Special Article

How to Manage Bowel Endometriosis: The ETIC Approach Endometriosis Treatment Italian Club: Giulia Alabiso, MD, Luigi Alio, MD, Saverio Arena, MD, Allegra Barbasetti di Prun, MD, Valentino Bergamini, MD, Nicola Berlanda, MD, Mauro Busacca, MD, Massimo Candiani, MD, Gabriele Centini, MD, Annalisa Di Cello, MD, Caterina Exacoustos, MD, Luigi Fedele, MD, Laura Gabbi, MD, Elisa Geraci, MD, Elena Lavarini, MD, Domenico Incandela, MD, Lucia Lazzeri, MD, Stefano Luisi, MD, Antonio Maiorana, MD, Francesco Maneschi, MD, Alberto Mattei, MD, Ludovico Muzii, MD, Luca Pagliardini, MD, Alessio Perandini, MD, Federica Perelli, MD, Serena Pinzauti, MD, Valentino Remorgida, MD, Ana Maria Sanchez, MD, Renato Seracchioli, MD, Edgardo Somigliana, MD, Claudia Tosti, MD, Roberta Venturella, MD, Paolo Vercellini, MD, Paola Vigan
o, MD, Michele Vignali, MD, Fulvio Zullo, MD, and Errico Zupi, MD* From the Department of Obstetrics and Gynecology, Macedonio Melloni Hospital, University of Milan, Milan (Drs Alabiso, Barbasetti di Prun, Busacca, and Vignali), Department of Obstetrics and Gynecology, Civico Hospital, Palermo (Drs. Alio, Incandela, and Maiorana), Department of Obstetrics and Gynecology, Santa Maria della Misericordia Hospital, Perugia (Dr. Arena), Department of Obstetrics and Gynecology, University of Verona, Verona (Dr. Bergamini, Lavarini, and Perandini), Department of Obstetrics and Gynecology, Isituto Luigi Mangiagalli, University of Milan, Milan (Drs. Berlanda, Fedele, and Vercellini), Department of Obstetrics and Gynecology, University of Siena, Siena (Drs. Centini, Lazzeri, Luisi, Pinzauti, Tosti, and Zupi), Department of Obstetrics and Gynecology, San Raffaele Hospital, University of Milan, Milan (Drs. Candiani, Sanchez, Pagliardini, and Vigan
o), Infertility Unit, Fondazione Ca’ Granda, Ospedale Maggiore Policlinico, Milan (Dr. Somigliana), Department of Obstetrics and Gynecology, University of Magna Graecia, Catanzaro (Drs. Di Cello, Venturella, and Zullo), University of Tor Vergata, Rome (Dr. Exacoustos), Department of Obstetrics and Gynecology, Santa Maria Goretti Hospital, Latina (Dr. Maneschi), Department of Obstetrics and Gynecology, University of Florence, Florence (Drs. Mattei and Perelli), Department of Obstetrics and Gynecology, ‘‘Sapienza’’ University of Rome, Rome (Dr. Muzii), Department of Obstetrics and Gynecology, University of Genova, Genova (Drs. Remorgida and Gabbi), and Department of Obstetrics and Gynecology, University of Bologna, Bologna (Dr. Seracchioli and Geraci), Italy.

ABSTRACT A panel of experts in the field of endometriosis expressed their opinions on management options in a 35-year-old patient desiring pregnancy with a history of previous surgery for endometrioma and bowel obstruction symptoms. Many questions that this paradigmatic patient may pose to the clinician are addressed, and various clinical scenarios are discussed. A decision algorithm derived from this discussion is proposed as well. Journal of Minimally Invasive Gynecology (2015) 22, 517–529 Ó 2015 AAGL. All rights reserved. Keywords:

DISCUSS

Bowel endometriosis; Previous surgery; Diagnosis; Treatment

You can discuss this article with its authors and with other AAGL members at http://www.AAGL.org/jmig-22-4-JMIG-D-14-00612

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The Endometriosis Treatment Italian Club (ETIC) comprises a panel of Italian experts on endometriosis and pelCorresponding author: Prof Errico Zupi, Department of Molecular and Developmental Medicine, University of Siena, Viale Bracci, 53100 Siena, Italy. E-mail: [email protected] Submitted December 11, 2014. Accepted for publication January 8, 2015. Available at www.sciencedirect.com and www.jmig.org 1553-4650/$ - see front matter Ó 2015 AAGL. All rights reserved. http://dx.doi.org/10.1016/j.jmig.2015.01.021

vic pain disorders. The primary goal of the ETIC, starting always from the patient’s desire, is to clarify insofar as possible the controversies in the management of endometriosis, herein focusing attention on deep infiltrating endometriosis (DIE). Distribution of deep endometriotic lesions is variable [1], but the disease typically has a multifocal presentation. The most common site of extragenital endometriosis is the intestinal tract, which

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accounts for approximately 80% of this type of endometriosis [2,3]. Although bowel endometriosis may cause severe gastrointestinal symptoms, these disturbances frequently are not adequately investigated, resulting in unexpected findings at surgery, and the lesions might not be treated owing to a lack of preoperative informed consent or surgical incompetence [4]. Surgical treatment must be carried out by a surgical team expert in the disease. The patient should be informed preoperatively of surgical risks, including bowel and bladder dysfunction. The aim of the present study was to address all potential questions posed by a paradigmatic case of bowel endometriosis, to clarify the main problems that potentially could be encountered when managing the disease. Clinical Case A 35-year-old patient currently desiring pregnancy presented with severe dysmenorrhea (grade 9 of 10 on a visual analog scale [VAS]), moderate dyspareunia and moderate dyschezia (graded 5 of 10 and 4 of 10, respectively, on a VAS), and intermittent lumbar bilateral pain that worsened with menses. She had a background of 6 months of obstructive symptoms, with constipation and diarrhea. In 2001, she had undergone surgery for right endometrioma, followed by 7 years of medical treatment (continuous oral contraceptives) and 3 failed attempts at in vitro fertilization (IVF). Physical examination revealed normal blood pressure and no systemic disease. Results of abdominal examination were significant for mild left upper quadrant tenderness, but the abdomen was otherwise nondistended with well-healed laparoscopy incisions. Vaginal examination undertaken before transvaginal ultrasound revealed a normal-sized, anteverted uterus that was extremely sore on side-to-side mobility. There was a palpable, markedly tender deep nodule in the posterior vaginal fornix infiltrating the left parametrium and no palpable adnexal masses giving a positive finding. In general, bimanual examination is considered positive and therefore suggestive of endometriotic infiltration if a palpable nodule, a thickened area, or a palpable cystic expansion with topographic-anatomic correlation to the left and/or right USLs, vagina, uterus, rectovaginal space, pouch of Douglas, rectosigmoid, and urinary bladder are found. Vaginal and cervical exposure to detect the potential presence of visible blue lesions using a disposable speculum completes the examination. Role of Pelvic Ultrasound Imaging in Detecting Bowel Disease Standard Ultrasound Examination Bimanual pelvic-gynecologic examination may suggest the presence of DIE by the presence of tender nodules and fibrosis in the vagina and cul de sac, but it has poor accuracy

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for determining the extent of disease [5–7]. Knowing the anatomic location, size, and number of DIE nodules, the depth of nodule infiltration, and the degree of bowel lumen stenosis aids in planning appropriate surgical and/or medical management, choosing an adequate surgical team, and providing better patient counseling. In cases of posterior DIE when the rectosigmoid is infiltrated by endometriotic tissue, the bowel is so retracted that the upper segments can adhere to the posterior wall of the uterus, with complete disruption of the normal anatomy, making it difficult to distinguish between the rectum and sigma. From a surgical standpoint, it is important that the diagnostic imaging determine the lowest limit of the nodule on the bowel wall, because lower rectal lesions are more difficult to remove by shaving or segmental resection and carry a higher complication rate. Regarding infiltration of the mucosal layer, this seems to not be the determining factor when deciding whether or not to perform segmentary resection; more likely, this decision depends on the diameter of infiltrating tissue and degree of lumen stenosis [6]. Knowledge and related, detailed information about disease spread and its localization are extremely useful to the surgeon and patient care team from a medical standpoint. AFSr classification [8] is commonly used to assess disease stage, presence and extension of adhesions, endometrioma size, and pouch of Douglas obliteration. Deep endometriotic lesions are not described in this classification scheme, however. All potential locations of DIE in the anterior (bladder) or posterior-lateral compartment (rectovaginal septum [RVS], uterosacral ligaments [USLs], torus uterinum [i.e. tissue behind the cervix in the midsagittal plane between the USLs], posterior vaginal fornix, rectum and rectosigmoid junction, parametria, and ureteral involvement) can be evaluated by transvaginal sonography (TVS). Two-dimensional (2D) sonographic findings of adenomyosis [9,10] are useful for proper management and patient counseling. It was recently reported that on a coronal section of the uterus obtained with 3-dimensional (3D) TVS, it is possible to visualize the junctional zone more clearly [11–13]. Alterations of the junctional zone are defined as distortion and infiltration of the hypoechoic inner myometrium by hyperechoic endometrial tissue. Endometriotic nodules of the bladder and rectum can be evaluated with transvaginal probe, and a transrectal examination with the same convex probe can be performed if necessary. During the transrectal examination, a fluid contrast medium can be inserted in the vagina to visualize better the rectovaginal septum (sonovaginography). Transabdominal ultrasound (TAS) cannot accurately detect DIE, mainly because of bowel gas, which hinders the ability to evaluate abdominal retroperitoneal or small bowel lesions, which are difficult to detect with a TAS probe. Only endometriotic nodules of the abdominal wall can be readily evaluated using a high-frequency TAS probe.

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Deep nodes appear as hypoechoic lesions, linear or nodular retroperitoneal thickening with irregular borders, and few vessels on color Doppler evaluation [14–17]. Patients with suspected pelvic endometriosis should first undergo a detailed examination of the pelvis to evaluate the anatomy of the uterus and adnexa in both the sagittal and horizontal planes, with gentle probe movements to assess the presence of adhesions. Transvaginal sonographic examination is based on a detailed evaluation of organ and tissues dividing the pelvis in anterior and posterior compartment according to the DIE classification of Chapron et al [18]. Using TVS and, if necessary, transrectal sonography, an accurate assessment of the vagina, particularly the areas of the posterior and lateral vaginal fornix, the retrocervical area with torus uterinum and uterine sacral ligaments, the parametria laterally, and the rectovaginal septum, should be performed. In cases of endometriotic lesion of USLs and homolateral parametria, special attention should be given to ureteral evaluation in the paracervical tract. Suspected rectal wall infiltration is assessed by transrectal evaluation with the transvaginal probe. Special attention must be given to pain reported by the patient, with careful evaluation of all the painful sites evocated by a gentle pressure of the probe (i.e., ‘‘tenderness-guided’’ ultrasonography) [19]. The following structures must be evaluated by TVS in the pelvis and are strictly anatomically defined by sonographic landmarks: vagina, RVS, torus, USLs, parametria and lateral pelvis, ureter, pouch of Douglas, rectum, and rectosigmoid junction. Rectosigmoid nodules are visualized as an irregular hypoechoic mass penetrating into the intestinal wall, distorting its normal structure. TVS shows the normal rectal wall layers; the rectal serosa and smooth muscle layer appear as a thin, hypoechogenic line covered by the rectal submucosa and mucosa, which is visualized as a hyperechogenic rim covering the rectal smooth muscle layer [20]. With respect to the posterior uterine wall, intestinal nodules located below the level of the insertion of the USLs on the cervix are considered low rectal lesions, whereas ones above this level are considered upper rectal or rectosigmoid junction lesions. This virtual line delimits the plane under the peritoneum of the pouch of Douglas and corresponds laterally to the parametria and medially to the rectovaginal septum. In addition, the distance from the anus can be taken by transrectal sonography. TVS has low accuracy in diagnosing infiltration of the mucosal layer [6]. Transrectal ultrasound, which is a valuable tool for detecting rectal endometriosis as endometriotic infiltration of the muscularis layer, is less accurate in assessing submucosal/mucosal layer involvement [16,21]. Therefore, transvaginal and transrectal sonography do not help surgeons determine whether or not to perform segmental or discoid resection of the lesion. More likely, this decision is dependent on patient symptoms, as well as the diameter of infiltrating tissue and degree of lumen stenosis. Recent studies have shown that TVS when carried out by experienced sonographers may indeed be a

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highly valuable test for detecting DIE [14–17,22,23]. The reported accuracy of the ultrasonographic diagnosis of DIE varies among studies, which may reflect variations in examination technique, quality of ultrasound equipment, and operator experience. Despite the high sensitivity and specificity of TVS for predicting DIE in previous studies [14,15,19,20,22,23], evaluating DIE by TVS is difficult and requires expertise. Therefore, some readily detectable utrasonographic signs to predict the risk of DIE have been proposed recently. Real-time dynamic TVS evaluation of the posterior compartment using the ‘‘sliding sign’’ seems to establish whether the pouch of Douglas is obliterated and also may be useful in identifying women who may be at increased risk for bowel endometriosis and needs further imaging performed by an expert sonographer or radiologist [24,25]. It has been reported that adding water contrast in the rectum during transvaginal sonography (RWC-TVS) might improve the diagnosis of rectal infiltration in women with rectovaginal endometriosis, with RWC-TVS detecting infiltration of the rectal muscularis propria more accurately than TVS alone [26]. RWC-TVS might be used when TVS cannot exclude the presence of rectal infiltration. The surgical management of low intestinal endometriosis depends mainly on the depth of infiltration of the lesion and the degree of bowel stenosis [27]. In our present case, the detailed transvaginal and transrectal examination revealed a deep endometriotic plaque of the posterior compartment that infiltrated not only the rectal and sigmoid wall (both caudal and cranial tract), but extended laterally to the left USL and left parametrium and centrally and caudally to the torus uterinum, RVS, and posterior vaginal fornix (Fig. 1). No pelvic ureter dilatation was seen; however, owing to localization of the DIE, an extrinsic compression of the ureter was suspected. In addition, mild hydronephrosis detected by TAS may be an indirect sign that such nodules involve the left ureter along its pelvic course. The right ovary was adherent to the posterior uterine wall, with slightly reduced volume and normal ovarian tissue. The left ovary was completely attached to the uterus and to the deep endometriotic fibrotic plaque. No endometrioma were seen. The pouch of Douglas was completely obliterated. Our patient also had clear 2D TVS findings of adenomyosis of the posterior uterine wall, with the presence of an asymmetric diffuse thickness of the myometrium and hyperechoic areas with scattered vessel distribution. In addition, on 3D TVS the uterine junctional zone appeared to be infiltrated, especially posteriorly and laterally on the left. The posterior uterine adenomyotic wall was attached to the posterior deep endometriotic tissue and appeared like an extension or invasion of it. This careful evaluation of TVS diagnostic imaging findings gave the clinicians the opportunity to (1) determine the need for further imaging to clarify the involvement of specific sites (i.e., ureter, bowel stenosis, upper intestinal

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Fig. 1 (A) Detailed transvaginal and transrectal examination revealing a deep endometriotic plaque of the posterior compartment infiltrating the rectal and sigmoid wall (both caudal and cranial tract) and extending laterally to the left USL and left parametrium and centrally and caudally to the torus uterinum, RVS, and posterior vaginal fornix. (B) Longitudinal section of the uterus centrally with TVS probe in the anterior vaginal fornix a nodule located above the level of a virtual line passing through the insertion of the uterosacral ligaments on the cervix in the upper rectum or recto-sigmoid junction is seen (DIE1). An apparently second nodule located below the level of a virtual line passing through the insertion of the uterosacral ligaments of the lower rectum is seen (DIE 2). Note also the thickening of the uterine posterior wall with hyperechoic and anechoic adenomyotic foci and the myometrium attached to the DIE nodule. (C) Pushing the TVS probe in posterior vaginal fornix slightly on the left at the uterosacral ligament level only one large nodule of DIE along all the rectum and sigmoid junction is seen. Note also the retraction, infiltration and thickening of the posterior vaginal wall.

localization); (2) establish a tailored approach to disease management; (3) properly inform the patient of the extent of the disease and therapeutic options; and (4) identify the best surgical approach and the potential need to involve other surgical specialists besides a gynecologic surgeon (e.g. colorectal surgeon, urologist). Saline Contrast Sonovaginography and RWC-TVS To increase accuracy when evaluating rectosigmoid involvement, new ultrasound techniques have been developed and others already in use have been adapted to the study of endometriotic lesions. These techniques are best

performed after some bowel preparation, such as a rectal enema 1 hour before the examination [15]. Saline contrast sonovaginography (SCSV), first described by Dessole et al in 2003 [28], combines TVS with the introduction of saline solution in the vagina to provide better imaging of the vaginal walls, fornix, pouch of Douglas, USLs, and RVS. A specifically developed rubber ring (ColpoPneumo Occluder; Cooper Surgical, Berlin, Germany) is inflated with saline at the base of the vaginal ultrasound probe to occlude the meatus, after which the vagina is dilated with a variable quantity of saline solution (w60–120 mL) inserted through a Foley catheter. The acoustic window thus created allows a highly detailed scan of the anterior as

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well as the posterior compartments. Published data show a positive predictive value (PPV) and negative predictive value (NPV) better than or at least similar to those of traditional TVS and magnetic resonance imaging (MRI) in studies of vaginal fornix, USL, and RVS involvement, as well as in the evaluation of bowel infiltration by deep endometriotic nodules [29]. Despite the fact that SCVS may take longer than conventional TVS, the level of discomfort reported by the 54 women of that study did not differ between the 2 techniques (VAS, 2.1 6 1.8 vs 2.6 6 1.7; p 5 .14) [29]. RWC-TVS is performed using a flexible 25 Fr catheter (e.g., Pharma-Plast; Redditch, UK) inserted into the rectal lumen up to 20 cm from the anus. Saline solution is then instilled in the rubber balloon of the catheter under ultrasound control. The amount of water required to get a suitable image typically ranges from 100 to 300 mL, depending on wall distensibility. This adjustable water contrast allows the capture of high-definition images of the rectal wall and its layers, allowing a dynamic evaluation of endometriotic lesion and rectal stenosis. Bergamini et al [30] showed that this method had the same accuracy as transrectal sonography and barium enema in the preoperative assessment of low intestinal endometriosis in a series of 61 patients undergoing surgical management for bowel lesions. In particular, the method had a PPV of 98% and an NPV of 81.8% for diagnosing endometriosis of the rectosigmoid tract, and a PPV of 82.3% and an NPV of 94.1% for assessing the degree of bowel stenosis. Another study compared the accuracy of multidetector computed tomography (CT) enteroclysis (MDCT-e) and RWC-TVS in determining the presence and extent of bowel endometriosis [31]. RWC-TVS and MDCT-e showed similar accuracy in the detecting rectosigmoid endometriosis, but RWC-TVS was tolerated better than MDCT-e. Thus, RWC-TVS could be used whenever TVS cannot exclude the presence of rectal infiltration [26] or where an evaluation of the degree of penetration is needed. It provides a single low-cost and minimally invasive procedure for the preoperative assessment of rectosigmoid endometriosis and can be used to predict the need for segmental bowel resection. Rectal Endoscopic Sonography Rectal endoscopic sonography (RES) is another valuable tool for investigating the depth of nodule infiltration in the sigma and rectum. It consists of a colonscope coupled with a high-frequency ultrasound transducer (7.5 and/or 12 MHz). The transducer is positioned in the sigmoid and then slowly withdrawn through the sigmoid and rectum. Evaluation of the bowel wall and adjacent areas is done by moving the probe up and down several times before and after instilling water into the intestinal lumen. Involvement of the USLs, vagina, and colon/rectum is analyzed. Normal intestinal wall usually appears as a 5-layer structure. The surrounding areas are also scanned, with particular attention

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given to the ovaries, cervix and body of the uterus, pouch of Douglas, USL areas, and torus uterinum. Deep pelvic endometriosis is defined as the presence of a hypoechoic nodule or mass with regular or irregular contours. In the rectum and/or sigmoid colon, because the hypoechoic muscolaris layer is clearly different from the hyperechoic submucosa, it is possible to define the depth of invasion and to accurately measure the nodule. The largest diameter of the lesions, their location from the anus margins, and infiltration of adjacent pelvic organs can be recorded [32]; however, this approach not routinely recommended, because of the need for a high-frequency probe, the procedure’s invasiveness, and in some cases the need for anesthesia [33]. In a retrospective longitudinal study, Bazot et al [33] compared physical examination, TVS, RES, and MRI for the assessment of different locations of DIE. The sensitivity of physical examination, TVS, RES and MRI were, respectively, 73.5%, 78.3%, 48.2%, and 84.4% for USL endometriosis; 50%, 46.7%, 6.7%, and 80% for vaginal endometriosis; and 46%, 93.6%, 88.9%, and 87.3% for intestinal endometriosis [33]. A comparison of RES results with surgical findings showed that RES can help identify the presence and degree of wall infiltration in bowel sites [21]. For the detection of muscularis layer infiltration by endometriosis, the PPV of RES was 100%, whereas for the detection of submucosal/mucosal layer involvement, RES had a sensitivity of 89%, specificity of 26%, PPV of 55%, NPVof 71%, test accuracy of 58%, and positive and negative likelihood ratios of 1.21 and 0.40, respectively. The final evaluation of this technique, based on several studies, is that this is a valuable tool for detecting bowel endometriosis in the muscularis layer, but not in the submucosal/mucosal layer. Finally, given that RES has demonstrated low accuracy in detecting uterosacral and RVS endometriosis involvement, it can be viewed as a second-level examination for diagnosing posterior compartment disease [21,34]. MRI, CT, and Virtual Colonoscopy Nowadays, MRI is widely used for imaging of endometriotic lesions owing to its extremely good results. MRI is a highly efficient and accurate technique, with a sensitivity of 88%, specificity of 98%, PPV of 95%, and NPV of 96% coupled with a diagnostic accuracy of 96% [35]. The presence of blood (iron) inside the nodule undoubtedly aids in identifying pathological localizations. Unfortunately, not all nodules are the same, and in some cases the fibrotic component is predominant over the glandular compartment, which explains why this ‘‘atypical’’ lesions might be missed on MRI examination [36]. Adding a paramagnetic contrast medium does not increase the diagnostic accuracy, because the ‘‘atypical’’ nodules tend to be fibrotic and to have a reduced vascularization, and thus the contrast medium scarcely delineates them. Distending the bowel walls with a solution can provide helpful support for the diagnosis of bowel endometriosis, aiding detection of wall defects

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against other anatomic structures, such as small bowel loops, flexures of the colon, vessels, and lymph nodes. Unfortunately, to date no large study on the usefulness of MRI coupled with bowel distension for the detection of bowel endometriosis has been reported in the literature. In contrast, more data are available for MDCT-e. Since 2007 [37], this approach has been proposed as the primary method for detecting both colonic and ileal pathology. The enteroclysis coupled with mechanical bowel preparation yields very high sensitivity for detecting even minute bowel nodules, with a 7- to 8-mm minimal spatial resolution. It is clear that even if direct visualization at surgery remains unsurpassed among imaging techniques, this approach is extremely successful. MDCT-e not only allows detection of the nodule and its measurement, but also clearly defines the degree of infiltration among the different bowel wall layers. In the last 3 years, the amount of radiation used in this examination has been reduced by 60% to 70%, a very important factor for fertile women. Unfortunately, the contrast medium is still an organ-iodized one, which is not the best for young women. To abolish the use of this contrast medium, virtual colonoscopy has been proposed for this pathology. Virtual colonoscopy involves a CT scan with a low radiation dose and no contrast media. Preliminary clinical data do not suggest a wide application of this approach for this pathology, given that its main area of application is in endoluminal (mucosal) disease, whereas bowel endometriosis is almost exclusively an extraluminal (muscular) pathology that only rarely reaches the wall lumen. Although bowel preparation and distension certainly aid in detecting bowel abnormalities, the absence of contrast prevents clear differentiation of normal and abnormal bowel wall, making evaluation of the degree of infiltration very difficult. Similarly, distinguishing between colic and ‘‘pericolic ’’ findings (e.g., small bowel loops, flexures of the colon, vessels and lymph nodes) is more difficult in the absence of contrast media. Pretreatment and Posttreatment Counseling The management of patients with DIE is very difficult for both clinical and psychological considerations. For this reason, careful and proper counseling represents a key moment in preoperative and postoperative communication with patients. Above all, it is necessary to inform the patient about the actual indications for proposed treatment, debating the efficacy and the risk of surgical complications. DIE is related to a wide range of symptoms closely depending on the type, location, and extent of the lesions. The presence of large nodules protruding in the bowel lumen produces catamenial pain and major intestinal symptoms (e.g., diarrhea, constipation, dyschezia) in almost all patients [38,39]. The patient should be informed preoperatively that in her case, as in 60% to 80% of patients [40,41], the severity of bowel symptoms are the main indication for surgical treatment [42]. In addition, the patient should be

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informed that the surgery for DIE is challenging; whereas resolution of dysmenorrhea and dyspareunia is expected in 70% and 65% of cases after surgery, respectively [43], surgery is not without possible (serious) complications or sequelae. Furthermore, the immediate resolution of the intestinal symptoms that occurs in 60% to 70% of cases) along with of dysmenorrhea [44,45] might not be long-lasting (especially when surgery is not supported by a postoperative medical treatment), with absence of improvement in 30% to 40% and recurrence in 50% to 70% of cases [42,44,45]. The patient should be made aware of the complexity of surgery and of the relationship between surgical strategy and the risk of complications, for instance, that a higher rate of postsurgical complications may be expected with increased surgical aggressiveness (for bowel resection, an overall rate of complications of 22%, with an 11% rate of major complications; for shaving or discoid resection, an overall complication rate of 3%–5%, with a 1%–2% rate of postoperative complications) [46]. In addition, the surgeon should advise the patient preoperatively on the need for a protective colostomy, keeping in mind that bowel resection is performed in 30% to 35% of women with DIE undergoing surgery, with a colostomy required in 10% to 14% of cases [47]. Unfortunately, in more than 80% of cases, the decision to perform resection is made during surgery [46]. The surgeon also should inform the patient of her realistic postoperative likelihood of conception, if she is interested. Although postsurgical pregnancy rates of 40% to 45%, including 75% spontaneous pregnancies [48–50], have been reported in the general population, these rates are much lower in women who were infertile before surgery and who achieved conception after surgery [51–53]. Thus, although pain is always the indication for surgery, the use of IVF/intracytoplasmic sperm injection (ICSI) techniques should be always kept in mind [53]. Offering adequate counseling about the best preoperative and postoperative support to achieve pregnancy [52–54] requires reliable information about the patient’s ovarian reserve (which could be already reduced owing to previous surgery). Finally, infertility counseling should be based on a personalized evaluation of the patient’s specific likelihood of reproduction, and not on indicators referring to the general female population [55]. Surgical Treatment Numerous variables may be taken into account when planning surgery, including the anatomic site(s) involved; depth, infiltration and size of lesion; and the possibility of multifocal or multicentric involvement. Other factors that influence surgical decision making are quality of life, presenting symptoms, associated infertility, and failure of previous medical therapy. One of 2 surgical approaches is usually used: colorectal resection or nodule excision. The latter technique can be performed without opening the bowel wall (shaving) or by removing the nodule along with surrounding rectal wall (discoid resection) [41]. Unfortunately, there are

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no universal guidelines on which technique to chose or when to perform surgery. In fact, although the ultimate aim is to remove all visible endometriotic lesions while avoiding surgical complications and preserving or restoring reproductive function if necessary [56], removing all endometriotic cells from all sites might represent overtreatment, even if it were feasible. This explains the emerging surgical trend toward less-aggressive approaches [6]. Therefore, considering endometriosis a benign disease, the surgical approach to rectal endometriosis should focus primarily on relief of digestive symptoms and pelvic pain, rather than on mandatory ‘‘oncologic’’ resection of lesions [41]. The most commonly accepted indications for a bowel resection approach are bowel stenosis, multifocal lesions, sigmoid involvement, and lesions larger than 3 cm or involving .50% of the circumference of the bowel wall [57]. Bowel resection is associated with improved patient symptoms (both gynecologic and digestive) and quality of life, and is also associated with good results in terms of recurrence rate and long-term pain relief [3,56,58]. The main complications reported in the literature are laparoconversion, rectovaginal fistulae, pelvic abscess, dehiscence of bowel anastomosis, and urinary dysfunction, with differing rates in different series [3,46,51]. Similar to what occurs for oncology, improved clinical outcomes and reduced complication rates can be achieved if surgery is performed by experienced surgeons in a referral center [56]. When the resection is ultra-low (,6 cm from the anal verge) or when a defective anastomosis is suspected, a protective ileostomy may be considered [57] to reduce the risk of fistulae and dehiscence of the anastomosis. An original technique for rectal endometriosis, involving use of a PlasmaJet to reduce thermal spread when shaving endometriotic implants even in the lowest part of the rectal wall, was described by Roman [59] in 2013. This new technique appears very promising, although large series are not yet available [59]. The less-invasive shaving technique may be performed for lesions of %3 cm diameter, cases with ,50% bowel wall infiltration, and cases of fewer than 3 lesions infiltrating the muscular layer [38]. This technique may have the advantages of preserving vascularization and innervation of the bowel, and preventing opening of the bowel wall [57,60]. In a study series of 500 patients operated on using the shaving technique, the authors reported that in young women, conservative surgery was associated with higher pregnancy rate and lower complication and recurrence rates compared with resection (0% vs 12.5%) [61]. The risk of persistent lesions has been estimated as almost 50% in women who undergo this procedure [38]. A recent review by Vercellini et al [62] found an expected lesion recurrence rate of 20% at 1-year follow-up. Furthermore, approximately 50% of the patients required analgesics or hormonal treatments because of recurrent pain, and the reoperation rate was 25%. As stated previously, there is no clear evidence regarding the effects on fertility rate of surgery for DIE. Because other

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relevant locations (e.g., ureter, bladder, ovary, diaphragm) besides the bowel are often involved, other factors must be taken into account [63]. Regardless of the technique used, there is a general consensus that patients with DIE should be operated on the least number of times (ideally only once) and only by a multidisciplinary surgical team experienced in removal of the disease. Does the Patient Need Drug Therapy After Surgery? Treatment of DIE requires long-term planning, including both surgery and medical therapy. As for many other chronic diseases (e.g., Crohn disease), a combined approach based on a long-life medical therapy and an occasional surgical treatment is currently the best treatment strategy. Moreover, endometriosisdespecially DIEdoften affects nerve fibers, resulting in central sensitization. This condition is responsible for chronic pain syndrome [64], which can be reduced not only by surgery, but also with life-long medical therapy. Identifying the single best postoperative approach to managing DIE is difficult, however. Published studies often are not comparable, and results are strongly influenced by center preference. The rationale behind administering medical treatment after surgery is, as reported in European Society of Human Reproduction and Embryology (ESHRE) guidelines, to reduce or prevent ‘‘pain symptoms (dysmenorrhea, dyspareunia, nonmenstrual pelvic pain) and the recurrence of disease in the long-term (more than 6 months after surgery)’’ [43]. We should divide patients with endometriosis into 2 main groups: those wishing to become pregnant immediately after surgery and those not wishing to become pregnant immediately after surgery. The pregnancy-seeking group should receive appropriate counseling to help conceive as soon as possible. The second group needs secondary prevention therapy, with protection against disease relapse as long as she is receiving postoperative hormone therapy [65]. Published data strongly support the idea of prescribing postoperative medical therapy [66]. ESHRE guidelines reported the results of drug therapy after surgery for ovarian endometrioma, but we believe that this statement can be applied to DIE as well. If the patient is not trying to become pregnant, medical therapy should be prolonged for roughly 18 to 24 months [65], because we all know that endometriosis can recur (even if, according to Busacca et al [65], we should define this as disease persistence rather than disease recurrence). Recurrence rates increase constantly over time, but high-risk factors include younger age, lack of radical surgery, stage III-IV disease, and not achieving pregnancy in the pregnancy-seeking group [67]. What Is the Best Medical Therapy? Given that published studies have failed to identify the perfect molecule and all of the considered studies report good results with different molecules [68,69], it is reasonable for the patient to continue with the treatment

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administered during the preoperative period. In long-term therapy, patient compliance is more important than the molecule administered. Regardless of type and route of administration, there is a real benefit in postoperative hormone therapy compared with expectant management [65]. Longterm hormone therapy should always be considered in the treatment of endometriosis, and strategies should be developed for increasing the low compliance seen in the long term and in those women presenting with absolute contraindications to steroid treatment. The rationale for medical treatment is to reduce intralesional and perilesional inflammation with diminished production of prostaglandins and cytokines, and thereby reduce stimulation of pain fibers, using drugs to control pain symptoms. A reduction in nodule size also has been reported in the majority of women with DIE of the RVS or pouch of Douglas undergoing medical treatment [70–74]. Accordingly, in these women the rationale for medical treatment before surgery may be to reduce the extent of the disease to facilitate radical surgery or to allow for surgical procedures that are more conservative, such as shaving or discoid resection of intestinal nodules rather than segmental bowel resection. On the other hand, this approach may be questionable, considering that it also has been reported that medical therapy shrinks the endometriotic lesions, but does not treat the fibrosis that usually surrounds deep endometriosis and is responsible for bowel obstruction [4]. Unfortunately, however, no previous studies have compared the outcomes of surgical treatment for DIE with and without preoperative medical therapy. Available medical treatments that could possibly effectively control pain in women with DIE include estrogenprogestin oral contraceptives (OCs), progestin alone, gonadotropin-releasing hormone agonist (GnRH-a), danazol, and aromatase inhibitors. When long-term medical therapy is planned, low-dose progestin only (e.g., oral norethindrone acetate 2.5 mg/day) may be considered as first-line treatment [70,75], based on a good balance among efficacy, side effects, and cost. Alternatively, OCs may be proposed as therapy for these women, with continuous rather than cyclic administration given that dysmenorrhea is often the main complaint [76]. Finally, if surgery is inevitable, a 3- to 6-month preoperative treatment with a GnRH-a or an association of progestin with an aromatase inhibitor [77] may be considered, especially in patients with a history of poor response to OCs or progestin alone. OCs and Progestins The sole available randomized controlled trail evaluating the medical treatment of rectovaginal endometriosis compared a combined estrogen-progestin regimen (ethinyl E2 plus cyproterone acetate) with low-dose progestin (norethindrone acetate) alone [70]. Both regimens were effective in reducing pain from dysmenorrhea, dyspareunia, and dyschezia. Overall, 62% of the women in the estrogen-

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progestin group reported being satisfied or very satisfied after 12 months of treatment, compared with 73% in the progestin-only group (p, not significant). After treatment, 6% to 11% of women continued to have moderate to severe symptoms. The therapies were well tolerated; few women withdrew from the study because of side effects (2 in the estrogen-progestin group and 3 in the progestin-only group). Another study evaluated the effect of low-dose norethindrone (2.5 mg per day) in relieving gastrointestinal symptoms in 40 women with rectosigmoid endometriosis who were still symptomatic after nonradical surgery [75]. At 12-month follow-up, treatment was associated with significant improvements in diarrhea, intestinal cramping, passage of mucus with stool, and cyclic rectal bleeding. Constipation was improved only in the women who had cyclic symptoms. No significant improvement was seen in abdominal bloating or feelings of incomplete evacuation. With the aim of detecting possible differences across different preparations, a prospective study including 59 women with rectovaginal endometriosis who were still symptomatic after conservative surgery compared a contraceptive vaginal ring (15 mg ethinyl estradiol and 120 mg etonogestrel per day) with a patch (20 mg ethinyl estradiol and 150 mg norelgestromin per day). The ring was associated with a significantly greater improvement in dysmenorrhea, whereas improvement in dyspareunia and chronic pelvic pain was similar for the 2 preparations [78]. A recent study reported that both a desogestrel-only pill and the vaginal ring are efficacious in treating symptoms caused by rectovaginal endometriosis infiltrating the rectum. Patient satisfaction was greater for the former treatment compared with the latter [79]. GnRH-a GnRH-a has been found to improve both pain symptoms and intestinal symptoms in women with rectovaginal endometriosis [73]; however, long-term use of these agents is generally avoided because it may result in menopausal symptoms and decreased bone density. Danazol Oral danazol is often not well tolerated because of androgenic side effects. One study evaluated the postoperative vaginal administration of danazol (one 200-mg vaginal capsule/day) in 21 women with rectovaginal endometriosis. After 12 months of treatment, a significant reduction in pain symptoms was observed, without major side effects and with no significant changes in metabolic and coagulative parameters [72]. Levonorgestrel-Releasing Intrauterine Device (LNGIUD) A small study showed that insertion of an LNG-IUD was associated with improvements in dysmenorrhea, pelvic pain,

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and dyschezia in 11 women with rectovaginal endometriosis [71]. Aromatase Inhibitors The aromatase inhibitor letrozole, in a combination therapy with norethindrone acetate, has proven effective in improving symptoms in women with rectovaginal endometriosis [77,80]. Treatment of Coexisting Infertility Impact of DIE on Fertility Status Mechanisms that account for a negative impact of DIE on fertility may include mechanical distortion of pelvic anatomy and interference with the reproductive process owing to the presence of adhesions. Moreover, peritoneal factors are dramatically altered in the presence of DIE, and inflammatory effects associated with activated macrophages or alterations in cytokine signaling affecting fallopian tube, gamete, and endometrium function have been reported as well [81–84]. As a matter of fact, DIE is known to have a detrimental effect on assisted reproductive technology (ART) outcomes. The pregnancy rate varied considerably, however, depending mainly on the presence of adenomyosis, serum anti-M€ ullerian hormone (AMH) level, and patient age. Two prospective studies from the same group have provided information on the effect of DIE on ART outcomes and on determinant factors of fertility outcomes [55,85]. In a prospective longitudinal study of 142 consecutive women with endometriosis who had undergone ICSI-IVF treatment, Ballester et al [85] found a clinical pregnancy rate of 58% in women with DIE and 83% in those without DIE (p 5 .03). Approximately 60% of the patients had received a previous intervention for endometriosis. Increased patient age, serum AMH level %1 ng/mL, and increased number of ICSI-IVF cycles were associated with a decreased clinical pregnancy rate, but the presence of DIE was the strongest determining factor of clinical pregnancy rate [85]. In a multicenter study, the same group evaluated 75 patients with colorectal endometriosis and proven infertility after ICSI-IVF cycles. Three-quarters of the patients had undergone previous surgery for endometriosis. In the entire study population, the cumulative pregnancy rate was 29.3%, after 1 ICSI-IVF cycle, 52.9% after 2 cycles, and 68.6% after 3 cycles. The presence of adenomyosis, patient age .35 years, and serum AMH level ,2 ng/mL were associated with decreased cumulative pregnancy per patient [55]. These data were confirmed in studies comparing ART outcomes in patients with endometriomas with DIE and without DIE. Role of Surgery for DIE in Relation to Infertility The data on the impact of surgery for DIE on fertility are controversial. In a patient preference trial comparing women with rectovaginal endometriosis opting for surgery (n 5 44)

525

with those choosing expectant management (n 5 61), the 24month cumulative pregnancy rate was 44.9% in the former group and 46.8% in the latter group [86]. In another, patient-based choice study, the outcomes of ART treatment were compared in infertile women who had undergone extensive laparoscopic excision of endometriosis before ICSI-IVF and those who underwent ICSI-IVF only. Significantly higher rates of implantation (32.1% vs 19%; p 5 5.03) and pregnancy (41% vs 24%; p 5 5.004) were seen in the surgical group. The odds ratio (OR) for achieving pregnancy was 2.45 (95% confidence interval, 51.34–4.51) in women in the combined surgery/ART group [49]. Given the foregoing, the overall infertility picture of the couple, not just the endometriosis, should be considered [87]. Assessment of current infertility status, including evaluation of ovarian reserve and of male factors, should be suggested before proceeding with a surgical intervention. In this scenario, the gynecologist should be able to formulate a reproductive prognosis. The aim of surgery is to normalize the anatomy and improve the chance of spontaneous pregnancy. After surgery, a strict time line should be devised for the couple can follow. If pregnancy has not occurred after 6 months, then IVF should be offered. Pregnancy Outcomes It is important that all women with endometriosis be aware that pregnancy, thanks to the rise in progesterone levels, will probably have a great beneficial effect on the disease and its symptoms, and also that the disease may be an independent risk factor for adverse pregnancy outcomes in both spontaneous and ART pregnancies. Surgical treatment does not completely prevent the development of complications associated with these pregnancies. Fortunately, even if potentially dangerous for the mother and the child, all of these events are extremely rare. One serious complication described in the literature is spontaneous hemoperitoneum in pregnancy (SHiP), which can occur in the second half of pregnancy, in labor, and infrequently in the early postpartum period and is caused by ectopic decidualization of deep endometriotic implants with vascular invasion. A maternal fatality rate of 22% and a fetal fatality rate of 56% have been reported. A total of 25 SHiP cases have been published over the last 2 decades. Among these, endometriosis was reported in 13, representing the major risk factor for ShiP [88,89]. Pregnancy also may increase the risk of severe bowel complications arising during the third trimester in both treated and untreated patients. Fifteen cases of bowel perforation have been reported to date [90]. Although pregnancy-related constipation (owing to hormone-mediated reduction of colon mobility) causing colonic hyperpressure ending in rupture of the operated weakened tract may be the most likely pathogenetic mechanism in surgical patients, the pathogenetic mechanism in untreated patients remains largely unclear. An extensive decidualization weakening the bowel wall,

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Fig. 2 Decision algorithm for our case.

coupled with traction on the associated adhesions, has been speculated. The same authors also reported 6 cases of bowel occlusion in pregnant patients with deep endometriotic lesions [91]. The same decidualization of ectopic implants in pregnant women may occasionally result in episodes of massive gastrointestinal bleeding [91]. The patient should be informed that endometriosis also can increase the risk of many pregnancy-associated disorders such as placenta praevia (OR, 1.7), preterm birth (OR, 1.33), and postpartum

hemorrhage (OR, 1.3). There is no association between endometriosis and fetal growth restriction [92,93], whereas findings for preeclampsia risk are controversial, with different studies reporting it as decreased, increased, and unchanged. Thus, more studies are needed to define a potential relationship between these 2 diseases [94]. A series of old uncontrolled and retrospective studies seemed to suggest an increased rate of miscarriage in patients with endometriosis [95] with a reduction in rate after

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surgical treatment, but more recent prospective studies have not detected such an improvement after surgery; thus, clinical evidence of an association between endometriosis and miscarriage is still lacking [96]. A decision algorithm derived from this discussion is proposed in Figure 2. Some of these decisions are based not on evidence from randomized controlled trials, but rather on the consensus opinion of a panel of 29 experts in the field of endometriosis. In conclusion, management of bowel endometriosis remains one of the most challenging aspects of benign gynecology. In our opinion, it is mandatory to emphasize the role of appropriate patient counseling to clarify in advance the surgery-related risks, the likelihood of future pregnancy, and the need for continuous medical treatment.

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