Analysis of risk factors for the removal of normal ovarian tissue during laparoscopic cystectomy for ovarian endometriosis

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1 Human Reproduction, Vol.24, No.6 pp , 2009 Advanced Access publication on February 26, 2009 doi: /humrep/dep043 ORIGINAL ARTICLE Gynaecology Analysis of risk factors for the removal of normal ovarian tissue during laparoscopic cystectomy for ovarian endometriosis Sachiko Matsuzaki 1,3,Céline Houlle 1, Claude Darcha 2, Jean-Luc Pouly 1,Gérard Mage 1, and Michel Canis 1 1 CHU Clermont-Ferrand, Polyclinique-Hôtel-Dieu, Gynécologie Obstétrique et Médecine de la Reproduction, Boulevard Léon Malfreyt, Clermont-Ferrand, France 2 CHU Clermont-Ferrand, Hôtel-Dieu, Service d Anatomie et Cytologie Pathologiques, Clermont-Ferrand, France 3 Correspondence address. Fax: þ ; sachikoma@aol.com background: The aim of this study was to identify risk factors for the removal of normal ovarian tissue during laparoscopic cystectomy for endometriosis. methods: A total of 121 patients who had histologically confirmed ovarian endometriosis and 56 control patients who had other histologically confirmed benign cysts were included for the present analysis. The blocks of removed tissue were sectioned at 120 mm intervals and a total of five sections were analyzed for each ovarian cyst. Eight variables (age, pre-operative medical treatment, previous surgery for ovarian endometriosis, single or multiple cysts, size of the largest cyst, side of cyst, co-existence of deep endometriosis, revised American Society for Reproductive Medicine classification) were evaluated using a generalized linear modeling analysis to identify major factors associated with the removal of normal ovarian tissue. results: Normal ovarian tissue adjacent to the cyst wall was detected in 71 patients (58.7%) with endometriosis, whereas normal ovarian tissue was removed from only three patients (5.4%) with other benign cysts. A significant factor that was independently associated with the removal of normal ovarian tissue with ovarian endometriosis was pre-operative medical treatment. conclusions: The present retrospective, controlled study suggests that pre-operative medical treatment might be a risk factor for the removal of normal ovarian tissue during laparoscopic cystectomy for ovarian endometriosis. Key words: ovarian endometriomas / laparoscopic cystectomy / ovarian tissue / pre-operative hormonal treatment / risk factors Introduction Laparoscopic surgery has become the gold standard for treatment of ovarian endometriosis (Canis et al., 2003). A Cochrane review concluded that excisional surgery of ovarian endometriosis results in a more favorable outcome than drainage and ablation with regard to recurrence, pain symptoms and subsequent spontaneous pregnancy in women who were previously subfertile (Hart et al., 2008). Consequently, excisional surgery for ovarian endometriosis should be the preferred surgical approach (Hart et al., 2008). However, both excision and ablation may damage normal ovarian cortex. The current technique of ovarian endometrioma capsule excision may lead to the removal of normal ovarian tissue, causing loss of follicles (Hachisuga and Kawarabayashi, 2002). On the other hand, capsule ablation may lead to thermal (heat) damage to the underlying ovarian cortex (Maouris and Brett, 2002). Ovarian endometriosis is found almost exclusively in women of reproductive age, and many women intend to conceive after endometriosis surgery (Chapron et al., 2002; Vercellini et al., 2003). Therefore, surgeons would benefit from knowing which factors, if any, predispose a patient to losing normal ovarian tissue during laparoscopic cystectomy for ovarian endometriosis (Chapron et al., 2002; Vercellini et al., 2003). The goal of this study was to identify these factors. As controls, we included patients who underwent laparoscopic cystectomy for other Presented in part at the 63th Annual Meeting of the American Society for Reproductive Medicine, San Francisco, CA, 8 12 November 2008 & 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@oxfordjournals.org

2 Normal ovarian tissue removal and endometriomas 1403 benign cysts. The findings from this study could aid in the development of improved surgical cystectomy techniques designed to spare normal ovarian tissue. Materials and Methods Patients Patients who underwent laparoscopic cystectomy for ovarian endometriosis and other benign ovarian cysts from 1 January 2001 to 31 December 2007 were retrospectively identified. To minimize inter-operator variability in surgical technique, we included only laparoscopic cystectomies performed by three experienced surgeons (J.-L.P., G.M. and M.C.). A total of 121 patients (age range, years; median, 31.5 years) who had histologically confirmed ovarian endometriosis and 56 patients (age range, years; median, 30.0 years) who had other histologically confirmed benign cysts (serous, mucinous or dermoid cysts) were included for the present analysis. Clinical characteristics are shown in Tables I and II. Decisions regarding pre-operative medical treatments were made by the referring physicians after discussion with the patients. In the endometriosis group, patients received pre-operative medical treatments for severe pain symptoms. However, some patients with severe pain symptoms, trying to conceive, did not wish to receive any pre-operative hormonal treatments. In other benign cyst group, patients received pre-operative treatments in order to differentiate an organic cyst from a functional cyst. One patient received GnRHa treatment because of uterine leiomyoma. Laparoscopic surgical treatment for ovarian endometriosis as well as other co-existing endometriotic lesions and lysis of adhesions were performed with a four-puncture technique. Ovarian endometriomas were excised by the stripping technique previously described by our group (Canis et al., 1995). Deep infiltrating endometriosis was completely excised using mechanical instruments and electrosurgery. Peritoneal superficial endometriotic lesions were excised or coagulated with Table I Characteristics of patients with endometrioma Characteristics Number of patients (%), median (range) or mean + SEM Age 31.5 (17 44) years Pre-operative medical treatment GnRH agonist 19 (15.7) Continuous oral progestogens 21 (17.4) Cyclic oral contraceptive pills 6 (5.0) Continuous oral contraceptive pills 1(0.8) Previous surgery for ovarian 32 (26.4) endometriosis Multiple cysts 34 (28.1) Diameter of the largest cyst Side of cyst Right: 54 (44.6) Left: 44 (36.4) Bilateral: 23 (19.0) Co-existence of deep endometriosis 48 (39.7) rasrm Stage III: 61 (50.4) Stage IV: 60 (49.6) rasrm: revised American Society for Reproductive Medicine classification. Table II Characteristics of patients with other benign ovarian cyst Characteristics Number of patients (%), median (range) or mean + SEM Age 30.0 (19 45) years Pre-operative medical treatment GnRH agonist 1 (1.7) Continuous oral progestogens 10 (17.6) Cyclic oral contraceptive pills 13 (23.2) Previous surgery for benign ovarian 14 (25.0) cyst Multiple cysts 7 (12.5) Diameter of the largest cyst Side of cyst Right: 25 (44.6) Left: 27 (48.2) Bilateral: 4 (7.1) bipolar current. The severity of the endometriosis was scored according to the revised American Society for Reproductive Medicine classification (American Society for Reproductive Medicine, 1997). Institutional Review Board approval was not required for this retrospective study. Immediately after collection, the tissues were fixed in 10% formalin-acetic acid and embedded in paraffin for routine histopathological examination. The presence of glandular epithelium surrounding the stroma defined the histopathological diagnosis of endometriosis. Histopathological examination In order to assess if normal ovarian tissue was removed with the ovarian cyst, the entire cyst specimen was fixed in 10% formalin-acetic acid, embedded in paraffin wax, cut into 4 mm sections and stained with hematoxylin and eosin. Sections were taken at 120 mm intervals and a total of five sections were analyzed for each ovarian cyst (Schubert et al., 2005) for the present study. The presence or absence of ovarian tissue adjacent to the cyst wall was evaluated. If ovarian tissue was present, the morphologic characteristics of this tissue were graded on a semi-quantitative scale of 0 4 (0, complete absence of follicles; 1, primordial follicles only; 2, primordial and primary follicles; 3, primordial, primary and some secondary follicles only; 4, normal pattern of primordial, primary and secondary follicles seen in normal ovaries) as described previously (Maneschi et al., 1993; Muzii et al., 2002). Statistical analysis Eight variables [age, pre-operative medical treatment, previous cystectomy for ovarian endometriosis on the same side as in the present study, single or multiple cysts, diameter of the largest cyst, side of cyst, co-existence of deep endometriosis, revised American Society for Reproductive Medicine Classification (American Society for Reproductive Medicine, 1997)] were evaluated to identify major factors associated with the removal of normal ovarian tissue. Comparison of proportions were made using Fisher s exact test, whereas more complex analyses involving several potential explanatory variables were carried out using generalized linear modeling (GLM) methods, in particular logistic regression.

3 1404 Matsuzaki et al. Results Ovarian endometriosis versus other benign cysts Normal ovarian tissue adjacent to the cyst wall was detected in 71 patients (58.7%) with ovarian endometriosis, whereas it was detected in only three patients (5.4%) with other types of benign cysts (P, 0.001). Risk factor analysis for ovarian endometriosis In the present study population, we detected four significant associations among the potential risk factors. A significantly higher number of patients with deep infiltrating endometriosis had received pre-operative medical treatments than those without deep infiltrating endometriosis (P ¼ 0.025). A significantly higher number of patients with multiple cysts had a prior history of cystectomy than patients with a single cyst (P ¼ 0.031). Of the patients with endometriomas, those without deep infiltrating endometriosis had larger cysts than those with deep infiltrating endometriosis (P ¼ 0.009). In addition, the endometrioma diameter was significantly larger in patients with multiple cysts than in those with a single cyst (P ¼ 0.003). A simple, pair-wise comparison showed that normal ovarian tissue was detected significantly more frequently in patients with pre- operative medical treatments (P, 0.001, Table III). Although the relevant difference did not quite attain statistical significance at the 5% level, normal ovarian tissue was detected less frequently in patients with a previous cystectomy for ovarian endometriosis (P ¼ 0.057, Table III). In addition, normal ovarian tissue was removed more frequently in patients with a deep infiltrating nodule (P ¼ 0.061, Table III). There were no significant differences in cyst diameter and age between the groups with and without normal ovarian tissue adjacent to the cyst wall. A GLM analysis identified pre-operative medical treatment as a significant factor independently associated with the removal of normal ovarian tissue with ovarian endometriosis [85.1% (40/47) versus 41.9% (31/74) for pre-operative medical treatment versus nontreatment, respectively, P,0.001, Table III]. Previous cystectomy clearly did not predispose to the risk of removing normal ovarian tissue (P ¼ 0.060, Table III). There was no significant difference in frequencies of normal ovarian tissue removal among patients with different pre-operative medical treatments (Table IV). Morphologic characteristics of ovarian tissue adjacent to the cyst wall of endometrioma and other benign cysts Results of the morphological assessments are shown in Tables V and VI. When we compared the frequencies between patients with Grade 4 ovarian tissue and those with Grade 0, 1, 2 or 3 ovarian tissue, we detected a higher proportion of Grade 4 tissue in patients with the pre-operative medical treatment compared with those without preoperative medical treatment in the endometriosis group (P ¼ 0.017) (Table V). In patients with other benign cysts, normal ovarian tissue adjacent to the cyst wall was detected in three patients. All of these three patients had received pre-operative medical treatment. In these cases, the ovarian tissue excised with the cyst wall was graded as 0 in one patient, 3 in one patient and 4 in the other patient (Table VI). Table III Risk factors for the removal of normal ovarian tissue during laparoscopic cystectomy for ovarian endometriosis Removal of normal ovarian P-value a tissue... No Yes Age b Diameter of the largest cyst b Pre-operative medical 14.0% (7/ 56.3% (40/71),0.001 treatment c Previous surgery for 36.0% (18/ 19.7% (14/71) ovarian endometriosis Multiple cysts c 30.0% (15/ 26.8% (19/71) Side of cyst c Right: 52.0% (26/ Right: 39.4% (28/71) Discussion Left: 34.0% (17/ Bilateral: 14% (7/ Left: 38.0% (27/71) Bilateral: 22.5% (16/71) Co-existence of deep 30.0% (15/ 46.5% (33/71) endometriosis c rasrm c Stage III Stage III % (26/ 47.9% (34/71) Stage IV Stage IV 48.1% (24/ 52.1% (37/71) rasrm, revised American Society for Reproductive Medicine classification. a Two classes of analyses were carried out; simple pair-wise comparisons and logistic regression analyses, where allowance was made for confounding variables. Since the findings from the two analyses were virtually identical, only one set of P-values is quoted. b Mean + SEM. c Proportions of patients with the property displayed as a row heading. The present study confirmed previous findings that ovarian endometriosis, itself, is a risk factor for the removal of normal ovarian tissues during laparoscopic cystectomy (Muzii et al., 2002). The present study demonstrated that pre-operative medical treatment was a significant factor independently associated with the removal of normal ovarian tissue with ovarian endometriosis. In addition, the present study suggested that pre-operative medical treatment might predispose to the risk of removing normal ovarian tissue containing primordial, primary and secondary follicles as seen in normal ovaries. In the present study, normal ovarian tissue adjacent to the cyst wall was detected in three patients with other types of benign cysts. Interestingly, all of these three patients received pre-operative medical treatment. Further studies both in vitro and in vivo should be necessary to investigate pharmacological mechanisms as to why preoperative medical treatment could predispose to the risk of removing normal ovarian tissue during laparoscopic cystectomy. Previous retrospective studies have demonstrated that previous pre-operative medical treatment is a risk factor for recurrence after cystectomy of ovarian endometriomas (Koga et al., 2006; Liu et al., 2007). Both recurrence and removal of normal ovarian tissues are

4 Normal ovarian tissue removal and endometriomas 1405 Table IV Frequencies of normal ovarian tissue removal among patients with different pre-operative medical treatments in patients with ovarian endometriosis GnRH agonist Pre-operative medical treatments... Continuous oral Cyclic oral Continuous oral progestogens contraceptive pills contraceptive pills... Removal of normal ovarian tissues No Yes Table V Morphologic characteristics of ovarian tissues adjacent to the cyst wall of endometrioma Number of patients (%)... Grade 0 Grade 1 Grade 2 Grade 3 Grade 4... Pre-operative medical treatment 9 (22.5) 5 (12.5) 2 (5.0) 2 (5.0) 22 (55.0) a No pre-operative medical treatment 8 (25.8) 9 (29.0) 4 (12.9) 2 (6.5) 8(25.8) a P ¼ versus those without pre-operative medical treatment, when the frequencies between patients with Grade 4 and those with Grade 0, 1, 2 or 3 are compared. Table VI Morphologic characteristics of ovarian tissues adjacent to the cyst wall of other benign cyst Number of patients... Grade 0 Grade 1 Grade 2 Grade 3 Grade 4... Pre-operative medical treatment No pre-operative medical treatment clinical problems in the surgical management of ovarian endometriosis (Chapron et al., 2002; Vercellini et al., 2003). Therefore, these and our present findings argue that pre-operative medical treatment may actually be detrimental for patients with ovarian endometriosis. A Cochrane review found insufficient evidence to conclude that hormonal suppression in association with surgery for endometriosis was associated with a significant benefit with regard to any of the outcomes identified (Yap et al., 2004). In ovarian endometriosis, Donnez et al. (1994) demonstrated that pre-operative medical treatment significantly reduced total American Fertility Society (AFS) scores. However, it is not clear if reduced AFS scores before surgery result in a better surgical outcome. Another study showed that pre-operative medical GnRHa treatment for ovarian endometriosis did not offer any advantage in terms of surgical performance, although this was not a randomized study (Muzii et al., 1996). However, to date, no study has investigated whether pre-operative medical treatment could offer any benefit to patients with both ovarian and deep infiltrating endometriosis, the most severe form of endometriosis. In the present study, significantly more patients with deep infiltrating endometriosis had pre-operative medical treatment than those without deep infiltrating endometriosis. Regardless of whether pre-operative medical treatment is employed, surgical excision of deep infiltrating endometriosis is challenging and should be performed by an experienced surgeon (Donnez et al., 2004). To date, no randomized controlled study has investigated whether pre-operative medical treatment offers any advantages for patients with deep infiltrating endometriosis with regard to facilitating surgery, operative time and post-operative complications. In addition, in our study, patients with deep infiltrating endometriosis had severe pain symptoms that were alleviated by pre-operative medical treatment. Thus, for such patients, pre-operative medical treatment may improve their quality of life. However, none of the prior studies included quality of life as an outcome. Further studies are necessary to determine whether pre-operative medical treatment offers any benefit for patients with ovarian endometriosis and deep infiltrating endometriosis. In the present study population, we detected that previous cystectomy clearly did not predispose to the risk of removing normal ovarian tissue. Loh et al. (1999) demonstrated that repeat surgeries for ovarian endometriosis did not further compromise ovarian response when such ovaries were compared with ovaries that have undergone one previous cystectomy. Another study demonstrated that postoperative FSH levels between patients with primary ovarian endometriosis and those with recurrent disease were comparable (Fedele et al., 2005). These and the present findings suggest that multiple cystectomies might not be a risk factor for the removal of normal ovarian tissue provided the procedures are performed by experienced surgeons. A previous study has shown that the ovarian tissue adjacent to the endometrioma wall differs morphologically from normal ovarian tissue, lacking the normal pattern of primordial, primary and secondary follicles as seen in normal ovaries (Muzii et al., 2002). Although the

5 1406 Matsuzaki et al. ovarian tissues bordering most of the endometriomas in this study had few primordial follicles, 30 did have primordial, primary and secondary follicles within the adjacent ovarian tissue. There are several possible explanations for these findings. First, unlike the prior study that evaluated only a portion of each cyst, the present study evaluated sections from the entire ovarian cyst. Additionally, a total of five different levels were evaluated per specimen, whereas previous studies have investigated only one level. The present study has demonstrated that folliclecontaining ovarian tissue is presented adjacent to the endometrioma and that pre-operative medical treatment might be a risk factor for its removal. Further studies are needed to confirm whether the follicles in the ovarian cortex adjacent to the endometrioma wall are functionally normal. Regardless, care should be taken to minimize the removal of normal ovarian tissue, particularly in patients with preoperative medical treatment. However, there are several methodological limitations to this study. First, this is not a prospective study. In the present retrospective study, we assessed only if normal ovarian tissue was removed with the ovarian cyst. However, it is also very important to assess the amount of removed normal ovarian tissue and post-operative ovarian reserve. Further prospective studies should be necessary to confirm the present findings and to investigate if there is any association between the amount of removed normal ovarian tissues and ovarian reserve after laparoscopic cystectomy. Second, this is not a randomized study. However, it would be unethical to randomize patients into the groups of no treatment and pre-operative hormonal treatments. Some patients, trying to conceive, do not wish to receive any preoperative hormonal treatments. In addition, side effects and cost profiles of hormonal medical treatments differ (Kennedy et al., 2005). Acknowledgements We are indebted to the staff in the Department of Pathology, Hôtel- Dieu, CHU Clermont-Ferrand (Clermont-Ferrand, France). Funding This study was supported in part by Karl Storz Endoscopy & GmbH (Tuttlingen, Germany). References American Society for Reproductive Medicine. Revised American Society for Reproductive Medicine classification of endometriosis: Fertil Steril 1997;67: Canis M, Boughizane S, Loh FH, Pouly JL, Wattiez A, Manhes H, Mage G, Bruhat MA. Techniques for ablation and excision of endometriosis. In: Shaw RD (ed). Endometriosis Current Understanding and Management. Oxford, Blackwell Science, 1995, Canis M, Mage G, Wattiez A, Pouly JL, Bruhat MA. The ovarian endometrioma: why is it so poorly managed? Laparoscopic treatment of large ovarian endometrioma: why such a long learning curve? Hum Reprod 2003;2:5 7. Chapron C, Vercellini P, Barakat H, Vieira M, Dubuisson JB. Management of ovarian endometriomas. Hum Reprod Update 2002;8: Donnez J, Nisolle M, Gillerot S, Anaf V, Clerckx-Braun F, Casanas-Roux F. Ovarian endometrial cysts: the role of gonadotropin-releasing hormone agonist and/or drainage. Fertil Steril 1994;62: Donnez J, Pirard C, Smets M, Squifflet J. Surgical management of endometriosis. Best Pract Res Clin Obstet Gynaecol 2004;18: Fedele L, Bianchi S, Zanconato G, Berlanda N, Raffaelli R, Fontana E. Laparoscopic excision of recurrent endometriomas: long-term outcome and comparison with primary surgery. Fertil Steril 2005; 85: Hachisuga T, Kawarabayashi T. Histopathological analysis of laparoscopically treated ovarian endometriotic cysts with special reference to loss of follicles. Hum Reprod 2002;17: Hart RJ, Hickey M, Maouris P, Buckett W. Excisional surgery versus ablative surgery for ovarian endometriomata. 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Cochrane Database Syst Rev 2004:CD Submitted on September 24, 2008; resubmitted on January 27, 2009; accepted on January 29, 2009