Deep infiltrating endometriosis is frequent in all stages of endometriosis and the depth of infiltration influences surgical parameters proportionally

Journal of Endometriosis 2; 2 ( 4) : 25-22 ORIGINAL ARTICLE Deep infiltrating endometriosis is frequent in all stages of endometriosis and the depth of infiltration influences surgical parameters proportionally Andreas Hackethal, Catharina Luck, Lutz Konrad, Karsten Muenstedt, Hans-Rudolf Tinneberg, Frank Oehmke Department of Obstetrics and Gynecology, Justus-Liebig-University of Giessen, Giessen - Germany Ab s t r a c t Background: Deep infiltrating endometriosis (DIE) in contrast to superficial endometriosis is known to cause intense pain-related symptoms depending on the anatomic region and depth of infiltration. Despite the known impact of DIE, clinical comparison to superficial endometriosis is difficult to accomplish because no DIE classification is used regularly and the rasrm score does not consider DIE adequately. Methods: We regularly use the ENZIAN classification to group DIE additionally to the rasrm score. The surgical treatment of patients without prior known endometriosis from January 26 to December 28 was evaluated in relation to the classification systems used. Results: The study population included patients and all were scored according to the rasrm score. Forty-two percent (42/) presented with DIE and were additionally classified to the ENZIAN score. In all rasrm stages of endometriosis, a high rate of over 33% DIE was found with a maximum of 8% in stage 4 patients. Patient characteristics did not differ between patients with superficial EM and DIE. Laparoscopy was the main surgical approach regardless of the type of endometriosis. The presence of intra-abdominal adhesions, duration of excisional surgery and hospital stay correlated with the depth of infiltration according to the ENZIAN. Conclusions: This is the first study to reveal that the presence of DIE is an unexpectedly frequent finding in all rasrm stages. Though patient characteristics do not differ between DIE and superficial EM, the surgical parameters for adequate excisional surgery are significantly different and proportionally influenced by the depth of infiltration. Key words : Deep infiltrating endometriosis, ASRM, ENZIAN, Endometriosis Accepted: November 2, 2 INTRODUCTION Deep infiltrating endometriosis (DIE) is defined as endometriotic lesions infiltrating more than 5 mm underneath the peritoneal surface. Morphologically these are the most active lesions (). Others define DIE by the presence of endometrial implants, fibrosis and muscular hyperplasia below the peritoneum (2). Pain as the cardinal symptom might be related to the anatomic location, and its severity appears to be correlated with the depth of infiltration (3, 4). Vaginal examination, ultrasonography and magnetic resonance imaging are available diagnostic tools but the presurgical diagnosis and mapping of DIE lesions represent a clinical challenge (5, 6). Though the prevalence of EM in all reproductive women is 5% to 5% and subgroups have a much higher rate of EM (i.e., infertile women) (7), little is 2 Wichtig Editore - ISSN 235-9969 25 JE 5_HACKETHAL.indd 25 3--2 5:55:5

Impact of deep infiltrating endometriosis known about the prevalence of DIE. Koninckx suggested that DIE is found in about one third of the laparoscopies performed because of pelvic pain symptoms (8). The complete excision of infiltrative nodules is mandatory if an improvement in patient symptoms, reduction of recurrence, enhancement of fertility and satisfaction for the patient is intended (9-2). To specify and categorize EM, the American Fertility Society suggested a classification score based on visible lesions and the organs involved during surgery, which has been revised by the American Society for Reproductive Medicine (3, 4). In previous studies, concerns have been raised that DIE is not satisfactorily considered in the rasrm classification (5, 6). Considering the clinical and surgical impact of DIE, the foundation of EM research (Stiftung Endometriose Forschung) suggested the ENZIAN classification for DIE as an adjunct classification to the rasrm score (7). Similar to the oncologic TNM classifications, there are four different stages for defining DIE. The localization and infiltrating character is encoded in different subgroups (a=vertical compartment including the vagina and uterus, b=horizontal compartment including the uterosacral and cardinal ligaments and c=vertical compartment including the rectovaginal and pararectal space and rectum). A combination of letter for the anatomical site, and number for the extent of disease are used to describe the endometriotic lesion. The classification protocol is added as Appendix. The ENZIAN classification is not yet validated and therefore its acceptance is limited. In our clinic we mandatorily score EM according to the rasrm classification. Furthermore, all DIE lesions are classified additionally according to ENZIAN postoperatively. This study aims to evaluate the incidence of DIE according to rasrm scores in patients without previously undiagnosed EM. Parameters were analyzed according to the depth of infiltration. PATIENTS AND METHODS All endometriosis surgeries at the Department of Gynecology, Giessen University in Giessen, Germany follow a standardized procedure. Independent of the surgical approach, we support the idea of radical surgery with the complete excision of all endometriotic implants as adequate treatment for suspected and incidental endometriotic lesions. To minimize the need for subsequent surgeries in the case of suspected EM, we seek consent for radical surgery with patients before surgery. All surgeries were performed or assisted by a group of experienced surgeons to ensure adequate resection. The University hospital s patient database was searched for all surgeries encoded with postoperative ICD- diagnosis of EM (N85. N85.9) from January 26 to December 28. All patients charts and surgical reports were identified from the hospital archives or the digitalized database for further evaluation. To sort the data we established a digital database consisting of 25 parameters for each patient and surgery. Only patients with no prior diagnosis of EM and histologically confirmed EM during surgery were included in this study. All surgical reports and histological findings were assessed and evaluated to score and classify the stage of EM retrospectively. Surgical data were analyzed subject to the rasrm score and ENZIAN classification. Patients with solitary adenomyosis, classified with FU according to ENZIAN were separated from the remaining group of patients with DIE. To analyze the influence of infiltration depth on surgical parameters, the ENZIAN scores were grouped according to the size of infiltrative lesions as defined in the ENZIAN classification. Four groups were defined (E=ENZIAN Ea, Eb, Ebb, Ec), (E2=ENZIAN E2a, E2b, E2bb, E2c), (E3=ENZIAN E3a, E3b, E3bb, E3c), (E4=ENZIAN E4a, E4b, E4bb, E4c). The most infiltrative ENZIAN score for each patient was selected and characteristics and surgical data were compared according to the depth of infiltration of DIE. Patients with DIE of other organs were not considered (ENZIAN FA, FB, FU, FI, FO). The study was approved by the university s ethics committee. Statistical analysis was carried out quantitatively and qualitatively. The students t-test and cross tabulation with Chi square were used to compare mean values and a p<.5 was considered significant. Results are given as percentage (number/ total) or as mean values±standard deviation. For statistical analysis, SPSS software 8. for Windows was used. RESULTS Within the examined time period, 39 women with histologically confirmed EM and without prior diagnosis of EM were identified from hospital records (Fig. ). Thirty-nine women with solitary adenomyosis (ENZIAN FU) which was incidentally diagnosed at hysterectomy were excluded from analysis. Therefore, the total study group comprised 42% (42/) of patients with an ENZIAN score, referred 26 2 Wichtig Editore - ISSN 235-9969 JE 5_HACKETHAL.indd 26 3--2 5:55:5

Hackethal et al Fig. - Flow chart showing the study group selection process. Fig. 2 - Ratio of Deep Infiltrating Endometriosis (DIE) in patients with endometriosis classified according to the revised-american Society for Reproductive Medicine (rasrm) score. to as the DIE Group and 58% (58/) of patients without an ENZIAN score, referred to as the Superficial EM Group. The ratio of DIE according to the rasrm score is shown in Figure 2. Interestingly, even in the minimal stage disease, a rate of 42% and 39% DIE were observed. Stage III and Stage IV were associated with 33% and 8% DIE, respectively. Patient characteristics and surgical data of the DIE Group and the Superficial EM Group are summarized in Table I. Whether related to DIE or Superficial EM, pain and infertility made up the majority of the indications for surgery and laparoscopy was the preferred surgical approach. However, demolitive surgery was significantly more frequent in the DIE group, whereas endometrioma resection was more frequent in the Superficial EM group (9% vs. 3.5% and 4.3% vs. 36.2%, respectively). The posterior department (rectovaginal space, uterosacral ligaments, rectosigmoid) but not the peritoneum of the Pouch of Douglas was significantly more often the surgical site. DIE lead to significant prolongation of the operation time and postoperative hospital stay. The 42 patients were diagnosed with 57 localizations of DIE and were subsequently classified with 57 ENZIAN scores in total (Tab. II). According to the infiltration depth, the four defined groups comprised 24 patients in group E, nine in E2, one in E3 and four patients in group E4. As summarized in Table III, the infiltration depth of DIE was associated with the combined rasrm score and there was a significant correlation between the presence of adhesions, the duration of surgery, and the postoperative hospital stay as well as depth of infiltration. No statistical correlation was performed because of the small size of groups. DISCUSSION This study examined differences of surgical parameters between DIE and Superficial EM according to the rasrm score and the ENZIAN classification. DIE influences the surgical therapy extensively and therefore emphasis has to be put on adequate preoperative diagnosis and counseling of patients concerning the possible surgical and postoperative course. The ENZIAN classification allows for differentiating the infiltration depth of DIE. This is the first study showing the direct influence of DIE infiltration depth and surgical parameters. Especially for chronic diseases affecting young women, a classification system should categorize the extent of disease, provide the basis for further treatment, and help prognosticate the risk of recurrence or impairment of fertility. The main objective of the revised rasrm score is to stratify women with different reproductive prognoses (8). However, this classification only concerns the extent of visible lesions that are suspicious for EM. Even without histological proof, a rasrm score can be assigned and no additional option for the evaluation of subperitoneal nodules and infiltrating EM are available. Recently, the Endometriosis Fertility Index, which combines the ASRM score and a surgical evaluation of the ovaries, fimbrias and tubes was 2 Wichtig Editore - ISSN 235-9969 27 JE 5_HACKETHAL.indd 27 3--2 5:55:5

Impact of deep infiltrating endometriosis TABLE I - PATIENT CHARACTERISTICS AND SURGICAL DATA OF DEEP INFILTRATING ENDOMETRIOSIS ACCORDING TO THE ENZIAN CLASSIFICATION COMPARED TO HISTOLOGICALLY proven SUPERFICIAL ENDOMETRIOSIS DIE 42% (42/) Superficial EM 58% (58/) p Age (y) mean±sd 35.9±7.8 33.7±7.7.6 + Suspected EM 57.% (24/42) 58.6% (34/58).52 + Indication* Pain Infertility Ovarian cyst Myoma BDO 52.4% (22/42) 33.3% (4/42) 28.6% (2/42) 6.7% (7/42) 2.4% (/42) 48.3% (28/58) 39.7% (23/58) 37.9% (22/58) 8.6% (5/58) 5.2% (3/58).42.33.22.8.2 Surgical approach LSK LAP CB VAG 8.% (34/42).9% (5/42) 4.8% (2/42) 2.4% (/42) 89.7% (52/58) 6.9% (4/58) 3.4% (2/58).7.3.7.62 Procedure* Infertility surgery EM Excision HE OC 35.7% (5/42) 73.8% (3/42) 9.% (8/42) 4.3% (6/42) 27.6% (6/58) 65.5% (38/58) 3.5% (2/58) 36.2% (2/58).26.3.. Surgical site* Adnexae Peritoneum/Pouch of Douglas Uterosacral ligament/ rectovaginal Uterus Rectosigmoid 48.8% (2/4) 55.% (22/4) 62.5% (25/4) 4.% (6/4) 25.% (/4) 63.7% (37/58) 65.5% (38/58) 3.7% (8/58) 24.% (4/58) 8.6% (5/58).3.2..7.3 r-asrm Stage I Stage II Stage III Stage IV 3.% (3/42) 35.7% (5/42).9% (5/42) 9.% (8/42) 33.3% (8/54) 46.3% (25/54) 8.5% (/54) 3.7% (2/54).59.3.33. Duration of surgery (min) mean±sd 8.6±85.9 86.3±54.3.3 + Hospital stay (d) mean±sd 4.3±3.7 2.9±2.3.2 + * = more than one answer possible; + = t-test; = Chi square; DIE = Deep Infiltrating Endometriosis; EM = Endometriosis; rasrm score = revised American Society for Reproductive Medicine score; BMI = Body Mass Index; BDO = Bleeding Disorders; LSK = Laparoscopy; LAP = Laparotomy; CB = Combined approaches; VAG = Vaginal surgery; EM = Endometriosis; HE = Hysterectomy; OC = Ovarian cyst excision; SD= Standard deviation 28 2 Wichtig Editore - ISSN 235-9969 JE 5_HACKETHAL.indd 28 3--2 5:55:5

Hackethal et al TABLE II - SUMMARY OF SCORES ACCORDING TO THE ENZIAN CLASSIFICATION OF PATIENTS WITH DEEP INFILTRATING ENDOMETRIOSIS (Compare Appendix) ENZIAN* Infiltration of vagina/ cul-de-sac Ea E3a Infiltration of uterosacral ligaments Eb E2b E2bb E4b Infiltration of Bowel Ec E2c E3c others FA FU FI FO * = More than one score possible DIE 42% (42/) (5/42) 4 (23/42) 6 2 4 (6/42) 2 3 (3/42) 6 4 2 introduced as a tool to predict pregnancy rates after validation on 8 patients (9). Our findings support previous studies, that the rasrm score might not reflect the extent of disease sufficiently, as 37% of patients with score I also present with DIE. Potential benefits of the ENZIAN compared to previous DIE classifications are the mandatory histologic proof of endometriosis, the distinct anatomical mapping, and the consideration of infiltration depth (2-23). Our results suggest a correlation between the ENZIAN classification and surgical parameters, which could help to counsel patients for adequate surgical therapy. EM is commonly associated with a range of pain symptoms such as dysmenorrhea, chronic pelvic pain, dysuria, dyspareunia or dyschezia with a possible premenstrual peak (24). While superficial EM has a poor correlation between the severity of pain symptoms and anatomical staging of the disease, for DIE this correlation has been postulated (5, 3). However pain symptoms did not differ in these study groups and neither did the rate of preoperative suspected endometriosis. The macroscopically heterogeneous appearance of EM results in a lack of consistency between laparoscopic and histologic diagnosis (2). Therefore, the laparoscopic ap- TABLE III - DEPTH OF INFILTRATION GROUPED ACCORDING TO THE ENZIAN CLASSIFICATION E (n=24) E2 (n=9) E3 (n=)* E4 (n=4) Age 35±6.3 35.7±8.8 29. 4.3±4.9 Previous abdominal surgeries 33.3% (8/24) 77.8% (7/9) % (/) 5.% (2/4) Nulliparous 54.2% (3/24) 55.6% (5/9) % (/) 75.% (3/4) r-asrm Stage I Stage II Stage III Stage IV 8 4 6 2 4 Intra-abdominal adhesions 33.3% (8/24) 88.9% (8/9) % (4/4) Duration of surgery 87.4±46.3 23.2±5. 29. 38.8±9.7 Hospital stay 3.2±2. 3.2±.2 2..8±3.3 The depth of infiltration is grouped according to the ENZIAN classification (E=Ea, Eb, Ebb, Ec), (E2=E2a, E2b, E2bb, E2c), (E3=E3a, E3b, E3bb, E3c), (E4=E4a, E4b, E4bb, E4c). The highest score for each patient was selected and characteristics and surgical data are compared according to the depth of infiltration of deep infiltrating endometriosis. Patients with DIE of other organs are not considered (FA, FB, FU, FI, FO) * One patient was transvaginally operated on a rectovaginal DIE excision without surgical evaluation of the abdomen 2 Wichtig Editore - ISSN 235-9969 29 JE 5_HACKETHAL.indd 29 3--2 5:55:5

Impact of deep infiltrating endometriosis proach with histologic proof is defined as the gold standard for the diagnosis of EM. If extensive EM or DIE is suspected in patients, ureter stents to guard the ureters and reduce intraoperative complications during surgery can be inserted (26). The main indications for surgery in this retrospective study were abdominal pain and infertility regardless of the stage of rasrm or the presence of DIE. The young age of patients and desire for a pregnancy can be inconsistent with the need for extensive destructive radical surgery involving numerous organs to treat EM. DIE with its multifocal expansion within the pelvis and potential infiltration of organs might especially necessitate a multidisciplinary surgical approach. In this study, laparoscopy was feasible at mainly all EM stages and also in DIE, but only two systematic reviews have investigated its role so far (24, 3). This study found the operating time for DIE excision was significantly longer and positively correlated with the infiltration depth. Given the fact that DIE is also frequent in rasrm stage I disease, a possible high rate of undiagnosed or under- staged EM during surgical evaluation might exist. Since the mean depth and volume of the Pouch of Douglas is significantly reduced in women with deep infiltrating endometriosis (29), this may explain why a superficial visual evaluation of the pelvis may not detect DIE. Furthermore, it may explain the inconsistently high recurrence rate of 2% to 47%, since DIE lesions often have to be aggressively discovered by dissecting the retroperitoneum (32-34). Laparoscopy was performed in over 8% of cases, but what is important for the patients benefit is the extent of excisional surgery rather than the surgical approach. The established digitalized database lacks information on follow-up concerning EM-related symptoms, recurrence and fertility outcome after surgery. For further evaluation we will provide EM patients with regular follow-up questionnaires. The evaluated group of patients in this retrospective evaluation of DIE is relatively small and might have influenced the results. No statement can be obtained from group E3, which only consists of one patient. A criticism can be made that the ENZIAN score is subjective for any given surgeon and for different surgeons. Furthermore the diagnosis of DIE is clinically based on the surgical record and not on histological records, as Redwine recommended (33). Another missing link is the follow-up evaluation of surgical and fertility data, helping to further validate the ENZIAN score. Further studies are necessary to assess patient followup and evaluate the possible prognostic relevance of the classification systems. Since infertility is a major indication for EM surgery, a predictive classification system can help concentrate on subsequent and adequate infertility treatment. As in oncologic staging, the prognostic or predictive aspect of classification systems has not yet been recognized in EM. To standardize DIE and as a possible adjunct to recent classifications, histological proof of infiltration should be demanded instead of the surgeon s estimation on infiltration depth. As for the oncologic staging, prognostic or predictive factors might arise from cellular or molecular genetic features and could be included in a staging system. Furthermore, DIE as an extensive EM disease should be classified according to the ICD- to be adequately pictured within the medical Diagnosis Related Group (DRG) system. In conclusion, the clinical relevance of the ENZIAN classification system was documented. This is the first study to show that DIE is frequent in all EM stages and highly affects the surgical procedure. The depth of infiltration influences surgical parameters proportionally. Laparoscopy is the most important surgical approach in the treatment of superficial EM and DIE. In this retrospective study on surgical data based on the rasrm scores and the ENZIAN classification, no investigated patient data or surgical indication correlated with the stage of disease. However, destructive surgery is more frequent in DIE. The use of the ENZIAN classification may differentiate between superficial EM and DIE and enhance a specific DIE classification. Nevertheless, there is an urgent need for a scoring or classification system that can be the base for continuative treatment and help prognosticate the risk of recurrence. ACKNOWLEDGEMENTS The authors would like to thank Wolfgang Pabst from the Medical Statistics Department of the Giessen University Clinic for his precious advice. Conflict of interest: No financial support was obtained and no conflicts of interest are known to the authors. Address for correspondence: Dr med. Andreas Hackethal Department of Obstetrics and Gynecology Justus-Liebig-University of Giessen Klinikstrasse 32 35392 Giessen, Germany andreas.hackethal@gyn.med.uni-giessen.de 2 2 Wichtig Editore - ISSN 235-9969 JE 5_HACKETHAL.indd 2 3--2 5:55:5

Hackethal et al APPENDIX* * [7] Permission for reprint granted by Georg Thieme Verlag Suttgart, New York 2 Wichtig Editore - ISSN 235-9969 2 JE 5_HACKETHAL.indd 2 3--2 5:55:52

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