Addendum to the consensus opinion from the International Deep Endometriosis Analysis (IDEA) group: sonographic evaluation of the parametrium.

Preoperative sonographic staging in patients with suspected parametrial endometriosis is essential to plan the surgical intervention and to anticipate the need for a multidisciplinary approach, and hence optimize surgical outcome. The results of a recent metanalysis suggest that defining more accurately the ultrasonographic criteria of parametrial involvement in endometriosis is needed. The aim of this addendum to the IDEA-consensus is to highlight the sonographic characteristics of the parametrium and identify ultrasound techniques to diagnose deep endometriosis in this area. This article is protected by copyright. All rights reserved.

Strengths and limitations of diagnostic tools for endometriosis and relevance in diagnostic test accuracy research.

Endometriosis is a chronic systemic disease that can cause pain, infertility and reduced quality of life. Diagnosing endometriosis remains challenging, which yields diagnostic delays for patients. Research on diagnostic test accuracy in endometriosis can be difficult due to verification bias, as not all patients with endometriosis undergo definitive diagnostic testing. The purpose of this State-of-the-Art Review is to provide a comprehensive update on the strengths and limitations of the diagnostic modalities used in endometriosis and discuss the relevance of diagnostic test accuracy research pertaining to each. We performed a comprehensive literature review of the following methods: clinical assessment including history and physical examination, biomarkers, diagnostic imaging, surgical diagnosis and histopathology. Our review suggests that, although non-invasive diagnostic methods, such as clinical assessment, ultrasound and magnetic resonance imaging, do not yet qualify formally as replacement tests for surgery in diagnosing all subtypes of endometriosis, they are likely to be appropriate for advanced stages of endometriosis. We also demonstrate in our review that all methods have strengths and limitations, leading to our conclusion that there should not be a single gold-standard diagnostic method for endometriosis, but rather, multiple accepted diagnostic methods appropriate for different circumstances. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Endometriosis classification, staging and reporting systems: a review on the road to a universally accepted endometriosis classification.

BACKGROUND: In the field of endometriosis, several classification, staging and reporting systems have been developed. However, endometriosis classification, staging and reporting systems that have been published and validated for use in clinical practice have not been systematically reviewed up to now. OBJECTIVES: The aim of the current review is to provide a historical overview of these different systems based on an assessment of published studies. MATERIALS AND METHODS: A systematic Pubmed literature search was performed. Data were extracted and summarised. RESULTS: Twenty-two endometriosis classification, staging and reporting systems have been published between 1973 and 2021, each developed for specific and different purposes. There is still no international agreement on how to describe the disease. Studies evaluating different systems are summarised showing a discrepancy between the intended and the evaluated purpose, and a general lack of validation data confirming a correlation with pain symptoms or quality of life for any of the current systems. A few studies confirm the value of the Enzian system for surgical description of deep endometriosis. With regards to infertility, the endometriosis fertility index has been confirmed valid for its intended purpose. CONCLUSIONS: Of the 22 endometriosis classification, staging and reporting systems identified in this historical overview, only a few have been evaluated, in 46 studies, for the purpose for which they were developed. It can be concluded that there is no international agreement on how to describe endometriosis or how to classify it, and that most classification/staging systems show no or very little correlation with patient outcomes. WHAT IS NEW?: This overview of existing systems is a first step in working towards a universally accepted endometriosis classification.

An International Terminology for Endometriosis, 2021.

BACKGROUND: Different classification systems have been developed for endometriosis, using different definitions for the disease, the different subtypes, symptoms and treatments. In addition, an International Glossary on Infertility and Fertility Care was published in 2017 by the International Committee for Monitoring Assisted Reproductive Technologies (ICMART) in collaboration with other organisations. An international working group convened over the development of a classification or descriptive system for endometriosis. As a basis for such system, a terminology for endometriosis was considered a condition sine qua non. OBJECTIVES: The aim of the current paper is to develop a set of terms and definitions on endometriosis that would be the basis for standardisation in disease description, classification and research. MATERIALS AND METHODS: The working group listed a number of terms relevant to be included in the terminology, documented currently used and published definitions, and discussed and adapted them until consensus was reached within the working group. Following stakeholder review, further terms were added, and definitions further clarified. Although definitions were collected through published literature, the final set of terms and definitions is to be considered consensus-based. After finalisation of the first draft, the members of the international societies and other stakeholders were consulted for feedback and comments, which led to further adaptations. RESULTS: A list of 49 terms and definitions in the field of endometriosis is presented, including a definition for endometriosis and its subtypes, different locations, interventions, symptoms and outcomes. Endometriosis is defined as a disease characterised by the presence of endometrium-like epithelium and/or stroma outside the endometrium and myometrium, usually with an associated inflammatory process. CONCLUSIONS: The current paper outlines a list of 49 terms and definitions in the field of endometriosis. The application of the defined terms aims to facilitate harmonisation in endometriosis research and clinical practice. Future research may require further refinement of the presented definitions. WHAT IS NEW?: A consensus based international terminology for endometriosis for clinical and research use.

Bowel preparation prior to transvaginal ultrasound improves detection of rectosigmoid deep infiltrating endometriosis and is well tolerated: prospective study of women with suspected endometriosis without surgical criteria.

OBJECTIVES: To analyze the effect of bowel preparation prior to transvaginal ultrasound (TVS) examination on the detection of bowel involvement and the description of rectosigmoid nodules of deep infiltrating endometriosis (DIE), and to evaluate patient tolerance of bowel preparation. METHODS: This was a prospective study of paired data obtained between September 2015 and March 2016 from a cohort of women referred, on suspicion of DIE but without surgical criteria, to the endometriosis unit of a tertiary university hospital. In all patients, the wall of the rectum and lower sigmoid colon was evaluated by two TVS examinations: the first was performed without bowel preparation and the second was done after the patient had followed a 3-day low-residue diet and received two 250-mL enemas, one the night before TVS and the second 1-3 h before the examination. The presence of adhesions, number and size of rectosigmoid nodules, deepest layer of the rectum affected, percentage of the circumference of the bowel affected and distance from the most caudal part of the bowel nodule to the anal verge were determined. Patient tolerance to bowel preparation was assessed using a 5-point Likert scale, in which 1 represented 'very well tolerated' and 5 represented 'very poorly tolerated'. RESULTS: The mean ± SD age of the 110 patients included in the study was 36.8 ± 5.07 years. As many as 55% of those identified during the first examination (TVS alone) as having adhesions were identified at the second examination (TVS with prior bowel preparation) as having rectosigmoid nodules, and 22 additional nodules were observed on TVS following bowel preparation. These newly detected rectosigmoid nodules, initially assessed mainly as adhesions, were smaller and more superficial compared with the nodules detected on TVS alone, or located in the anterior sigmoid wall. Patient tolerance overall to bowel preparation scored a mean of 1.81 on the 5-point Likert scale. CONCLUSIONS: Bowel preparation is well tolerated by patients. When bowel preparation is performed before TVS, the detection of small and superficial nodules and those in the anterior sigmoid wall is improved, allowing more detailed description of these nodules in patients with suspected endometriosis. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

B lymphocytes inactivation by Ibrutinib limits endometriosis progression in mice.

STUDY QUESTION: What are the effects of B lymphocyte inactivation or depletion on the progression of endometriosis? SUMMARY ANSWER: Skewing activated B cells toward regulatory B cells (Bregs) by Bruton's tyrosine kinase (Btk) inhibition using Ibrutinib prevents endometriosis progression in mice while B cell depletion using an anti-CD20 antibody has no effect. WHAT IS KNOWN ALREADY: A polyclonal activation of B cells and the presence of anti-endometrial autoantibodies have been described in a large proportion of women with endometriosis though their exact role in the disease mechanisms remains unclear. STUDY DESIGN, SIZE, DURATION: This study included comparison of endometriosis progression for 21 days in control mice versus animals treated with the anti-CD20 depleting antibody or with the Btk inhibitor Ibrutinib that prevents B cell activation. PARTICIPANTS/MATERIALS, SETTING, METHODS: After syngeneic endometrial transplantation, murine endometriotic lesions were compared between treated and control mice using volume, weight, ultrasonography, histology and target genes expression in lesions. Phenotyping of activated and regulatory B cells, T lymphocytes and macrophages was performed by flow cytometry on isolated spleen and peritoneal cells. Cytokines were assayed by ELISA. MAIN RESULTS AND THE ROLE OF CHANCE: Btk inhibitor Ibrutinib prevented lesion growth, reduced mRNA expression of cyclooxygenase-2, alpha smooth muscle actin and type I collagen in the lesions and skewed activated B cells toward Bregs in the spleen and peritoneal cavity of mice with endometriosis. In addition, the number of M2 macrophages decreased in the peritoneal cavity of Ibrutinib-treated mice compared to anti-CD20 and control mice. Depletion of B cells using an anti-CD20 antibody had no effect on activity and growth of endometriotic lesions and neither on the macrophages, compared to control mice. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: It is still unclear whether B cell depletion by the anti-CD20 or inactivation by Ibrutinib can prevent establishment and/or progression of endometriosis in humans. WIDER IMPLICATIONS OF THE FINDINGS: Further investigation may contribute to clarifying the role of B cell subsets in human endometriosis. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by a grant of Institut National de la Santé et de la Recherche Médicale and Paris Descartes University. None of the authors has any conflict of interest to disclose.

The role of the B lymphocytes in endometriosis: A systematic review.

The physiopathology of endometriosis is not completely understood and its progression is associated with a local and systemic inflammatory reaction. It is important to clarify the potential role of the immune system to better understand its implication in the pathogenesis of endometriosis, which includes the study of the role of B cells and antibodies. The aim of this study was to review the literature about the role of B lymphocytes in endometriosis. A search for "endometriosis", "B cells" and "B lymphocytes" in databases resulted in 140 citations; after applying inclusion and exclusion criteria, a total of 22 studies were assessed. The analyzed samples in the studies varied and different markers and techniques were used by the authors to evaluate the direct or indirect role of B lymphocytes in endometriosis. Most studies demonstrated increased number and/or activation of B cells while seven studies found no difference and two studies showed decreased number of B cells. Increased B lymphocytes and excessive production of autoantibodies in endometriosis have been described in the literature, but their role in the development of the disease is not well understood. Moreover, the association of these factors with clinical symptoms, location and severity of the disease has not been investigated. Further studies are necessary to clarify the role of B cells in the development of endometriosis and propose new therapeutic strategies such as the use of drugs that target these cells.

Recent insights on the genetics and epigenetics of endometriosis.

Endometriosis is a gynecologic disease affecting up to 10% of the women and a major cause of pain and infertility. It is characterized by the implantation of functional endometrial tissue at ectopic positions generally within the peritoneum. This complex disease has an important genetic component with a heritability estimated at around 50%. This review aims at providing recent insights into the genetic bases of endometriosis, and presents a detailed overview of evidence of epigenetic alterations specific to this disease. In the future, these alterations may constitute therapeutic targets for pharmacological compounds able to modify the epigenetic code.

Systematic approach to sonographic evaluation of the pelvis in women with suspected endometriosis, including terms, definitions and measurements: a consensus opinion from the International Deep Endometriosis Analysis (IDEA) group.

The IDEA (International Deep Endometriosis Analysis group) statement is a consensus opinion on terms, definitions and measurements that may be used to describe the sonographic features of the different phenotypes of endometriosis. Currently, it is difficult to compare results between published studies because authors use different terms when describing the same structures and anatomical locations. We hope that the terms and definitions suggested herein will be adopted in centers around the world. This would result in consistent use of nomenclature when describing the ultrasound location and extent of endometriosis. We believe that the standardization of terminology will allow meaningful comparisons between future studies in women with an ultrasound diagnosis of endometriosis and should facilitate multicenter research. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Consensus on Recording Deep Endometriosis Surgery: the CORDES statement.

STUDY QUESTION: Which essential items should be recorded before, during and after endometriosis surgery and in clinical outcome based surgical trials in patients with deep endometriosis (DE)? SUMMARY ANSWER: A DE surgical sheet (DESS) was developed for standardized reporting of the surgical treatment of DE and an international expert consensus proposal on relevant items that should be recorded in surgical outcome trials in women with DE. WHAT IS KNOWN ALREADY: Surgery is an important treatment for symptomatic DE. So far, data have been reported in such a way that comparison of different surgical techniques is impossible. Therefore, we present an international expert proposal for standardized reporting of surgical treatment and surgical outcome trials in women with DE. STUDY DESIGN, SIZE, DURATION: International expert consensus based on a systematic review of literature. PARTICIPANTS/MATERIALS, SETTING, METHODS: Taking into account recommendations from Consolidated Standards of Reporting Trials (CONSORT), the Innovation Development Exploration Assessment and Long-term Study (IDEAL), the Initiative on Methods, Measurement and Pain Assessment in Clinical trials (IMMPACT) and the World Endometriosis Research Foundation Phenome and Biobanking Harmonisation Project (WERF EPHect), a systematic literature review on surgical treatment of DE was performed and resulted in a proposal for standardized reporting, adapted by contributions from eight members of the multidisciplinary Leuven University Hospitals Endometriosis Care Program, from 18 international experts and from audience feedback during three international meetings. MAIN RESULTS AND THE ROLE OF CHANCE: We have developed the DESS to record in detail the surgical procedures for DE, and an international consensus on pre-, intra- and post-operative data that should be recorded in surgical outcome trials on DE. LIMITATIONS, REASONS FOR CAUTION: The recommendations in this paper represent a consensus among international experts based on a systematic review of the literature. For several items and recommendations, high-quality RCTs were not available. Further research is needed to validate and evaluate the recommendations presented here. WIDER IMPLICATIONS OF THE FINDINGS: This international expert consensus for standardized reporting of surgical treatment in women with DE, based on a systematic literature review and international consensus, can be used as a guideline to record and report surgical management of patients with DE and as a guideline to design, execute, interpret and compare clinical trials in this patient population. STUDY FUNDING/COMPETING INTERESTS: None of the authors received funding for the development of this paper. M.A. reports personal fees and non-financial support from Bayer Pharma outside the submitted work; H.T. reports a grant from Pfizer and personal fees for being on the advisory board of Perrigo, Abbvie, Allergan and SPD. TRIAL REGISTRATION NUMBER: N/A.

(Partial) Loss of BAF250a (ARID1A) in rectovaginal deep-infiltrating endometriosis, endometriomas and involved pelvic sentinel lymph nodes.

STUDY HYPOTHESIS: Loss of protein BAF250a (ARID1A) expression is present in women with rectovaginal deep-infiltrating endometriosis (DIE) and endometriosis affecting the pelvic sentinel lymph nodes (PSLN). STUDY FINDING: Partial loss of protein BAF250a was found in some of our patient samples, comprising all endometriosis entities, including rectovaginal DIE and endometriosis affecting the PSLN. WHAT IS KNOWN ALREADY: Loss of BAF250a (BRG-associated factor 250a)/ARIDIA (AT-rich interactive domain 1A) protein expression was identified among endometriosis-associated ovarian carcinomas and ovarian endometriosis, and this phenomenon was described as a possible early event in the transformation of endometriosis into cancer. DIE affecting the bowel/rectovaginal site is the most aggressive presentation of endometriosis and its 'risk' of malignant transformation has not been studied so far. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: We evaluated the immunohistochemical expression of BAF250a protein in 70 samples from patients enrolled in this study who were surgically treated at a tertiary center, university Hospital. The samples submitted to investigation were from rectovaginal DIE (n= 25/30), endometriosis affecting the PSLN (n= 5/7), ovarian endometriosis (n= 20/20) and endometrium from patients without endometriosis used as controls (n= 20/20). MAIN RESULTS AND THE ROLE OF CHANCE: Partial loss (i.e. in one tissue section some cells stained positive for BAF250a while other cells, usually an adjacent group, were negative) of BAF250a protein was identified in 36% (9/25) of rectovaginal DIE samples, 40% (2/5) of endometriosis lesions involving the PSLN, 30% (6/20) of endometriomas, and also in 25% (5/20) of endometrium from controls. We found no statistical correlation between occurrence of partial loss of BAF250a protein and the use or not of hormone medications (P = 0.106), cycle phase (P = 0.917) and stage of disease (P = 0.717). LIMITATIONS, REASONS FOR CAUTION: We only found partial loss of BAF250a protein expression, and in a small population of women, with relatively high frequency in all benign tissues assessed in the present analysis. Therefore, this finding alone should not be correlated directly with the risk of malignant transformation in these lesions. WIDER IMPLICATIONS OF THE FINDINGS: The occurrence of partial loss of BAF250a protein expression in women with rectovaginal DIE and endometriosis affecting the PSLN is described for the first time. The value of this finding as a predictor of malignant transformation in endometriosis must still be clarified and further studied in association with other molecular events, such as PTEN (phosphatase and tensin homolog) deletion and PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) mutation. We might then be able to identify in the future which patients with endometriosis are at higher risk of cancer. STUDY FUNDING AND COMPETING INTERESTS: This study was supported by an internal Charité grant to the Endometriosis Research Center and the authors declare no conflicts of interest.

Immunohistochemical Investigation of Metastasis-Related Chemokines in Deep-Infiltrating Endometriosis and Compromised Pelvic Sentinel Lymph Nodes.

Endometriosis is a prevalent benign disease, despite sharing several similarities with malignancies, such as the possibility of lymphatic spread. In malignancies, chemokines play a sovereign role in the process of metastasis. Metastasis-related chemokine axes have not yet been assessed in deep-infiltrating endometriosis (DIE), and this investigation was the aim of our study. The expression of these chemokines was investigated by immunohistochemistry in rectovaginal DIE lesions and in matched pelvic sentinel lymph nodes (PSLNs) of patients with endometriosis (n = 27), and their expression in the eutopic endometrium (EE) of endometriosis-free women (n = 20) was used as controls. Their staining pattern in rectovaginal DIE, in endometriotic lesions affecting the PSLN as well as in the EE of patients without endometriosis was characterized for the first time. Overall, these chemokines were highly expressed in DIE and endometriosis in PSLN. Chemokines might be involved in the spread of endometriosis and should be further investigated.

Addition of MCP-1 and MIP-3ß to the IL-8 appraisal in peritoneal fluid enhances the probability of identifying women with endometriosis.

Chemokines have been associated with endometriosis. Our study was aimed at evaluating the levels of six chemokines--CXCL8 (IL-8), CXCL12 (SDF-1), CCL2 (MCP-1), CCL5 (RANTES), CCL19 (MIP-3ß), and CCL21 (6-Ckine)--in the peritoneal fluid (PF) of patients with and controls without endometriosis by multiplexed cytokine assay. In this retrospective case-control study conducted at the Charité University Hospital, patients (n = 36) and controls (n = 27) were enrolled. The patients were separated into groups according to stage of the disease: I-II (n = 21), III-IV (n = 1 5), and according to clinical findings: peritoneal endometriosis (PE; n = 7), deep-infiltrating endometriosis (DIE) affecting the retrocervical area (n = 13) or the bowel/rectovaginal site (n = 14). The subjects were also separated according to the cycle phase: follicular (n = 14) or luteal (n = 8) and the previous use (n = 25) or not (n = 38) of hormones. PF was collected from all subjects (n = 63) consecutively during laparoscopy. The concentration of chemokines in the PF was assessed using Luminex(®) x-MAP(®) technology. Sensitivity and specificity were calculated. A model of multiple logistic regressions estimated the odds of endometriosis for each combination of the chemokines detected. We observed significantly higher concentrations of IL-8 (p < 0.001), MCP-1 (p = 0.014), and MIP-3ß (p = 0.022) in the PF of women with endometriosis than in the controls. A joint evaluation revealed that elevated levels of the three chemokines had a positive endometriosis prediction value of 89.1%. The combined assessment of MCP-1, MIP-3ß, and IL-8 concentration in PF improved the likelihood of identifying patients with endometriosis. Future studies should investigate this panel in peripheral blood samples.

Peripheral blood telomere content is greater in patients with endometriosis than in controls.

UNLABELLED: The etiology of endometriosis remains poorly understood but circulating stem cells may contribute. Telomeres shorten with cell divisions and age. Stem cells attempt to compensate for telomere attrition through the action of telomerase. Since circulating stem cells may contribute to endometriosis, we compared telomere content in lymphocytes of patients with and without endometriosis. METHODS: Observational study comparing peripheral lymphocytes telomere content, measured by quantitative polymerase chain reaction, in patients with (n = 86) and without endometriosis (n = 21). FINDINGS: Patients with endometriosis had longer telomeres than that of matched, endometriosis-free controls (telomere to single copy gene ratio [T/S ratio] of 1.62 vs 1.34, respectively, P = .00002). Patients with endometriosis were 8.1-fold more likely to have long telomeres. (odds ratio = 8.1, 95% confidence interval: 1.28-51.57, P = .0264). INTERPRETATION: Longer telomeres could be consistent with a stem cell origin of endometriosis.

Can chemokines be used as biomarkers for endometriosis? A systematic review.

STUDY QUESTION: Can we use chemokines as biomarkers to diagnose patients with endometriosis in clinical practice? SUMMARY ANSWER: Some chemokines, especially CXCL8 (IL-8), CCL-2 (MCP-1) and CCL5 (RANTES), have the potential to work as biomarkers to identify patients with endometriosis but their accuracy could be improved by combination with other non-inflammatory markers in a panel of biomarkers. WHAT IS ALREADY KNOWN: The need for a good marker to diagnose endometriosis has increased in recent years and research in this field has intensified. Chemokines have been reported to be associated with endometriosis in several studies over the last 20 years. Many of these studies measured one or more chemokines in peritoneal fluid (PF) and peripheral blood (PB) or through endometrial biopsies in patients with and without endometriosis. STUDY DESIGN, SIZE, DURATION: A systematic review was done on all published studies that compared chemokine concentrations in patients with and without endometriosis to evaluate their potential as biomarkers for the disease. PARTICIPANTS/MATERIALS, SETTING, METHODS: Using MEDLINE database from December 1993 to August 2013 and the MeSH terms 'Endometriosis' and 'Chemokines', we identified relevant studies to include in the present review, which was based on the PRISMA statement. Studies that measured at least one chemokine in patients with endometriosis and matching controls in PB, PF or endometrial samples were included. We did not include samples from ectopic lesions. All review articles as well as studies with animals and those not written in English were excluded from this systematic review. The studies were assessed using a modified version of the Quality Assessment of Diagnostic Accuracy Studies criteria. Two authors independently assessed studies for inclusion and risk of bias, and extracted data. MAIN RESULTS AND THE ROLE OF CHANCE: After inclusion and exclusion criteria, 62 studies were selected to be included in this systematic review. A total of 27 different chemokines or their receptors were evaluated in the reviewed studies. The most studied chemokines (including their receptors) were CXCL8 (51.6%), CCL2 (38.7%) and CCL5 (19.3%) (% of studies). CXCL8 (IL-8) appears to have the best results among all the other chemokines as a marker for endometriosis. LIMITATIONS, REASONS FOR CAUTION: Some studies included have low power due to small sample size and study designs vary in the assessment criteria for the markers, the state of the patients (e.g. phase of the cycle and stage of disease) and the nature of the controls. WIDER IMPLICATIONS OF THE FINDINGS: Our findings could guide future research in this field to select the chemokines with the best potential, and to stimulate better-designed studies to determine whether they can become a useful diagnostic tool in clinical practice. STUDY FUNDING/COMPETING INTEREST(S): There was no funding to support this systematic review. The authors have no competing interest to declare.