Ovarian endometrioma: severe pelvic pain is associated with deeply infiltrating endometriosis

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1 Human Reproduction, Vol.27, No.3 pp , 2012 Advanced Access publication on January 16, 2012 doi: /humrep/der462 ORIGINAL ARTICLE Gynaecology Ovarian endometrioma: severe pelvic pain is associated with deeply infiltrating endometriosis Charles Chapron 1,2,3, *, Pietro Santulli 1,2,3,4, Dominique de Ziegler 1, Jean-Christophe Noel 5, Vincent Anaf 6, Isabelle Streuli 1, Hervé Foulot 1, Carlos Souza 1,7, and Bruno Borghese 1,2,3 1 Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Assistance Publique Hôpitaux de Paris (AP- HP), Groupe Hospitalier Universitaire (GHU) Ouest, Centre Hospitalier Universitaire (CHU) Cochin Saint Vincent de Paul, Department of Gynecology Obstetrics II and Reproductive Medicine (Professor Chapron), Paris, France 2 Université Paris Descartes, Sorbonne Paris Cité, Institut Cochin, CNRS (UMR 8104), Paris, France 3 Inserm, Unité de Recherche U1016, Paris, France 4 Faculté de Médecine, EA 1833, ERTi, CHU Cochin, Paris, France 5 Department of Gynecopathology, Academic Hospital Erasme, Université Libre de Bruxelles, Bruxelles, Belgium 6 Depatment of Gynecology, Academic Hospital Erasme, Université Libre de Bruxelles, Bruxelles, Belgium 7 Serviço de Ginecologia e Obstetrícia, Hospital de Clínicas de Porto Alegre (HCPA), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Porto Alegre, Brazil *Correspondence address. Service de Gynécologie Obstétrique II et Médecine de la Reproduction, Pavillon Lelong, CHU Cochin Saint Vincent de Paul, 82, Avenue Denfert Rochereau, Paris, France. Tel: ; Fax: ; charles. chapron@cch.aphp.fr Submitted on February 15, 2011; resubmitted on September 26, 2011; accepted on October 5, 2011 background: The objective of this study was to evaluate the significance of severe preoperative pain for patients presenting with ovarian endometrioma (OMA). methods: Three hundred consecutive patients with histologically proven OMA were enrolled at a single university tertiary referral centre between January 2004 and May Complete surgical excision of all recognizable endometriotic lesions was performed for each patient. Pain intensity was assessed with a 10-cm visual analogue scale (VAS). Pain was considered as severe when VAS was 7. Prospective preoperative assessment of type and severity of pain symptoms (VAS) was compared with the peroperative findings (surgical removal and histological analysis) of endometriomas and associated deeply infiltrating endometriosis. Correlations were sought with univariate analysis and a multiple regression logistic model. results: After multiple logistic regression analysis, uterosacral ligaments involvement was related with a high severity of chronic pelvic pain [odds ratios (OR) ¼ 2.1; 95% confidence interval (CI): ] and deep dyspareunia (OR ¼ 2.0; 95% CI: ); vaginal involvement was related with a higher intensity of lower urinary symptoms (OR ¼ 13.4; 95% CI: ); intestinal involvement was related with an increased severity of dysmenorrhoea (OR ¼ 5.2; 95% CI: ) and gastro-intestinal symptoms (OR ¼ 7.1; 95% CI: ). conclusions: In case of OMA, severe pelvic pain is significantly associated with deeply infiltrating lesions. In this situation, the practitioner should perform an appropriate preoperative imaging work-up in order to evaluate the existence of associated deep nodules and inform the patient in order to plan the surgical intervention strategy. Key words: endometrioma / pelvic pain / deeply infiltrating endometriosis / multivariate analysis / nerve fibres Introduction Endometriosis is a disease that affects 6 10% of women of childbearing age (Giudice and Kao, 2004) and is histologically defined by the presence of endometrial-like tissue outside the uterus (Sampson, 1927). Endometriosis is histologically categorized into three types: peritoneal superficial endometriosis (SUP), ovarian endometrioma (OMA) and deeply infiltrating endometriosis (DIE). Endometriosis, whose cause remains enigmatic to this date (Borghese et al., 2008; Bulun, 2009; Ngo et al., 2009), is associated with infertility (Matzuk and Lamb, 2008; de Ziegler et al., 2010) and/or pelvic pain (Fauconnier and Chapron, 2005). Different hypotheses have been proposed to explain the relationship that exists between endometriosis and pain (Berkley et al., 2005; Evans et al., 2007). For DIE, entrapment of nerves within the endometriotic nodules represents a possible mechanism explaining pain (Anaf et al., 2000) with the severity of & The Author Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please journals.permissions@oup.com

2 Severe pelvic pain and endometrioma 703 pain being strongly associated with the depth of infiltration (Koninckx et al., 1991; Porpora et al., 1999; Chapron et al., 2003). Moreover, the nature and intensity of the patient s pain are closely related to the anatomic location of DIE nodules (Fauconnier et al., 2002). Conversely, the relationship between OMA and painful symptoms is not well established and is still controversial (Fauconnier and Chapron, 2005). Studies that found an association between OMA and chronic pelvic pain were performed by using univariate analysis (Fedele et al., 1992; Muzii et al., 1997). This methodological approach does not take into account the fact that ovarian endometrioma/endometriomas are frequently associated with other endometriotic lesions (Redwine, 1999; Chapron et al., 2009), which themselves could cause pain. In studies that used multivariate analysis (Koninckx et al., 1991; Porpora et al., 1999; Chapron et al., 2003), results were less clear with pain symptoms apparently not correlated with the presence of an OMA. Thus, currently little is known about the mechanisms by which pain might be associated with OMA. The purpose of the present study was to evaluate the significance of associated severe pain in women presenting with a proven OMA in a large prospective database with multivariate analysis. Materials and Methods The local ethics committee (CCPPRB: Comité Consultatif de Protection des Personnes dans la Recherche Biomédicale) of our institution approved the study protocol. The study population consisted of a continuous series of 300 patients who underwent surgery between January 2004 and May All were diagnosed with an OMA. 2 cm in diameter and presented various degrees of pelvic pain and/or infertility. The endometriotic nature of the cysts was histologically confirmed in all cases. When conservative treatment was sought, OMA were removed through a laparoscopically intraperitoneal cystectomy (Canis et al., 2001), as opposed to ablative laparoscopic surgery with fenestration and electrocoagulation of the cyst wall, since with this type of conservative surgery full histological proof of OMA may be missed. When radical treatment was indicated we performed an adnexectomy with or without retroperitoneal approach and/or ureterolysis depending on the degree of adhesions (Chapron et al., 2002). Associated endometriotic lesions were managed during the same surgical procedure: destruction of superficial peritoneal endometriosis (SUP) by bipolar coagulation; excision of DIE nodules (Chapron et al., 2010a,b,c; Dousset et al., 2010). During surgery, endometriosis was staged and scored (total, implants and adhesions scores) according to the revised American Fertility Society (rafs) Classification (AFS, 1985). The study analysis used a prospectively managed database. For each patient, personal history data were obtained during face-to-face interviews conducted by the surgeon during the month preceding surgery. We used a highly structured previously published questionnaire (Chapron et al., 2010a,b,c). The following data were recorded: age, parity, gravidity, height, weight, BMI, previous history of rectorragia and/or haematuria, past history of hormonal and/or surgical treatment for endometriosis, existence of gynaecologic pain symptoms [dysmenorrhoea, deep dyspareunia, non-cyclic chronic pelvic pain (NCCPP)], gastrointestinal (GI) (Dousset et al., 2010) and lower urinary (LU) tract (Fauconnier et al., 2002) symptoms. Pain intensity was evaluated preoperatively using a 10-cm visual analogue scale (VAS) (Huskisson, 1974). For the purpose of this study, the intensity of each type of preoperatively existing pain symptom was denoted as moderate (VAS, 7) or severe (VAS 7). Concerning OMA, the following data were recorded: mean size (cm) at preoperative transvaginal ultrasonography (TVUS); unilateral (right or left) or bilateral nature. The severity of DIE was assessed on the basis of two parameters (Chapron et al., 2009): the number and the classification (Chapron et al., 2006) of the DIE lesions. By definition, when a patient presented with multiple DIE locations we classified her in the group corresponding to the most severe lesion, according to the following order from least to worst: uterosacral ligament(s), vagina, bladder, intestine and ureter (Chapron et al., 2006). All data were collected in a computerized database and analysed by SPSS software (SPSS Inc., Chicago, IL, USA). For each type of pain symptom, comparisons were performed according whether pain intensity was judged as moderate or severe. P, 0.05 was considered statistically significant. For univariate statistical analysis we used the following tests: Pearson s x 2 test for qualitative variables or Fisher s exact test as appropriate; Student s t-test for quantitative variables. Subsequently, for each type of pain symptom, the variables associated with a severely intense pain at the threshold of P 0.10 in univariate analysis were tested in a multiple logistic regression model. Backward stepwise selection was used to retain variables with a P-value of,0.05 in each final model. The parameter values for each of the final models were estimated by the maximum likelihood method. In case of significant differences odds ratios (OR) and their 95% confidence intervals (95% CI) were calculated from the model s coefficients and their standard deviations. Results Patients characteristics were detailed in Table I. The 300 patients presented 378 histologically proved OMA (right: 83; left: 139; bilateral: 78). In the series 112 patients or 37.3% presented a mean number of previous surgery for endometriosis of (range 1 5). Seventy patients (70; 23.3%) presented a previous history of surgery for OMA: right OMA (23 patients; 33%), left OMA (32 patients; 46%), bilateral OMA (15 patients; 21%). Two hundred and eighty-six patients (95.3%) presented adhesions associated with OMA. Two hundred and thirty-seven patients (79.0%) presented rafs adhesion scores 8 and 152 patients (50.7%) presented scores 16. In our study sample, OMA was associated with histologically proven DIE nodules in 121 patients (40.3%): 1 DIE nodule (23 patients), 2 DIE nodules (19 patients) and 3 DIE nodules (79 patients). The presence of associated DIE lesions was significantly increased for patients presenting with previous history of surgery for endometriosis [79 cases (70.5%) versus 42 cases (22.3%); P, ]. Patients distribution according to the worst lesion of DIE classification was: uterosacral ligament(s) (23 patients; 7.7%), vagina (8 patients; 2.7%), bladder (2 patients; 0.7%), intestine (76 patients; 25.3%), ureter (12 patients; 4%). These 121 patients, presenting a total of 440 histologically proved DIE lesions, distributed as follow: 135 uterosacral ligaments lesions (30.7%: 22 right, 23 left and 45 bilateral), 66 vaginal lesions (15%), 15 bladder lesions (3.4%), 210 intestine lesions (47.7%; a single intestinal lesion in 28 patients and a multiple intestinal lesion in 60 patients) and 14 ureteral lesions (3.2%: bilateral lesions in two patients). The mean number of DIE nodules per patient was (range 0 10). Mean preoperative pelvic pain scores are presented in Table I. Dysmenorrhoea was judged as moderate in 115 patients (38.3%) and severe in 185 patients (61.7%). On univariate analysis, the following variables were related to severe dysmenorrhoea: existence of infertility, rectal bleeding, previous history of surgery for endometriosis and/or OMA, mean total, implants and adhesions

3 704 Chapron et al. Table I Baseline characteristics in patients with endometrioma. Patient characteristics Values (n 5 300)... Age (years) a (range 17 41) Height (cm) a (range ) Weight (kg) a (range ) Body Mass Index (kg/m 2 ) a (range ) Parity (87.3%) 1 23 (7.7%) 2 15 (5%) Gravidity (73.7%) 1 48 (16%) 2 31 (10.3%) Infertility (n, %) 116 (38.7%) Since (month) a (range ) Previous treatment for endometriosis Hormonal treatment (n, %) 186 (62.0%) Number of previous surgery (n, %): (62.7%) (33.0%) 3 13 (4.3%) Previous endometrioma s surgery 70 (23.3%) (n,%) Preoperative painful symptoms scores a,b,c Dysmenorrhoea (range 0 10) Deep dyspareunia d (range 0 10) Non-cyclic chronic pelvic pain (range 0 10) Gastrointestinal symptoms (range 0 10) LU symptoms (range 0 10) Rectal bleeding (n, %) 38 (12.7%) Hematuria (n, %) 8 (2.7%) Mean implants score rafs a,e (range 6 46) Mean adhesions score rafs a,e (range 0 104) Mean total score rafs a,e (range ) rafs stage (n, %): e III 151 (50.3%) IV 149 (49.7%) SUP (n, %) 123 (41.0%) Endometrioma size (cm) a Right (range 2 14) Left (range 2 21) Endometrioma laterality (n,%) Bilateral 78 (26.0%) Right 83 (27.7%) Left 139 (46.3%) Associated adhesions (n, %) 286 (95.3%) Associated DIE lesions (n,%) f 121 (40.3%) Continued Table I Continued Patient characteristics Values (n 5 300)... Mean number of DIE lesions a (range 0 10) Total number of DIE lesions (n,%) (59.7%) (14%) 3 79 (26.3%) Anatomical distribution of DIE (n,%) b,f USL 90 (30%) Vagina 66 (22%) Bladder 15 (5%) Intestine 88 (29%) Ureter 12 (4%) Worst DIE lesion (n,%) f USL 23 (7.7%) Vagina 8 (2.7%) Bladder 2 (0.7%) Intestine 76 (25.3%) Ureter 12 (4.0%) a Data are presented as mean + standard deviation. b Sometimes more than one for the same patient. c Visual analogue scale. d Six per cent of patients have no sexual intercourse at the moment of the surgery. e Score according to the American Fertility Society Classification (AFS, 1985). f According to a previously published surgical classification for DIE by Chapron et al. (2006). rafs scores, rafs stages, OMA laterality, existence of associated DIE lesion, total and mean number of DIE lesions, anatomical distribution of DIE nodules and worst DIE lesion (Table II). Deep dyspareunia was judged as moderate in 201 patients (67.0%) and severe in 80 patients (26.7%). The other 19 patients (6.3%) were not sexually active at the moment of surgery. On univariate analysis, the following variables were related to severe deep dyspareunia: previous history of hormonal treatment for endometriosis and surgery for OMA, mean total rafs scores, existence of associated DIE lesions, total and mean number of DIE lesions, anatomical distribution of DIE nodules and worst DIE lesion (Table II). NCCPP was considered as moderate in 254 patients (84.7%) and severe in 46 patients (15.3%). On univariate analysis, the following variables were related to severe NCCPP: previous history of hormonal treatment and surgery for endometriosis, OMA laterality, existence of associated DIE lesion, total number of DIE lesions and anatomical distribution of DIE nodules (Table III). GI symptoms were labelled as moderate in 225 patients (75.0%) and severe in 75 patients (25.0%). On univariate analysis, the following variables were related to severe GI symptoms: rectal bleeding, previous history of hormonal treatment for endometriosis, previous history of surgery for endometriosis and OMA, mean total, implants and adhesions rafs scores, rafs stages, associated SUP, existence of associated DIE lesion, total and mean number of DIE lesions, anatomical distribution of DIE nodules and worst DIE lesion (Table III).

4 Severe pelvic pain and endometrioma 705 Table II Patients characteristics according to the severity of the dysmenorrhoea and the dyspareunia. Variables DM... P-value DP... P-value (n 5 115) (n 5 185) (n 5 201) (n 5 80)... Age (years) a b b Height (cm) a b b Weight (kg) a b b Body Mass Index (kg/m 2 ) a b b Parity 0 94 (81.7%) 168 (90.8%) c 179 (89.1%) 65 (81.3%) d 1 13 (11.3%) 10 (5.4%) 15 (7.5%) 8 (10%) 2 8 (16%) 7 (3.8%) 7 (3.5%) 7 (8.8%) Gravidity 0 82 (71.3%) 139 (75.1%) c 152 (75.6%) 51 (63.8%) c 1 17 (14.8%) 31 (16.8%) 31 (15.4%) 17 (21.3%) 2 16 (13.9%) 15 (8.1%) 18 (9%) 12 (15%) Infertility (n, %) 36 (31.3%) 80 (43.5%) c 86 (43.2%) 30 (37.5%) c Rectal bleeding (n, %) 8 (7.0%) 30 (16.2%) c 23 (11.4%) 14 (17.5%) c Hematuria (n, %) 1 (0.9%) 7 (3.8%) d 5 (2.5%) 3 (3.8%) d Previous hormonal treatment for endometriosis (n, %) 69 (61.6%) 117 (66.1%) c 116 (59.8%) 56 (73.7%) c Previous surgeries for endometriosis (n,%) 0 85 (73.9%) 103 (55.7%) d 131 (65.2%) 42 (52.5%) d (24.4%) 71 (38.4%) 63 (31.3%) 32 (40.0%) 3 2 (1.7%) 11 (5.9%) 7 (3.5%) 6 (7.5%) Previous endometrioma s surgery (n, %) 18 (16.2%) 52 (28.3%) c 39 (19.8%) 27 (34.2%) c Mean implants score rafs a,e b b Mean adhesions score rafs a,e b b Mean total score rafs a,e ,0.001 b b rafs stage (n, %): a,e III 73 (63.5%) 78 (42.2%),0.001 c 105 (52.2%) 35 (43.8%) c IV 42 (36.5%) 107 (57.8%) 96 (47.8%) 45 (56.3%) SUP (n, %) 49 (42.6%) 74 (40.0%) c 84 (41.8%) 30 (37.5%) c Endometrioma size (cm) a Right b b Left b b Endometrioma laterality (n,%) Bilateral 20 (17.3%) 58 (31.4%) c 53 (26.4%) 21 (26.3%) c Right 41 (31.7%) 42 (22.7%) 61 (30.3%) 16 (20.0%) Left 54 (47.0%) 85 (45.9%) 87 (43.3%) 43 (53.8%) Associated DIE lesions (n,%) f 23 (20.0%) 98 (53.0%),0.001 c 71 (35.3%) 47 (58.8%),0.001 c Mean number of DIE lesions a ,0.001 b b Total number of DIE lesions (n,%) f 0 92 (80.0%) 87 (47.0%),0.001 d 130 (64.7%) 33 (41.3%) c (7.8%) 33 (17.8%) 25 (12.4%) 15 (18.8%) 3 14 (12.2%) 65 (35.1%) 46 (22.9%) 32 (40.0%) Anatomical distribution of DIE (n,%) f,g USL 19 (16.5%) 71 (38.4%),0.001 c 52 (25.9%) 36 (45.0%) c Vagina 14 (12.2%) 52 (28.1%) c 40 (19.9%) 26 (32.5%) c Bladder 6 (5.2%) 9 (4.9%) d 11 (5.5%) 4 (5.0%) d Continued

5 706 Chapron et al. Table II Continued Variables DM P-value DP P-value (n 5 115) (n 5 185) (n 5 201) (n 5 80)... Intestine 14 (12.2%) 74 (40.0%),0.001 c 52 (25.9%) 35 (43.8%) c Ureter 4 (3.5%) 8 (4.3%) d 8 (4.0%) 4 (5.0%) d Worst DIE lesion (n,%) f USL 7 (6.1%) 16 (8.6%),0.001 d 12 (6.0%) 9 (11.3%) d Vagina 2 (1.7%) 6 (3.2%) 5 (2.5%) 3 (3.8%) Bladder 0 (0.0%) 2 (1.1%) 2 (1.0%) 0 (0.0%) Intestine 10 (8.7%) 66 (35.7%) 44 (21.9%) 31 (38.8%) Ureter 4 (3.5%) 8 (4.3%) 8 (4.0%) 4 (5.0%) DM, dysmenorrhoea; DP, deep dyspareunia; DIE, deeply infiltrating endometriosis. a Data are presented as mean + standard deviation. b Student s t-test. c Pearson s x 2 test. d Fisher s exact test. e Score according to the American Fertility Society Classification (AFS, 1985). f According to a previously published surgical classification for DIE by Chapron et al. (2006). g Sometimes more than one for the same patient. LU symptoms were reported as moderate in 289 patients (96.3%) and severe in 11 patients (3.7%). On univariate analysis, the following variables were related to severe LU symptoms: weight (P ¼ 0.027), BMI (P ¼ 0.049), haematuria (P ¼ 0.03), previous history of surgery for endometriosis (P ¼ 0.008), existence of associated DIE lesion (P, 0.001), total (P, 0.001) and mean number (P ¼ 0.02) of DIE lesions, anatomical distribution of DIE nodules and worst DIE lesion (P, 0.001). Mean preoperative painful symptoms are detailed in Table IV according to the existence or not of associated DIE lesions. Whatever the associated DIE lesions (uterosacral ligament(s), vagina, bladder, intestine and/or ureter), the mean scores were significantly higher when OMAs were associated with deep nodules (P, 0.001). Pain analysis is detailed in Table V according to the fact that patients presented one DIE nodule or more ( 2). Independent predictors for severity of painful symptoms after multiple regression analysis are detailed in Table VI. Uterosacral ligaments involvement was related with a high severity of chronic pelvic pain (OR ¼ 2.1; 95% CI: ) and deep dyspareunia (OR ¼ 2.0; 95% CI: ); vaginal involvement was related with a higher intensity of LU symptoms (OR ¼ 13.4; 95% CI: ); intestinal involvement was related with an increased severity of dysmenorrhoea (OR ¼ 5.2; 95% CI: ) and gastro-intestinal symptoms (OR ¼ 7.1; 95% CI: ). Discussion Our prospective study of symptoms experienced by women diagnosed with histologically proven OMA indicates that severe pain was associated with the co-finding of DIE. In cases of severe pain, OMA were associated with DIE lesions that were more often multifocal, severe and with intestinal infiltration. The intensity of pain was however not related to the size of OMA. Left side location and bilaterality of OMA correlated with the severity of NCCPP and dysmenorrhoea, respectively. The nature of the mechanism(s) responsible for pain in endometriosis is complex. One hypothesis put forward is the close relationship between nerves and endometriotic lesions (Anaf et al., 2000; Tokushige et al., 2006; Mechsner et al., 2007). Intense immunostaining for neural cell adhesion molecule, which is related to the formation of neuronal networks (Cunningham et al., 1987), was observed for the three types of human endometriotic lesions (SUP, OMA, DIE) (Odagiri et al., 2009). Nerve growth factor (NGF), which plays an important role in mediating pain (Apfel, 2000), is expressed in the three different forms of endometriosis (SUP, OMA, DIE) (Anaf et al., 2002; Odagiri et al., 2009). Endometriotic lesions (SUP, OMA, DIE) contain significantly more mast cells, which can secrete NGF, than unaffected tissues (Anaf et al., 2006). In OMAs, not only NGF, but also other neurotrophins (NT) were significantly expressed (Borghese et al., 2010). Nerve fibres stained with protein gene-related product 9.5 (PGP9.5), involved in pain pathogenesis (Berkley et al., 2004), were detected in SUP (Tokushige et al., 2006; Mechsner et al., 2009; Yao et al., 2010), OMA (Tokushige et al., 2010; Zhang et al., 2010) and DIE lesions (Wang et al., 2009a,b). The density of PGP9.5-positive nerve fibres was markedly denser in OMA when compared with normal ovarian tissue from women with OMA or without endometriosis (Tokushige et al., 2010). PGP9.5-positive nerve fibres density in OMA was correlated with the severity of pain symptoms (Zhang et al., 2010). Taken together, nerve fibres in OMA clearly demonstrate that OMA receive sensory, sympathetic and parasympathetic, nerve fibres (Tokushige et al., 2010). Hence, OMA should be viewed as a painful endometriotic lesion. Pelvic adhesions, that are frequently observed in cases of OMA (Sampson, 1922; Vercellini et al., 1991), can also contribute to pain

6 Severe pelvic pain and endometrioma 707 Table III Patients characteristics according to the severity of the non-cyclic chronic pelvic pain and gastrointestinal symptoms. Variables NCCPP P-value GIS P-value (n 5 254) (n 5 46) (n 5 225) (n 5 75)... Age (years) a b b Height (cm) a b b Weight (kg) a b b Body mass index (kg/m 2 ) a b b Parity (87.0%) 41 (89.1%) c 198 (88.0%) 64 (85.3%) d 1 20 (7.9%) 3 (6.5%) 18 (8.0%) 5 (6.7%) 2 13 (5.1%) 2 (4.3%) 9 (4.0%) 6 (8.0%) Gravidity (74.0%) 33 (71.7%) d 165 (73.3%) 56 (74.7%) d 1 38 (15.0%) 10 (21.7%) 36 (16.0%) 12 (16.0%) 2 28 (11.0%) 3 (6.5%) 24 (10.7%) 7 (9.3%) Infertility (n, %) 101 (39.9%) 15 (32.6%) d 81 (36.2%) 35 (46.7%) d Rectal bleeding (n, %) 29 (11.4%) 9 (19.6%) d 21 (9.3%) 17 (22.7%) d Hematuria (n, %) 7 (2.8%) 1 (2.2%) c 5 (2.2%) 3 (4.0%) c Previous hormonal treatment for endometriosis (n, %) 150 (61.5%) 36 (80.0%) d 124 (56.9%) 62 (87.3%),0.001 d Previous surgeries for endometriosis (n,%) (66.1%) 20 (43.5%) c 157 (69.8%) 31 (41.3%),0.001 d (30.3%) 22 (47.8%) 63 (28.0%) 36 (48.0%) 3 9 (3.5%) 4 (8.7%) 5 (2.2%) 8 (10.7%) Previous endometrioma s surgery (n, %) 55 (22.1%) 15 (32.6%) d 41 (18.6%) 29 (38.7%),0.001 d Mean implants score rafs a,e b b Mean adhesions score rafs a,e b ,0.001 b Mean total score rafs a,e b ,0.001 b rafs stage (n,%) a,e III 131 (51.6%) 20 (43.5%) d 127 (56.4%) 24 (32.0%),0.001 d IV 123 (48.4%) 26 (56.5%) 98 (43.6%) 51 (68.0%) SUP (n, %) 106 (41.7%) 17 (37.0%) d 104 (46.2%) 19 (25.3%) d Endometrioma size (cm) a Right b b Left b b Endometrioma laterality (n,%) Bilateral 72 (28.3%) 6 (13.0%) d 55 (24.4%) 23 (30.7%) d Right 75 (29.5%) 8 (17.4%) 68 (30.2%) 15 (20.0%) Left 107 (42.1%) 32 (69.6%) 102 (45.3%) 37 (49.3%) Associated DIE lesions (n,%) f 95 (37.4%) 26 (56.5%) d 62 (27.6%) 59 (78.7%),0.001 d Mean number of DIE lesions a b ,0.001 b Total number of DIE lesions (n,%) f (62.6%) 20 (43.5%) c 163 (72.4%) 16 (21.3%),0.001 d (13.0%) 9 (19.6%) 26 (11.6%) 16 (21.3%) 3 62 (24.4%) 17 (37.0%) 36 (16.0%) 43 (57.3%) Anatomical distribution of DIE (n,%) g,f USL 68 (26.8%) 22 (47.8%) d 50 (22.2%) 40 (53.3%),0.001 d Vagina 55 (21.7%) 11 (23.9%) d 32 (14.2%) 34 (45.3%),0.001 d Continued

7 708 Chapron et al. Table III Continued Variables NCCPP... P-value GIS... P-value (n 5 254) (n 5 46) (n 5 225) (n 5 75)... Bladder 12 (4.7%) 3 (6.5%) c 9 (4.0%) 6 (8.0%) c Intestine 69 (27.2%) 19 (41.3%) d 38 (16.9%) 50 (66.7%),0.001 d Ureter 10 (3.9%) 2 (4.3%) c 8 (3.6%) 4 (5.3%) c Worst DIE lesion (n,%) f USL 18 (7.1%) 5 (10.9%) c 18 (8.0%) 5 (6.7%),0.001 c Vagina 7 (2.8%) 1 (2.2%) 4 (1.8%) 4 (5.3%) Bladder 1 (0.4%) 1 (2.2%) 2 (0.9%) 0 (0.0%) Intestine 59 (23.2%) 17 (37.0%) 30 (13.3%) 46 (61.3%) Ureter 10 (3.9%) 2 (4.3%) 8 (3.6%) 4 (5.3%) NCCPP, non-cyclic chronic pelvic pain; GIS, gastrointestinal symptoms; DIE, deeply infiltrating endometriosis. a Data are presented as mean + standard deviation. b Student s t-test. c Fisher s exact test. d Pearson s x 2 test. e Score according to the American Fertility Society Classification (AFS, 1985). f According to a previously published surgical classification for DIE by Chapron et al. (2006). g Sometimes more than one for the same patient. Table IV Relationship between preoperative painful symptoms intensity and the existence of associated DIE lesions. Painful symptoms... DM DP NCCPP GIS LUS... OMA without DIE (n ¼ 179) a , OMA associated with DIE (n ¼ 121) a OMA associated with USL (n ¼ 90) a OMA associated with Vagina (n ¼ 66) a OMA associated with Bladder (n ¼ 15) a OMA associated with Intestine (n ¼ 88) a OMA associated with Ureter (n ¼ 12) a OMA, ovarian endometrioma; DIE, deeply infiltrating endometriosis; USL, uterosacral ligament(s); DM, dysmenorrhoea; DP, deep dyspareunia; NCCPP, non-cyclic chronic pelvic pain; GIS, gastrointestinal symptoms; LUS, lower urinary tract symptoms. All comparisons between OMA with or without DIE are significantly different for each painful symptoms (P, 0.001). a Data are presented as mean + standard deviation. generation for women presenting with OMA. Periovarian adhesions contain endometrial and inflammatory cells which may generate painful symptoms (Jirasek et al., 1998). The presence of PGP9.5-positive nerve fibres in ovarian endometriotic lesions when pelvic adhesions were associated with OMA is sufficient to generate painful symptoms, regardless of the PGP9.5-positive nerve fibres in pelvic adhesions tissues (Zhang et al., 2010). Histological data on nerves fibres could explain the fact that patients with OMA present with pain. The remaining question however is why pelvic pain is more severe when OMAs are associated with DIE lesions? This clinical observation may be explained by the following mechanisms: (i) In glands and stroma, NGF and Trk-A expression are significantly stronger in DIE nodules than in OMA or peritoneal lesions, both in the proliferative and secretory phases (Anaf et al., 2002). Growth-associated protein 43, a marker for axogenesis and synaptogenesis, is strongly expressed in endometriosis-associated nerve fibres, which suggests that nerve fibres detected in DIE lesions are newly formed (Wang et al., 2009a,b). This is confirmed by the observation that in DIE, nerve fibre density is significantly more important in the nodules than in the adjacent unaffected tissue, both in the proliferative and secretory phases (Anaf et al., 2011); (ii) Nerve fibre density detected by immunohistochemistry was significantly higher in DIE lesions than in peritoneal endometriosis (Wang et al., 2010; Zhang et al., 2010) or OMA (Wang et al., 2010);

8 Severe pelvic pain and endometrioma 709 Table V Relationship between painful symptoms and number of DIE nodules. Painful DIE symptoms... 1 lesions 2 lesions P (n 5 23) (n 5 98)... DM a b DP a b NCCPP a b GIS a ,0.001 b LUS a b DM severe 16 (69.6%) 82 (83.7%) d (VAS 7) c DP severe 8 (38.1%) 39 (40.2%) e (VAS 7) c NCCPP severe 7 (30.4%) 19 (19.4%) d (VAS 7) c GIS severe 7 (30.4%) 52 (53.1%) e (VAS 7) c LUS severe 3 (13.0%) 8 (8.2%) d (VAS 7) c DIE, deeply infiltrating endometriosis; DM, dysmenorrhoea; DP, deep dyspareunia; NCCPP, non-cyclic chronic pelvic pain; GIS, gastrointestinal symptoms; LUS, lower urinary tract symptoms. a Data are presented as mean + standard deviation. b Student s t-test. c Data are presented as n (%). d Fisher s exact test. e Pearson s x 2 test. Table VI Determinants for severity of painful symptoms results from multiple logistic regression analysis. Independent Variable expressed as OR (95%IC)... Dysmenorrhoea Main DIE lesion: intestine a 5.2 ( ) Bilateral endometrioma 2.8 ( ) Deep dyspareunia Main DIE lesion: USL a 2.0 ( ) Non-cyclic chronic pelvic Main DIE lesion: USL a 2.1 ( ) pain Left sided endometrioma 3.5 ( ) Previous surgeries for 2.2 ( ) endometriosis Gastrointestinal Main DIE lesion: intestine a 7.1 ( ) symptoms LU symptoms Main DIE lesion: vagina a 13.4 ( ) Hematuria 10.0 ( ) DIE, deeply infiltrating endometriosis; USL, uterosacral ligament(s). a According to a previously published surgical classification for DIE by Chapron et al. (2006). All P, (iii) Perineural and intraneural invasion by endometriotic lesions was observed only in DIE lesions and not in the others forms of endometriosis (SUP, OMA) (Anaf et al., 2002). This is essential because percentages of nerves encapsulation within endometriotic lesions together with perineural and intraneural invasion were correlated to the intensity of preoperative pain scores (Anaf et al., 2000); (iv) DIE lesions contain significantly more mast cells in close relationship with nerves than ovarian endometriosis (Anaf et al., 2006); (v) For patients presenting with DIE lesions, nerve fibres density was correlated with DIE nodule location. The density of nerve fibres was significantly higher in intestinal DIE than in DIE from other sites (Wang et al., 2009a,b). In intestinal DIE, endometriotic lesions infiltrate the large bowel wall with predilection around the nerves, even at a distance from the palpated nodule (Anaf et al., 2004). These histological observations concur with our clinical observation after multivariate analysis that intestinal DIE is an independent factor for severe pain symptoms in cases of dysmenorrhoea and gastrointestinal symptoms (Table VI). Our findings have clinical implications that are of prime importance in daily practice. Severely painful OMAs should not be considered as a simple OMA but rather as OMA associated with DIE lesions. OMA is well known by all gynaecologists and diagnosed with simple TVUS (Brosens et al., 2004), but this is not the case of DIE, which are not easily diagnosed, except in few referral centres. Underestimation of the DIE extension prior to surgery is one main reason explaining why surgery is often incomplete (Chapron et al., 2009), which leads to repetitive operative procedures (Fedele et al., 2005; Vignali et al., 2005). In this series 112 patients (37.3%) have a previous surgery for endometriosis. The prevalence of DIE lesions in patients with previous surgery is higher than in patients without previous surgery (P, 0.001), corresponding to an increase risk of recurrence in cases of DIE, probably due to an underestimation of the extent of the disease at the time of the previous intervention(s). A severely painful OMA constitutes an indication for searching possibly associated DIE lesions. In this context, TVUS must be the first-line imaging process (Abrao et al., 2007; Bazot et al., 2007; Piketty et al., 2009). According to the TVUS results performed at first intention, addition of magnetic resonance imaging, transrectal ultrasonography or multislice computerized tomography may be indicated (Piketty et al., 2009). Multifocality of DIE lesions (Chapron et al., 2006) justifies a multidisciplinary approach for patients with severely painful OMA. In conclusion, numerous immunohistochemical results demonstrate clearly that OMA should be considered as a painful endometriotic lesion. In the context of OMA, existence of severe pelvic pain however is in favour of associated DIE lesions. In cases of severely painful OMA, the endometriosis as such should be considered as severe. Severely painful OMA is an indication for undertaking a proper non-invasive imaging work-up in order to look for associated DIE lesions. The objective is to preoperatively determine the exact nature, location and extension of associated endometriotic lesions so that the patient can understand and consent to the planned surgical treatment strategy. Acknowledgements The authors want to warmly thank staff members from our department operating room for their expert assistance with data collection and Dr Nicolas Chopin for his help in preparing the statistical analysis. The authors also thankfully acknowledge Nathalie Girma for unabatedly managing the patient database.

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