Abstract
Background:
The endoscopic appearance in patients with “pouchitis” after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) can be quite heterogenous. Patients with an endoscopic phenotype resembling Crohn’s disease (CD) are at high risk of pouch loss.
Aims:
We aimed to assess how the histopathology of colectomy specimens predicts endoscopic pouch phenotypes in UC.
Methods:
We retrospectively assessed pouchoscopies from patients with UC who underwent IPAA and classified pouch findings into 7 main phenotypes: (1) normal, (2) afferent limb involvement, (3) inlet involvement, (4) diffuse, (5) focal inflammation of the pouch body, (6) cuffitis, and (7) pouch with fistulas noted ≥6 months from ileostomy takedown. We assessed the clinical and pathological data including deep, focal inflammation, granulomas, and terminal ileal involvement in the colectomy specimens. Logistic regression analysis was performed to identify contributing factors to each phenotype.
Results:
This study included 1,203 pouchoscopies from 382 patients with UC. On multivariable analysis, deep inflammation was significantly associated with pouch fistulas (Odds ratio 3.27; 95% confidence interval 1.65–6.47; P=0.0007). Of the 75 patients with deep inflammation, only two patients (2.7%) were diagnosed with CD based on pathology review. Terminal ileal involvement significantly increased the risk of afferent limb involvement (Odds ratio 2.96; 95% confidence interval 1.04–8.47; P=0.04). There were no significant associations between other microscopic features and phenotypes.
Conclusions:
We identify histologic features of colectomy specimens in UC that predict subsequent pouch phenotypes. Particularly, deep inflammation in the resected colon was significantly associated with pouch fistulas, a pouch phenotype with poor prognosis.
Keywords: deep inflammation, colectomy specimens, Chicago classification of pouchitis
Introduction
The 10-year proctocolectomy rate of patients with ulcerative colitis (UC) is reported as 10% to 30% in Western countries, with many patients seeking reconstructive ileal pouch-anal anastomosis (IPAA) [1]. Given that pouchitis is a common postoperative complication, endoscopic pouch assessment is often required. However, pouchitis presents heterogeneously both clinically and endoscopically.
We recently proposed the “Chicago Classification of Pouchitis” with 7 endoscopic pouch phenotypes: (1) normal, (2) afferent limb (“AL”) involvement, (3) inlet (“IL”) involvement, (4) diffuse inflammation of the pouch body, (5) focal inflammation of the pouch body, (6) cuffitis, and (7) pouch with fistulas noted ≥6 months after ileostomy takedown [2]. We found that the phenotypes “IL stenosis”, “diffuse inflammation of the pouch body”, and “cuffitis” significantly increased the risk of pouch excision. In particular, the “diffuse inflammation” phenotype was independently associated with subsequent pouch excision [2]. We suggested that endoscopic pouch phenotype would enable the stratification of patients at high risk for pouch loss and may determine the frequency of pouch monitoring.
High risk of pouch loss was also found in patients whose diagnosis was revised from UC to Crohn’s disease (CD) based on pathological findings of their colectomy specimens [3]. However, distinguishing between UC and CD may be difficult, particularly in patients with fulminant colitis because their colectomy specimens often showed deep ulcerations, and, rarely can show transmural inflammation as well [4]. The percentage of patients who show overlapping histologic features of UC and CD is reported as 5–20% [5]. Following colon resection, 10% of patients with UC may develop a pouch phenotype with a poor prognosis which share features similar to CD [6]. A previous prospective study including patients with UC or inflammatory bowel disease (IBD) unclassified assessed 17 histopathological features of colectomy specimens atypical for UC and showed that these findings did not predict pouch outcomes including acute pouchitis, chronic pouchitis, and de novo Crohn’s disease [7]. However, this study did not classify the endoscopic pouch phenotypes. Hence, we hypothesized that detailed endoscopic classification of pouch phenotypes may be key to underpinning the effectiveness of using microscopic features in the resected colon to predict both pouch phenotypes and outcomes in patients with UC.
In this current study, we assessed if histopathological features in the resected colon subsequently determined the development of specific endoscopic pouchitis phenotypes in patients with a preoperative diagnosis of UC.
Materials and Methods
Study design
We performed a retrospective cohort study including patients who carried a preoperative diagnosis of UC from expert review of their preoperative clinical, endoscopic, radiographic and histological data. All of patients were treated with total proctocolectomy with IPAA in a “J pouch” configuration and subsequently underwent pouchoscopy at the University of Chicago between June 1997 and December 2019 [2]. This study was approved by the Institutional Review Board of the University of Chicago (IRB # 16–0061, # 15–573A).
Endoscopic Findings
We reviewed images and reports and identified endoscopic findings of inflammation that include “erythema/edema”, “erosions/friability”, “ulceration”, “stenosis”, “granularity”, and “loss of vascular pattern” based on the Pouchitis Disease Activity Index (PDAI) [8, 9]. Features of perianal, anal or perineal disease included fistulas, skin tags or hemorrhoids. We reviewed all available reports of pouchoscopies after ileostomy takedown and characterized pouch phenotypes. If the endoscopic description was not explicit and the findings were not noted, the endoscopy images were assessed to characterize the findings by the first author. If the endoscopic description and images were not available, we assigned these data as “not available”.
Pouch phenotypes
We classified each pouchoscopy into 7 main pouch phenotypes based on the anatomic location of abnormalities: (a) “normal”, (b) afferent limb (“AL”) involvement, (c) inlet (“IL”) involvement, (d) “diffuse inflammation of the pouch body”, (e) “focal inflammation of the pouch body”, (f) “cuffitis”, and (g) “pouch fistulas” [2]. A “normal pouch” was defined as a pouch without any abnormal endoscopic findings at any anatomical location of the J pouch, anastomosis, cuff, anal canal and perianal area and any type of fistulas. “AL involvement”, “IL involvement”, or “cuffitis” was defined as a patient with any type of endoscopic inflammation in the AL, IL, or rectal cuff, respectively. “Pouchitis” was defined as one or more endoscopic findings of inflammation in any of the tip, proximal, or distal pouch. “Diffuse inflammation of the pouch body” was defined as two or more endoscopic findings of inflammation in all anatomical locations of the pouch body (the tip, proximal, and distal pouch). “Focal inflammation of the pouch body” was defined as pouchitis that did not meet the criteria for diffuse inflammation.
“Pouch fistulas” included pouches with any type of fistula noted by pouchoscopy or other imaging studies ≥6 months from ileostomy takedown to exclude fistulas that occur temporally proximate to surgery as a postoperative complication [10]. If all of a patient’s pouchoscopies had normal findings, the patient was categorized into the “normal pouch” group. It is possible for one patient to be categorized into more than one of the pouch phenotypes with abnormal findings previously described. If a phenotype was identified at least once in a patient’s pouchoscopies, the patient was included in the analysis for their respective phenotypic categories.
Clinical and pathological findings
We retrospectively reviewed clinical charts and collected the following data: age at IBD diagnosis and colectomy (<18 vs ≥18 years old), gender, body mass index (BMI) (<25 vs ≥25), race, smoking status, family history of IBD and CD, disease duration until colectomy (<7 vs ≥7 years), pathological diagnosis of CD, indication for surgery, preoperative Clostridioides difficile infection (CDI), UC disease extent based on Montreal classification (E1, proctitis; E2, left-sided disease; E3, extensive disease) [11], number of stages of IPAA (3-stage vs 1- or 2-stage), technique of IPAA (stapled vs hand-sewn), postoperative complications (abscess requiring drainage, anastomotic leak, and pelvic sepsis) and preoperative therapies. We also assessed preoperative extraintestinal manifestations (EIMs) including arthritis/arthralgia, mouth ulcers, erythema nodosum, iritis/uveitis, pyoderma gangrenosum, and primary sclerosing cholangitis (PSC). The following preoperative manifestations which are frequently observed in CD patients were also evaluated: perianal fistulas, perianal abscess, skin tag, external and internal fistulas, and intestinal stricture.
We reviewed pathological reports of colectomy specimens and assessed pathological findings including deep, focal inflammation, granulomas, and terminal ileal (TI) involvement often observed in patients with CD [4, 12]. Deep inflammation included ulcerations and/or lymphoid aggregates/follicles observed below the level of the mucosa [13]. Depth of deep inflammation was determined as the deepest layer involved by inflammation. Pathological descriptions of “deep inflammation” include: deep ulcerations, deep fissuring ulcerations, knife-like ulcerations, and extensive ulcerations with submucosal fibrosis. Focal inflammation was defined as chronic inflammation with patchy distribution [12]. TI involvement included any microscopic inflammation observed in the TI. Study data were collected and managed using REDCap electronic data capture tools hosted at the University of Chicago [14].
Statistical analysis
Fisher’s exact test was used for a univariable analysis to assess factors contributing to the pouch endoscopic phenotypes. Logistic regression analysis was also performed as a multivariable analysis that included univariable variables with a P-value <0.10. P values <0.05 were considered statistically significant. Data were analyzed by EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan) [15], which is a graphical user interface for R (The R Foundation for Statistical Computing, version 2.13.0, Vienna, Austria).
Results
Patient background
We identified 382 patients with a preoperative diagnosis of UC treated by total proctocolectomy and IPAA in J pouch configuration at the University of Chicago between June 1997 and December 2019 who subsequently underwent pouchoscopies. The demographic and clinical characteristics of the patients are summarized in Table 1 and 2. Of these patients, 217 were men (56.8%) and 342 were Caucasian (89.5%). Three-stage IPAA was performed in 190 patients (49.7%), and the remaining patients had either 1-stage (27, 7.1%) or 2-stage (125, 32.7%) procedures. Mean disease duration until initial surgery was 6.9 years (± 7.2 years).
Table 1.
Demographic characteristics of patients with preoperative diagnosis of ulcerative colitis (N = 382)
| Variable | N (%) |
|---|---|
| Age at diagnosis | |
| <18 years old ≥18 years old NA |
86 (22.5) 290 (75.9) 6 (1.6) |
|
| |
| Gender | |
| Male Female |
217 (56.8) 165 (43.2) |
|
| |
| BMI | |
| <25 ≥25 NA |
164 (42.9) 201 (52.6) 17 (4.5) |
|
| |
| Race | |
| Caucasian African American Asian American Indian/ Alaska Native Native Hawaiian or other pacific Islander More than one race Unknown or NA |
342 (89.5) 14 (3.7) 18 (4.7) 2 (0.5) 0 (0) 3 (0.8) 3 (0.8) |
|
| |
| Primary sclerosing cholangitis | |
| Yes No |
16 (4.2) 366 (95.8) |
|
| |
| Smoker | |
| Current smoker Past smoker Non-smoker NA |
11 (2.9) 104 (27.2) 264 (69.1) 3 (0.8) |
|
| |
| Family history of IBD | |
| Yes | 111 (29.1) |
| Ulcerative colitis (UC) | 70 (63.1) |
| Crohn’s disease (CD) | 39 (35.1) |
| No | 255 (66.8) |
| NA | 16 (4.2) |
|
| |
| Mean disease duration until surgery, years (SD) | 6.9 (7.2) |
|
| |
| Disease duration until surgery | |
| <7 years ≥7 years NA |
242 (63.4) 133 (34.8) 7 (1.8) |
|
| |
| Diagnosis after colectomy | |
| UC CD IC Other or NA |
257 (67.3) 118 (30.9) 4 (1.0) 3 (0.8) |
|
| |
| Indication for surgery | |
| Medically refractory Dysplasia/Colorectal Cancer Fulminant colitis Toxic megacolon Other or NA |
303 (79.3) 44 (11.5) 46 (12.0) 8 (2.1) 32 (8.4) |
|
| |
| Prior Clostridioides difficile infection, | |
| Yes No NA |
65 (17.0) 272 (71.2) 45 (11.8) |
|
| |
| Disease extent | |
| E1: proctitis (proximal extent to the sigmoid colon) E2: left-sided disease (to the splenic flexure) E3: extensive disease (beyond the splenic flexure) NA |
4 (1.0) 43 (11.3) 269 (70.4) 66 (17.3) |
|
| |
| Surgical procedure | |
| Stage of ileal pouch-anal anastomosis (IPAA) | |
| 3-stage 2-stage 1-stage NA |
190 (49.7) 125 (32.7) 27 (7.1) 40 (10.5) |
| Anastomosis type | |
| Staple Hand-sewn NA |
215 (56.3) 82 (21.5) 85 (22.3) |
| Postoperative complications | |
| Yes | 186 (48.7) |
| Anastomosis leak Pelvic sepsis Abdominal abscess requiring drainage Fistulas or sinus tracts developed until ileostomy takedown |
18 (9.7) 5 (2.7) 42 (22.6) 14 (7.5) |
| No | 138 (36.1) |
| NA | 57 (14.9) |
BMI, body mass index; IBD, inflammatory bowel disease; IC, indeterminate colitis; SD, standard deviation; NA, not available.
Table 2.
. Pre- and postoperative therapies and pouch outcomes in patients with preoperative diagnosis of ulcerative colitis (N = 382)
| Variable | N (%) |
|---|---|
| Preoperative steroid use | |
| Yes No NA |
324 (84.8) 29 (7.6) 29 (7.6) |
|
| |
| Preoperative anti-tumor necrosis factor alpha (TNFα) | |
| Yes No NA |
164 (42.9) 189 (49.5) 29 (7.6) |
|
| |
| Preoperative immunomodulators | |
| Yes No NA |
205 (53.7) 148 (38.7) 29 (7.6) |
|
| |
| Postoperative metronidazole or ciprofloxacin | |
| Yes No NA |
311 (81.4) 64 (16.8) 7 (1.8) |
|
| |
| Postoperative corticosteroids | |
| Yes No NA |
102 (26.7) 273 (71.5) 7 (1.8) |
|
| |
| Postoperative anti-TNFα | |
| Yes No NA |
107 (28.0) 268 (70.2) 7 (1.8) |
|
| |
| Postoperative immunomodulators | |
| Yes No NA |
82 (21.5) 293 (76.7) 7 (1.8) |
|
| |
| Chicago Classification of Pouchitis | |
| Normal Afferent limb involvement (AL) Inlet involvement (IL) Diffuse inflammation of the pouch body Focal inflammation of the pouch body Cuffitis Pouch fistulas |
20 (5.2%) 116 (30.4%) 157 (41.1%) 106 (27.7%) 198 (51.8%) 171 (44.8%) 71 (18.6%) |
|
| |
| Pouch excision | |
| Yes No |
41 (10.7) 341 (89.3) |
NA, not available.
We identified 1,203 pouchoscopies (mean, 3.1 pouchoscopies per patient) that fulfilled the criteria for inclusion in the study. There were 20 patients with normal pouch (5.2%), 116 patients (30.4%) with AL involvement, 157 (41.1%) with IL involvement, 106 (27.7%) with diffuse inflammation, 198 (51.8%) with focal inflammation of the pouch body, 171 (44.8%) with cuffitis, and 71 (18.6%) with pouch fistulas (Table 2). Among patients with AL involvement, stenosis and ulcers were observed in 9 (2.4%) and 83 (21.7%) patients, respectively. Among patients with IL involvement, stenosis and ulcers were observed in 43 (11.3%) and 111 (29.1%) patients, respectively (Table S1).
Correlation between histopathology of the colectomy specimens and subsequent endoscopic phenotypes of the pouch
Among 382 patients with UC, 291 patients (76.2%) had available pathological reports of the colectomy specimens. The frequencies of IL involvement and pouch fistulas were significantly lower in patients with a pathological report compared with those without a report (P = 0.002 and P <0.001, respectively) (Table S2).
Seventy-five patients (25.9%) had deep inflammation and 11 patients (3.8%) had focal inflammation. Among 6 patients (2.1%) who had granulomas, 2 (33.3%) had crypt rupture-associated granulomas. Among 15 patients (5.2%) who had TI involvement in the resected specimen, 9 patients (60%) had the pathological diagnosis of backwash ileitis or findings of neutrophilic infiltrates suggestive of backwash ileitis. We found that TI involvement was significantly associated with AL involvement and AL ulcers (P = 0.04 and P = 0.02, respectively) (Table 3, S1). Notably, patients with deep inflammation were at significantly increased risk of pouch fistula development ≥6 months after ileostomy takedown (P = 0.001). There were no significant associations between the other endoscopic phenotypes and microscopic features of the colectomy specimens (Table 3).
Table 3.
Correlation between histopathology of the colectomy specimens and subsequent endoscopic phenotypes of the pouch
| N = 382# | Normal N = 20 (5.2%) |
AL involvement N = 116 (30.4%) |
IL involvement N = 157 (41.1%) |
Diffuse inflammation N = 106 (27.7%) |
Focal inflammation N = 198 (51.8%) |
Cuffitis N = 171 (44.8%) |
Pouch fistulas N = 71 (18.6%) |
||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | ||
|
Deep inflammation,
n (%) |
Yes No |
3 (16.7) 15 (83.3) |
72 (26.5) 200 (73.5) |
22 (26.5) 61 (73.5) |
51 (25.1) 152 (74.9) |
29 (27.1) 78 (72.9) |
46 (25.4) 135 (74.6) |
19 (24.4) 59 (75.6) |
56 (26.5) 155 (73.5) |
42 (27.8) 109 (72.2) |
33 (23.9) 105 (76.1) |
42 (30.2) 97 (69.8) |
31 (22.3) 108 (77.7) |
20 (47.6)
**
22 (52.4) |
55 (22.3)
192 (77.7) |
|
Focal inflammation,
n (%) |
Yes No |
0 (0) 18 (100) |
11 (4.0) 261 (96.0) |
3 (3.6) 80 (96.4) |
8 (3.9) 195 (96.1) |
4 (3.7) 103 (96.3) |
7 (3.9) 174 (96.1) |
3 (3.8) 75 (96.2) |
8 (3.8) 203 (96.2) |
6 (4.0) 145 (96.0) |
5 (3.6) 133 (96.4) |
7 (5.0) 132 (95.0) |
4 (2.9) 135 (97.1) |
3 (7.1) 39 (92.9) |
8 (3.2) 239 (96.8) |
|
Granuloma,
n (%) |
Yes No |
1 (5.6) 17 (94.4) |
5 (1.8) 267 (98.2) |
2 (2.4) 81 (97.6) |
4 (2.0) 199 (98.0) |
2 (1.9) 105 (98.1) |
4 (2.2) 177 (97.8) |
1 (1.3) 77 (98.7) |
5 (2.4) 206 (97.6) |
3 (2.0) 148 (98.0) |
3 (2.2) 135 (97.8) |
1 (0.7) 138 (99.3) |
5 (3.6) 134 (96.4) |
1 (2.4) 41 (97.6) |
5 (2.0) 242 (98.0) |
| Terminal ileal involvement, n (%) | Yes No |
0 (0) 18 (100) |
15 (5.5) 258 (94.5) |
8 (9.6)*
75 (90.4) |
7 (3.4)
197 (96.6) |
5 (4.7) 102 (95.3) |
10 (5.5) 172 (94.5) |
6 (7.7) 72 (92.3) |
9 (4.2) 203 (95.8) |
8 (5.3) 144 (94.7) |
7 (5.1) 131 (94.9) |
9 (6.4) 131 (93.6) |
6 (4.3) 133 (95.7) |
3 (7.0) 40 (93.0) |
12 (4.9) 235 (95.1) |
The number of UC patients who had available pathological reports of colectomy specimens was 291.
Fisher exact test P = 0.04,
Fisher exact test P = 0.001 AL, afferent limb; IL, inlet
We also performed the same analysis with an exclusion of patients who were definitely diagnosed with CD based on pathological findings of colectomy specimens (N = 2). The result showed that TI involvement and deep inflammation were significantly associated with AL involvement (P = 0.03) and pouch fistulas (P = 0.002), respectively (Table S3).
Correlation between patient factors and afferent limb involvement or pouch fistulas
On univariable analysis, we found that AL involvement was not increased in patients with PSC (P = 0.08) (Table 4, 5). We assessed the frequency of TI involvement and found no significant difference in the rate of TI involvement between patients with PSC (9.1%) and those without PSC (5%) (P = 0.45).
Table 4.
Correlation between patient factors and afferent limb involvement or pouch fistulas
| Variables, n (%) | AL inv (−) N (%) |
AL inv (+) N (%) |
P-value | Fistulas (−) N (%) |
Fistulas (+) N (%) |
P-value |
|---|---|---|---|---|---|---|
| N = 376 | 260 | 116 | 304 | 71 | ||
|
| ||||||
| Age at diagnosis | ||||||
| <18 years old ≥18 years old |
53 (20.8) 202 (79.2) |
30 (26.1) 85 (73.9) |
0.28 | 67 (22.3) 233 (77.7) |
16 (22.9) 54 (77.1) |
1.00 |
|
| ||||||
| Age at colectomy | ||||||
| <18 years old ≥18 years old |
21 (8.1) 239 (91.9) |
13 (11.2) 103 (88.8) |
0.34 | 29 (9.6) 274 (90.4) |
7 (9.9) 64 (90.1) |
1.00 |
|
| ||||||
| Gender | ||||||
| Male Female |
146 (56.2) 114 (43.8) |
68 (58.6) 48 (41.4) |
0.74 | 177 (58.2) 127 (41.8) |
36 (50.7) 35 (49.3) |
0.29 |
|
| ||||||
| BMI | ||||||
| <25 ≥25 |
116 (47.5) 128 (52.5) |
45 (39.1) 70 (60.9) |
0.14 | 128 (44.1) 162 (55.9) |
31 (45.6) 37 (54.4) |
0.89 |
|
| ||||||
| Race | ||||||
| Caucasian Others |
234 (91.1) 23 (8.9) |
103 (88.8) 13 (11.2) |
0.57 | 271 (89.7) 31 (10.3) |
64 (91.4) 6 (8.6) |
0.83 |
|
| ||||||
| Smoker | ||||||
| Ever smoker Non-smoker |
75 (29.2) 182 (70.8) |
39 (33.6) 77 (66.4) |
0.40 | 89 (29.5) 213 (70.5) |
24 (34.3) 46 (65.7) |
0.47 |
|
| ||||||
| Family history | ||||||
| No history of IBD Hx of IBD |
175 (70.9) 72 (29.1) |
79 (69.9) 34 (30.1) |
0.90 | 209 (71.8) 82 (28.2) |
42 (60.9) 27 (39.1) |
0.08 |
|
| ||||||
| Family history | ||||||
| No history of CD Hx of CD |
224 (90.7) 23 (9.3) |
98 (86.7) 15 (13.3) |
0.27 | 264 (90.7) 27 (9.3) |
59 (85.5) 10 (14.5) |
0.19 |
|
| ||||||
| Disease duration until surgery | ||||||
| <7 years ≥7 years |
162 (63.5) 93 (36.5) |
77 (67.0) 38 (33.0) |
0.56 | 192 (64.2) 107 (35.8) |
48 (68.6) 22 (31.4) |
0.58 |
|
| ||||||
| Preoperative CDI | ||||||
| Yes No |
43 (18.7) 187 (81.3) |
21 (20.2) 83 (79.8) |
0.77 | 56 (20.4) 219 (79.6) |
9 (15.0) 51 (85.0) |
0.47 |
|
| ||||||
| Indication for surgery | ||||||
| Other Dysplasia/Cancer |
217 (88.6) 28 (11.4) |
92 (86.0) 15 (14.0) |
0.49 | 248 (87.0) 37 (13.0) |
62 (91.2) 6 (8.8) |
0.41 |
|
| ||||||
| Disease extent | ||||||
| E1/E2 E3 |
37 (17.0) 181 (83.0) |
9 (9.6) 85 (90.4) |
0.12 | 41 (15.6) 222 (84.4) |
6 (11.8) 45 (88.2) |
0.67 |
|
| ||||||
| 3-stage IPAA | ||||||
| Yes No |
135 (56.7) 103 (43.3) |
52 (52.5) 47 (47.5) |
0.55 | 159 (57.4) 118 (42.6) |
29 (46.8) 33 (53.2) |
0.16 |
|
| ||||||
| Anastomosis | ||||||
| Staple Hand-sewn |
156 (75.4) 51 (24.6) |
57 (66.3) 29 (33.7) |
0.12 | 182 (72.5) 69 (27.5) |
33 (73.3) 12 (26.7) |
1.00 |
|
| ||||||
| Pathological diagnosis of CD | ||||||
| Yes No |
2 (1.0) 200 (99.0) |
0 (0.0) 83 (100.0) |
1.00 | 1 (0.4) 245 (99.6) |
1 (2.4) 41 (97.6) |
0.27 |
|
| ||||||
| Postoperative abscess drained | ||||||
| Yes No |
30 (13.4) 194 (86.6) |
10 (10.3) 87 (89.7) |
0.58 | 34 (13.1) 226 (86.9) |
8 (13.1) 53 (86.9) |
1.00 |
|
| ||||||
| Postoperative anastomosis leak | ||||||
| Yes No |
14 (6.2) 210 (93.8) |
2 (2.1) 95 (97.9) |
0.16 | 16 (6.2) 244 (93.8) |
2 (3.3) 59 (96.7) |
0.54 |
|
| ||||||
| Postoperative pelvic sepsis | ||||||
| Yes No |
5 (2.2) 219 (97.8) |
0 (0.0) 97 (100.0) |
0.33 | 3 (1.2) 257 (98.8) |
2 (3.3) 59 (96.7) |
0.24 |
|
| ||||||
| Preoperative steroids use | ||||||
| Yes No |
223 (92.1) 19 (7.9) |
97 (91.5) 9 (8.5) |
0.83 | 254 (90.7) 26 (9.3) |
66 (95.7) 3 (4.3) |
0.23 |
|
| ||||||
| Preoperative anti-TNFα drugs | ||||||
| Yes No |
113 (46.7) 129 (53.3) |
50 (47.2) 56 (52.8) |
1.00 | 136 (48.6) 144 (51.4) |
26 (37.7) 43 (62.3) |
0.11 |
|
| ||||||
| Preoperative immunomodulators | ||||||
| Yes No |
141 (58.3) 101 (41.7) |
62 (58.5) 44 (41.5) |
1.00 | 168 (60.0) 112 (40.0) |
35 (50.7) 34 (49.3) |
0.18 |
AL inv, afferent limb involvement; BMI, body mass index; IBD, inflammatory bowel disease; CD, Crohn’s disease; CDI, Clostridioides difficile infection; IPAA, ileal pouch-anal anastomosis; TNF, tumor necrosis factor; NA, not available.
Fisher exact test P < 0.05
Table 5.
Correlation between preoperative extra-intestinal manifestations and afferent limb involvement or pouch fistulas
| Variables, n (%)# | AL inv (−) N (%) |
AL inv (+) N (%) |
P-value* | Fistulas (−) N (%) |
Fistulas (+) N (%) |
P-value* |
|---|---|---|---|---|---|---|
| N = 238 | 167 | 70 | 197 | 41 | ||
|
| ||||||
| Arthritis/Arthralgia, | ||||||
| Yes No |
40 (24.0) 127 (76.0) |
17 (24.3) 53 (75.7) |
1.00 | 47 (23.9) 150 (76.1) |
12 (29.3) 29 (70.7) |
0.55 |
|
| ||||||
| Mouth ulcers | ||||||
| Yes No |
7 (4.2) 160 (95.8) |
2 (2.9) 68 (97.1) |
1.00 | 10 (5.1) 187 (94.9) |
0 (0.0) 41 (100.0) |
0.22 |
|
| ||||||
| Erythema nodosum | ||||||
| Yes No |
3 (1.8) 164 (98.2) |
0 (0.0) 70 (100.0) |
0.56 | 3 (1.5) 194 (98.5) |
0 (0.0%) 41 (100.0) |
1.00 |
|
| ||||||
| Iritis/Uveitis | ||||||
| Yes No |
3 (1.8) 164 (98.2) |
0 (0.0) 70 (100.0) |
0.56 | 3 (1.5) 194 (98.5) |
0 (0.0) 41 (100.0) |
1.00 |
|
| ||||||
| Pyoderma gangrenosum | ||||||
| Yes No |
2 (1.2) 165 (98.8) |
0 (0.0) 70 (100.0) |
1.00 | 1 (0.5) 196 (99.5) |
1 (2.4) 40 (97.6) |
0.32 |
|
| ||||||
| Perianal fistula | ||||||
| Yes No |
0 (0.0) 167 (100.0) |
1 (1.4) 69 (98.6) |
0.30 | 1 (0.5) 196 (99.5) |
0 (0.0) 41 (100) |
1.00 |
|
| ||||||
| Perianal abscess | ||||||
| Yes No |
2 (1.2) 165 (98.8) |
0 (0.0) 70 (100.0) |
1.00 | 2 (1.0) 195 (99.0) |
0 (0.0) 41 (100.0) |
1.00 |
|
| ||||||
| Skin tag | ||||||
| Yes No |
9 (5.4) 158 (94.6) |
3 (4.3) 67 (95.7) |
1.00 | 10 (5.1) 187 (94.9) |
2 (4.9) 39 (95.1) |
1.00 |
|
| ||||||
| Internal fistula | ||||||
| Yes No |
1 (0.6) 166 (99.4) |
0 (0.0) 70 (100.0) |
1.00 | 0 (0.0) 197 (100.0) |
1** (2.4) 40 (97.6) |
0.17 |
|
| ||||||
| External fistula | ||||||
| Yes No |
1*** (0.6) 166 (99.4) |
0 (0.0) 70 (100.0) |
1.00 | 0 (0.0) 197 (100) |
0 (0.0) 41 (100) |
1.00 |
|
| ||||||
| Intestinal stricture, | ||||||
| Yes No |
4 (2.4) 163 (97.6) |
1 (1.4) 69 (98.6) |
1.00 | 3 (1.5) 194 (98.5) |
2 (4.9) 39 (95.1) |
0.21 |
|
| ||||||
| N = 376 | 260 | 116 | 304 | 71 | ||
|
| ||||||
| PSC | ||||||
| Yes No |
7 (2.7) 253 (97.3) |
8 (6.9) 108 (93.1) |
0.08 | 13 (4.3) 291 (95.7) |
2 (2.8) 69 (97.2) |
0.75 |
No available data regarding clinical manifestations in 142 patients,
Fisher’s exact test P = 0.05,
Gastrocolic fistula,
Rectovaginal fistula.
AL inv, afferent limb involvement; PSC, Primary sclerosing cholangitis.
Among 71 patients who developed pouch fistulas, the most frequent type of fistula was perianal fistula (43, 60.6%), followed by rectovaginal or anovaginal fistulas (17, 23.9%), and fistulas from the pouch (6, 8.5%) (Table S4). A univariable analysis showed that the risk of pouch fistulas trended toward an increase in patients with family history of IBD (P = 0.08) (Table 4). In terms of preoperative EIMs, there were no significant factors contributing to pouch fistulas (Table 5).
Multivariable analysis to assess contributing factors to afferent limb involvement or pouch fistulas
Multivariable analysis showed that TI involvement significantly increased the risk of AL involvement (Odds ratio (OR) 2.96; 95% confidence interval (CI) 1.04–8.47; P = 0.04) and deep inflammation was significantly associated with pouch fistula (OR 3.27; 95%CI 1.65–6.47; P = 0.0007) (Table 6).
Table 6.
Logistic regression model to analyze risk factors for afferent limb involvement or pouch fistulas
| Pouch Phenotype | Risk Factor | Odds ratio (95% CI) | P-value |
|---|---|---|---|
| AL involvement | PSC | 1.59 (0.43–5.90) | 0.49 |
| TI involvement | 2.96 (1.04–8.47) | 0.04 | |
| Pouch fistulas | Family History of IBD | 1.64 (0.81–3.31) | 0.17 |
| Deep inflammation | 3.27 (1.65–6.47) | <0.001 |
AL, afferent limb; IBD, inflammatory bowel disease; PSC, Primary sclerosing cholangitis; TI, terminal ileum
Subgroup analysis for terminal ileal (TI) involvement or deep inflammation of colectomy specimens
Among 15 patients with TI involvement in their colectomy specimens, 5 patients (33.3%) were diagnosed with UC by our pathologists, 5 patients (33.3%) were diagnosed with IBD favoring UC rather than CD, and 2 patients (13.3%) were diagnosed with IBD favoring CD rather than UC. Only one patient (6.7%) was definitely diagnosed with CD on pathology.
Among 75 patients with deep colonic inflammation in their colectomy specimens, 32 patients (42.7%) with a diagnosis of UC on pathology. Further, 38 patients (50.7%) had a diagnosis favoring UC rather than CD and 2 patients (2.7%) favoring CD rather than UC. Only two patients (2.7%) were clearly diagnosed with CD based on the colectomy specimen.
Subgroup analysis of patients with deep inflammation showed that the most common finding of deep inflammation was deep or deep fissuring ulcerations (53, 70.7%), followed by lymphoid aggregates/follicles (8, 10.7%) and knife-like ulcerations (7, 9.3%) (Table S5). In terms of the depth of deep inflammation, 36 patients (48.0%) had inflammation involving the serosa or transmural inflammation. The depth of inflammation was reported as submucosa in 12 patients (16.0%), muscularis propria in 11 patients (14.7%), and subserosa in 5 patients (6.7%). Eleven patients (14.7%) had no data regarding the depth of inflammation and 10 patients (91%) had deep or deep fissuring ulcerations (Table S5). Patients with inflammation of the submucosal layer or deeper had a significant risk of the pouch fistulas as well (OR 3.32; 95%CI 1.65–6.69; P <0.001) (Table S6).
Discussion
The development of surgical reconstruction of bowel continuity (i.e. IPAA) in patients with UC who require a total proctocolectomy has provided patients with a realistic exception to the requirement for a permanent ileostomy. The development of inflammation in these resulting “J pouches” can be challenging to manage and predict. In this study, we identify histologic features of colectomy specimens in UC that predict subsequent endoscopic pouch phenotypes. Particularly, deep inflammation in the resected colon is an independent risk factor for the development of pouch fistulas.
The frequency of pouch fistulas in patients with IPAA has been reported as 2.6–14% [16–18]. Pouch fistula is a poor prognostic phenotype, with a high rate of pouch failure requiring ileostomy and/or pouch excision (21–71%) [17, 19, 20]. Our recent study demonstrated that the 20-year pouch survival with pouch fistulas was 71.5% (95% CI 56.4%−82.2%), which was lower than pouches without fistulas (83.9%, 95% CI 76.2%−89.4%) [2]. Previous studies have reported that 6% of patients with a preoperative diagnosis of UC or indeterminate colitis (IC) experienced a diagnosis revision to CD based on the pathological assessment of colectomy specimens [21] and the postoperative pathological diagnosis of CD was reported as a risk factor of pouch fistulas [17, 19]. However, we found that only 2.7% of patients with deep inflammation were diagnosed with CD by our experienced gastrointestinal pathologists, suggesting that pathological evaluation for deep inflammation in the colectomy specimens is more valuable than the explicit histopathologic diagnosis of CD. This finding highlights the challenges and perhaps even somewhat arbitrary nature of pathologic distinction between UC, CD, or IBD-unclassified (IBD-U) in some patients. Overreliance on pathologic diagnosis may compromise expectations regarding outcomes.
The timing and etiology of pouch fistulas might be interrelated. Nisar et al. divided patients with IPAA into those who developed pouch fistulas within 12 months (early-onset group) and after 12 months of IPAA creation (late-onset group) [22]. They found a correlation between procedure-related sepsis and early-onset fistulas, suggesting that they might be attributed to surgery-related complication. Meanwhile, the frequency of a delayed diagnosis and revision to CD was greater in the late-onset group than in the early-onset group [22]. Our recent study also found that preoperative diagnosis of CD was significantly associated with pouch fistulas noted 6 months or more after ileostomy takedown [2]. All these findings support that patients with pouch fistulas which developed after 6–12 months from surgery might have a pathophysiology similar to patients with CD without IPAA. Although the data regarding exact locations of internal and external fistula openings were limited by the current study’s retrospective design, the location of fistulas is also important to differentiate CD of the pouch from surgical complications. While surgical leak/sinus frequently develop at the pouch-anal anastomosis or tip of “J”, the fistulizing CD of the pouch often involves other anatomical locations such as the anal canal [23]. Our data showed that the most common type of fistulas was perianal fistulas (61%), followed by rectovaginal or anovaginal fistulas (24%). Furthermore, given that fistula from the pouch (8.5%) was found to be less frequent in this study, fistulas developed at the anastomosis or tip of “J” would be less frequent and pouch fistulas in our definition may be a category of fistulizing CD of the pouch.
We also found that TI involvement in the colectomy specimens was significantly associated with AL involvement and 60% of patients with TI involvement were diagnosed with backwash ileitis or neutrophilic infiltrates suggestive of backwash ileitis. Backwash ileitis is defined as mucosal inflammation proximal to the ileocecal valve and is frequently observed in patients with PSC-IBD [24, 25]. Given that there was no significant difference in the rate of TI involvement between patients with PSC (9.1%) and those without PSC (5%) in our data, TI involvement might independently increase the risk of AL involvement. On the other hand, Shen et al. demonstrated that patients with PSC do have an increased risk of AL involvement based on endoscopic and histologic scores in PDAI [8, 26]. A recent retrospective study including 182 patients with PSC also showed that patients with PSC-pouchitis were more likely to develop AL involvement compared to UC-pouchitis [27]. Meanwhile, our data showed that PSC was not significantly associated with the risk of AL involvement. There is a possibility that our data may be underpowered because only 16 patients with PSC were included.
A retrospective study assessing 15 patients with UC who underwent IPAA and experienced AL involvement showed no radiological and histologic evidence of CD [28]. Our previous work also showed that AL involvement was not associated with a preoperative diagnosis of CD [2], suggesting that AL involvement appears to have a distinct pathophysiology from CD. Indeed, our current work did not find any positive association between AL involvement and preoperative EIMs suggestive of CD in this study. Thus, we postulate that some patients with AL involvement might have a pathophysiology similar to PSC such as a change in fecal bile pool rather than CD [26, 29].
There are several strengths and limitations to this study. A significant strength was that the findings of this study come from a tertiary center with expertise in gastrointestinal pathology and in medical and surgical management of IBD, and these findings may be translatable to actual clinical practices. However, we acknowledge that it also was a limitation that this study was performed at a single tertiary care center which may limit generalization of the results and that a larger, multi-center study is important to confirm our results with other patient populations who also experience pouchitis. Furthermore, a limitation is the retrospective design of the study, which limited available data for some patients. For example, our data did not necessarily include an indication of each pouchoscopies such as clinical symptoms or neoplasia surveillance. Furthermore, pathology reports were not available in about a quarter of patients, and availability of pathology reports may contribute to a selection bias.
There is a possibility that all pathologists did not necessarily describe the absence or presence of atypical findings for UC. Hence, the possibility of intra- and/or inter-observer biases also needs to be considered, though all findings followed the standard operating protocol at our center, and in prior publications, we have described the approach to pathological interpretation and inter-observer reliability between pathologists [30]. To minimize such biases, future work should include a systematic re-review of all of the pathological slides.
We acknowledge that some may believe that these patients simply had undiagnosed CD, which in this retrospective review and in consideration of IPAA outcomes has become more obvious. We were quite specific to consider this possibility in our approach. All patients in this analysis carried a preoperative diagnosis of UC from expert review of their prior clinical, endoscopic, radiographic and histological data. Patients with prior CD were excluded, and the mean duration of follow-up with that diagnosis was 6.9 years (± 7.2 years). We believe that given this approach, we can be confident that this patient population would be similar to that in other practices.
More objective measures may need to be established to define deep inflammation of the colectomy specimens as well. In addition, we acknowledge that these findings and the risk of pouch progression may not change a patient’s mind about proceeding with a J pouch, but certainly argue that additional information may influence future clinical research and shared decision making about surgery and follow-up. We therefore believe that these findings have identified an important need to develop reliable and reproducible histological grading of pre- and post-colectomy pathology assessments that will influence management decisions in patients who are considering IPAA. Development of such a system will undoubtedly provide information that will inform future research studies and may influence the approach to post-operative monitoring and strategies for prevention of pouch complications.
In conclusion, we found that the histopathology of colectomy specimens in patients with UC undergoing total proctocolectomy and IPAA predicted subsequent ileal pouch findings. Our study demonstrated that deep inflammation in the resected colon was significantly associated with a phenotype consistent with penetrating CD. These findings have important implications for gastroenterologists, colorectal surgeons and for patients.
Supplementary Material
Acknowledgements
The authors thank funding in part provided by NIDDK P30 DK42086, NIDDK RC2 DK122394, and the GI Research Foundation of Chicago
FUNDING:
Funding in part provided by NIDDK P30 DK42086, NIDDK RC2 DK122394, and the GI Research Foundation of Chicago
DISCLOSURES:
SA, JEO, VR, LRG, YY, CT, JR, ADO, CRW, KSO, RDH, KU, BDS, NHH, AS, and JH have no relevant disclosures.
RDC is on the speaker’s bureau from AbbVie and Takeda. He is a consultant/advisor for AbbVie Laboratories, BM/celgene, Eli Lilly, Gilead Sciences, Janssen, Pfizer, Takeda, UCB Pharma. He has received clinical trial support/grants from Abbvie, BMS/Celgene, Boehringer Ingelheim, Crohn’s and Colitis Foundation of America, Genentech, Gilead Sciences, Hollister, Medimmune, Mesoblast Ltd., Osiris Therpeutics, Pfizer, Receptos, RedHill Biopharma, Sanofi-Aventis, Schwarz Pharma, Seres Therapeutics, Takeda Pharma, UCB Pharma. His wife is on the board of directors of Aerpio Theraoeutics, Novus Therapeutics, Vital Therapeutics, Inc, and NantKwest.
MAR has served as a consultant for Pfizer.
SRD has served as a consultant for Pfizer and is on the speaker’s bureau for AbbVie.
JP has received grant support from AbbVie and Takeda. He has served as a consultant for Veraste,. CVS Caremark and is on the advisory board for Takeda, Janssen and Pfizer.
EBC is the founder and chief medical officer of AVnovum Therapeutics
DTR has received grant support from Takeda; and has served as a consultant for Abbvie, Abgenomics, Allergan Inc., Arena Pharmaceuticals, Bellatrix Pharmaceuticals, Boehringer Ingelheim Ltd., Bristol-Myers Squibb, Celgene Corp/Syneos, Check-cap, Dizal Pharmaceuticals, GalenPharma/Atlantica, Genentech/Roche, Gilead Sciences, Ichnos Sciences S.A., InDex Pharmaceuticals, Iterative Scopes, Janssen Pharmaceuticals, Lilly, Materia Prima, Narrow River Mgmt, Pfizer, Prometheus Laboratories,Reistone, Takeda, and Techlab Inc. He is also co-founder of Cornerstones Health, Inc. and GoDuRn, LLC; on the Board of Trustees of the American College of Gastroenterology.
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