ESGO/ESHRE/ESGE Guidelines for the fertility-sparing treatment of patients with endometrial carcinoma.

Background: The standard surgical treatment of endometrial carcinoma (EC) consisting of total hysterectomy with bilateral salpingo-oophorectomy drastically affects the quality of life of patients and creates a challenge for clinicians. Recent evidence-based guidelines of the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy & Oncology (ESTRO) and the European Society of Pathology (ESP) provide comprehensive guidelines on all relevant issues of diagnosis and treatment in EC in a multidisciplinary setting. While also addressing work-up for fertility preservation treatments and the management and follow-up for fertility preservation, it was considered relevant to further extend the guidance on fertility sparing treatment. Objectives: To define recommendations for fertility-sparing treatment of patients with endometrial carcinoma. Materials and Methods: ESGO/ESHRE/ESGE nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of EC (11 experts across Europe). To ensure that the guidelines are evidence-based, the literature published since 2016, identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 95 independent international practitioners in cancer care delivery and patient representatives. Results: The multidisciplinary development group formulated 48 recommendations for fertility-sparing treatment of patients with endometrial carcinoma in four sections: patient selection, tumour clinicopathological characteristics, treatment and special issues. Conclusions: These recommendations provide guidance to professionals caring for women with endometrial carcinoma, including but not limited to professionals in the field of gynaecological oncology, onco-fertility, reproductive surgery, endoscopy, conservative surgery, and histopathology, and will help towards a holistic and multidisciplinary approach for this challenging clinical scenario. What is new?: A collaboration was set up between the ESGO, ESHRE and ESGE, aiming to develop clinically relevant and evidence-based guidelines focusing on key aspects of fertility-sparing treatment in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide.

ESGO/ESHRE/ESGE Guidelines for the fertility-sparing treatment of patients with endometrial carcinoma.

Background: The standard surgical treatment of endometrial carcinoma (EC) consisting of total hysterectomy with bilateral salpingo-oophorectomy drastically affects the quality of life of patients and creates a challenge for clinicians. Recent evidence-based guidelines of the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy & Oncology (ESTRO) and the European Society of Pathology (ESP) provide comprehensive guidelines on all relevant issues of diagnosis and treatment in EC in a multidisciplinary setting. While also addressing work-up for fertility preservation treatments and the management and follow-up for fertility preservation, it was considered relevant to further extend the guidance on fertility sparing treatment. Objectives: To define recommendations for fertility-sparing treatment of patients with endometrial carcinoma. Materials and Methods: ESGO/ESHRE/ESGE nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of EC (11 experts across Europe). To ensure that the guidelines are evidence-based, the literature published since 2016, identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 95 independent international practitioners in cancer care delivery and patient representatives. Results: The multidisciplinary development group formulated 48 recommendations for fertility-sparing treatment of patients with endometrial carcinoma in four sections: patient selection, tumour clinicopathological characteristics, treatment and special issues. Conclusions: These recommendations provide guidance to professionals caring for women with endometrial carcinoma, including but not limited to professionals in the field of gynaecological oncology, onco-fertility, reproductive surgery, endoscopy, conservative surgery, and histopathology, and will help towards a holistic and multidisciplinary approach for this challenging clinical scenario. What is new? A collaboration was set up between the ESGO, ESHRE and ESGE, aiming to develop clinically relevant and evidence-based guidelines focusing on key aspects of fertility-sparing treatment in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide.

Congenital Uterine Malformation by Experts (CUME): diagnostic criteria for T-shaped uterus.

OBJECTIVES: To identify uterine measurements that are reliable and accurate to distinguish between T-shaped and normal/arcuate uterus, and define T-shaped uterus, using Congenital Uterine Malformation by Experts (CUME) methodology, which uses as reference standard the decision made most often by several independent experts. METHODS: This was a prospectively planned multirater reliability/agreement and diagnostic accuracy study, performed between November 2017 and December 2018, using a sample of 100 three-dimensional (3D) datasets of different uteri with lateral uterine cavity indentations, acquired from consecutive women between 2014 and 2016. Fifteen representative experts (five clinicians, five surgeons and five sonologists), blinded to each others' opinions, examined anonymized images of the coronal plane of each uterus and provided their independent opinion as to whether it was T-shaped or normal/arcuate; this formed the basis of the CUME reference standard, with the decision made most often (i.e. that chosen by eight or more of the 15 experts) for each uterus being considered the correct diagnosis for that uterus. Two other experienced observers, also blinded to the opinions of the other experts, then performed independently 15 sonographic measurements, using the original 3D datasets of each uterus. Agreement between the diagnoses made by the 15 experts was assessed using kappa and percent agreement. The interobserver reliability of measurements was assessed using the concordance correlation coefficient (CCC). The diagnostic test accuracy was assessed using the area under the receiver-operating-characteristics curve (AUC) and the best cut-off value was assessed by calculating Youden's index, according to the CUME reference standard. Sensitivity, specificity, negative and positive likelihood ratios (LR- and LR+) and post-test probability were calculated. RESULTS: According to the CUME reference standard, there were 20 T-shaped and 80 normal/arcuate uteri. Individual experts recognized between 5 and 35 (median, 19) T-shaped uteri on subjective judgment. The agreement among experts was 82% (kappa = 0.43). Three of the 15 sonographic measurements were identified as having good diagnostic test accuracy, according to the CUME reference standard: lateral indentation angle (AUC = 0.95), lateral internal indentation depth (AUC = 0.92) and T-angle (AUC = 0.87). Of these, T-angle had the best interobserver reproducibility (CCC = 0.87 vs 0.82 vs 0.62 for T-angle vs lateral indentation depth vs lateral indentation angle). The best cut-off values for these measurements were: lateral indentation angle ≤ 130° (sensitivity, 80%; specificity, 96%; LR+, 21.3; LR-, 0.21), lateral indentation depth ≥ 7 mm (sensitivity, 95%; specificity, 77.5%; LR+, 4.2; LR-, 0.06) and T-angle ≤ 40° (sensitivity, 80%; specificity, 87.5%; LR+, 6.4; LR-, 0.23). Most of the experts diagnosed the uterus as being T-shaped in 0% (0/56) of cases when none of these three criteria was met, in 10% (2/20) of cases when only one criterion was met, in 50% (5/10) of cases when two of the three criteria were met, and in 93% (13/14) of cases when all three criteria were met. CONCLUSIONS: The diagnosis of T-shaped uterus is not easy; the agreement among experts was only moderate and the judgement of individual experts was commonly insufficient for accurate diagnosis. The three sonographic measurements with cut-offs that we identified (lateral internal indentation depth ≥ 7 mm, lateral indentation angle ≤ 130° and T-angle ≤ 40°) had good diagnostic test accuracy and fair-to-moderate reliability and, when applied in combination, they provided high post-test probability for T-shaped uterus. In the absence of other anomalies, we suggest considering a uterus to be normal when none or only one criterion is met, borderline when two criteria are met, and T-shaped when all three criteria are met. These three CUME criteria for defining T-shaped uterus may aid in determination of its prevalence, clinical implications and best management and in the assessment of post-surgical morphologic outcome. The CUME definition of T-shaped uterus may help in the development of interventional randomized controlled trials and observational studies and in the diagnosis of uterine morphology in everyday practice, and could be adopted by guidelines on uterine anomalies to enrich their classification systems. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Congenital Uterine Malformation by Experts (CUME): better criteria for distinguishing between normal/arcuate and septate uterus?

OBJECTIVES: To assess the level of agreement between experts in distinguishing between septate and normal/arcuate uterus using their subjective judgment when reviewing the coronal view of the uterus from three-dimensional ultrasound. Another aim was to determine the interobserver reliability and diagnostic test accuracy of three measurements suggested by recent guidelines, using as reference standard the decision made most often by experts (Congenital Uterine Malformation by Experts (CUME)). METHODS: Images of the coronal plane of the uterus from 100 women with suspected fundal internal indentation were anonymized and provided to 15 experts (five clinicians, five surgeons and five sonologists). They were instructed to indicate whether they believed the uterus to be normal/arcuate (defined as normal uterine morphology or not clinically relevant degree of distortion caused by internal indentation) or septate (clinically relevant degree of distortion caused by internal indentation). Two other observers independently measured indentation depth, indentation angle and indentation-to-wall-thickness (I:WT) ratio. The agreement between experts was assessed using kappa, the interobserver reliability was assessed using the concordance correlation coefficient (CCC), the diagnostic test accuracy was assessed using the area under the receiver-operating characteristics curve (AUC) and the best cut-off value was assessed using Youden's index, considering as the reference standard the choice made most often by the experts (CUME). RESULTS: There was good agreement between all experts (kappa, 0.62). There were 18 septate and 82 normal/arcuate uteri according to CUME; European Society of Human Reproduction and Embryology (ESHRE)-European Society for Gynaecological Endoscopy (ESGE) criteria (I:WT ratio > 50%) defined 80 septate and 20 normal/arcuate uteri, while American Society for Reproductive Medicine (ASRM) criteria defined five septate (depth > 15 mm and angle < 90°), 82 normal/arcuate (depth < 10 mm and angle > 90°) and 13 uteri that could not be classified (referred to as the gray-zone). The agreement between ESHRE-ESGE and CUME was 38% (kappa, 0.1); the agreement between ASRM criteria and CUME for septate was 87% (kappa, 0.39), and considering both septate and gray-zone as septate, the agreement was 98% (kappa, 0.93). Among the three measurements, the interobserver reproducibility of indentation depth (CCC, 0.99; 95% CI, 0.98-0.99) was better than both indentation angle (CCC, 0.96; 95% CI, 0.94-0.97) and I:WT ratio (CCC, 0.92; 95% CI, 0.90-0.94). The diagnostic test accuracy of these three measurements using CUME as reference standard was very good, with AUC between 0.96 and 1.00. The best cut-off values for these measurements to define septate uterus were: indentation depth ≥ 10 mm, indentation angle < 140° and I:WT ratio > 110% . CONCLUSIONS: The suggested ESHRE-ESGE cut-off value overestimates the prevalence of septate uterus while that of ASRM underestimates this prevalence, leaving in the gray-zone most of the uteri that experts considered as septate. We recommend considering indentation depth ≥ 10 mm as septate, since the measurement is simple and reliable and this criterion is in agreement with expert opinion. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

New cases of accessory and cavitated uterine masses (ACUM): a significant cause of severe dysmenorrhea and recurrent pelvic pain in young women.

BACKGROUND: To raise awareness about the accessory and cavitated uterine masses (ACUM) with functional endometrium as a different entity from adult adenomyosis and to highlight the importance of a correct diagnosis, we studied four new cases of ACUM and 15 cases reported as juvenile cystic adenomyoma (JCA) by reviewing the literature from the last year. This entity is problematic because of a broad differential diagnosis, including rudimentary and cavitated uterine horns; and is generally underdiagnosed, being more frequent than previously thought. METHODS: We report four cases of young women who underwent surgery in our hospital from January to July 2011 after presenting with an ACUM. We also reviewed and tabulated the cases from literature beginning in 2010. Main outcome measures were diagnostic tools, surgical and histopathological findings and improvement of symptoms. RESULTS: The addition of the four cases reported here to the 15 published as JCA raises the total number of cases of ACUMs to 19, which is more than all of the cases reported prior to 2010. In our cases, it is interesting to highlight that one of them also had an adjacent accessory rudimentary tube and another had two ACUMs at the same location. All patients suffered from severe dysmenorrhea and pelvic pain and were young women. Suspicion, transvaginal ultrasound and magnetic resonance image were found to be the best diagnostic tools. Most of the cases were treated by laparoscopic tumorectomy. CONCLUSIONS: ACUMs are generally underdiagnosed and often reported as JCAs but they are not adenomyosis. Early surgical treatment involving the laparoscopic or laparotomic removal of the mass could prevent the usual prolonged suffering of these young women. In our opinion, this entity is a new variety of Müllerian anomaly.

Cervicovaginal agenesis: spontaneous gestation at term after previous reimplantation of the uterine corpus in a neovagina: Case Report.

We present an exceptional case of a patient with complete cervical atresia and total vaginal aplasia. After McIndoe vaginoplasty, cervicoitsmic resection with implantation and reimplantation of the uterine corpus in the neovagina, and conservative surgery for endometriosis, the patient had normal menstruations and became pregnant spontaneously. A Caesarean section was performed at week 36. This is the third published case report of a successful spontaneous pregnancy and Caesarean section at term in a patient with complete cervicovaginal aplasia, and the first published case study of a patient becoming pregnant after McIndoe vaginoplasty, cervicoistmic resection and utero-neovaginal anastomosis. Gestation developed successfully without cerclage. We recommend conservative surgery in patients with congenital cervical atresia. McIndoe vaginoplasty should be performed as soon as possible in adolescence if there is associated vaginal aplasia. Nevertheless, fibrotic stenosis can occur, even after several years and, therefore, additional operations and uterine reimplantation may be required.

Experimental contributions to the study of the embryology of the vagina.

BACKGROUND: Acién's hypothesis, deduced from patients with malformations of the female genital tract, especially those with renal agenesis and ipsilateral blind hemivagina, affirms the embryology of the human vagina as deriving from the Wolffian ducts and the Müllerian tubercle and could explain the embryological origin of all the female genital malformations reported. In this study, we investigated the hypothesis in rats. METHODS: Twenty-five pregnant rats were used to analyse female embryos (64) from day 15 (stage indifferent) to day 20 postcoitum (vagina completely formed). We performed transverse and longitudinal sections of embryos, haematoxylin-eosin tinction and immunohistochemical staining using markers specific to Wolffian derivatives. We also analysed the presence of these markers in the vagina of four adult rats. RESULTS: The Müller ducts converge until they fuse into one tube, but caudally they diverge and finally they fuse with the 'urogenital sinus bulbs' that are actually the distal portion of the Wolffian ducts according to the immunohistochemical marking with GZ1 and GZ2. The Müllerian tubercle is observed between those elements. Then, the immunohistochemical staining can be seen all along the completely formed vagina, which is also observed in the vagina of the adult rat. CONCLUSION: We prove the participation of Müller tubercle and Wolffian ducts in the formation of the vagina in rats, so we confirm experimentally Acién's hypothesis about the human vagina embryology.

Peso, lípidos y presiónarterial en relación con laterapia hormonal sustitutivaen la posmenopausia / Body weight, lipids and blood pressure in relation to postmenopausal hormone replacement therapy

Objetivos: Relacionar la evolución del peso y el índice de masa corporal (IMC), así como de lípidos y la presión arterial, con el seguimiento o no de terapia hormonal sustitutiva (THS) en la posmenopausia. Sujetos y métodos: Un total 250 mujeres con seguimiento entre uno y 15 años, 186 con THS y 64 sin ella. La evolución de los parámetros de estudio se analizó en función de la THS y de la edad, comparando variables dependientes antes de la menopausia, antes de THS, durante el seguimiento y en el momento de la recogida de datos. Resultados: En todas las mujeres, con y sin THS, aumenta ligeramente el peso y el IMC, pero no de forma significativa, estando más relacionado con la edad. El aumento mayor ocurre en la transición menopáusica y al abandonar la THS. De todas formas, la vía oral parece influir menos en el aumento de peso. Por otro lado, el IMC desciende a partir de los 57-60 años si la mujer no sigue THS. Igualmente, el colesterol total, los triglicéridos y la presión arterial sistólica aumentan más en estas mujeres. Conclusiones: La THS no parece tener una influencia significativa en el aumento de peso y el IMC de la mujer posmenopáusica, pero es probable que lo tenga en su mantenimiento después de los 57-60 años. El efecto sobre los lípidos y la presión arterial parece favorable (AU)

Cirugía radical en el carcinoma cervical en estadio IIB o inferior. Estadificación clínica frente a quirurgicopatológica / Radical surgery in cervical carcinoma stage IIB or less. Clinical versus surgicalpathological staging

Objetivos: Correlacionar los estadios clínico y quirurgicopatológico del cáncer cervical y analizar los resultados terapéuticos tras haber realizado cirugía radical de Wertheim-Meigs en la mayoría de los mismos con estadio IIB o inferior. Sujetos y métodos: Análisis retrospectivo de 115 pacientes diagnosticadas de carcinoma cervical en estadio IIB o inferior entre los años 1984 y 1999; fueron operados 100 casos y se realizó cirugía radical en el 65 por ciento de los cánceres en estadio IIB; asimismo, 58 de los casos operados recibieron radioterapia; las otras 15 pacientes no operadas se trataron con radioterapia sola. Resultados: El 21 por ciento de los casos en estadio clínico IA-IB se hallaba en realidad en un estadio quirurgicopatológico más elevado, mientras que entre aquellas pacientes operadas con un estadio clínico IIB, el 48 por ciento se encontraba realmente en un estadio más bajo. Las tasas de supervivencia actuarial a 5 años en los 100 casos operados fueron del 100 por ciento para el estadio IA, el 88 por ciento para el IB, el 100 por ciento para el IIA y el 59,4 por ciento para el IIB; a los 10 años fueron del 100, el 88, el 100 y el 52 por ciento, respectivamente. En los casos de estadio IIB no operados, las tasas de supervivencia a los 5 años fueron del 71,7 y a los 10 años del 40 por ciento. No hubo diferencias en lo que respecta a la supervivencia o recurrencias entre las pacientes en estadio IB/IIA a las que se practicó cirugía radical con o sin radioterapia posterior. Tampoco hubo diferencias en las tasas referidas al comparar la presencia o no de ganglios positivos. Sin embargo, en el estadio posquirúrgico IIB, la supervivencia a los 5 años fue del 80 por ciento si los ganglios linfáticos fueron negativos, frente al 17,8 por ciento si éstos eran positivos para cáncer. Conclusiones: En primer lugar, en condiciones apropiadas, mediante la cirugía radical de Wertheim-Meigs se obtienen buenos resultados de supervivencia (más del 90 por ciento) en los estadios IB-IIA, que se mantienen tras la radioterapia adicional para aquellos casos con factores pronósticos adversos. En segundo lugar, la comparación entre cirugía y radioterapia no puede establecerse en el estadio clínico IIB puesto que entre los casos operados, el 47 por ciento se encontraba realmente en un estadio más bajo. Por último, en el estadio quirurgicopatológico IIB, si los ganglios linfáticos son negativos, la supervivencia es buena (80 por ciento) y las tasas de recurrencia, bajas. Por tanto, estos casos también podrían beneficiarse de la cirugía radical (AU)

Insulin, androgens, and obesity in women with and without polycystic ovary syndrome: a heterogeneous group of disorders.

OBJECTIVE: To analyze the correlations among insulin, androgens, body mass index (BMI), and other related metabolic anomalies in women with and without polycystic ovary syndrome (PCOS). DESIGN: Retrospective study of normal and obese women with and without PCOS. SETTING: Gynecologic endocrinology units of Elche, San Juan, and Alicante Hospitals and Hormone Laboratory at Alicante University Hospital ("Miguel Hernández" University). PATIENT(S): A total of 212 women were studied: 137 with PCOS and 75 without PCOS. INTERVENTION(S): BMI, gonadotropins, insulin, androgens (T, androstenedione, DHEAS), 17alpha-hydroxyprogesterone, sex hormone-binding globulin, and triglycerides were studied. Glycemia and insulin response to the tolerance test (GTT) with a 100-g oral glucose load were also assessed in 103 women. RESULT(S): A good correlation between insulin and BMI was found in normal and obese women without hormonal dysfunction and in patients with or without PCOS. Good correlations, although lower, between insulin and T, and BMI, insulin, and T with triglycerides were also found in patients with PCOS. These patients fell into clearly distinct categories: with or without insulin resistance and with or without obesity, but slim women with PCOS had insulin and metabolic variables similar to those without PCOS, and most obese women with PCOS were insulin-resistant and more hyperandrogenic and hypertriglyceridemic. CONCLUSION(S): Insulin, androgens, and BMI are related in women both with PCOS and without PCOS, especially in obese ones. Insulin and metabolic indices are similar in lean women with PCOS and those without PCOS, but obese women with PCOS are more insulin-resistant, hyperandrogenic, and hypertriglyceridemic. Three types of disorders can be distinguished: simple nonhyperandrogenic obesity, typical nonhyperinsulinemic PCOS, and insulin-resistant PCOS.