Introduction

Despite many improvements in the multidisciplinary treatment of Crohn’s disease (CD), there is still a substantial risk of surgical resection for lack of response to medical management or complications during a patient’s lifetime [1]. Although disease patterns within the gastrointestinal system vary, the terminal ileum and cecum are the most frequently impacted areas (55%). Other areas include small bowel disease only (11–48%), colon disease only (19–51%) and combined small and large intestine (26–48%) [2].

Intestinal resection for CD has a high reported rate of postoperative complications [3, 4] increased by risk factors such as malnutrition, active inflammation or infection at the time of surgery and immune suppression [3,4,5], with reported rates of intra-abdominal sepsis and anastomotic leak as high as 14% and 17%, respectively [6].

In addition, a high rate of recurrence following ileocaecal resection for CD has been reported, which can lead to reoperation in 20–30% of patients at 5 years after surgery [7], with approximately 40 to 50% of patients who underwent surgery likely to need further operations within 10 to 15 years [8]. Recurrence generally happens at the anastomosis and the neo-terminal ileum [9], and different anastomotic techniques have been assessed with the belief that a wide calibre anastomosis, such a side-to-side configuration, can result in reduced recurrence rates [10]. It is important to note that a more radical surgical approach, extending the margins of resection proximally and distally to the diseased segment, does not reduce the risk of recurrence, but contributes to the occurrence of short bowel syndrome and must be avoided [11], and for this reason, a macroscopically normal margin is accepted in CD surgery [12]. However, the association of the microscopic resection margin status with perioperative complications is still to be evaluated. The aim of this observational study was to appraise the association between positive resection margin status and anastomotic complications following ileocaecal resection for primary CD.

Methods

Study design

This retrospective observational study included all patients receiving ileocaecal resection for primary CD from 1st of January 2010 to 31th of December 2018. All patients undergoing emergency operations or surgery for CD recurrence were excluded. Patients in whom an anastomosis was not fashioned at the time of the surgery or in whom the anastomosis was protected by a diverting ileostomy were also excluded. The study was designed according to the STROBE checklist [13].

The indication for surgical resection was agreed at dedicated inflammatory bowel disease (IBD) multidisciplinary team meetings involving gastroenterologists, colorectal surgeons, radiologists and pathologists. Preoperative evaluation included ileocolonoscopy, MRI enterography and intestinal ultrasound.

Data collection

Preoperative parameters included age, sex, body mass index (BMI), comorbidities, American Society of Anaesthesiologists (ASA) status, smoking status, weight loss, indication for surgery and preoperative medical treatment.

Operative data included operating time, occurrence of intraoperative complications, estimated operative blood loss and conversion to open surgery with reason for conversion. Follow-up data included postoperative length of hospital stay (LOS), time to tolerate oral fluids and oral diet, time to resolution of ileus and complications reported according to the Dindo-Clavien classification [14]. The definition of intraabdominal anastomotic complications included intraabdominal abscesses, pus collections and anastomotic leaks [6]. Histopathology data collected from the pathology report included specimen length and macroscopic description, presence of macroscopic and microscopic involvement of the proximal and distal resection margins, presence in the resected specimen of granulomas, crypt abscesses, myenteric plexitis and pyloric metaplasia. Resection margins where inflammation or granuloma was identified at histopathological assessment were classified as positive.

Primary and secondary outcomes

The primary outcome was the rate of positive resection margins in patients who developed anastomotic complications compared to patients with a negative resection margin following elective ileocaecal resection for CD. The secondary outcomes were overall complications rate, LOS, reoperations and readmissions within 30 days.

Statistical analysis

Categorical variables are reported as frequency counts and associated percentage and were compared with the use of the Chi-square test or Fisher’s exact test, as appropriate. Continuous variables are presented as mean (±standard deviation) or median (range) and were compared with the use of Student’s t test. The Mann-Whitney U test was used for continuous, not normally distributed outcomes. Statistical analysis was performed by using GraphPad Prism version 8.0.2 for Windows (GraphPad Software, La Jolla California, USA). All reported p values were two-tailed, and p values of less than 0.05 were considered to indicate statistical significance.

Ethics

The study is conducted in accordance with the principles of the Declaration of Helsinki and ‘good clinical practice’ guidelines. Informed consent has been obtained from the patients.

Results

Patient characteristics

A total of 165 patients underwent ileocaecal resection during the study period. Fifty-one patients underwent emergency surgery and were excluded, while 10 patients were excluded because an ileostomy was fashioned at the time of the index operation. A total of 104 patients were finally included in the analysis, and baseline patients’ characteristics and cumulative postoperative outcomes are detailed in Table 1.

Table 1 Patients’ baseline characteristics and postoperative outcomes
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Postoperative outcomes

No mortalities occurred. Twenty-six patients (25%) developed postoperative complications within 30 days of surgery. These consisted in wound infection in six patients (5.7%), prolonged postoperative ileus requiring total parenteral nutrition in four patients (3.8%), chest infection in two patients (1.9%), urinary tract infection in two patients (1.9%), bleeding requiring transfusion in one patient (0.9%) and re-feeding syndrome in one patient (0.9%). No statistically significant difference was present in the preoperative use of anti-TNF and steroids between patients who developed postoperative complications and patients who did not. Ten anastomosis-related complications (9.6%) were reported (Table 2).

Table 2 Patients who developed anastomosis-related complications
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Resection margin status and histopathological assessment

The proximal resection margin was microscopically involved in 19 patients (18.2%). The median length of the resected terminal ileum was 19.5 cm (range 3.5–50). Granulomas were identified in the resected specimen in 23 patients (22.1%), while crypt abscesses were found in 21 patients (20.2%). Myenteric plexitis occurred in 19 patients (18.2%) and pyloric metaplasia in 3 (2.9%).

Resection margin status in patients with anastomotic complications

Ten patients (9.6%) developed intra-abdominal anastomosis-related complications, consisting in four anastomotic leaks (3.8%) and six intra-abdominal collections (5.7%) requiring radiological guided drainage. Three patients with anastomotic leak required relaparotomy and stoma formation, while one case was successfully treated conservatively.

Five patients out of 10 (50%) in the group of postoperative anastomotic complications had a positive proximal margin at histology, compared to 14 patients (14.9%) in the group that did not develop anastomosis-related complications (p < 0.0001) as summarised in Table 3. Having a positive microscopic resection margin was associated with postoperative anastomotic complications in 5 cases out of 19, with a 26.3% reported rate. No differences were found in the rate of crypt abscesses, myenteric plexitis, granulomas and pyloric metaplasia between the two groups.

Table 3 Patients with a microscopically positive resection margin with or without postoperative anastomosis-related complications
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Discussion

Repeated surgery for anastomotic-related complications represents one of the main reasons for short bowel syndrome in CD [15] rather than multiple resections over time for surgical recurrence [16]. More importantly, multiple resections may result in functional diarrhoea, fat malabsorption and only ultimately in short bowel syndrome requiring parenteral nutrition treatment, while affecting patients’ quality of life with selective vitamin deficiencies and malnutrition. The Lémann index evaluates globally the cumulative structural bowel damage that can occur in CD [17]. Surgical resection of the bowel, being irreversible, is considered the maximum level of bowel damage in this index. For these reasons, preoperative optimisation of patients and experienced decision making on when to operate and whether to fashion an anastomosis or to create a diverting stoma [18] is paramount to minimise the risk of anastomotic-related complications.

We found a 50% rate of positive proximal resection margin in the group of patients who suffered postoperative anastomosis-related complications, which was significantly higher than the rate of positive margin in patients without anastomotic complications (14.9%). There are conflicting data regarding the prognostic value of CD histologic features in bowel resection specimens [19]. Karesen et al. [20] initially reported that the presence of microscopic CD at surgical resection margins was associated with increased postoperative CD recurrence, recommending a wide resection with frozen section evaluation of the margins. This finding was also confirmed by Heimann et al. [21], while other studies [22, 23] suggested no association between positive margin status and surgical recurrence. Finally, Fazio et al. [11] demonstrated no advantage in terms of lower surgical recurrence rate for wider resection margins in a randomised study. As surgery cannot cure CD, but only treat complications of the disease, a segmental resection of the diseased bowel within macroscopically normal margins is widely accepted [24] and the results of our study do not support a more extended resection. It would be erroneous to assume that margin status per se influences the anastomotic failure, as demonstrated by the 14 patients who did not develop complications despite a positive microscopic margin. As we acknowledge that CD recurrence is multifactorial and unlikely to be influenced only by a single surgical variable, such as anastomosis configuration or mesenteric resection for example, we must do the same for CD anastomosis-related complications, as nutritional status, preoperative medical therapy and disease phenotype may all play a role. A recent meta-analysis [25] found a mean reported rate of histopathological margin involvement of 41% in CD resections, with significant heterogeneity across the included 18 studies due to the lack of a standardised definition. For all these reasons, a standardised reporting of CD histopathological specimen is required as advocated by Setoodeh et al. [19], and our study highlights a possible correlation between positive microscopic proximal resection margin status with anastomotic complications, adding to the existing literature mainly focused on the association between extent of resection and CD surgical recurrence.

Current discussion on CD recurrence is concentrating on the role of the mesentery, with Coffey et al. showing a significantly decreased surgical recurrence rate when incorporating a substantial portion of mesentery in the resected specimen [26]. While the mesentery is likely to play a pathogenic role in CD, it is also crucial for intestinal perfusion, and extensive removal may compromise bowel tissue with concerns also regarding haemorrhagic dangers associated with division of the mesentery in patients with CD and potential need for increased length of resected bowel if larger mesenteric segments are excised [27]. For, now it still remains unclear how much mesentery should be resected in CD surgery and it does represent a limitation that our study did not assess histopathological features of the mesenteric involvement. Another limitation of our study is that no direct patient-reported outcome measures have been assessed as well as the single-centre retrospective nature of the study with limited power and patients being recruited within a study period of several years.

Our study highlights the importance of dedicated histopathology support to the IBD multidisciplinary team [28]. It is, in fact, a quality requirement that patients having surgery for IBD have it undertaken by a colorectal surgeon who is a core member of the IBD multidisciplinary team [29] auditing stoma rate, complications, re-interventions and mortality [30]. Larger studies are needed to evaluate the association between margin status and anastomotic complications in CD.

Conclusions

Microscopic involvement of the proximal resection margin is more frequent in patients who develop postoperative anastomotic complications following elective ileocaecal resection for primary Crohn’s disease.