{"paper_id":"9549e7e7-8a37-4c03-adeb-e73acabdbeb8","body_text":"PERSPECTIVE\nAn endometriosis classification, designed to be validated\nPhilippe R. Koninckx & Anastasia Ussia &\nLeila Adamyan & Arnaud Wattiez\nReceived: 2 August 2010 / Accepted: 22 August 2010 / Published online: 2 October 2010\n# Springer-V erlag 2010\nAbstract Several endometriosis classifications were pro-\nposed, based on the assumption that endometriosis is a\nprogressive disease, and designed to score severity of\nvisible lesions. In addition, several specific classifications,\ne.g., for deep endometriosis, were proposed. None of these\nclassifications however, have been validated to be predic-\ntive for diagnosis, treatment prognosis, recurrence, progres-\nsion or for the associated infertility or pain. The difficulties\nderive from the fact that pathophysiology and the natural\nhistory are still uncertain. A classification should avoid\nassumptions. It seems established beyond reasonable doubt\nthat endometriosis presents as subtle, typical, cystic, and\ndeep lesions and that severity of each lesion is related to\nsize or volume. By pathology, these four lesions present as\nactive, burnt-out, inactive, and active lesions, respectively.\nBesides this, there are many uncertainties. It is unclear\nwhether endometriosis is one disease progressing ultimately\ninto severe endometriosis or whether typical, cystic, and\ndeep endometriosis represents three different diseases, each\nbeing an end stage. It is unclear whether endometriotic cells\nare different from endometrial cells or whether only the\nenvironment is different. It is unclear how adenomyosis,\nMüllerianosis, and peritoneal pockets should be considered.\nWe therefore suggest a descriptive classification with the\nseverity of Subtle, Typical, Cystic, Deep, Adenomyotic,\nand peritoneal pocket lesions, estimated by their area or\nvolume. This classification should permit to evaluate the\nactual uncertainties in order to build subsequently a\nvalidated classification. The similarity of the classes for\nsuperficial and cystic lesions with the rAFS classification is\nconsidered an advantage. It is discussed why adhesions\nneed not to be scored. In conclusion, a simple classification\nscoring separately severity of subtle, typical, cystic, deep,\nadenomyotic, and peritoneal pocket lesions is suggested.\nThis will permit to confirm or reject statistically many of\nthe actual uncertainties on endometriosis and to evaluate\nwhat the predictive power of the severity of each type of\nlesion is, both essential elements for a validated endome-\ntriosis classification.\nKeywords Classification . Endometriosis . Adenomyosis .\nPeritoneal pockets . Müllerianosis\nIntroduction\nEndometriosis remains an enigmatic disease defined more\nthan 100 years ago as endometrial glands and stroma\noutside the uterus. Yet we still do not have a solid\nunderstanding of the pathophysiology and natural history,\nwhich is not surprising in the absence of an appropriate\nanimal model and of accurate non-invasive diagnostic\nmethods. Also, the associated infertility and/or pain is\npoorly understood. Except for adhesions, we do not\nP . R. Koninckx (*)\nDepartment of Obstetrics and Gynaecology, U. Z. Gasthuisberg,\nK. U. Leuven,\nLeuven 3000, Belgium\ne-mail: pkoninckx@gmail.com\nP . R. Koninckx\n: A. Ussia\nGruppo Italo Belga,\nRome, Italy\nL. Adamyan\nMoscow State University,\nMoscow, Rusland\nA. Wattiez\nIrcad, Strassbourg University,\nStrassbourg, France\nGynecol Surg (2011) 8:1 –6\nDOI 10.1007/s10397-010-0626-8\n\nunderstand the mechanisms of the associated infertility\nAlso for pain, we do not understand why so many of the\ntypical, cystic, and deep lesions do not cause pain.\nWith this 100-year-old microscopical definition, endo-\nmetriosis presents clinically as subtle or non-pigmented\nlesions [ 1, 2], typical black puckered lesions in a white\nsclerotic area, cystic ovar ian endometriosis, and deep\nendometriosis. Microscopically the glands and stroma of\nthese lesions are active, burnt-out, inactive, and active,\nrespectively. Other lesions as stromatosis, peritoneal pockets,\nendosalpingiosis [3–6], mullerianosis [ 7], and adenomyosis\ndo not fit the strict definition\nHistorically, adenomyosis externa and cystic ovarian\nendometriosis were described more than 100 years ago [ 8–\n13]. In the 70 ’s, with laparoscopy came the awareness of\nthe high incidence of typical lesions in women with pain\nand infertility [ 14, 15]. In the mid-80 ’s, subtle or non-\npigmented lesions were recognized to contain endometrial\nglands and stroma [ 1], leading to the search for microscop-\nical endometriosis, a concept that was neither substantiated\nnor refuted [ 16]. In the 90 ’s, the prevalence of deep lesions\nincreased rapidly probably as a consequence of awareness\nand improved diagnosis [ 17].\nWe do not have an adequate animal model for\nendometriosis. Rodents do not have spontaneous endome-\ntriosis which is not surprising since they do not have a\nmenstrual cycle with a long luteal phase and menstruation.\nTransplanted human endometriotic tissue to immunocom-\npromised mice or to the chicken allantoic membrane\nobviously has a different immunologic and endocrine\nenvironment. Also, primates are not an adequate model\nfor endometriosis. The rhesus monkey only occasionally\ndevelops cystic ovarian endometriosis, possibly more after\ndioxin administration [ 18]. Also, in the baboon, we failed to\ninduce the more severe cystic or deep endometriosis.\nWhether useful for superficial lesions also remains contro-\nversial since most results would have been negative if the\npoints of the revised American Fertility Society (rAFS)\nclasses would not have been multiplied by two.\nA classification of endometriosis should permit to orient\ntreatment based upon the prediction of pain, infertility,\nprogression, and recurrence. Today, treatment remains\nempirical, either by medically inactivating the endometrial\ntissue, or by surgical removal, based upon the never proven\nassumption that all endometriotic tissue that can be visually\nidentified should be removed.\nThe history of the endometriosis classifications\nThe variability in clinical expression and in severity\nprompted the development of a series of classifications,\nnone of which today has been validated as a guidance to\ntherapy nor as a predictor of endpoints as pain, infertility,\nprogression, or recurrence.\nMany classifications were proposed highlighting the\nneed and the difficulty. (for review [ 19]). As milestones,\nwe consider Acosta [ 20] who suggested to distinguish\nbetween superficial lesions (class I) and cystic ovarian\nendometriosis including diameter, surgical difficulty, and\nadhesions (classes II and III). With this, the tone was set to\ndistinguish superficial and cystic endometriosis. Subse-\nquent attempts to be more complete with less ambiguity by\nKistner and Buttram [ 21, 22] received no widespread\nacceptance or use; this prompted the American Fertility\nSociety (AFS) to create a panel to design a classification\nsystem for endometriosis, published in 1979 and revised in\n1985 [ 23, 24]. The AFS and the revised AFS classification\nbecame widely used. It was a point scoring system,\nattributing few points for superficial endometriosis accord-\ning to the area involved, more points for cystic ovarian\nendometriosis increasing with size, and a lot of points for\nadhesions. Few attempts were made to evaluate the\npredictive value [ 23, 25] of these classifications while the\nclinical value was soon recognized as limited [ 26].\nAnalyzing the type of lesions found in each of the rAFS\nclasses [ 24], it was shown that over 95% of women with\nrAFS class I and II had superficial lesions of less or more\nthan 3 cm in diameter, respectively, while rAFS classes III\nand IV consisted of cystic ovarian endometriosis either\nsmall and unilateral or large and bilateral. The similarity\nbetween the Acosta and the rAFS classification thus is\nremarkable.\nSince deep endometriosis is not scored in the rAFS\nclassification, while varying widely in size and localization,\nseveral specific classifications were suggested by Koninckx\n[27], distinguishing between invading lesions and adeno-\nmyosis externa; by Adamyan [ 28], distinguishing between\nthe degree of Douglas occlusion; and more recently, more\nsurgically oriented classifications [ 29] and the ENZIAN\nscore [ 30] specifying diameter and localization.\nElements to consider for an endometriosis classification\nThe pathophysiology is unclear\nThe first and most fundamental concept of a classification\nis whether the clinical presentations of subtle-typical-cystic-\ndeep lesions results from progression to more severe forms\n[31], or whether each of these clinical forms constitute an\nendpoint of a different disease [ 32, 33].\nThe Sampson hypothesis [ 31], that endometrial cells\nregurgitated during menstruation could implant and develop\ninto endometriotic lesions seems supported by the implan-\ntation and developmental potential of menstrual endome-\n2 Gynecol Surg (2011) 8:1 –6\n\ntrium as demonstrated in women [ 34] and models as\nimmuno-suppressed mice and the chicken allantoic mem-\nbrane. Doubt came however, with the realization that\nretrograde menstruation occurred almost systematically in\nall women [ 35] and the question was asked why not all\nwomen developed endometriosis. It was even suggested\nthat the lower steroid hormone concentrations in peritoneal\nfluid of women with a luteinized unruptured follicle\nsyndrome might facilitate implantation [ 36]. Endometriosis\nthus would be a consequence of infertility instead of a\ncause. The observations that total body radiation and dioxin\ncould increase the incidence of severe endometriosis, and\nthat endometriosis was a hereditary disease moreover\nsuggested a genomic alteration or predisposition. Also, the\nperitoneal fluid constituents did not bring an explanation\nfor progression in some women only. More important is that\nprogression—the key element of the Sampson hypothesis —\nhave not been confirmed. Besides subtle lesions developing\ninto typical lesions, there is no evidence of typical lesions\ndeveloping into deep of cystic ovarian or of cystic lesions\ndeveloping into deep lesions. Circumstantial evidence sug-\ngests, moreover, the opposite. In the late 70s, typical lesions\nwere the focus of research at Leuven University. Two decades\nlater, we realized that the women diagnosed with severe cystic\nor deep endometriosis were not specifically those diagnosed\nwith typical lesions previously in this small community of the\nLeuven area. Also, the concept that endometriosis is a recurrent\ndisease seems contradicted by the recurrence of cystic\nendometriosis which is only 5% following excision while the\nrecurrence of deep endometriosis is even lower.\nThe endometriotic disease theory [ 32, 33] suggested that\nsubtle endometriosis was a benign condition occurring\nintermittently in all women, whereas typical, cystic, and\ndeep endometriosis would be the end points of three\ndifferent diseases. It was postulated that implantation of\nregurgitated cells occasionally occurs in all women, but that\nthe other types of lesions would require some genomic\na l t e r a t i o ns i m i l a ra sf o u n di nm a n yb e n i g nt u m o r s .\nAccording to the type of mutation, these cells would then\ndevelop into typical, cystic, or deep lesions. This hypothesis\neasily explains the effects of dioxin, of total body radiation,\nand the hereditary aspects. A strong argument is the findings\nthat cystic and deep endometriosis is clonal in origin.\nProgression thus would be the consequence of a genomic\nmutation, and the altered peritoneal fluid environment would\nbecome a consequence instead of a cause.\nIn conclusion, it is unclear today whether the different\nclinical manifestations, typical-cystic-deep, are one disease\nand are the various forms of a progressive development of\nan implanted normal cell; or whether they represent three\ndifferent diseases arising from three different types of\nmutations. It should, moreover, be realized that this not\nonly applies to implanted menstrual cells, but also to the\nmetaplasia theory, to development of embryological rests,\nand to implanted stem cells [ 37, 38]. Hematogenic and\nlymphogenic [ 39–42] spread probably variably consist of\nnormal and abnormal cells.\nSubtle endometriosis should be classified separately\nThe significance of subtle lesions is unclear. Subtle lesions\nare considered the first lesions after implantation of\nendometrial cells. It remains unclear however, whether\nsubtle lesions are the initial phase of a progressive disease\n[31], or whether subtle lesions do occur intermittently in all\nwomen [ 43, 44] emerging, regressing, and re-emerging at\nother places of the pelvis.\nSubtle lesions have not been demonstrated to be associated\nwith pain or infertility. The luteinized unruptured follicle\nsyndrome (LUF) [14, 36, 45, 46] was found to be associated\nwith typical lesions but not with subtle lesions [ 47]t h e\nassociation of typical endometriosis and LUF disappearing\nafter 1986 when women with subtle lesions were no longer\nconsidered normal but as having endometriosis.\nDeep endometriosis should be classified separately\nDeep endometriosis suffers from a lack of definition. It is\nsuggested to add the pathologic appearance of adenomyosis\nexterna to the initial definition of deeper than 5 mm under\nthe peritoneum [ 27]. Indeed by pathology, some deep\nendometriosis lesions, gener ally smaller, are burnt-out\nlesions as typical lesions, while other lesions present with\nsparse glands and stroma in a fibromuscular nodule\nresembling adenomyosis (externa). If defined only as more\nthan 5 mm under the peritoneum, we risk to include a\nvariable number of larger typical lesions. Adding to the\ncriterium of depth the pathologic aspect of adenomyosis\nexterna, deep endometriosis nodules almost invariable are\nlarger, rarely less than 1 cm in diameter, mostly unique, two\nnodules being rare, three or more exceptional.\nDeep endometriosis is specific in being associated with\nmetastasis in the regional lymp nodes [ 39–42] while being\nthe strongest predictor of pelvic pain.\nAdenomyosis, peritoneal pockets, and mullerianosis\nThe relationship between adenomyosis and endometriosis,\npain and infertility remains unclear. Also the exact clinical\nsignificance of uterine junctional zone thickening and of\nadenomyotic nodules, which can become huge in size,\nremains debated [ 48].\nPeritoneal pockets and Mullerianosis are debated since\nover two decades [ 49]. Peritoneal pockets almost invariably\ncontain endometriotic lesions or mullerianosis. It is unclear\nwhether these cells of embryological origin occasionally\nGynecol Surg (2011) 8:1 –6 3\n\nprogress or undergo mutations to develop into endometriotic\nlesions.\nSuggestions for a classification designed to test\nstatistically hypotheses in order to permit validation\nSubtle, typical, cystic, and deep endometriosis should be\nscored separately together with the adenomyosis and\nperitoneal pockets, becoming a STCDAP classification.\nThe severity of each lesion can be scored by the mean\ndiameter of the pelvic area, or of the nodule. We however,\nsuggest a scoring in classes (Table 1).\nSubtle endometriosis (S) and typical lesions (T) can be\nscored according to a total area smaller or larger than 3 cm\nas S1 and S2 or as T1 and T2, respectively. This would\ncorrespond in over 95% of women to the actual rAFS\nclasses I and II.\nCystic ovarian endometriosis (C) is suggested to be\nclassified as: C1 being unilateral and less than 5 cm in\ndiameter, C2 being bilateral or more than 5 cm in diameter,\nagain because of the 95% similarity with the actual rAFS\nclasses III and IV .\nFor deep endometriosis (D) we suggest to classify them\nas D1, D2, and D3 being the total volume corresponding to\na nodule of less than 1 cm, between 1 and 3 cm and more\nthan 3 cm in diameter. Since the importance for the\nassociated pelvic pain, it is suggested to score in addition\nthe localization, (rectovaginal, sigmoid, bladder) and the\npresence of hydronefrosis.\nFor adenomyosis (A), we should distinguish between a\nthickened junctional zone (A1) and a focal adenomyotic\nnodule of more than 1 cm (A2). For peritoneal pockets a\ndiameter of less or more than 1 cm could be distinguished\n(P1 and P2, respectively).\nIt is strongly suggested to indicate explicitly the absence\nof lesions and the absence of information in order to avoid\ndoubt during subsequent statistical analysis. A negative\nlaparoscopy without an MRI or ultrasound of the uterus\nbeing performed, thus would become S0T0C0D0A.P0.\nDiscussion\nA classification today should avoid unproven assumptions.\nIt should preferably be descriptive containing the elements\nthat will permit subsequent statistical analysis and hypothesis\ntesting. Scoring each clinical type of endometriotic lesion\nindependently as subtle, typical, cystic, and deep while adding\nadenomyosis, and pockets will permit to calculate the\npredictive value of each individual phenotype, to evaluate\nwhich variables behave as independent variables, and to test\nthe hypothesis that the different phenotypes can be considered\nas progressive steps of severity. The VCUAM classification\nfor congenital anomalies is an example of a similar approach\n[50].\nTo assess the importance of the severity of each type of\nlesion as a predictor of fertility, pain, recurrence, progres-\nsion, etc., a measure of severity is required. The severity of\neach lesion could be indicated by the diameter or volume of\nthe lesions, permitting for each lesion to assess the\nrelationship between severity and prediction. This could\nbecome the basis of distinguishing clinical useful sub-\nclasses. It is anticipated however that this will require huge\namounts of data for meaningful results. Whereas using the\nexact diameters obviously would be ideal, we however\nsuggest a more simple classification of severity. First, the\n95% similarity between the newly proposed classes T1, T2,\nC1 and C2, and the rAFS classes I, II, III, and IV ,\nrespectively, will maintain continuity with the actually used\nrAFS classification. Secondl y, the clinical acceptance/\nusefulness of a classification increases with simplicity.\nThirdly, in order to demonstrate the clinical impression that\nfor subtle, typical, and cystic lesions, the area involved or\nTable 1 A simple descriptive endometriosis classification with either the exact diameter of lesions or classes designed to permit statistical\nvalidation and analysis\nType of lesion Localization Mean diameter Classes\nSubtle mm 1=<3 cm 2=>3 cm\nTypical mm 1=<3 cm 2=>3 cm\nCystic mm 1=<5 cm and unilateral 2=>5 cm and/or bilateral\nDeep Rectovaginal mm 1=<1 cm 2=2 –3c m 3 = > 3c m\nLeft/right 1=<1 cm 2=2 –3c m 3 = > 3c m\nSigmoid mm 1=<1 cm 2=2 –3c m 3 = > 3c m\nBladder mm 1=<1 cm 2=2 –3c m 3 = > 3c m\nUreter hydronefrosis mm 1=<1 cm 2=2 –3c m 3 = > 3c m\nAdenomyosis 1=junctional zone 2=focal nodule\nPockets 1=<1 cm 2=>1 cm\n4 Gynecol Surg (2011) 8:1 –6\n\nthe diameter of the cyst matters, simple 0/1/2 and absent/\nmild/severe classes should be sufficient to calculate for\nwhich types of lesions severity matters. Finally, using\npredefined classes instead of real diameters, will prevent\nfuture authors to use different cutoffs for classes making\ncomparisons more difficult. For those entering data directly\ninto a database, we suggest, however, that they enter mean\ndiameters, although it is unclear whether an increased\nclinical predictive value will outbalance the increased\ncomplexity of using the exact diameters\nAdhesions are not included and are suggested not to be\nscored. First, it was demonstrated that cystic ovarian endome-\ntriosis and adhesions are so strongly associated [ 8]; that\nstatistically (logistic regression) they carry the same informa-\ntion and that identical rAFS classes can be obtained by\nincreasing the points of either adhesions or cystic endome-\ntriosis and omitting the other. More importantly, adhesions\nare so variable in severity following previous surgery that it\nbecomes difficult to distinguish between surgery-related and\nendometriosis-related adhesions. Finally, the occurrence of\ncystic ovarian endometriosis without adhesions is so rare that,\nanyway, a statistical evaluation of this potentially different\ngroup will be practically impossible by lack of numbers.\nSubtle endometriosis is scored separately from typical\nlesions. By pathology, they are different, the former being\nactive lesions, the latter being burnt-out lesions. Subtle lesions\nin contrast with typical lesions are not associated with the\nLUF syndrome while no data indicate today that subtle lesions\ncause pain or infertility. Another important argument to score\nsubtle lesions separately is that typical lesions are readily\nrecognized during laparoscopy, whereas the recognition of\nsubtle lesions varies with the expertise and the scrutiny of the\nsurgeon. A separate classification will permit to evaluate\nwhether subtle lesions are clinically important for pain,\ninfertility, progression, and most importantly whether subtle\nlesions predict more severe lesions in the future. For the\npatient, it indeed would be important to know whether subtle\nlesions herald the onset of more severe lesions or whether they\nshould be considered less important.\nDeep endometriosis also is scored separately, and to the\ndefinition of depth the, microscopical aspect of adenomyo-\nsis externa is added. Thus deep endometriosis would\nbecome a homogeneous group of active, larger, generally\nunique lesions while the definition of depth only risks to\ninclude the larger typical lesions. Since women with two or\nmore larger nodules are rare, we suggest classifying the\ntotal volume since multiple nodules are so rare that the\nnumbers required for meaningful statistics are expected to\nbe prohibitively large. It is unclear whether other aspects as\nlocalization, lateral extension, and bowel or ureter infiltra-\ntion or hydronephrosis should be included. Given the\nrelationship with pain symptoms we however do consider\nit an advantage to add localization.\nThe classification as suggested is a descriptive classifi-\ncation aimed to investigate the relationship between type\nand severity of endometriosis and symptoms, progression,\npathophysiology, and therapy. To do this obviously, other\nvariables will have to be used as co-variables. For fertility\nfactors as severity of adhesions, surgical aspects, age, and\nthe duration of infertility will have to be used as co-factors\n[51]. To assess surgical difficulty and complications\nDouglas obliteration [ 28], depth of bowel invasion [ 30],\ndegree of hydronephrosis, and number of previous surgeries\nare important. This points to the fundamental difference\nbetween the endometriosis classification proposed aimed to\ninvestigate the type and severity of endometriosis while\ncontrolling for other variables, and a (multivariate) predic-\ntion model as the fertility index [ 51]. Our main concern\nindeed is to limit the variables as much as possible, since\notherwise the series required for multivariate statistical\nanalysis would become unrealistically high.\nPeritoneal pockets, mullerianosis, and uterine adenomyosis\nare suggested to be added to an endometriosis classification.\nAfter decades of discussion, little is known with certainty. The\nproposed classification will at least permit to evaluate whether\nperitoneal pockets are a pathology that should be treated and\nwhat the relationship with mullerianosis is. For adenomyosis\nthe relationship with pain, infertility, and with endometriosis\nor more, specifically deep endometriosis, is unclear but is\nimportant to be investigated.\nAcknowledgments We do thank Ivo Brosens, Leuven for the many\nyears of discussing endometriosis. His ideas are fundamental to this\nmanuscript as reflected in the many common publications. We do\nthank Ronald Batt, New Y ork for the many critical comments and\nsuggestions made.\nDeclaration of interest The authors report no conflicts of interest. The\nauthors alone are responsible for the content and writing of the paper.\nReferences\n1. Jansen RPS, Russel P (1986) Nonpigmented endometriosis:\nclinical, laparoscopic, and pathologic definition. Am J Obstet\nGynecol 155:1154–1159\n2. Martin DC, Hubert GD, V ander ZR, El Zeky FA (1989)\nLaparoscopic appearances of peritoneal endometriosis. Fertil\nSteril 51:63 –67\n3. Martin DC, Khare VK, Parker LS (1994) Clear and opaque\nvesicles: endometriosis, psammoma bodies, endosalpingiosis or\ncancer? J Am Assoc Gynecol Laparosc 1:S21\n4. Keltz MD, Kliman HJ, Arici AM, Olive DL (1995) Endo-\nsalpingiosis found at laparoscopy for chronic pelvic pain. Fertil\nSteril 64:482 –485\n5. Hesseling MH, De Wilde RL (2000) Endosalpingiosis in\nlaparoscopy. J Am Assoc Gynecol Laparosc 7:215 –219\n6. Heinig J, Gottschalk I, Cirkel U, Diallo R (2002) Endosalpingiosis\n—an underestimated cause of chronic pelvic pain or an accidental\nfinding? A retrospective study of 16 cases. Eur J Obstet Gynecol\nReprod Biol 103:75 –78\nGynecol Surg (2011) 8:1 –6 5\n\n7. Batt RE, Smith RA, Buck Louis GM, Martin DC, Chapron C,\nKoninckx PR et al (2007) Mullerianosis. Histol Histopathol\n22:1161–1166\n8. Cullen TS (1896) Adenoma-myoma uteri diffusum benignum. J\nHopkins Hosp Bull 6:133 –137\n9. Lockyer C (1913) Adenomyoma in the recto-uterine and recto-\nvaginal septa. Proc R Soc Med 6:112 –120\n10. Cullen TS (1919) The distribution of adenomyomata containing\nuterine mucosa. Am J Obstet Gynecol 80:130 –138\n11. Meighs V (1920) An interest in endometriosis and its consequences.\nAm J Obstet Gynecol 79:625\n12. Judd EJ (1921) Adenomyomata presenting as a tumor of the\nbladder. Surg Clin North Am 1:1271 –1278\n13. Sampson JA (1927) Peritoneal endometriosis due to the menstrual\ndissemination of endometrial tissue into the peritoneal cavity. Am\nJ Obstet Gynecol 14:422 –469\n14. Brosens IA, Koninckx PR, Corveleyn PA (1978) A study of\nplasma progesterone, oestradiol-17beta, prolactin and LH levels,\nand of the luteal phase appearance of the ovaries in patients with\nendometriosis and infertility. Br J Obstet Gynaecol 85:246 –250\n15. Koninckx PR, Meuleman C, Demeyere S, Lesaffre E, Cornillie FJ\n(1991) Suggestive evidence that pelvic endometriosis is a\nprogressive disease, whereas deeply infiltrating endometriosis is\nassociated with pelvic pain. Fertil Steril 55:759 –765\n16. Balasch J, Creus M, Fabregues F, Carmona F, Ordi J,\nMartinez-Roman S et al (1996) Visible and non-visible endome-\ntriosis at laparoscopy in fertile and infertile women and in patients\nwith chronic pelvic pain: a prospective study. Hum Reprod\n11:387–391\n17. Koninckx PR, Martin D (1994) Treatment of deeply infiltrating\nendometriosis. Curr Opin Obstet Gynecol 6:231 –241\n18. Rier SE, Martin DC, Bowman RE, Dmowski WP , Becker JL\n(1993) Endometriosis in rhesu s monkeys (Macaca mulatta)\nfollowing chronic exposure to 2, 3, 7, 8-tetrachlorodibenzo-p-\ndioxin. Fundam Appl Toxicol 21:433 –441\n19. Batt RE (2009) Emergence of endometriosis in North America: a\nstudy in the history of ideas. PhD Dissertation, State University of\nNew Y ork at Buffalo\n20. Acosta AA, Buttram-VC J, Besch PK, Malinak LR, Franklin RR,\nV anderheyden JD (1973) A proposed classification of pelvic\nendometriosis. Obstet Gynecol 42:19 –25\n21. Kistner RW, Siegler AM, Behrman SJ (1977) Suggested classifi-\ncation for endometriosis: relationship to infertility. Fertil Steril\n28:1008–1010\n22. Buttram-VC J (1978) An expanded classification of endometriosis.\nFertil Steril 30:240–242\n23. The American Fertility Society (1979) Classification of endome-\ntriosis. Fertil Steril 32:633 –634\n24. Revised American Fertility Society (1985) Classification of\nendometriosis 1985. Fertil Steril 43:351 –352\n25. Guzick DS et al (1982) Assessing the efficacy of The American\nFertility Society ’s classification of endometriosis: application of a\ndose-response methodology. Fertil Steril 38:171 –176\n26. Candiani GB (1986) The classification of endometriosis: historical\nevolution, critical review and present state of the art. Acta Eur\nFertil 17:85 –92\n27. Koninckx PR, Martin DC (1992) Deep endometriosis: a conse-\nquence of infiltration or retraction or possibly adenomyosis\nexterna? Fertil Steril 58:924 –928\n28. Adamyan LV (1993) Additional international perspectives. In:\nNichols DH (ed) Gynecologic and obstetric surgery. Mosby, St\nLouis, pp 1167 –1182\n29. Chapron C, Fauconnier A, Vieira M, Barakat H, Dousset B,\nPansini V et al (2003) Anatomical distribution of deeply\ninfiltrating endometriosis: surgical implications and proposition\nfor a classification. Hum Reprod 18:157 –161\n30. Tuttlies F, Keckstein J, Ulrich U, Possover M, Schweppe KW,\nWustlich M et al (2005) ENZIAN-score, a classification of deep\ninfiltrating endometriosis. Zentralbl Gynäkol 127:275 –281\n31. Sampson JA (1940) The development of the imlantation theory for\nthe development of endometriosis. Am J Obstet Gynecol 40:549–557\n32. Koninckx PR, Kennedy SH, Barlow DH (1999) Pathogenesis of\nendometriosis: the role of peritoneal fluid. Gynecol Obstet Invest\n47(Suppl 1):23 –33\n33. Koninckx PR, Barlow D, Kennedy S (1999) Implantation versus\ninfiltration: the Sampson versus the endometriotic disease theory.\nGynecol Obstet Invest 47(1):3 –9\n34. Keebiel WC, Stein RJ (1951) The viability of cast-off menstrual\nendometrium. Am J Obstet Gynecol 61:440 –442\n35. Koninckx PR, Ide P , V andenbroucke W, Brosens IA (1980) New\naspects of the pathophysiology of endometriosis and associated\ninfertility. J Reprod Med 24:257 –260\n36. Koninckx PR, De MP , Brosens IA (1980) Diagnosis of the\nluteinized unruptured follicle syndrome by steroid hormone assays\non peritoneal fluid. Br J Obstet Gynaecol 87:929 –934\n37. Masuda H, Matsuzaki Y , Hiratsu E, Ono M, Nagashima T,\nKajitani T et al (2010) Stem cell-like properties of the endometrial\nside population: implication in endometrial regeneration. PLoS\nONE 5:e10387\n38. Sasson IE, Taylor HS (2008) Stem cells and the pathogenesis of\nendometriosis. Ann NY Acad Sci 1127:106 –115\n39. Mechsner S, Weichbrodt M, Riedlinger WF, Kaufmann AM,\nSchneider A, Kohler C (2009) Immunohistochemical evaluation of\nendometriotic lesions and disseminated endometriosis-like cells in\nincidental lymph nodes of patients with endometriosis. Fertil Steril\n40. Noel JC, Chapron C, Fayt I, Anaf V (2008) Lymph node\ninvolvement and lymphovascular invasion in deep infiltrating\nrectosigmoid endometriosis. Fertil Steril 89:1069 –1072\n41. Barrier BF, Dick EJ Jr, Butler SD, Hubbard GB (2007)\nEndometriosis involving the ileocaecal junction with regional\nlymph node involvement in the baboon-striking pathological\nfinding identical between the human and the baboon: a case\nreport. Hum Reprod 22:272 –274\n42. Abrao MS, Podgaec S, Dias JA Jr, Averbach M, Garry R, Ferraz\nSilva LF et al (2006) Deeply infiltrating endometriosis affecting\nthe rectum and lymph nodes. Fertil Steril 86:543 –547\n43. Koninckx PR, Oosterlynck D, D ’Hooghe T, Meuleman C (1994)\nDeeply infiltrating endometriosis is a disease whereas mild\nendometriosis could be considered a non-disease. Ann NY Acad\nSci 734:333 –341\n44. Koninckx PR (1994) Is mild endometriosis a condition occurring\nintermittently in all women? Hum Reprod 9:2202 –2205\n45. Brosens IA, Koninckx PR (1980) Luteinized unruptured follicle\n(LUF) syndrome and endometriosis [letter]. Fertil Steril 34:179–181\n46. Koninckx PR, Muyldermans M, Brosens IA (1984) Unexplained\ninfertility: ‘Leuven’ considerations. Eur J Obstet Gynecol Reprod\nBiol 18:403 –413\n47. Koninckx PR (1998) Biases in the endometriosis literature —\nillustrated by 20 years of endometriosis research in Leuven. Eur J\nObstet Gynecol Reprod Biol 81:259 –271\n48. Gordts S, Brosens JJ, Fusi L, Benagiano G, Brosens I (2008)\nUterine adenomyosis: a need for uniform terminology and\nconsensus classification. Reprod Biomed Online 17:244 –248\n49. Batt RE, Smith RA, Buck GM, Severino MF, Naples JD (1990)\nMullerianosis. Prog Clin Biol Res 323:413 –426\n50. Oppelt P , Renner SP , Brucker S, Strissel PL, Strick R, Oppelt PG\net al (2005) The VCUAM (vagina cervix uterus adnex-associated\nmalformation) classification: a new classification for genital\nmalformations. Fertil Steril 84:1493 –1497\n51. Adamson GD, Pasta DJ (2009) Endometriosis fertility index: the\nnew, validated endometriosis st aging system. Fertil Steril.\ndoi:10.1016/j.fertnstert.2009.09.035\n6 Gynecol Surg (2011) 8:1 –6","source_license":"CC0","license_restricted":false}