs. 20.5%; p<0.001). For lower limbs lymphedema, no difference was found between the groups by the perimetric evaluation of the SLN group compared to the SLN+LND (23.2% vs. 13.3%; p=0.25). The same occurred for the clinical evaluation of lymphedema, being found in 21.2% for the SLN group and 33.3% for the SLN+LND group (p=0.14). However, when evaluating the presence of lymphedema using the EORTC symptom score, there was a higher number of lymphedema reports in the SLN+LND group (score 23.52) compared to the SLN group (score 12.45) at the 12-month evaluation (p=0.02). In addition, we found an association between clinical evaluation and lymphedema reported by the patient. The lymphedema score had a higher mean score when lymphedema was detected by clinical examination at 6 months (30.10 vs. 7.8; p<0.001) and 12 months (36.4 vs. 6.0; p<0.001), however with no association between perimetry and clinical evaluations (p=0.76). Regarding the overall assessment of quality of life, there was no difference between the groups at 12 months (p=0.21). Conclusions: There was a higher overall rate of complications for the group undergoing systematic lymphadenectomy, as well as higher rates of lymphocele and lymphedema according to the symptom score. No difference was found regarding quality of life between the LNS and LNS+LND groups

Trans-ethnic Mendelian randomization study of systemic lupus erythematosus and common female hormone-dependent malignancies / 中华医学杂志(英文版)

BACKGROUND@#Observational research has reported that systemic lupus erythematosus (SLE) is related to common female hormone-dependent cancers, but the underlying causal effect remains undefined. This study aimed to explore the causal association of these conditions by Mendelian randomization (MR) analysis.@*METHODS@#We selected instrumental variables for SLE from genome-wide association studies (GWASs) conducted in European and East Asian populations. The genetic variants for female malignant neoplasms were obtained from corresponding ancestry GWASs. We utilized inverse variance weighted (IVW) as the primary analysis, followed by sensitivity analysis. Furthermore, we conducted multivariable MR (MVMR) to estimate direct effects by adjusting for the body mass index and estradiol. Finally, we implemented reverse direction MR analysis and gave a negative example to test the reliability of MR results.@*RESULTS@#We found SLE was significantly negatively associated with overall endometrial cancer risk (odds ratio [OR] = 0.961, 95% confidence interval [CI] = 0.935-0.987, P  = 3.57E-03) and moderately inversely related to endometrioid endometrial cancer (ENEC) (OR = 0.965, 95% CI = 0.936-0.995, P  = 0.024) risk in the European population by IVW. We replicated these results using other MR models and detected a direct effect by MVMR (overall endometrial cancer, OR = 0.962, 95% CI = 0.941-0.983, P  = 5.11E-04; ENEC, OR = 0.964, 95% CI = 0.940-0.989, P  = 0.005). Moreover, we revealed that SLE was correlated with decreased breast cancer risk (OR = 0.951, 95% CI = 0.918-0.986, P  = 0.006) in the East Asian population by IVW, and the effect was still significant in MVMR (OR = 0.934, 95% CI = 0.859-0.976, P  = 0.002). The statistical powers of positive MR results were all >0.9.@*CONCLUSION@#This finding suggests a possible causal effect of SLE on the risk of overall endometrial cancer and breast cancer in European and East Asian populations, respectively, by MR analysis, which compensates for inherent limitations of observational research.

Role of steroid receptor-associated and regulated protein in tumor progression and progesterone receptor signaling in endometrial cancer / 中华医学杂志(英文版)

BACKGROUND@#Steroid receptor-associated and regulated protein (SRARP) suppresses tumor progression and modulates steroid receptor signaling by interacting with estrogen receptors and androgen receptors in breast cancer. In endometrial cancer (EC), progesterone receptor (PR) signaling is crucial for responsiveness to progestin therapy. The aim of this study was to investigate the role of SRARP in tumor progression and PR signaling in EC.@*METHODS@#Ribonucleic acid sequencing data from the Cancer Genome Atlas, Clinical Proteomic Tumor Analysis Consortium, and Gene Expression Omnibus were used to analyze the clinical significance of SRARP and its correlation with PR expression in EC. The correlation between SRARP and PR expression was validated in EC samples obtained from Peking University People's Hospital. SRARP function was investigated by lentivirus-mediated overexpression in Ishikawa and HEC-50B cells. Cell Counting Kit-8 assays, cell cycle analyses, wound healing assays, and Transwell assays were used to evaluate cell proliferation, migration, and invasion. Western blotting and quantitative real-time polymerase chain reaction were used to evaluate gene expression. The effects of SRARP on the regulation of PR signaling were determined by co-immunoprecipitation, PR response element (PRE) luciferase reporter assay, and PR downstream gene detection.@*RESULTS@#Higher SRARP expression was significantly associated with better overall survival and disease-free survival and less aggressive EC types. SRARP overexpression suppressed growth, migration, and invasion in EC cells, increased E-cadherin expression, and decreased N-cadherin and Wnt family member 7A ( WNT7A ) expression. SRARP expression was positively correlated with PR expression in EC tissues. In SRARP -overexpressing cells, PR isoform B (PRB) was upregulated and SRARP bound to PRB. Significant increases in PRE-based luciferase activity and expression levels of PR target genes were observed in response to medroxyprogesterone acetate.@*CONCLUSIONS@#This study illustrates that SRARP exerts a tumor-suppressive effect by inhibiting the epithelial-mesenchymal transition via Wnt signaling in EC. In addition, SRARP positively modulates PR expression and interacts with PR to regulate PR downstream target genes.

Risk factor analysis of lymph node metastasis in endometrial carcinoma combined with molecular types / 中华妇产科杂志

Objective: To investigate the relationships between molecular types of the cancer genome atlas (TCGA) of patients with endometrial carcinoma (EC) and lymph node metastasis and other clinicopathological features. Methods: The clinical pathological information of 295 patients with EC who underwent initial inpatient surgical treatment and accepted the detection of the molecular types of TCGA with next-generation sequencing technology at Peking University People's Hospital were collected during April 2016 and May 2022. The TCGA molecular typing of EC was divided into four types: POLE-ultramutated (15 cases), high microsatellite instability (MSI-H; 50 cases), copy-number low (CNL; 175 cases), and copy-number high (CNH; 55 cases). The differences of clinical pathological features among different molecular types and the risk factors of lymph node metastasis were analyzed retrospectively. Results: Among 295 patients with EC, the average age was (56.9±0.6) years. (1) There was a statistically significant difference in lymph node metastasis (0, 8.0%, 10.3% and 25.5%) among the four molecular types (χ2=12.524, P=0.006). There were significant differences in age, stage, pathological type, grade (only endometrioid carcinoma), myometrium invasion, lymphatic vascular space infiltration, and estrogen receptor among the EC patients of four molecular types (all P<0.05). Among them, while in the patients with CNH type, the pathological grade was G3, the pathological type was non-endometrioid carcinoma, and the proportion of myographic infiltration depth ≥1/2 were higher (all P<0.05). (2) Univariate analysis suggested that pathological type, grade, myometrium infiltration depth, cervical interstitial infiltration, lymphatic vascular space infiltration, and progesterone receptor were all factors which significantly influence lymph node metastasis (all P<0.01); multivariate analysis suggested that the lymphatic vascular space infiltration was an independent risk factor for lymph node metastasis (OR=5.884, 95%CI: 1.633-21.211; P=0.007). (3) The factors related to lymph node metastasis were different in patients with different molecular types. In the patients with MSI-H, the non-endometrioid carcinoma of pathological type was independent risk factor for lymph node metastasis (OR=29.010, 95%CI: 2.067-407.173; P=0.012). In the patients with CNL, myometrium infiltration depth≥1/2 (OR=4.995, 95%CI: 1.225-20.376; P=0.025), lymphatic vascular space infiltration (OR=14.577, 95%CI: 3.603-58.968; P<0.001) were the independent risk factors for lymph node metastasis. While in the CNH type patients pathological type of non-endometrioid carcinoma (OR=7.451, 95%CI: 1.127-49.281; P=0.037), cervical interstitial infiltration (OR=22.938, 95%CI: 1.207-436.012; P=0.037), lymphatic vascular space infiltration (OR=9.404, 95%CI: 1.609-54.969; P=0.013), were the independent risk factors for lymph node metastasis. Conclusions: POLE-ultramutated EC patients have the lowest risk of lymph node metastasis, and CNH patients have the highest risk of lymph node metastasis. The risk factors of lymph node metastasis of different molecular types are different. According to preoperative pathological and imaging data, lymph node metastasis is more likely to occur in patients with non-endometrioid carcinoma in MSI-H and CNH type patients, and lymph node metastasis is more likely to occur in patients with myometrium infiltration depth ≥1/2 in CNL type patients.

Fertility-preserving treatment outcomes in endometrial cancer and atypical hyperplasia patients with different molecular profiles / 中华妇产科杂志

Objective: To investigate the impact of molecular classification and key oncogenes on the oncologic outcomes in patients with endometrial carcinoma (EC) and atypical endometrial hyperplasia (AEH) receiving fertility-preserving treatment. Methods: Patients with EC and AEH undergoing progestin-based fertility-preserving treatment and receiving molecular classification as well as key oncogenes test at Obstetrics and Gynecology Hospital, Fudan University from January 2021 to March 2023 were reviewed. Hysteroscopic lesion resection and endometrial biopsy were performed before initiating hormone therapy and every 3 months during the treatment to evaluate the efficacy. The risk factors which had impact on the treatment outcomes in EC and AEH patients were further analyzed. Results: Of the 171 patients analyzed, the median age was 32 years, including 86 patients with EC and 85 patients with AEH. The distribution of molecular classification was as follows: 157 cases (91.8%) were classified as having no specific molecular profile (NSMP); 9 cases (5.3%), mismatch repair deficient (MMR-d); 3 cases (1.8%), POLE-mutated; 2 cases (1.2%), p53 abnormal. No difference was found in the cumulative 40-week complete response (CR) rate between the patients having NSMP or MMR-d (61.6% vs 60.0%; P=0.593), while the patients having MMR-d had increased risk than those having NSMP to have recurrence after CR (50.0% vs 14.4%; P=0.005). Multi-variant analysis showed PTEN gene multi-loci mutation (HR=0.413, 95%CI: 0.259-0.658; P<0.001) and PIK3CA gene mutation (HR=0.499, 95%CI: 0.310-0.804; P=0.004) were associated with a lower cumulative 40-week CR rate, and progestin-insensitivity (HR=3.825, 95%CI: 1.570-9.317; P=0.003) and MMR-d (HR=9.014, 95%CI: 1.734-46.873; P=0.009) were independent risk factors of recurrence in EC and AEH patients. Conclusions: No difference in cumulative 40-week CR rate is found in the patients having NSMP or MMR-d who received progestin-based fertility-preserving treatment, where the use of hysteroscopy during the treatment might be the reason, while those having MMR-d have a higher risk of recurrence after CR. Oncogene mutation of PTEN or PIK3CA gene might be associated with a lower response to progestin treatment. The molecular profiles help predict the fertility-preserving treatment outcomes in EC and AEH patients.