Study Design and Outcomes A multicenter, retrospective, observational trial was conducted between January 2012 and December 2018 in 14 Italian Gynecological Departments (University-affiliated or Public Hospitals). All centers involved in the study were selected by the Italian School of Minimally Invasive Gynecologic Surgery (SICMIG). All participating Institutions routinely shared the same technique of endometrial biopsy to study endometrial abnormalities, based on hysteroscopically-driven tissue sampling. After obtaining the approval from the resident Institutional Ethical Committee, we performed a retrospective search from each Institutional pathology data base. Eligible patients were identified as those women in whom either a pathologic report of endometrial carcinoma of endometrioid histology was found on hysterectomy specimen and a preoperative hysteroscopy assessment with endometrial biopsy targeted under vision was available. As primary outcome we calculated the sensitivity of hysteroscopy-view and biopsy pathology on hysteroscopically-driven sampling in the diagnostic work-up of EC. In addition, we established the prevalence of hysteroscopy biopsies yielding a diagnosis of AH instead of a true one of EC. In this group of patients, secondary endpoints were the followings: a) To evaluate whether hysteroscopy-view diagnosis, based on current pathomorphology knowledges and consistent with an overt neoplastic growth, could be of diagnostic support to decrease the rate of missed EEC; b) To assess whether surgical variables such as the hysteroscopy sampling technique and hysteroscopy operative settings could affect the diagnosis of EEC; c) We highlighted on pathological grade and surgical stage of missed EECs to suggest if an underestimated diagnosis of AH could lead to a surgical under-treatment of poor-prognosis EECs.
Patients Selection Either premenopausal and postmenopausal women were recruited. In postmenopausal patients, diagnostic hysteroscopy was indicated because of abnormal uterine bleeding, afterward a transvaginal sonographic assessment showed an endometrial thickness measuring 3mm or more in the longitudinal plane of uterine scan. In asymptomatic menopausal women, hysteroscopy was carried out when a routinely accomplished transvaginal sonography showed an endometrial stripe of more than 4 to 6 mm, accordingly with the single institutional custom. In premenopausal women hysteroscopy examination was indicated because of abnormal uterine bleeding refractory to medical therapy and/or a non-homogeneous endometrial lining estimated by transvaginal ultrasonography in middle-late proliferative phase of menstrual cycle. From the search on pathology databases, we retrieved the medical record of all patients with a diagnosis of endometrial carcinoma obtained from hysterectomy specimens during the study-period. Hysteroscopy imaging reports, hysteroscopy technique of tissue collection and results of biopsy pathology were recorded and compared to hysterectomy histologic findings. The pathological assessment of either biopsies and hysterectomy specimens were accomplished by resident pathologists and each report was adapted to current WHO guidelines [17]. Surgical management of hysterectomy was at the discretion of the primary surgeon and surgical approaches included vaginal, open and laparoscopic techniques. The addition of lymphadenectomy was also at the surgeon’s discretion. EEC surgical stage and grade were classified according to 2009 International Federation of Obstetrics and Gynecology guidelines [18]. Patients suffering from endometrial carcinoma of clear-cells and serous histology, such as those affected by uterine sarcomas were excluded from the study.
Hysteroscopy Imaging The hysteroscopy-view diagnosis was made according to pathomorphologic correlations reported in previous trials [19-22] but it was based on the subjective impression and expertise of responsible surgeon. All participating centers shared the following definitions of hysteroscopy-view pictures.
Normal endometrium: An evenly lined atrophic or functional mucosa showing a regular distribution of gland openings without any architectural distortion of endometrial shape.
Endometrial polyp: Focal, single or multiple, sessile or pedunculated luminal projections fluttering under the distending medium flow, showing from soft to mild fibrous consistence, covered by an evenly lined functional or atrophic mucosa, frequently showing cyst-gland formation and supplied by a thin vascular network.
Endometrial hyperplasia: One or more of the following features suggested a diagnosis of hyperplasia. i. Focal or diffuse polypoid or papillary mucosal endometrial thickening without obvious necrosis ii. Abnormalities of endometrial glands architecture such as gland cysts detection sometimes with button-like whitish appearance, gland crowding, and irregularly spaced gland openings iii. A concurrent enhanced and irregular but not overtly atypical, vascular network.
Endometrial cancer: An endometrial cavity showing focal or extended polypoid, papillary, nodular or mixed patterns of mucosal overgrowth showing friable/cerebroid consistence, surface necrosis appearing as avascular whitish-grayish tissue and an overt atypical vascular network.
Biopsy Surgical Techniques Based on the custom of each participating center, hysteroscopy was carried-out either as outpatient office intervention with or without anesthetic local support and as inpatient procedure accomplished in surgical room under general anesthesia or conscious sedation. All procedures were assisted by video-camera and were conducted by using a fluid distending medium delivered by pressure bag or a peristaltic pump. Normal saline or hypotonic solutions were used according to the use of bipolar or monopolar technology, respectively. Endometrial biopsies were carried-out by using one of the following hysteroscopes: i. 12Fr-16Fr rigid hysteroscopes with a 5Fr operative channel ii. 16Fr mini-resectoscopes armed with a mini-loop electrode iii. 26Fr-27Fr resectoscopes armed with a loop electrode. The vaginoscopic technique was routinely used to gain uterine entering [23] with the exception of patients treated under general anesthesia by 26Fr-27Fr resectoscopes, in whom cervical dilatation was done before hysteroscopy assessment. The cutting devices used for endometrial sampling included: i. Mechanical tools such as sharp scissors and grasping forceps ii. Electrosurgical tools such as 5Fr co-axial or angled bipolar electrodes, bipolar or monopolar loops and bipolar or monopolar mini-loops. After a hysteroscopy inspection suggestive for EC, based on responsible hysteroscopist’s judgement, one or more endometrial biopsies under vison were accomplished, addressing the tissue sampling to the viable tissue showing the most predictive features of malignancy. When hysteroscopy-view was consistent with hyperplasia or polyp, biopsies targeted to the most significant mucosal abnormality or a full polypectomy were carried-out, respectively.
Data Collection The directory board of SICMIG addressed to single certified physicians of each Institution a xlsx database containing the clinical parameters of interest. These latter included: 1. Patient age 2. Menopausal status 3. Bleeding symptoms 4. Hysteroscopy operative setting 5. Hysteroscopy view diagnosis 6. Hysteroscopy technique of biopsy 7. Pathologic findings on biopsy 8. Grade of EEC on biopsy 9. Pathologic findings on hysterectomy specimens 10. Grade of EEC on hysterectomy specimens 11. Surgical stage of EEC. The written reports describing either the hysteroscopy imaging and the surgical technique of tissue sampling were used to draw the data about hysteroscopy assessment. We recorded, but excluded from the analysis all patients in whom a primary hysteroscopy tissue sampling yielded to the pathologist a too scant amount of tissue to provide any diagnosis.
Study Outcomes As primary outcome we calculated the sensitivity of hysteroscopy-view and biopsy pathology on hysteroscopically-driven sampling in the diagnostic work-up of EEC. In addition, we established the prevalence of hysteroscopy biopsies yielding a diagnosis of AH instead of a true one of EC. In this group of patients, secondary endpoints were the following i. To evaluate whether hysteroscopy-view diagnosis, based on current pathomorphology knowledges and consistent with an overt neoplastic growth, could be of diagnostic support to decrease the rate of missed EEC ii. To assess whether surgical variables such as the hysteroscopy sampling technique and hysteroscopy operative settings could affect the diagnosis of EEC iii. We highlighted on pathological grade and surgical stage of missed EECs to suggest if an underestimated diagnosis of AH could lead to a surgical under-treatment of poor-prognosis EECs.
Statistical Analysis
Data analyses were carried out by Jamovi software (version 1.2; https://www.jamovi.org). Sensitivity considered the probability that a test outcome will be positive when the illness is present and specificity referring to the probability that a test outcome will be negative when the illness is not present. To verify the hypotheses, binary logistic regressions were applied to assess which variables independently supported the correct classification of the patients having EEC. The estimated weights were given for each predictor to represent the change in probability and thus identify the target modality in the dependent variable. The Odds Ratios measures the strength of the association between each independent and dependent (outcome) variable. The odds ratios measured the strength of the association between each independent and dependent (outcome) variable, with p ≤ .05 considered statistically significant.