An International Terminology for Endometriosis, 2021

Different definitions are used for endometriosis, endometriosis subtypes, treatments and outcomes. This has significant consequences for research and clinical practice. The current paper is prepared by an international group of experts and lists a number of terms used in endometriosis, with a relevant and appropriate definition. Endometriosis is defined as an inflammatory disease process characterized at surgery by the presence of endometrium-like epithelium and/or stroma outside the endometrium and myometrium, usually with an associated inflammatory process. These definitions should result in harmonisation both in endometriosis research and in clinical practice.

As a starting point for standardisation and to be able to universally use the classification, definitions of terms were structured in four sections: endometriosis, subtypes and locations ( Table I ); anatomical spaces and other locations where endometriosis can be detected ( Table II ); endometriosis treatments and interventions ( Table III ); and outcome parameters ( Table IV ). For symptoms associated with endometriosis, the definitions are generally clear and can be consulted in other papers ( Zegers-Hochschild et al., 2017 ; Vitonis et al., 2014 ). Terms and definitions for endometriosis, subtypes and locations. Terms and definitions for anatomical spaces and other locations where endometriosis can be detected. Terms and definitions for treatments and interventions used in the context of endometriosis. Terms and definitions for treatments and interventions used in the context of endometriosis. *Brain haemorrhage, ischemic stroke, subarachnoid bleeding, but excluding transient ischemic attacks. The terms and definitions are listed in Tables I-IV. For endometriosis, previous definitions have focussed on pathology or on the symptoms suffered by those with the disease. The WES definition, a strong consensus from 55 expert representatives of 29 national and international organisations (which was considered unanimous, where fewer than 5% of experts disagreed with the definition) introduced the concept that symptoms are an important aspect of ‘disease’ suffered by patients. Without symptoms, the occurrence of lesions per se might not necessarily be considered a disease, given that occurrence of lesions in the absence of symptoms may be considered a ubiquitous finding ( Johnson et al., 2017 ; Koninckx et al., 1994 ). A more comprehensive, contemporary characterisation of endometriosis has been provided through WES consensus that alludes to other essential elements including incidence, pathogenesis, multifactorial aetiology including genetic factors with possible epigenetic influences, possible effects of environmental exposures, pain syndrome elements, proliferative nature, hormone responsiveness (oestrogen-dependence and progesterone-resistance), and overlap with other conditions characterised by pelvic–abdominal pain and infertility ( https://endometriosis.ca/endometriosis/ ). In the International Glossary on Infertility and Fertility Care, endometriosis is defined as a disease characterised by the presence of endometrium-like epithelium and stroma outside the endometrium and myometrium, with further specification that intrapelvic endometriosis can be located superficially on the peritoneum (peritoneal endometriosis), can extend 5mm or more beneath the peritoneum (deep endometriosis) or can be present as an ovarian endometriotic cyst (endometrioma) ( Zegers-Hochschild et al., 2017 ). For the current terminology, it was decided to focus on the pathology, and define endometriosis- associated symptoms separately. The definition from the International Glossary on Infertility and Fertility Care was further adapted with addition of the most important characteristic of endometriosis “inflammatory”, in line with a recent WHO document stating that endometriosis causes a chronic inflammatory reaction that may result in the formation of scar tissue (adhesions, fibrosis) within the pelvis and other parts of the body ( WHO, 2021 ). The specificities of the subtypes were removed from the definition, as they are defined separately ( Table I ). Recent observations suggest to focus on the fibrotic nature of the disease in its definition ( Vigano et al., 2018 ), but further evidence is needed before such adaptation can be made. For peritoneal or superficial endometriosis, some cases may only be identified following microscopic histological assessment of macroscopically normal peritoneum. This concept includes that the presence of endometrial-like tissue, and even if only endometrial stroma is found by the pathologist, can be considered endometriosis ( Abrao et al., 2003 ). However, this was not considered a relevant addition to the definition. A consensus was reached to adapt the definition from the International Classification of Diseases and Related Health Problems (ICD) ( ICD-11, 2020 ), reading “superficial endometriosis of pelvic peritoneum is characterised by ectopic growth and function of endometrial tissue extending 5 millimetres or less under the visceral or parietal pelvic peritoneal surface and appearing as black- brown or light red-orange lesions.” Existing definitions, such as this one, typically define the depth of the lesions and provide examples of the appearances of them. With regard to the depth, it was argued that the depth of the lesions cannot be accurately measured (in mm). Alternatively, it can be assessed whether the lesion is on the peritoneal surface or under the surface, and this could be integrated in the definition. With regards to the appearances of the lesions, it was considered that a specific list of appearances would never be exhaustive and a general statement was included. Deep endometriosis is historically defined as extending 5mm under the peritoneal surface ( Zegers-Hochschild et al., 2017 ; Johnson et al., 2017 ; Whitaker et al., 2019 ; Koninckx and Martin, 1992 ). As argued for peritoneal disease, assessing the depth of the infiltration cannot accurately be measured, and therefore it was decided to remove this from the definition. The definition of Whitaker and colleagues (including elements from the ICD code) for ovarian endometriosis (cystic) or endometrioma was slightly rephrased, similar to the definition of peritoneal and deep endometriosis ( Whitaker et al., 2019 ). As it is not clear whether endometrioma are invagination cysts or true cysts, it was decided to keep both in the definition. Although not subtypes, a definition was added for bowel and bladder endometriosis. Fallopian tube, pelvic sidewall and other lesions are to be included as peritoneal endometriosis or deep endometriosis, depending on the depth of the lesions. For extrapelvic endometriosis, there was consensus in the group that it should be defined as a separate entity. With regards to defining the possible locations, it was considered that vaginal disease and diaphragmatic disease may be extended abdominal endometriosis (in analogy with oncological definitions). For all other locations (outside the abdominal cavity), it was agreed to use the term extra-abdominal endometriosis and to define it as endometrium-like tissue outside the abdominal cavity. Similarly, there was consensus to define iatrogenic endometriosis as an endometriosis subtype. The definition was formulated as lesions resulting from direct or indirect dissemination of endometrium following during surgery. Iatrogenic endometriosis has various manifestations resulting from different surgical procedures. The most common form of iatrogenic endometriosis is abdominal wall endometriosis - commonly involving the skin or subcutaneous layer of abdominal wall, but it can also involve the fascia and muscular layer - following Caesarean section. Other manifestations include episiotomy scar endometriosis or laparoscopic trocar site endometriosis, which involves various layers of abdominal wall, and endometriosis implants at various locations in the abdomen including peritoneum and visceral structures, such as bowel or bladder, attributed to mechanical uterine morcellation. Finally, (peritoneal) adhesions were defined based on the definition from the International Glossary on Infertility and Fertility Care, i.e. bands of fibrous scar tissue that may bind the abdominal and pelvic organs, including the intestines and peritoneum, to each other. They can be dense and thick or filmy and thin ( Zegers-Hochschild et al., 2017 ). Within the context of endometriosis, adhesions can result from the inflammatory process of the disease and this was specified in the definition. Adenomyosis is defined by the International Glossary on Infertility and Fertility Care as a form of endometriosis marked by the presence of endometrium-like epithelium and stroma outside the endometrium in the myometrium ( Zegers- Hochschild et al., 2017 ). Different theories have been postulated with regards to adenomyosis and whether or not it is a subtype of endometriosis or a different entity. The first theory was based on similar features between endometriosis and adenomyosis and the fact that they often coexist in the same patient. However, recent reports suggest the theory of two different entities because of specific pathogenic pathways and clinical presentation ( Vannuccini and Petraglia, 2019 ). It was agreed to define adenomyosis as the presence of ectopic endometrial tissue (endometrial stroma and glands) within the myometrium ( Chapron et al., 2020 ), but not consider it a form of endometriosis To support the correct application of any future anatomical descriptive system, the locations where endometriosis lesions can be found were defined ( Table II ). The main resources for these definitions include the ICD ( ICD-11, 2020 ), and publications or textbooks on anatomy ( Puntambekar and Manchanda, 2018 ; Rogers, 2007 ). Specific terminology for interventions to treat endometriosis is often used, but not consistently. For endometrioma interventions, definitions were deduced from a recent good practice paper for endometrioma surgery (Working Group of ESGE, ESHRE and WES, 2017 a, Working Group of ESGE, ESHRE and WES, 2017b). Interventions for deep endometriosis were previously defined ( Vanhie et al., 2016 ) and good practice recommendations formulated ( Working Group of ESGE, ESHRE and WES Part 2, 2020a ; Working Group of ESGE, ESHRE and WES Part 2, 2020b ). An overview of the different interventions and their definitions is available in Table III . The definition of reproductive surgery from the International Glossary on Infertility and Fertility Care was specified towards female patients, as the original definition includes both male and female reproductive surgery ( Zegers-Hochschild et al., 2017 ). Bowel shaving was previously defined as superficial excision of bowel serosal and subserosal endometriosis (mechanically, with electrosurgery, laser or other energy source) that does not require suturing/closure ( Vanhie et al., 2016 ), but other definitions and interpretations have also been proposed and applied. The working group considered shaving to be a form of partial thickness discoid excision, but agreement on a more specific definition could not be reached. The working group therefore recommends using the more accurate and specific terms included in this terminology and abandon the term ‘shaving’. With regards to ablation, the term is limited to obliteration of theinner surface of the cyst wall in cases of endometriomas and/or endometriotic lesions in cases of peritoneal endometriosis using electro- orultrasound high frequency-modes, laser, or plasma energy. Nonsurgical treatment options, such as sclerotherapy, can be defined as the destruction of the endometrial tissue using, for example, alcohol installation. For the different surgical techniques and definitions, it can be considered that surgery can be complete or incomplete, i.e. with visually fibrotic and/or endometriotic lesions left in place. This was not considered a relevant addition to the definitions, but should be included in the patient records. The lack of internationally agreed outcome parameters for endometriosis interventions largely affects the value of individual studies when attempting to draw conclusions for clinical practice ( Meuleman et al., 2011 ). Specifically for outcomes in endometriosis (pain, recurrence, quality of life [QoL]), their definition may affect the conclusions from the studies. A recently published consensus defines a core outcome set that should be implemented when evaluating potential treatments for endometriosis to standardise outcome selection, collection and reporting ( Duffy et al., 2020 ), yet this outcome set does not include a specific definition of all outcomes. Pain, infertility and QoL are included in the terminology as symptoms or outcomes with previously published definitions ( Table IV ). With regards to evaluating pain outcomes, a patient-based 11-point Numerical Rating Score, in which the preoperative and post-operative symptoms are given by the patient, allows a better evaluation of the post- operative pain situation as well as the evaluation of de novo pain symptoms possibly associated with a specific type of surgery, when compared with the rating of symptom prevalence and severity by others (physicians, nurses) ( Vincent et al., 2010 ). For QoL outcomes, preference should be given to validated QOL questionnaires, such as the Endometriosis Health Profile Questionnaire (EHP-5 and EHP-30). Recurrence has been defined depending on symptom or lesion recurrence, but a time frame was not included. Further terms included are complications (according to the Clavien-Dindo grading), sequelae and residual disease.

The current paper outlines a list of 49 terms and definitions in the field of endometriosis, as a result of a consensus-based approach. The list includes a definition for endometriosis and its subtypes, different locations, interventions, symptoms and outcomes. The aim of this terminology is to provide a standardised language for the description of endometriosis, to be disseminated and applied widely and to be used as the basis for a new descriptive system for endometriosis. Furthermore, the use of the defined terms should lead to harmonisation in endometriosis research and clinical practice. Further research in endometriosis, its diagnosis and pathogenesis may allow further refinement of the definitions provided.

Endometriosis is considered a spectrum disease with a variety of subtypes and clinical presentations. One consequence of this ambiguity is a large heterogeneity in published studies that are either evaluating diagnostic and therapeutic interventions in endometriosis patients in general, or investigating a certain subgroup based on a published classification, or a disease subtype, with a study-specific definition. The resulting heterogeneity makes it difficult to interpret and summarise published data and draw conclusions on best practice in care for patients with endometriosis. The need for standardisation has been repeatedly mentioned by experts in the field ( Meuleman et al., 2011 ; Rogers et al., 2013 ). The lack of a uniform and widely accepted terminology for endometriosis has created difficulties in standardising and in comparing interventions and outcomes. This has further led to difficulty in defining clinical recommendations for endometriosis management ( Nisolle and Donnez, 1997 ). In absence of a specific terminology of endometriosis, definitions for endometriosis have been included in international glossaries, such as the International Glossary on Infertility and Fertility Care ( Zegers-Hochschild et al., 2017 ), the International Statistical Classification of Diseases and Related Health Problems (ICD) published by the World Health Organization (WHO) [ https://www.who.int/classifications/icd/icdonlineversions/en/ ], and other recent publications attempting standardisation ( Vanhie et al., 2016 ; Johnson et al., 2017 ). However, the definitions are either not very detailed or elaborate, not widely accepted or not comprehensive for endometriosis. This paper describes a terminology for endometriosis prepared by an international working group representing four international societies with a focus on endometriosis [American Association of Gynaecologic Laparoscopists (AAGL), European Society for Gynecological Endoscopy (ESGE), European Society of Human Reproduction and Embryology (ESHRE) and World Endometriosis Society (WES)].

The current paper is a consensus paper, predominantly based on the opinion of the working group members. The working group constructed a list of terms to be defined on different topics, including endometriosis and its subtypes, locations of the endometriosis lesions, treatments and interventions, and outcome parameters. Published literature and information was collected for the different terms, and definitions were extracted from the key papers. All collected definitions were discussed and, where needed, adapted to fit the aim of the current paper. Whenever definitions were significantly adapted, a justification for the adaptations was formulated in the results section. Before finalisation of the paper, a stakeholder review was organised. The collaborating organisations and individual experts formulated a total of 160 comments, which were tabulated and discussed by the working group. Where relevant, corrections, clarifications and adaptations were made to the text and the terms listed. The review report is available on the societies’ websites.