Original Article. Chloé Coton, Léon Maggiori, Diane Mège, Clotilde Naudot, Justine Prost à la Denise, Yves Panis ABSTRACT. 1.

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1 Journal of Crohn's and Colitis, 2017, doi: /ecco-jcc/jjx044 Advance Access publication March 22, 2017 Original Article Original Article Ileal Pouch-Anal Anastomosis for Dysplasia or Cancer Complicating Inflammatory Bowel Disease: Is Total Mesorectal Excision Always Mandatory? An Analysis of 36 Consecutive Patients Chloé Coton, Léon Maggiori, Diane Mège, Clotilde Naudot, Justine Prost à la Denise, Yves Panis Department of Colorectal Surgery, Beaujon Hospital, University Paris VII, Clichy, France Corresponding author: Professor Yves Panis, MD, PhD, Service de Chirurgie Colorectale, Pôle des Maladies de l Appareil Digestif, Hôpital Beaujon Assistance Publique des Hôpitaux de Paris [APHP], Université Paris VII [Denis Diderot], 100 Boulevard du Général Leclerc, Clichy cedex, France. Tel: ; Fax: ; yves.panis@aphp.fr ABSTRACT Background and Aims: The extent of lymph node harvesting during surgery for colorectal neoplasm [dysplasia and/or cancer] complicating inflammatory bowel disease [IBD] is a matter of debate. This study aimed to assess the risk of invasive rectal cancer in patients undergoing ileal pouch-anal anastomosis [IPAA] for colonic neoplasm complicating IBD, and thus to clarify whether a systematic total mesorectal excision [TME] should be systematically performed, or not, in those patients. Methods: From 1998 to 2015, all patients who underwent IPAA for colorectal neoplasm complicating IBD were included. Patients with preoperatively known rectal cancer were excluded. Pathological results were compared with preoperative endoscopic results. Results: A totalof 36 patients [mean age 49 ± 14 years], comprising 10 women [31%] and 26 men [69%], underwent IPAA for colorectal neoplasm complicating IBD, with [n = 8; 22%] or without [n = 28; 78%] TME. Rectal cancer rate in pathological specimens was 0% [0/20] in patients with preoperatively known neoplasm only limited to the colon, 0% [0/8] among patients with preoperative rectal low-grade dysplasia, and 62% [5/8] among patients with preoperatively rectal high-grade dysplasia. Conclusions: These results do not support systematic TME during IPAA for colonic neoplasm complicating IBD. Considering its association with postoperative sexual disorder, TME should be discussed only on a case-by-case basis. Key Words: Ileal pouch-anal anastomosis; inflammatory bowel disease; total mesorectal excision; surgery 1. Introduction Colorectal neoplasia is a well-established complication of inflammatory bowel disease [IBD]. 1,2 A meta-analysis reported that the cumulative risk of cancer in ulcerative colitis patients was 2%, 8%, and 18% after 10, 20, and 30 years of disease, respectively. 3 Natural history of colorectal cancer in IBD is characterised by an inflammation-dysplasia-carcinoma sequence, suggesting that the occurrence of dysplasia indicates that the entire mucosal lining of the colon and rectum is at increased risk of cancer. 4 As carcinogenesis in IBD rises from chronic intestinal inflammation, 5 tumours are frequently multiple and spread in multiple sections of the colon and rectum. 6 These points led both European and American guidelines to propose regular screening endoscopy 6 to 8 years after the beginning of symptoms, to identify colorectal neoplasia at a curable stage. 7,8 In Copyright 2017 European Crohn s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please journals.permissions@oup.com 936

2 Surgery for Neoplasia Complicating IBD 937 patients with identified colorectal dysplasia or cancer, the European Crohn s and Colitis Organisation [ECCO] recommends that patients should undergo restorative coloproctectomy with ileal pouch-anal anastomosis [IPAA] to treat the lesion and to prevent recurrence. 8 However, the necessity to performed an oncological surgical resection, including extensive lymph node harvesting, is still a matter of debate. This is especially problematic during the rectal part of the surgery, as the realisation of a total mesorectal excision [TME] might expose the patient to postoperative urinary and sexual disorders due to the vicinity of the pelvic nerves. 9,10 TME during IPAA was also associated in a randomised study with higher morbidity rate and lower quality of life. 11 On the other hand, a pelvic dissection performed closer to the rectum might expose the patient to a risk of incomplete lymph node harvesting, leading to increased local recurrence risk in cases of rectal cancer. 12 This conflict between oncological and functional outcomes is mainly due to the difficulty in preoperatively assessing the risk of rectal cancer, which will require oncological resection The ECCO guidelines regarding surgery for ulcerative colitis [UC] state that in patients with high-grade dysplasia or colorectal cancer, the colon and rectum should be removed with en-bloc oncological resection of lymph nodes in all segments, due to the high risk of multiple synchronous tumours, suggesting that a TME should be performed in all patients, even in the absence of neoplasia in the rectum. 16 This recommendation might expose patients to unnecessary postoperative sexual and urinary disorders if a TME is performed despite the absence of invasive rectal cancer. For many years in our department, our policy has been more restrictive than recent ECCO statements regarding TME during IPAA. TME is only performed on a case-by-case basis and not systematically in all patients with colorectal neoplasm complicating IBD. The aim of this study was to report our experience in order to assess whether or not TME should be systematically performed in these patients, and thus to assess the risk of invasive rectal cancer in patients operated on for colonic neoplasm complicating IBD. 2. Patients and Methods 2.1. Study population All consecutive patients who underwent IPAA for colorectal neoplasm complicating IBD from 1998 to 2015 were identified from our prospective single-centre institutional prospective review boardapproved database. Patients with preoperatively known rectal cancer were excluded from this initial population, as TME should be always performed in this situation. Data collection included: patient characteristics: gender, age, body mass index [BMI], and American Society of Anesthesiology [ASA] score; disease features: diagnosis [UC, Crohn s disease, or indeterminate colitis], disease duration, and colorectal neoplasm location and tumour staging defined according to the tumour-node-metastasis [TNM] classification, and neoadjuvant and adjuvant treatments; surgical features: two- or three-step IPAA, approach [open or laparoscopy], conversion into laparotomy for laparoscopic cases [defined as an unplanned abdominal incision longer than 5 cm], and type of anastomosis [handsewn or stapled]; postoperative outcomes; and pathological features, assessed on the specimen Preoperative workup Colorectal neoplasia screening for IBD patients managed in our institution was performed according to the ECCO guidelines 17 : a screening endoscopy was performed 6 to 8 years after the beginning of symptoms and was then repeated every 1 to 4 years according to patient risk factors and histological results of the previous endoscopy. When an endoscopy was performed, a chromoendoscopy with targeted biopsies was the procedure of choice. An endoscopy with random biopsies [quadrant biopsies every 10 cm] was performed otherwise. All suspicions of colorectal cancer and/or dysplasia after pathological examination of the performed biopsies were reviewed by a second pathologist Surgical procedures All procedures were performed using a standardised technique. IPAA was performed as a two- or three-stage coloproctectomy or as a completion proctectomy in patients who had a previous total colectomy with ileorectal anastomosis. For laparoscopic two-stage IPAA, a total laparoscopic approach, as previously described, was used. 18 Briefly, using a five-trocar technique, total restorative proctocolectomy and IPAA were performed during the same operation, with temporary ileostomy at the site of specimen extraction, in the lower right quadrant. For three-stage IPAA, laparoscopic subtotal colectomy with double-end ileostomy and sigmoidostomy in the lower right quadrant were first performed, as previously described After 2 3 months, laparoscopic completion proctectomy with IPAA was performed, and temporary ileostomy was performed at the same site of the former double-end ileostomy and sigmoidostomy. 22 A J-pouch was performed in all cases. The study population was separated into two groups according to the type of IPAA performed: in the TME group, dissection was performed using a medial to lateral approach, the mesenteric artery was divided 2 cm from its origin, and the pelvic dissection was performed along the mesorectal plane with nerve preservation. In the non-tme group, dissection was performed using a lateral to medial approach, the mesenteric artery was divided close to the colon, and the pelvic dissection was performed according to our bad-tme technique within the mesorectum posteriorly and laterally and as a close rectal dissection anteriorly, with Denonviller s fascia and anterior mesorectum preservation. An ultrasonic dissection device [Harmonic scalpel, Ethicon Endo-Surgery, Inc., Cincinnati, OH] was used to perform the pelvic dissection in all cases. The decision to perform TME or non-tme dissection was taken on a case-by-case basis and always discussed in a dedicated IBD multidisciplinary team meeting Outcomes measures and statistical analysis Postoperative morbidity was defined as any postoperative 30-day or in-hospital complication and was graded according to the Clavien- Dindo classification. 23 Anastomotic leakage [AL] included both symptomatic and asymptomatic leakages. Symptomatic AL was defined by the presence of peritonitis, fever, or when gas, pus, or faeces was discharged from the abdominal drain or from the vagina. All clinical suspicion of AL led to early CT with contrast enema, or early reoperation. On CT, all anastomotic dehiscences with leakage into the perirectal cavity, leakages from the efferent limb of the J-pouch, and isolated pelvic abscesses with no evidence of fistula tract, were considered to be AL. Asymptomatic AL was considered if an AL was assessed on systematic CT with contrast enema performed before diverting stoma reversal, but without any relevant clinical symptoms. Quantitative data were reported as mean ± standard deviation [range]. Normally distributed quantitative data were analysed with Student s t test. The Mann-Whitney U test was used otherwise. Qualitative data were reported as number of patients [percentage of patients] and were compared with either the Pearson χ 2 test or

3 938 C. Coton et al. Fisher s exact test, depending of the sample size. All tests were twosided, with a level of significance set at p < All analyses were performed using the Statistical Package for the Social Sciences [SPSS] for Mac OSX software [version 22.0, Chicago, IL, USA]. This study was conducted according to the ethical standards of the Committee on Human Experimentation of our institution and reported according to the Strengthening the Reporting of Observational Studies in Epidemiology [STROBE] guidelines Results 3.1. Patients characteristics From 1998 to 2015, 47 patients underwent IPAA for colorectal neoplasm in our institution, including 11 patients with preoperatively known rectal cancer, who were excluded from the present study. The study population therefore included 36 patients, comprising 10 women [31%] and 26 men, with a mean age of 49 ± 14 years [range, 27 77], who underwent IPAA for colorectal neoplasm complicating UC [n = 32, 89%] or Crohn s disease [n = 4, 11%]. Patients characteristics are detailed in Table 1. IPAA was performed either as a two-stage coloproctectomy [n = 25, 69%], a three-stage coloproctectomy [n = 6, 17%], or a completion proctectomy after previous total colectomy with ileorectal anastomosis [n = 5, 14%]. Indication for surgery included colonic cancer or dysplasia without rectal neoplasm [n = 20, 48%], rectal low-grade dysplasia [n = 8, 17%], or rectal high-grade dysplasia [n = 8, 17%]. The dissection was performed with TME in eight patients [22%] and without TME in 28 patients [78%]. As detailed in Table 1, patients from TME and non-tme groups showed no difference regarding mean age (55 ± 12 [38 77] in the TME group vs 48 ± 14 [27 76] in the non-tme group; p = 0.130), mean BMI (21 ± 4 [15 27] vs 25 ± 3 [20 31]; p = 0.136), diagnosis [UC in 88% vs 89%; P = 0.887], disease duration before surgery (16 ± 9 [3 29] in the TME group vs 17 ± 11 years [2 40] in the non-tme group; p = 0.780), mean ASA score [1 2 in 88% in the TME group vs 96% in the non-tme group; p = 0.620], and type of IPAA [two-stage IPAA: 75%, three-stage IPAA: 25% in the TME group vs 2-stage IPAA: 68%, three-stage IPAA: 14%, completion proctectomy: 18% in the non-tme group; p = 0.386]. Finally, the TME group included a significantly lower proportion of men, as compared with the non-tme group [50% vs 82%; p = 0.024] Short-term outcomes A total of 34 patients [94%] underwent IPPA through a laparoscopic approach (n = 8, 100% in the TME group vs n = 26 [93%] in the non-tme group; p = 0.896). All patients underwent a stapled anastomosis. As detailed in Table 2, there were no differences in short-term outcomes comparing TME with non-tme groups. Postoperative mortality was nil. A total of 17 patients [47%] presented with postoperative complications [n = 3, 38% in the TME group vs n = 14, 50% in the non-tme group; p = 0.695] and four patients [10%] presented with severe postoperative morbidity [n = 1, 13% in the TME group vs n = 3, 11% in the non-tme group; p = 0.609], including pulmonary embolism requiring intensive care unit management [n = 1], pelvic abscess related to an AL and requiring CT-guided drainage [n = 2], and small bowel occlusion requiring emergent reoperation [n = 1]. AL occurred in eight patients [22%], including four patients [11%] with symptomatic AL. Neither overall nor symptomatic AL rates showed any significant discrepancy between the two groups [overall AL rates: n = 2, 25% in the TME group vs n = 6, 21% in the non-tme group, p = 0.830; symptomatic AL rates: n = 1, 13% vs n = 3, 11%, p = 0.887] Pathological results After pathological examination of the specimen, 22 patients [61%] presented with no dysplasia or cancer on the rectum, six patients [17%] presented with low-grade dysplasia in the rectum, three [8%] presented with high-grade dysplasia in the rectum, and five [14%] presented with rectal cancer, graded T1 [n = 1], T2 [n = 3], or T3 [n = 1] and N0 [n = 4] or N+ [n = 1]. As detailed in Figure 1, the rectal cancer rate on pathological specimens was 0% [0/20] in patients with preoperatively known neoplasm limited to the colon, 0% [0/8] among patients with preoperative rectal low-grade dysplasia, and 62% [5/8] among patients with preoperative rectal high-grade dysplasia. Table 1. Characteristics of 36 consecutive patients who underwent ileal pouch-anal anastomosis for colonic neoplasia complicating inflammatory bowel disease. Overall n = 36 TME n = 8 No TME n = 28 p-value Gender Female 10 [31] a 5 [50] 5 [18] Male 26 [69] 3 [50] 23 [82] Age at surgery [years] 49 ± 14 [27 77] b 55 ± 12 [38 77] 48 ± 14 [27 76] Body mass index [kg/m 2 ] 24 ± 4 [15 31] 21 ± 4 [15 27] 25 ± 3 [20 31] ASA [94] 7 [88] 27 [96] [6] 1 [12] 1 [4] Diagnosis Ulcerative colitis 32 [89] 7 [88] 25 [89] Crohn s disease 4 [11] 1 [12] 3 [11] Disease duration [years] 17 ± 10 [2 40] 16 ± 9 [3 29] 17 ± 11 [2 40] Surgical strategy for IPAA stage 25 [69] 6 [75] 19 [68] 3-stage 6 [17] 2 [25] 4 [14] Completion proctectomy 5 [14] 0 5 [18] a Number of cases [percentage of cases]. b Mean ± standard deviation [range].

4 Surgery for Neoplasia Complicating IBD 939 Table 2. Short-term postoperative outcomes of 36 consecutive patients who underwent ileal pouch-anal anastomosis for colonic neoplasia complicating inflammatory bowel disease. Overall n = 36 TME n = 8 No TME n = 28 p-value Approach Laparoscopy 34 [94] a 8 [100] 26 [93] Open 2 [6] 0 2 [7] Conversion to open approach 1 [3] b 0 [0] 1 [4] Overall postoperative morbidity 17 [47] 3 [38] 14 [50] Severe postoperative morbidity 4 [10] 1 [13] 3 [11] Anastomotic leakage Overall leakage 8 [22] 2 [25] 6 [21] Symptomatic leakage 4 [11] c 1 [13] 3 [11] a Number of patients [percentage of patients]. b Among patients with laparoscopic approach. c Mean ± standard deviation [range]. Preoperative Status No neoplasia n=20 Low Grade Dysplasia n=8 High Grade Dysplasia n=8 S p e c i m e n No neoplasia n=22 Low Grade Dysplasia n=6 High Grade Dysplasia n=3 17 (85%) 3 (38%) 2 (25%) 2 (10%) 4 (50%) 0 (0%) 1 (5%) 1 (12%) 1 (13%) Rectal Cancer n=5 0 (0%) 0 (0%) 5 (62%) Figure 1. Comparison of preoperative findings and pathological specimens of 36 consecutive patients who underwent ileal pouch-anal anastomosis for colonic neoplasia complicating inflammatory bowel disease. 4. Discussion The aim of this study was to assess whether a TME should be systematically performed or not in patients undergoing IPAA for colorectal neoplasia complicating IBD. Including 36 consecutive patients, we reported herein that the risk of rectal cancer in the pathological specimens is nil in patients with low-grade rectal dysplasia and in patients without preoperatively known rectal neoplasia. These results suggest that TME might not be systematically performed in those selected patients, as it might be associated with unnecessary impaired postoperative sexual function. In conclusion, we believed that the policy of systematic TME during IPAA must probably be restricted to patients with preoperatively known rectal high-grade dysplasia or cancer. IBD-related colorectal neoplasms occur in relatively young patients, more frequently sexually active, than in cases of sporadic colorectal cancer. 1 In this setting, the management strategy is based on the prevention of locally advanced colorectal cancer but also on the preservation of long-term sexual activity and quality of life. The latest ECCO guidelines regarding surgery for UC state that an oncological resection should be performed when a restorative proctocolectomy with IPAA is proposed for patients with IBD and at least high-grade dysplasia, due to the high risk of multiple synchronous tumours and preoperative under-staging. 16 This statement suggests that an extensive lymph node harvesting, including TME, should be routinely performed in the large majority of the patients. In their discussion, the authors nevertheless indicated that a more conservative procedure with Denonviller s fascia preservation and an accurate nerve-sparing procedure might be proposed in patients with negative rectal biopsies, but this point was hitherto not supported by the available literature. 16 To the best of our knowledge, the present study is the first to focus on the risk of invasive rectal cancer in patients operated on for colorectal neoplasm complicating IBD. In the present study, we compared two different techniques of pelvic dissection during IPAA performed for colorectal neoplasms complicating IBD. In the non-tme group, patients were operated on using our standard technique performed for benign cases. We routinely do not perform a close rectal dissection [except anteriorly] in this situation, but favour a dissection performed within the mesorectum in order to allow enough pelvic space for an optimal pouch expansion into the pelvis, which we find insufficient in case of clos -rectal dissection, especially in case of a very fatty pelvis. We nicknamed this technique a bad mesorectal excision. Although this

5 940 C. Coton et al. dissection is more technically challenging than a TME, as it does not follow a non-vascular outline in the holy plane described by Bill Heald, 12 it clearly avoids any risk of pelvic nerve injury because the dissection remains always far from the TME plane. In our experience, the choice to perform or not a TME is discussed on a case-by-case basis and based on collegial decision taken during a multidisciplinary team meeting. The benefit-risk ratio is discussed between the advantage of TME in case of an undiagnosed cancer and the risk of nerve injuries during TME. This discussion, taking in consideration the ECCO recommendations, also takes into account the histological results of rectal preoperative biopsies and preoperative workup. Our primary concern is to perform an optimal oncological resection in rectal cancer patients, but we also aim to reduce the number of TMEs performed unnecessarily in the absence of invasive carcinoma. This conflict strengthens the need for optimal screening and follow-up of long-standing IBD patients, using colonoscopy with random biospsies and/or chromoendoscopy. 8 The development of new screening tools such as narrow-band imaging and auto-fluorescence imaging might help improve identification of patients requiring an oncological resection. 25 The results of the present study suggest that a TME can safely be omitted, favouring a bad mesorectal excision technique, in patients with low-grade rectal dysplasia or without any dysplasia in the rectum after preoperative workout, as the risk of invasive carcinoma was nil in those patients. Conversely, TME should be routinely performed in case of rectal high-grade dysplasia, as the 62% risk of invasive carcinoma justifies the risk of impaired sexual function associated with TME. In young males, this impact on sexual function might highlight the necessity of preoperative sperm banking and postoperative medical treatment of erectile dysfunction. 26,27 The present study has some limitations. First, it is a retrospective study with small population. However, we decided not to include patients operated on for UC without dysplasia or cancer, in an attempt to maintain the homogeneity of the included population. Second, patients characteristics comparing TME and non-tme patients are not strictly equivalent, as patients from the TME group were more likely to be women and younger, although this latter was not statistically significant. However, this reflects our case-by-case discussion to perform a TME and our policy to try to reduce the rate of unnecessary TME. In conclusion, the results of the present study do not support systematic TME during IPAA for colorectal neoplasm complicating IBD. Considering its association with postoperative sexual disorder, TME should be discussed only on a case-by-case basis and should be omitted in patients with low-grade rectal dysplasia or without dysplasia in the rectum. Funding None. Conflict of Interest None. Author Contributions CC: data acquisition, data analysis and interpretation, manuscript drafting. LM: study design and concept, data analysis and interpretation, manuscript drafting. DM, JPD, CN: data acquisition, data analysis and interpretation. YP: study design and concept, data analysis and interpretation, manuscript drafting, final approval of the manuscript. References 1. Ekbom A, Helmick C, Zack M, Adami HO. Ulcerative colitis and colorectal cancer. A population-based study. N Engl J Med 1990;323: Ording AG, Horváth-Puhó E, Erichsen R, et al. Five-year mortality in colorectal cancer patients with ulcerative colitis or Crohn s disease: a nationwide population-based cohort study. 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