{"paper_id":"6aaea065-487d-4294-89f9-217fa03aabe6","body_text":"REPRODUCTIVE HEALTH  •  August 2021 EMJ60\nExamining Diagnostic Options and Classification \nSystems Available for Endometriosis\nAbstract\nIntroduction: Endometriosis is characterised by the presence of endometrium-like tissue outside \nthe uterus, and is often associated with chronic pelvic pain, infertility, and compromised quality of \nlife. Development of reliable methods of early diagnosis, staging, and classification of endometriosis \nwould allow for restriction of disease progression by its early detection and strategising towards its \nearly treatment and management. \nDiagnostic options: Typically, diagnosis and staging of endometriosis include a history and physical \nexamination followed by clinical, imaging, and laparoscopic findings. Surgical inspection of lesions at \nlaparoscopy with histological confirmation remains the most reliable procedure towards the detection \nof endometriosis and its classification. Although there are many putative peripheral biomarkers having \npotential diagnostic values for endometriosis, further studies are necessary for their validation.  \nClassification systems: Based on anatomical, clinical, imaging, and several pathophysiological \nfindings, various classifications and staging systems of endometriosis, e.g., revised American Society \nfor Reproductive Medicine (rASRM), ENZIAN, Endometriosis Fertility Index (EFI) and Foci–Ovarian \nendometrioma–Adhesion–Tubal endometriosis–Inflammation (FOATI) scoring systems, have so far \nbeen postulated. However, there is no fool-proof diagnostic and classification approach available for \nthe disease due to the general failure of current systems to reflect reproducible correlation with the \nmajor symptoms of endometriosis. \nConclusion: A ‘toolbox approach’, using all the available diagnostic and classification systems \nmaximising the information available to healthcare providers and females, is a recent recommendation. \nDevelopment of collaborative research networks for the harmonisation of patient information, \nbiological sample collection, and its storage, and that of methodological and analytical tools in a wider \npatient base is necessary to discover reliable leads for future diagnostic options and a classification \nsystem for endometriosis. \nAuthors: *Debabrata Ghosh, Jayasree Sengupta\nDepartment of Physiology, All India Institute of Medical Sciences, New Delhi, India\n*Correspondence to debabrata.ghosh1@gmail.com\nDisclosure: The authors have declared no conflicts of interest. \nReceived: 24.01.21\nAccepted: 16.04.21\nKeywords: Biomarkers, disease staging, early diagnosis, endometriosis, infertility, pelvic pain.\nCitation: EMJ Repro Health. 2021;7[1]:60-71. \n\nCreative Commons Attribution-Non Commercial 4.0 August 2021  •  REPRODUCTIVE HEALTH 61\nINTRODUCTION \nEndometriosis is a complex gynaecological \ndisorder characterised by the presence of \nendometrium-like tissue outside the uterus, \nprimarily on pelvic organs, and affects \napproximately 10% of females of reproductive \nage.1 One out of two patients with endometriosis \nsuffers from symptoms like painful periods \n(dysmenorrhea), non-menstrual chronic pelvic \npain, pain due to intercourse (dyspareunia), and \ninfertility.2 There is little curative medical care. \nSurgical treatments often result in high rates of \nrecurrence and loss of ovarian reserve, resulting \nin loss of fecundity .1-3 The quality of life (QoL) \nin patients with this disease thus is significantly \ncompromised, and it deteriorates even further \ndue to the loss of productive time along with \noft-present comorbidities, and resultant high \nhealthcare spending.2,4 Above all, the absence of \nrobust diagnostic markers often results in delay \nof its early diagnosis and medical intervention.5 \nEndometriosis appears to be a disorder with a \nvariegated pathophysiological basis and disease \nmanifestation. Endometriosis may present as \nsuperficial peritoneal endometriosis, ovarian \nendometriosis (or endometrioma), and deep \ninfiltrating endometriosis (or rectovaginal \nnodules) with discernible histological \ndifferences.6 Due to the inherent heterogeneity \nin phenotypes of endometriosis, the disease \nposes a serious challenge against attempts to \nimprovise any simple operative approaches to \nthe disease. Given the burden of individual stress, \nsocio-economic strain, and clinician’s anxiety \nlinked to the disease, special attention for the \ndevelopment of non-invasive and minimally \ninvasive but reliable diagnosis and classification \nof endometriosis appears a necessity. This would \nallow for the restriction of disease progression \nby its early detection and strategising towards \nits early treatment and management, and \nconsequent avoidance of pain, stress, and invasive \nsurgery. The aim of this article is to address the \nstate of current knowledge regarding various \ndiagnostic options as well as classification and \nstaging systems available for endometriosis. \nDIAGNOSTIC OPTIONS \nThe workup for diagnosis of endometriosis \nin a patient typically includes history noting \nand physical examination followed by clinical \nand imaging investigations, and laparoscopic \nexaminations. History and physical examinations \nyield non-specific, but occasionally useful, \ninformation. Familial tendency and history of pain \nand infertility, palpable tender nodular masses \non pelvic examination, and elevated cancer \nantigen-125, along with infertility and/or chronic \npelvic pain provide important but generally \nnon-specific cues. Among imaging techniques, \nultrasound and MRI bear some diagnostic value, \nthough those are not sufficiently specific and \nsensitive to different types of endometriosis \nand non-endometriotic lesions.7-8 According to a \nCochrane Database systematic review of imaging \nmodalities for the non-invasive diagnosis of \nendometriosis, none of the imaging modalities \nwere able to detect overall endometriosis with \nsufficient accuracy.9 \nDespite the fact that imaging may give useful \nindications, visual inspection of pelvic and extra-\npelvic lesions at laparoscopy with histological \nconfirmation remains the most reliable procedure \ntowards the detection of endometriosis and its \nclassification. Symptomatic individuals having \nlikelihood of endometriosis are recommended \nto undertake laparoscopic examination. One \nout of 4 women who undergo a laparoscopic \nprocedure due to symptoms of suspected \nendometriosis does not show endometriosis. 10 \nFor a myriad of phenotypical issues, surgeons \noften face a diagnostic dilemma while inferring \ntheir observations. 8 In addition, laparoscopic \nexamination is often hindered by the presence of \ndense pelvic adhesions.8 \nHistological confirmation in terms of any of \nthe two features, namely endometrial glands, \nendometrial stroma, and hemosiderin-laden \nmacrophages is the prerequisite of definitive \nconfirmation of disease after visualisation of \nlesions. Two out of three patients with lesions \nconsidered to be endometriosis on laparoscopic \nexamination were not histologically confirmed.8,10 \nAdditionally, false-negative results are often \nreported in cases of atypical lesions with \nhistologically confirmed endometriosis. 10 Even \nwith carefully conducted biopsy procedures \nby skilled surgeons and properly sampled \nspecimens sent for pathologic examination, one-\nquarter of biopsy samples do not turn out to \nbe endometriosis.10,11 Nevertheless, laparoscopy \nis considered to be the standard modality for \n\nREPRODUCTIVE HEALTH  •  August 2021 EMJ62\nthe diagnosis of endometriosis. 7 Furthermore, \nlaparoscopy can be applied for the treatments \nin which endometriomas may be cauterised \nor removed and adhesions can be lysed. 7 \nLaparoscopic surgery is, however, associated \nwith an increased risk of intraoperative injury \nto bowel, bladder, ureter, and blood vessels. 10,11  \nTable 1  summarises some of the cardinal \nadvantages and disadvantages of the above-\nmentioned different diagnostic methods.7,10\nGiven the insufficiency of available diagnostic \ntools, it is imperative that a biomarker-based \napproach may be devised to aid reliable \ndiagnosis and classification of endometriosis. \nTypically, a biomarker is a characteristic that \nmay be any substance, structure, or process in \nthe body or its products and can be objectively \nmeasured and evaluated as an indicator of \nbiological processes, normal or pathogenic, \nor pharmacologic responses to a therapeutic \nTable 1: Different diagnostic tools and their advantages and limitations.\nDiagnostic tool Advantage Limitation\nTVUS • Minimally invasive. Accessible, inexpensive, \nfast, and safe. \n• Allows real-time assessment of pain and \norgan mobility. Particularly helpful for \novarian and bladder endometriosis. \n• Useful in planning and ENZIAN and FOATI \nscoring. \n• Highly operator-dependent.\n• Limited to the focal length of the probe.\n• Non-specific to differential diagnosis with other \novarian lesions.\n• Ovarian cysts, subserosal leiomyomas, and acute \nretroflexion of the uterus, and also severe pelvic \nadhesions and other distortions of the pelvic \nanatomy may limit target visualisation.\nREUS • Minimally invasive.\n• Useful for patients with suspected DIE. \n• Provides a reliable method to evaluate \nintestinal wall infiltration.\n• Useful in ENZIAN and FOATI scoring.\n• Highly operator-dependent. \n• Provides restricted view field. \n• Not useful for assessing ovarian, peritoneal, or \nanterior compartments.\nMRI • Non-invasive.\n• Excellent soft-tissue contrast with \nmultiplanar capabilities and full panoramic \nand simultaneous assessment of both \nanterior and posterior compartments of \npelvic structures.\n• Particularly useful in diagnosis of extensive \npelvic adhesions and deep infiltration.\n• Useful in ENZIAN and FOATI scoring.\n• Highly specialised, expensive, lengthy procedures.\n• Limited use in patients with pacemakers or \ncochlear implants, and with claustrophobia and/or \nmorbid obesity.\n• Real-time evaluation is rare. \n• Bowel peristalsis may limit evaluation of intestinal \nDIE. Stool and gas may limit DIE visualisation.\nLaparoscopy • Highly standardised reference method.\n• Diagnostic as well as therapeutic. \n• Invasive.\n• Requires skilled surgeons. Possibility of post-\nsurgery issues of organ damage.\n• Low confidence in atypical cases, DIE, and in \ncases of adhesions. Digital images and visual \ninspection may yield different interpretations.\nDIE: Deep infiltrating endometriosis; FOATI: foci–ovarian endometrioma– adhesion–tubal endometriosis–\ninflammation; REUS: rectal endoscopic ultrasound; TVUS: transvaginal ultrasound. \nAdapted from Espada et al.7 and Taylor et al.10\n\nCreative Commons Attribution-Non Commercial 4.0 August 2021  •  REPRODUCTIVE HEALTH 63\nTable 2: Potential peripheral biomarkers for endometriosis.13-28\nTarget material Name of the molecule(s)\nUrine • Cytokeratin-19 (CK19)\n• Histone-4\n• Soluble fms-like tyrosine kinase (sFlt)-1\n• Vitamin D binding protein \nBlood • α-1-B glycoprotein \n• Brain-derived neurotrophic factor\n• Cancer antigen-125\n• Chemokine ligands (CCLs)-2, -5*\n• Chemokine ligand-8\n• Glycodelin A \n• Haptoglobin \n• Hepatocyte growth factor \n• IL-1, -6, -8 \n• Matrix metalloproteinases-2, -3, -9\n• Monocyte chemoattractant protein-1\n• TNF-α\n• miRNA-28-5p, miR-29a-3p, 125b-5p\nEndometrium • Annexin-A2, -V\n• Erythroblastic leukaemia viral oncogene homologue \nreceptors-1, -2\n• Heat shock protein-90\n• Platelet-derived growth factor receptor\n• miRNA-29C, miR-100, miR-200a, miR-200b\n*Also known at RANTES (Regulated on Activation, Normal T-cell Expressed and Secreted). \nMarkers may be specific to type and stage of the disease, and more correlated to specific symptom(s) of the disease \n(e.g., pain, infertility). None of these markers are fool-proof. A cohort of markers may present better specificity and \nsensitivity than any one of the biomarkers singularly. \nintervention. The measurable entity may be \nfunctional and physiological, biochemical at the \ncellular level, or a molecular interaction. 12 The \ndiscovery of biomarkers with cues for diagnostic \napplication potentially arises from a ‘hypothesis \ndriven’ approach that screens a single molecule \nor a cohort of molecules involved in cardinal \nendometriosis-associated processes (e.g., \nneovascularisation, inflammation, cell survival, \ncell adhesion, cell proliferation and migration, \nand pain modulation) .13 On the other hand, a \n‘screening -omics approach’ employs a relatively \n‘hypothesis neutral’ paradigm to investigate and \nanalyse multiple parameters (e.g., mRNAs, non-\ncoding RNAs [ncRNAs], proteins, peptides, lipids, \nand classes) that are considered to be associated \nwith the development and pathogenesis of \nendometriosis. Of all possible peripherally \nobtainable biological samples, urine, blood, and \nendometrium appear to be the obvious choices. \nIn the following section, an account of state-of-\nthe-art, clinically useful biomarkers as putative \ndiagnostic options for endometriosis yielded \nfrom both ‘hypothesis driven’ and ‘hypothesis \nneutral’ approaches are presented. Table 2 \nprovides a list of potential peripheral biomarkers \nof endometriosis.13-28\n\nREPRODUCTIVE HEALTH  •  August 2021 EMJ64\nUrinary Biomarkers \nIn a Cochrane Database systematic review, an \nattempt was made to assess the diagnostic \nperformances of non-neural enolase (enolase-1), \nvitamin D binding protein, urinary peptide \nprofiling, and cytokeratin-19. 14 The review \nreportedly failed to identify any significant \ndifferences in individuals with endometriosis \nfrom a disease-free control group. 14 In a \ncomprehensive review analysing reported \nstudies on the differential expression of urinary \nproteins as biomarkers of endometriosis, Gueye \net al. drew a similar conclusion. 15 The results of \na proteomic study indicated elevated histone 4 \nas a potential biomarker.16 Also, a combination \nof four urinary proteins, namely histone 4, ADP-\nribosylation factor 3, ribophorin 1, and myosin \nheavy chain 10 reflects significant promise of \ndiagnostic value.16 A secondary observation of \nthe study that the high mobility group box 1, \ncluster of differentiation 40, and lymphotoxin β \nreceptor signalling pathways were activated in \nendometriosis appears interesting. \nSince these signalling pathways are integral to \nthe inflammation process, the notion that chronic \ninflammation might take part in the development \nof endometriosis is being corroborated by this \nobservation.29,30 Thus, the combined urinary \nproteins may have significant promise for yielding \ncues for diagnostic and therapeutic options, but \nthis requires further robust validation. \nCirculatory Biomarkers \nThe results obtained from a multi-centre \nstudy have indicated CA-125 ≥30 unit/mL in \nperipheral circulation can act as a rule-in test \nfor early diagnosis of endometriosis amongst \nwomen presenting with symptoms of pain and/\nor subfertility.17 A multiplex profiling study of \ncytokines and angiogenic growth factors in \nplasma samples of patients with endometriosis \nand healthy controls revealed a potential panel \nof 14 cytokines (chemokine [C-C motif] ligand \n2 [CCL2], CCL17, CCL21, CXCL5, CXCL11, CD14, \ncarcinoembryonic antigen-related cell adhesion \nmolecule 1 [CEACAM-1], erythroblastic leukaemia \nviral oncogene homologue 3 [ERBB3], IL-7, \nLipocalin-2, neuronal cell adhesion molecule \n[NrCAM], receptor for advanced glycation \nend products [RAGE], TGF-β, and TNF-β) \nas a biomarker cohort with significance, \nspecificity, and sensitivity to endometriosis \ndisease samples.18 It is however noteworthy that \nnine cytokines (shown above) revealed only \nmarginal (p<0.05) differences in patients with \nendometriosis as compared to healthy controls \nand that a few (e.g., CCL21, IL-7, TGF-β) of those \ncytokines were seen to be differentially expressed \nin other inflammatory gynaecological disorders \nsuch as polycystic ovary syndrome, ovarian cysts, \nand pelvic adhesions.18 Further studies on larger \nsample sizes with confirmed disease phenotypes \nare necessary to reach a point of useful clinical \ndiagnostic option. It is notable in this regard \nthat a Cochrane Database systematic review \nof 70 studies evaluating 47 blood biomarkers \n(angiogenesis factors, growth factors, \napoptosis markers, cell adhesion molecules, \nhigh-throughput markers, hormonal markers, \nimmune system markers, inflammatory markers, \noxidative stress markers, microRNAs, tumour \nmarkers, and other proteins) with meta-analyses \nperformed for four markers (anti-endometrial \nantibodies, IL-6, CA-19.9, and CA-125) failed to \ndifferentiate people with endometriosis from  \ndisease-free controls.19\nWith pain being a common symptom of \nendometriosis, several studies were performed \nto examine whether neurotrophic molecules \ndetected in blood can be used as diagnostic \nmarkers. Brain-derived neurotrophic factor \n(BDNF) in circulation as a putative marker was \nreportedly able to differentiate cases between \nStage I and Stage II endometriosis.20 Although a \nhigher serum level of mature BDNF was detected \nin those with self-reported pain with Stages I–\nII endometriosis prior to surgery, independent \nof menstrual cycle phase and irrespective of \nlesion type, the difference based on receiver \noperating characteristic curve analysis was not \npredictive for the disease.21 In people with ovarian \nendometriosis and infertility with or without pain, \nBDNF levels in serum and peritoneal fluid were \nsignificantly higher in patients with pain but \nshowed no association with the disease stages \nor menstrual cycle phases, however, correlated \nwith BDNF mRNA and protein expression levels, \nand tyrosine receptor kinase B protein (receptor \nfor BDNF and neurotrophin-3, -4 ligands) \nexpressions in ectopic lesions in the presence of \nendometriosis pain.22 \nA large number of ncRNAs including microRNAs \n(miRNAs), long non-coding RNAs, and closed \n\nCreative Commons Attribution-Non Commercial 4.0 August 2021  •  REPRODUCTIVE HEALTH 65\nlong non-coding circular RNAs are involved in \ntissue-specific regulation of gene expressions \nat the transcriptional, post-transcriptional, and \ntranslational levels.29 Thus, specific species of \nncRNAs in peripheral biological samples, e.g., \nplasma, serum, saliva, and urine with high stability \nand pathophysiological relevance, bear potential \nbiomarker value for various complex diseases, \nfor example, endometriosis. 23-26,32 However, no \ncirculating ncRNA has as yet been identified \nthat could on their own comprise a reproducible, \nnon-invasive diagnostic test for endometriosis. \nThe observed lack of concordance between the \nreported studies could include geographic and \nethnic differences in the expression of ncRNA \nrepertoire, differences in sample handling, ncRNA \nextraction, normalisation, assay platforms, \nmethods of statistical analysis, and the absence \nof a harmonised approach to tissue collection, \nstorage, and of specimen characterisation on \nthe basis of disease severity, disease phenotype, \nmenstrual history, and fertility.33-38 \nEndometrial Biomarkers \nEutopic endometrium from patients with \nendometriosis differs from that of those without \nendometriosis.13,27 It is commonly believed that \nendometrial biopsies collected using minimally \ninvasive techniques with the aid of Pipelle or \nKarmen devices can be employed in the diagnosis \nof endometriosis. However, the dynamic \nnature of the cellular and molecular biology of \nendometrium, and additional complicating facets \nof the phenotypic and ethnic heterogeneity of \nendometriosis collectively pose challenges in \nthe development of biomarker discovery for this \ndisease.28,39 In fact, a close survey of the literature \nreveals multiple caveats that would require close \nattention in future studies aimed at developing \neutopic endometrium-based diagnostic targets \nfor endometriosis. In the following section, the \nauthors highlighted a few important issues in this \nregard.\n > The menstrual cycle phase of tissue collection \nis a strong variable since the ratios of various \nendocrine factors differentially influence \nthe cellular expressions of biomolecules in \nendometrium under disease compared to \nnormal conditions.13,35,40 \n > Potential biochemical differences in lesion \nsubtypes of peritoneal, ovarian, and deep \ninfiltrating endometriosis are reflected in \nstudies comparing eutopic endometria to \ncontrol tissues.13,41,42 \n > The fertility status of individual patients \nmay influence endometrial expressions.37,43 \nEndometrial expressions may vary depending \non the severity stages of disease in patients \nwith positive fertility compared with infertile \npeople with endometriosis.44,45\n > The choice of endometriosis-free controls \nis an important issue since the presence \nof fibroids, adenomyosis, and/or pelvic \norgan prolapse may differentially affect the \nendometrial behaviour compared to that \nwith no abnormality.46 Furthermore, the \nchoice of endometriosis-free control with \npain and without pain is likely to display \ndistinctions in the molecular expressions.42,47 \nA high prevalence (approximately 45%) \nof asymptomatic cases (no pain or other \nsymptoms) of endometriosis in individuals \nmay cast significant skew in the control data.48\n > The heterogeneity of tissue components \nthat include inflammatory cells, stromal cells, \nepithelial cells, endothelial cells in uterine wall \ncomponents, surrounding peritoneal tissue in \ndifferent biopsy specimens per se may affect \ntissue expressional repertoire of tissue.34,38,49 \nBriefly, it appears that many peripheral \nbiomarkers tentatively show promise in the \ndiagnosis of endometriosis, but not a single \nbiomarker or panel of biomarkers appears to be \nclinically fool-proof. It also appears that panels of \nmarkers rather than specific candidate markers \nmay allow increased sensitivity and specificity \nfor early diagnosis. Thus, after a decade of \nthe reports based on systematic reviews of \nperipheral biomarkers of endometriosis by May \net al., the present position remains similar: further \nresearch is warranted before any set of markers \nfor endometriosis may be recommended for \nroutine healthcare purposes.50 \nCLASSIFICATION AND STAGING  \nOF ENDOMETRIOSIS \nA reproducible classification system for a complex \ndisease like endometriosis bears an advantage \ntowards describing the pathological correlates \nof disease with acceptable levels of accuracy and \nprecision, and also towards strategising effective \nmedical and surgical interventions of the disease \nand disease-associated signs and symptoms. \n\nREPRODUCTIVE HEALTH  •  August 2021 EMJ66\nAdditionally, a simple and user-friendly \nclassification protocol would render great help \nfor communication between clinicians and other \nstakeholders, including patients. \nEndometriosis can be classified according to its \nprimary nidus (peritoneal, ovarian, rectovaginal \netc.). Sampson classified the endometrioma \ninto follicular, corpus luteal, stromal, and \nendometrial types depending on the presence \nof haemorrhagic cysts and adjoining adhesions.51 \nOn the basis of anatomical location, clinical \nfindings, and histology, endometriosis may \npresent as Sampson’s syndrome (infertility and/\nor chronic dyspareunia with no deep pelvic local \ntenderness, induration or nodule formation, and \nhistology showing superficial lesions of clear, \nred, black, or white lesions of endometrium-\nlike glands and stroma), and Cullen’s syndrome \n(tender palpable nodular or indurated lesion \nin the deep pelvis with histology of marked \nfibromuscular hyperplasia containing islands of \nendometrium-like glands).52 Endometriosis can \nalso be classified as subtle, typical, cystic, deep, \nadenomyotic, and peritoneal pocket lesions \nestimated by their size.53 Ideally, a classification \nsystem should be able to identify disease \nmorphology and severity with a high degree \nof accuracy and precision, and correlate the \nseverity with the reported signs and symptoms \nof the disease (e.g., pain and subfertility).54 \nAccordingly, several attempts have been made \nto chronicle this evolving chronic disease in order \nto assess the stages and nature of lesions in \nassociation with pain scores and infertility. \nIn the following section, a summary of various \nclassification systems available for endometriosis \nthat include anatomical findings and disease \nstaging based on imaging and laparoscopic \ninvestigations according to revised American \nSociety for Reproductive Medicine (rASRM) and \nENZIAN scores, and combinatorial approaches \nlike Endometriosis Fertility Index (EFI) scoring \nand the FOATI systems is presented. Figure 1 \nprovides the basic templates of the revised ASRM \nand ENZIAN protocols. \nRevised American Society for \nReproductive Medicine Scoring System  \nThe American Fertility Society (AFS) introduced \na scoring system for endometriosis in 1985 and \na revised scoring procedure of the ASRM in \n1996.55 According to rASRM, endometriosis \nis classified as superficial and deep lesions and \nstaged as minimal (Stage I; Score: 1–5), mild \n(Stage II; Score: 6–15), moderate (Stage III; Score: \n16–40), and severe (Stage IV; Score: >40). Some \nof the cardinal features of the rASRM scoring \nsystem are shown in Figure 1A. In the rASRM \nstages, weightage to endometriosis-associated \nvisual landmarks at laparoscopy is attributed \nusing arbitrarily designated scoring scales. This \nmay lead to scoring of the disease to the same \nstage despite inherent differences in the nature \nof lesions, the latter having obvious bearing on \nstrategising individual patient’s treatment.56 The \nfailure rate of such a protocol could reportedly \nbe as high as 50%, and it is around 20% at \nbest.57 Nevertheless, the rASRM protocol is \nwidely practised for its ease to administer, report, \nand communicate, and for its apparent objective \nmode of presentation. \nENZIAN Classification System  \nThis classification system was introduced to \nsupplement the rASRM system, especially taking \ninto account deep infiltrating endometriosis \nand its involvement with other organs.58 \nENZIAN classification was named after Hotel \nEnzian on Lake Weissensee in the Austrian \nAlps, where the 7 th Conference of the Stiftung \nEndometriose Forschung (Foundation for \nEndometriosis Research), 25 th–27th February \n2011 developed this classification system. The \noriginal ENZIAN system was revised to reduce \noverlap with the rASRM system. In the revised \nENZIAN classification system, the retroperitoneal \nstructures are divided into three compartments: \nCompartment A consists of the rectovaginal \nseptum and vagina; Compartment B consists of \nthe uterosacral ligament and pelvic walls; and \nCompartment C consists of the sigmoid colon \nand rectum. The severity of the lesion is graded \nfrom its invasiveness (Grade 1: <1 cm; Grade 2: \n1–3 cm; Grade 3: >3 cm). Deep endometriotic \nlesions in retroperitoneal distant locations (FA: \nadenomyosis; FB: involvement of the bladder; \nFU: intrinsic involvement of the ureter; FI: bowel \ndisease caudal to the rectosigmoid junction; \nand FO: other locations, such as abdominal wall \nendometriosis) are also indicated in the system. \nA succinct coverage of the ENZIAN classification \nsystem is available in the 2020 recommendation \nof the Working group of the European Society \n\nCreative Commons Attribution-Non Commercial 4.0 August 2021  •  REPRODUCTIVE HEALTH 67\nfor Gynaecological Endoscopy (ESGE), the \nEuropean Society of Human Reproduction \nand Embryology (ESHRE), and the World \nEndometriosis Society (WES).59 Some of the \ncardinal features of ENZIAN system are shown  \nin Figure 1B. \nEndometriosis <1 cm 1–3 cm >3 cm\nPeritoneum superficial 1 2 4\nPeritoneum deep 2 4 6\nRight ovary superficial 1 2 4\nRight ovary deep 4 16 20\nLeft ovary superficial 1 2 4\nLeft ovary deep 4 16 20\nPosterior cul-de-sac obliteration\nPartial    4\nComplete*    40\nAdhesions† <1/3 \nenclosure\n1/3–2/3  \nenclosure\n>2/3 \nenclosure\nRight ovary filmy 1 2 4\nRight ovary dense 4 8 16\nLeft ovary filmy 1 2 4\nLeft ovary dense 4 8 16\nRight tube filmy 1 2 4\nRight tube dense 4 8 16\nLeft tube filmy 1 2 4\nLeft tube dense 4 8 16\nAssign point 16 in case of complete enclosure of fimbriated end of the fallopian tube.  \nIn case of patients with only adenexa, assigned points are to be doubled.  \nA\n\nREPRODUCTIVE HEALTH  •  August 2021 EMJ68\nBroad  ligament \nUterus\nUterus\nBladder\nVesicovaginal\nspace\nRetrovaginal\nseptum\nRetrorectal\nspace\n[A] [B]\nBladder\nRectum\nPubocervical\nligament\nCardinal \nligament\nCervix\nSacrouterine\nligament\nUreter\n[C]\n[A] [B] [C]\nCompartment A B C\nAnatomical  \nlocalisation\nRectovaginal space\nvagina\nSacrouterine and cardinal \nligaments\nExternal ureter \ncompression\nSigmoid colon\nRectum\nFigure 1: \nA) Revised American Society for Reproduction Medicine (rASRM) scoring system for staging of endometriosis.55 \nDetermination of the stages of endometriosis based on examination of the pelvis at laparoscopy in a clockwise or \ncounter-clockwise manner to note the number, size, and location of endometrial implants, plaques, endometriomas, \nand adhesions. The surface of the uterus is considered as peritoneum. Adhesions and lesions in the peritoneum, \novary, fallopian tubes, uterus, and cul-de-sac are scored as shown. Superficial peritoneal implants are shown as red, \nred-pink, flame-like, vesicular blobs. Clear vesicles, white opacifications, or haemosiderin deposits seen as black, blue \ndeposits or yellow-brown deposits are also detected and scored. Adhesions are seen as filmy or dense, covering the \novary and tubes extending to the cul-de-sac, as shown in the different stages of endometriosis.  \nB) ENZIAN scoring system for deep infiltrating endometriosis.59  The ENZIAN scoring provides a scoring of deep \ninfiltrating endometriosis in retroperitoneal structures based on laparoscopic identification and the use of imaging \n(transvaginal ultrasonography, rectal endoscopic ultrasonography, MRI) techniques. The ENZIAN scores include \nlesions in the cul-de-sac, vagina, cervico-uterine ligaments, bladder, ureter, bowel, and uterus. The major anatomical \nsites of endometriotic lesions are sacrouterine ligament, cardinal ligament, and ureter [A]. Adenomyosis lesion sites \nin the uterus with the presence of heterotopic endometrial glands and stroma in the myometrium and reactive \nfibrosis of the surrounding smooth muscle cells of the myometrium, which often co-exists with endometriosis. \nEndometriotic lesion sites present in retrovaginal septum, bladder, vesicovaginal space, and retrorectal space [B] are \nshown. A schematic presentation of lesion sites detected within the pelvic compartment as shown in [A] and [B], \nexcluding adenomyotic lesions, is presented in [C]. \nC) ENZIAN scoring system showing the levels (1–3) of deep endometriosis lesions that may be present in \ncompartments like the rectovaginal space and vagina (A1–A3), sacrouterine, and cardinal ligaments to cause \ncompression of external ureter wall (B1–B3) and the rectum (C1–C3). Other major lesion sites include adenomyosis \n(FA), lesions on the bladder (FB) and the ureter (FU). Endometriotic lesions may also be detected in extragenital \nsites such as the intestine, lung, and diaphragm, and in inguinal regions.\n*Complete closure of the cul-de-sac by dense adhesions extending from the ovary and tube is scored as 40. The \naggregation of points as shown indicates the endometriosis disease stages as minimal (I), mild (II), moderate (III), or \nsevere (IV). \n† Complete closure of the fimbriated end of the tube by adhesions is scored as 16. \nAdapted from American Society for Reproductive Medicine 55 and Working Group of ESGE, ESHRE, and WES, \nKeckstein J et al.59\n(B)\n(C)\nRetrorectal\nspace\nRectouterine \npouch\n\nCreative Commons Attribution-Non Commercial 4.0 August 2021  •  REPRODUCTIVE HEALTH 69\nENZIAN classification can be determined \nby imaging modalities and used for surgical \nplanning, and it provides detailed descriptions \nof compartment-wise severity of lesion in the \nretroperitoneal structures, reportedly associated \nand correlated with the presence and severity of \ndifferent symptoms (e.g., pain).60,61 The ENZIAN \nclassification system has as yet received only \nmoderate reception, primarily due to its not \nbeing a user-friendly protocol and for not having \nan easy communication gait; the system is both \ncomplex and employs complicated terminologies. \nAlso, there are currently no sufficient evidence-\nbased reports regarding the usefulness of the \nENZIAN classification system in determining pre-\noperative prediction regarding surgical decision. \nCombinatorial Approaches: \nEndometriosis Fertility Index and Foci–\nOvarian Endometrioma– Adhesion–\nTubal Endometriosis–Inflammation–\nAdenomyosis– Recto-Vaginal  \nSpace System \nInfertility is one major issue affecting the QoL of a \nlarge percentage of patients with endometriosis. \nThe EFI provides a classification system on the \nbasis of scores obtained from the assessment \nof surgical factors and historical factors, and \nprojects to predict the clinical outcome of \npregnancy in patients who are infertile.2,62 EFI is \nconsidered a valid clinical tool to predict fertility \noutcome for people following surgical staging of \nendometriosis and may be used for developing \nsuitable treatment plans for infertile women  \nwith endometriosis.2,62,63 \nThe Foci–Ovarian endometrioma– Adhesion–\nTubal endometriosis–Inflammation–\nadenomyosis– Recto-Vaginal Space \n(FOATIaRVS) system of classification takes \ninto consideration the histology of ectopic \nlesions and functional repercussions for tubal \nand ovarian functions along with the nature of \ninflammation. Collectively, it may help to identify \nthe nature of medical and surgical treatments \nto be undertaken in patients who are infertile \nand have endometrioma; and the chances of  \nmalignant proliferation.64,65 \nTo date, the authors have no template to classify \n‘atypical endometriosis’, which is an intermediate \nprecursor lesion linking typical endometriosis \nand clear cell/endometrioid tumours observed \nin 1–3 patients out of 100 endometriosis patients \nwith endometrioma.66 DIE, affecting 1–2% of \nindividuals of reproductive age also bears the \nrisk of developing malignancy. 67 Development \nof a classification system for assessment of \nendometriosis as a pre-malignant field defect \nwhich can be used for pre-emptive monitoring \nand management of the disease in a high-risk \nvulnerable population is seriously warranted.68 \nPRACTICAL PERSPECTIVE AND \nRECOMMENDATIONS \nThere is no fool-proof diagnostic option and \nclassification or staging system for endometriosis \ndisease. The core problem exists in the \ngeneral failure of current systems to reflect a \nreproducible correlation with symptoms: \ninfertility and pain, especially with the differential \nnature and severity of pain associated with \nendometriotic lesions in different compartments. \nCentral and peripheral neural sensitisation and \ninflammation is causally associated with the \npain caused from endometriosis, independent of  \nanatomical distortion. \nConventional approaches to classifying \nendometriosis-associated pain based on disease, \nduration, and anatomy are grossly inadequate. \nAdditionally, available diagnostic measures and \nclassification systems fail to predict responses \nto medical and surgical interventions, disease \nrecurrence, risks for associated disorders \nincluding malignancy, QoL measures, and \nother endpoints important to patients and \nhealthcare providers for guiding appropriate \ntherapeutic options and prognosis. In the given \nsituation of a dearth of reliable diagnostic and \nclassification systems, the WES recommends \nthat clinicians adopt a ‘toolbox approach’ using \nall available diagnostic and classification systems, \nas appropriate, to maximise the information \navailable to healthcare providers and patients. \nIt appears that the development of collaborative \nresearch study networks to harmonise the \nprotocols for patient information, biological \nsample collection and their storage, and \nmethodological and analytical tools, as well as \napplying those protocols to a wider patient base \nof diverse ethnicity and population is needed. \nThis effort would pave the way to discovering \nreliable leads for future diagnostic options and a \n\nREPRODUCTIVE HEALTH  •  August 2021 EMJ70\nclassification-staging system helpful for an early \ndiagnosis of the disease and its management. \nThis, in turn, would give to the patients with this \ndebilitating disease a fair chance to lead lives free \nof disease-associated stress. \nReferences\n1. 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Cur Op Gyn Obs. \n2019;2(1):318-45. \nFOR REPRINT QUERIES PLEASE CONTACT:   INFO@EMJREVIEWS.COM","source_license":"CC0","license_restricted":false}