ORIGINAL ARTICLE
Disease Course and Management Strategy of Pouch Neoplasia in Patients with Underlying Inflammatory Bowel Diseases Xian-Rui Wu, MD, PhD,* Feza H. Remzi, MD,* Xiu-Li Liu, MD, PhD,† Lei Lian, MD, PhD,* Luca Stocchi, MD,* Jean Ashburn, MD,* and Bo Shen, MD‡
Background: To evaluate the disease course and management strategy for pouch neoplasia. Methods: Patients undergoing ileal pouch surgery for underlying ulcerative colitis who developed low-grade dysplasia (LGD), high-grade dysplasia, or adenocarcinoma in the pouch were identified.
Results: All eligible 44 patients were evaluated. Of the 22 patients with initial diagnosis of pouch LGD, 6 (27.3%) had persistence or progression after a median follow-up of 9.5 (4.1–17.6) years. Family history of colorectal cancer was shown to be a risk factor associated with persistence or progression of LGD (P ¼ 0.03). Of the 12 patients with pouch high-grade dysplasia, 5 (41.7%) had a history of (n ¼ 2, 16.7%) or synchronous (n ¼ 4, 33.3%) pouch LGD. Pouch high-grade dysplasia either persisted or progressed in 3 patients (25.0%) after the initial management, during a median time interval of 5.4 (2.2–9.2) years. Of the 14 patients with pouch adenocarcinoma, 12 (85.7%) had a history of (n ¼ 2, 14.3%) or synchronous dysplasia (n ¼ 12, 85.7%). After a median follow-up of 2.1 (0.6–5.2) years, 6 patients with pouch cancer (42.9%) died. Comparison of patients with a final diagnosis of pouch adenocarcinoma (14, 32.6%), and those with dysplasia (29, 67.4%) showed that patients with adenocarcinoma were older (P ¼ 0.04) and had a longer duration from IBD diagnosis or pouch construction to the detection of pouch neoplasia (P ¼ 0.007 and P ¼ 0.0013).
Conclusions: The risk for progression of pouch dysplasia can be stratified. The presence of family history of colorectal cancer seemed to increase the risk for persistence or progression for patients with pouch LGD. The prognosis for pouch adenocarcinoma was poor. (Inflamm Bowel Dis 2014;20:2073–2082) Key Words: ileal pouch, inflammatory bowel disease, pouch adenocarcinoma, pouch dysplasia
R
estorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) has been widely considered as the surgical treatment of choice for the majority of patients with medically refractory ulcerative colitis (UC) or colitis-associated neoplasia. IPAA significantly improves patients’ health-related quality of life (QOL) by preserving the natural route of defecation and by avoiding the need for permanent ileostomy. Good functional outcomes of IPAA have been reported in long-term follow-up studies.1–3 However, the risk for inflammatory bowel diseases (IBD)–associated neoplastic transformation in the anal transitional zone (ATZ) or pouch body per se may still persist, despite removal of the diseased colon.
Received for publication May 12, 2014; Accepted June 23, 2014. From the Departments of *Colorectal Surgery, †Anatomic Pathology, and ‡ Gastroenterology & Hepatology, Cleveland Clinic Foundation, Cleveland, Ohio. Supported in part by a grant from the Crohn’s and Colitis Foundation of America and the Ed and Joey Story Endowed Chair (B.S.). X-R. Wu is a research fellow from the Department of Colorectal Surgery, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. The remaining authors have no conflicts of interest to disclose. Reprints: Bo Shen, MD, Department of Gastroenterology & Hepatology, Desk A31, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195 (e-mail: [email protected]). Copyright © 2014 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000152 Published online 18 August 2014.
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The reported cumulative prevalence of pouch neoplasia ranges from 0% to 18.5%.4–9 Our recent study of 3203 patients with ileal pouches showed that the cumulative incidence for pouch neoplasia at 5, 10, 15, 20, and 25 years after pouch construction were 0.9%, 1.3%, 1.9%, 4.2%, and 5.1%, respectively.10 Reported risk factors for the development of pouch neoplasia after IPAA surgery for patients with underlying UC include diagnosis of UC-associated dysplasia or cancer based on either preoperative biopsies or surgical specimen,10,11 the presence of type C mucosa of the pouch, concurrent primary sclerosing cholangitis, a family history of colorectal cancer (CRC), and a long duration of underlying UC.7,10–15 There has been no consensus on how to manage pouch patients with LGD, either continuous close surveillance or surgical intervention. There are scant data in the literature on the natural history of pouch neoplasia, which would provide some guidance. Therefore, the aims of our study were to evaluate the disease course of pouch neoplasia, including low-grade dysplasia (LGD), high-grade dysplasia (HGD), and adenocarcinoma and to identify risk factors associated with the persistence or progression of LGD after the initial diagnosis.
PATIENTS AND METHODS Patients This study was approved by the Cleveland Clinic Institutional Review Board. Patients with pouch neoplasia were identified www.ibdjournal.org |
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using the Institutional Review Board–approved Pouchitis Registry at the Center for Ileal Pouch Disorders and Pouch Database at Department of Colorectal Surgery. Demographics and clinical data were all prospectively maintained in the Registry or Database. Both paper charts and electronic medical records would be carefully reviewed when necessary.
Inclusion and Exclusion Criteria Inclusion criteria were: (1) ileal pouches; (2) diagnosis of neoplasia in the ileal pouches, including LGD, HGD, or adenocarcinoma; and (3) underlying IBD. Patients with IPAA with a preoperative diagnosis of familial adenomatous polyposis or other colonic pathologies were excluded.
Diagnostic Criteria Neoplasia was documented and graded as LGD, HGD, or adenocarcinoma based on histology. Pouch neoplasia was defined as the presence of neoplasia at the ATZ, pouch body, and/or afferent limb. The patient (n ¼ 1) with HGD at the ATZ, which later on progressed to squamous cell carcinoma (SCC) was also evaluated in this study. As a part of our routine clinical practice, all the diagnoses of pouch dysplasia were confirmed with at least 2 expert gastrointestinal pathologists with a special interest in IBD.
Definition of Variables Demographic and clinicopathological variables were defined as follows: active smoking: consumption of more than 7 cigarettes per week for at least 6 months before the data entry; ex-smoking: cessation of smoking 6 months before data entry; family history of IBD: one or more of the first-degree (parents, offspring, or siblings of the index patients) or second-degree relatives who had IBD; family history of CRC: one or more of the first-degree (parents, offspring, or siblings of the index patients) or second-degree relatives who had CRC; history of pouch neoplasia: the presence of pouch neoplasia at least 3 months before the diagnosis of the current neoplasia; synchronous neoplasia: the presence of neoplasia within 3 months of the current neoplasia; persistent neoplasia: the diagnosis of dysplasia of the same grade at least 3 months after its initial diagnosis; extensive colitis: endoscopic, macroscopic, or microscopic disease extending proximal to the splenic flexure; extraintestinal manifestations: including the presence of arthralgia or arthropathy, primary sclerosing cholangitis, pyoderma gangrenosum, erythema nodosum, IBD-related ocular lesions, thromboembolic events; Significant comorbidities: congestive heart failure, coronary bypass surgery, chronic obstructive pulmonary diseases, renal stone or insufficiency, nongastrointestinal cancer, stroke, and liver failure; chronic pouchitis: a modified Pouchitis Disease Activity Index $5 points and symptoms lasting 4 weeks or more and failed to respond to a 4-week course of single antibiotic therapy (ciprofloxacin, metronidazole, or tinidazole); cuffitis: endoscopic and histologic inflammation of the rectal cuff; Crohn’s disease of the pouch: diagnosed based on our previously published criteria, i.e., the presence of non-surgery-related perianal
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fistula or inflammation or ulcerations at the prepouch neoterminal ileum or small bowel in the absence of non-steroidal anti-inflammatory drug use, or granulomas on histology.
Clinical Practice Pattern For patients with ileal pouch seen and followed up at our institution, surveillance pouchoscopy was routinely offered once every 1 to 3 years at the discretion of the IBD specialist (B.S.) or colorectal surgeons, largely based on the algorithm previous published by our group.16 Patients were given 1 to 2 Fleet (CB Fleet, Lynchburg, VA) enemas or oral PEG before the procedure. Sedated or unsedated pouchoscopy procedures included careful inspection of the ATZ, pouch body, and afferent limb. During the diagnostic and/or surveillance pouchoscopy, 2 to 6 pieces of biopsy were taken randomly from each of the 3 aforementioned areas. In addition, any abnormal or suspicious areas, such as polyps and deep ulcers, were sampled. The biopsy specimens were separately labeled and submitted for pathologists’ evaluation. The management strategy for the patients with pouch neoplasia also largely followed the treatment algorithm, which was previous proposed by our group.16
Outcome Measurement The primary outcomes of this study were the progression or “regression” of pouch neoplasia and risk factors associated with the persistence or progression of LGD after the initial diagnosis.
Statistical Analysis Descriptive statistics were computed for all variables. These included mean and SDs or medians and interquartile ranges (IQRs) for continuous factors, and frequencies for categorical factors. Comparisons between 2 groups were made by using the 2-tailed t test (or Wilcoxon rank sum test as appropriate) for continuous variables and chi-square test (or the Fisher’s exact test as appropriate) for categorical variables. Patient survival analysis and the impact of family history of CRC on the persistence or progression for patients with LGD was depicted with Kaplan– Meier curves with log-rank test. All statistical analyses were performed with the SPSS software version 16 (SPSS, Chicago, IL). P , 0.05 was considered statistically significant.
RESULTS A total of 44 patients with LGD, HGD, or adenocarcinoma in the ileal pouch were identified. The diagnosis at the first detection of the neoplasia was LGD in 22 patients (50.0%), HGD in 10 (22.7%) and adenocarcinoma in 12 (27.3%). The final diagnosis (the highest grade of dysplasia) of neoplasia was LGD in 19 patients (43.2%), HGD in 10 (22.7%), adenocarcinoma in 14 (31.8%) and SCC in 1 (2.3%) patient.
Disease Course of Pouch LGD A total of 22 patients were initially diagnosed with LGD in the ileal pouches. Male accounted for 68.2% (n ¼ 15), with a mean age at diagnosis of 48.0 6 15.9 years. The location of the pouch
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LGD was at the ATZ in 19 patients (86.4%), pouch body in 2 (9.1%), and ATZ and pouch body in 1 (4.5%) patient. Of the 22 patients, 1 (4.5%) had synchronous indefinite dysplasia. All of the 22 patients (100%) continued surveillance pouchoscopy as the primary management at the time of the diagnosis. After a median of 6.0 (IQR, 2.0–9.0) follow-up pouchoscopies during a time period of 9.5 (IQR, 4.1–17.6) years, pouch LGD either persisted or progressed in 6 patients (27.3%): 3 had persistence only, 1 had persistence then progressed to HGD, 1 progressed to HGD, and 1 had persistence then progressed to adenocarcinoma (Fig. 1). All the 6 patients (27.3%) underwent completion proctectomy with redo pouch as the management for persistence or progression (Table 1). Other clinicopathological features of pouch LGD were shown in Table 2.
Risk Factors for Persistence or Progression of Pouch LGD The 22 patients were further evaluated to identify risk factors associated with the persistence or progression of LGD in the ileal pouches. Comparison analyses between patients with persistence or progression (n ¼ 6, 27.3%) and those without (n ¼ 16, 72.7%) showed that patients with persistence or progression were more likely to have a family history of CRC (P ¼ 0.029) (Table 2). This was further confirmed by using the Kaplan–Meier survival analysis (log-rank test, P ¼ 0.03) (Fig. 2). No other demographics or clinical data were found to be significantly associated with dysplasia persistence or progression once pouch LGD was diagnosed (P . 0.05) (Table 2).
Disease Course of Pouch HGD A total of 12 patients were diagnosed with HGD in the ileal pouch, including 2 patients (16.7%) who progressed from pouch LGD and another 10 (83.3%) who were initially diagnosed with pouch HGD. Six patients (50%) were men, with a mean age at diagnosis of 43.9 6 7.4 years. The location of the pouch HGD was at the ATZ in 11 patients (91.7%) and afferent limb in 1 (8.3%). Of the 12 patients, 6 (50.0%) had synchronous pouch neoplasia, including 1 patient who had a history of pouch LGD. The synchronous lesions were indefinite dysplasia in 2 (16.7%), LGD in 3 (25.0%), and both indefinite dysplasia and LGD in 1
FIGURE 1. Flow chart for patients with LGD in the ileal pouches.
Disease Course of Pouch Neoplasia
TABLE 1. Management and Outcomes for Pouch Dysplasia Characteristics History of LGD (.3 mo from the diagnosis of index pouch neoplasia) Synchronous neoplasia (,3 mo from the diagnosis of index pouch neoplasia) LGD IND LGD and IND Management of index pouch neoplasia Completion proctectomy with redo pouch Pouch advancement flap Transanal excision Surveillance pouchoscopy Unclear Persistence or progression Adenocarcinoma Squamous cell cancer HGD LGD Management for recurrence or progression APR with end ileostomy APR with K pouch Completion proctectomy with redo pouch Unclear No. follow-up scopes Duration of follow-up, yr
LGD (N ¼ 22) (%)
HGD (N ¼ 12) (%)
NA
2 (16.7)
1 (4.5)
6 (50.0)
NA 1 (4.5) NA
3 (25.0) 2 (16.7) 1 (8.3)
0 (0)
4 (33.3)
0 (0) 0 (0) 22 (100) 0 (0) 6 (27.3) 1 (4.5) 0 (0) 3 (13.6) 5 (22.7) n¼6
1 (8.3) 1 (8.3) 5 (41.7) 1 (8.3) 3 (25.0) 1 (8.3) 1 (8.3) 2 (20.0) 0 (0) n¼3
0 (0) 0 (0) 6 (100)
1 (33.3) 1 (33.3) 0 (0)
0 (0) 6.0 (2.0–9.0) 9.5 (4.1–17.6)
1 (33.3) 3.0 (2.0–4.0) 5.4 (2.2–9.2)
IND, indeterminate for dysplasia.
(8.3%) patient. The primary management for the 12 patients included completion proctectomy with redo pouch (4, 33.3%), pouch advanced flap (1, 8.3%), transanal excision (1, 8.3%), ongoing surveillance pouchoscopy (5, 41.7%), and 1 patient (8.3%) was lost to follow-up (Table 1). Continued surveillance pouchoscopy without surgical treatment in 5 patients (41.7%) with pouch HGD was due to unifocal lesion with subsequently negative follow-up pouchoscopy (n ¼ 3, 25.0%), HGD contained in an inflammatory polyp (n ¼ 1, 8.3%) and patient refusal of surgical management (n ¼ 1, 8.3%). After a median of 3.0 (2.0– 4.0) follow-up pouchoscopies during a time period of 5.4 (2.2– 9.2) years, 3 patients (25.0%) had either persistence or progression of the pouch HGD (1 persisted only, 1 progressed to SCC, and 1 progressed to adenocarcinoma), including one who had undergone completion proctectomy with redo pouch after the initial diagnosis of pouch HGD, one who had underwent transanal www.ibdjournal.org |
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TABLE 2. Risk Factors Associated with Persistence or Progression for Patients with Ileal Pouch with LGD Persistence or Progression Characteristics No. patients Age at diagnosis of IBD, yr Age at pouch construction, yr Age at diagnosis of pouch LGD, yr Duration from IBD diagnosis to pouch construction, yr Duration from IBD diagnosis to pouch LGD, yr Duration from pouch construction to pouch LGD, yrs Body mass index, kg/m2 Male patients Smoking Ever Never Drinking alcohol Ever Never Significant comorbidities Autoimmune disorders Family history of IBD Family history of CRC Extent of colitis Extensive colitis Left-sided colitis Toxic megacolon Primary sclerosing cholangitis Extraintestinal manifestations Underlying diseases UC Indeterminate colitis CD Indication for colectomy Refractory disease Neoplasia Stage of pouch construction 1 or 2 3 Configuration of the pouch J pouch S pouch Location of pouch neoplasia ATZ Pouch body Pouch body and ATZ Any concurrent pouch disorders Concurrent chronic pouchitis Concurrent CD of the pouch Concurrent cuffitis No. follow-up scopes Duration of follow-up, yr CD, Crohn’s disease; IND, indeterminate for dysplasia.
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All Cases
No
Yes
22 29.3 6 10.3 43.5 6 13.6 48.0 6 15.9 13.8 (5.2–21.0) 15.3 (10.9–27.8) 2.7 (1.1–6.3) 26.5 6 5.3 15
16 29.0 6 10.7 42.2 6 13.6 47.0 6 15.8 12.8 (2.6–20.7) 16.3 (5.4–29.1) 2.8 (1.4–6.1) 25.9 6 5.2 10 (62.5%)
6 30.2 6 10.1 47.2 6 14.0 50.5 6 17.1 13.8 (5.8–26.2) 14.3 (10.9–29.0) 2.0 (0.5–7.1) 27.8 6 5.9 5 (83.3%)
6 13
4 (30.8%) 9 (69.2%)
2 (33.3%) 4 (66.7%)
8 11 14 5 2 3
5 8 9 3
3 3 5 2 2 3
19 3 3 1 5
15 (93.8%) 1 (6.2%) 3 (18.8%) 1 (6.2%) 4 (25.0%)
4 (66.7%) 2 (33.3%) 0 (0%) 0 (0%) 1 (16.7%)
17 4 1
12 (75.0%) 3 (18.8%) 1 (6.2%)
5 (83.3%) 1 (16.7%) 0 (0%)
11 11
9 (56.2%) 7 (43.8%)
2 (33.3%) 4 (66.7%)
15 7
9 (56.2%) 7 (43.8%)
6 (100%) 0 (0%)
16 6
11 (68.8%) 5 (31.2%)
5 (83.3%) 1 (16.7%)
19 2 1 10 7 1 4 6.0 (2.0–9.0) 9.5 (4.1–17.6)
13 (81.2%) 2 (12.5%) 1 (6.2%) 7 (43.8%) 4 (25.0%) 1 (6.2%) 3 (18.8%) 6.0 (3.0–10.5) 11.6 (5.3–17.1)
6 (100%) 0 (0%) 0 (0%) 3 (50.0%) 3 (50.0%) 0 (0%) 1 (16.7%) 4.0 (2.0–8.0) 5.4 (2.4–19.1)
P
0.81 0.45 0.66 0.61 1.0 0.46 0.49 0.62 1.0
1.0 (38.5%) (61.5%) (56.2%) (18.8%) 0 (0%) 0 (0%)
(50.0%) (50.0%) (83.3%) (33.3%) (33.3%) (50.0%)
0.35 0.59 0.11 0.029 0.17
0.53 1.0 1.0 1.0
0.64
0.12
0.63
1.0
1.0 0.33 1.0 1.0 0.57 0.61
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Disease Course of Pouch Neoplasia
TABLE 3. Management and Outcomes for Pouch Adenocarcinoma Characteristics
FIGURE 2. The impact of family history of CRC on the persistence or progression of LGD in the ileal pouches.
excision, and one who continued surveillance pouchoscopy without surgical intervention (Fig. 3). The management for the 3 patients with pouch HGD who either persisted or progressed included abdominoperineal resection (APR) with end ileostomy in 1 (33.3%) patient, APR with a K pouch in 1 (33.3%), and 1 (33.3%) was lost to follow-up (Table 1).
Disease Course of Pouch Adenocarcinoma A total of 14 patients were diagnosed with adenocarcinoma in the ileal pouch, including 2 (14.3%) had a history of pouch dysplasia (diagnosed at least 3 mo before the diagnosis of pouch adenocarcinoma) (Table 3). Ten patients (71.4%) were men, with a mean age at diagnosis of 54.9 6 14.5 years. The location of the pouch adenocarcinoma was at the ATZ in 10 patients (71.4%), ATZ and pouch body in 2 (14.3%), pouch body in 1 (7.1%), and afferent limb and pouch body in 1 (7.1%). Of the 14 patients, 3 (21.4%) had stage I diseases, 6 (42.9%) had stage II, 3 (21.4%) had stage III, and 2 (14.3%) had stage IV diseases. Twelve patients (85.7%), including the 2 patients who had a history of
FIGURE 3. Flow chart for patients with HGD in the ileal pouches.
Number (%)
History of neoplasia (.3 mo from the diagnosis of pouch adenocarcinoma) LGD LGD and HGD Synchronous neoplasia (#3 mo from the diagnosis of pouch adenocarcinoma) LGD and HGD HGD LGD Management APR with end ileostomy APR with K pouch Palliative resection with end ileostomy Loop ileostomy Completion proctectomy with redo J pouch Positive margin (patients with curative resection, n ¼ 11) Any complication Pelvic bleeding Pelvic abscess Deep vein thrombosis Urinary tract infection Ileus Wound infection Recurrence or metastasis (patients with curative resection, n ¼ 11) Local (presacral) recurrence Liver and omentum Bone Unclear site Death Duration of follow-up, yr
2 (14.3) 1 (7.1) 1 (7.1) 12 (85.7) 8 (57.1) 3 (21.4) 1 (7.1) 8 2 1 2 1 3
(57.1) (14.3) (7.1) (14.3) (7.1) (27.3)
8 3 2 2 1 1 1 5
(57.1) (21.4) (14.3) (14.3) (7.1) (7.1) (7.1) (45.5)
2 1 1 1 6 2.1
(18.2) (9.1) (9.1) (9.1) (42.9) (0.6–5.2)
pouch dysplasia, had synchronous dysplasia, which was defined as the presence of dysplasia within 3 months of the pouch adenocarcinoma diagnosis. The synchronous lesion was LGD in 1 patient (7.1%), HGD in 3 (21.4%), and both LGD and HGD in 8 (57.1%) patients. Regarding the primary management for the 14 patients with pouch adenocarcinoma, 8 (57.1%) underwent APR with end ileostomy, 2 (14.3) underwent APR with a Kock pouch, 1 (7.1%) underwent completion proctectomy with a redo J pouch, 2 (14.3) underwent loop ileostomy, and 1 (7.1%) underwent palliative resection with end ileostomy (Table 3). A detailed history review of the patient who underwent completion proctectomy with redo J pouch demonstrated that the patient only had a preoperative diagnosis of HGD at ATZ but the invasive stage I adenocarcinoma was confirmed based on the surgical specimen postoperatively. Eight patients (57.1%) experienced perioperative complications, including pelvic bleeding (n ¼ 3, 21.4%), pelvic www.ibdjournal.org |
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abscess (n ¼ 2, 14.3%), deep vein thrombosis (n ¼ 2, 14.3%), urinary tract infection (n ¼ 1, 7.1%), ileus (n ¼ 1, 7.1%), and wound infection (n ¼ 1, 7.1%). Of the 11 patients who underwent resection with curative intent, 3 (27.3%) were found to have microscopically positive radial margins. After a median followup of 2.1 (0.6–5.2) years, 2 patients (18.2%) had locoregional recurrence and another 3 (27.3%) developed distant metastasis. At the last follow-up, a total of 6 patients (42.9%) died, with a 5-year cumulative overall survival rate of 49.5% (Table 3 and Fig. 4). Other clinicopathological features of pouch adenocarcinoma were shown in Table 4.
Comparisons of Clinicopathological Features Between Pouch Adenocarcinoma and Dysplasia To further evaluate the natural history of pouch neoplasia, we compared the clinicopathological features between patients who had a final diagnosis of pouch adenocarcinoma (n ¼ 14, 32.6%) and those with pouch dysplasia (n ¼ 29, 67.4%). The patient with pouch HGD who progressed to SCC was not included in this analysis. The mean age at diagnosis of pouch adenocarcinoma was 54.9 6 14.5 years versus 45.6 6 12.9 years at the diagnosis of pouch dysplasia (P ¼ 0.04). Both median intervals from IBD diagnosis to the detection of pouch neoplasia (25.6 [IQR, 18.9–31.0] versus 16.0 [IQR: 11.5–24.4] yr, P ¼ 0.007) and duration from pouch construction to the detection of pouch neoplasia (10.5 [IQR, 3.3–16.2] versus 3.2 [IQR: 1.5–7.1] yr, P ¼ 0.013) were found to be significantly longer in patients with pouch adenocarcinoma than those with pouch dysplasia (Table 4). More patients with pouch adenocarcinoma had undergone mucosectomy with handsewn anastomosis than those with pouch dysplasia (42.9% versus 3.4%, P ¼ 0.003). All patients (100%, n ¼ 24) with pouch adenocarcinoma had a J pouch configuration, whereas only 72.4% (n ¼ 21) for patients with pouch dysplasia (P ¼ 0.039). The location of the ileal pouch neoplasia was at the ATZ in 35 patients (81.4%),
FIGURE 4. Survival curve of 14 patients with pouch adenocarcinoma.
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pouch body in 3 (7.0%), ATZ and pouch body in 3 (7.0%), afferent limb in 1 (2.3%), and afferent limb and pouch body in 1 (2.3%). There was no statistical difference in the location of pouch neoplasia between patients with a final diagnosis of pouch dysplasia and those with pouch adenocarcinoma (P ¼ 0.38). There was also no significant difference between the 2 groups in other variables (P . 0.05) (Table 4).
DISCUSSION Pouch neoplasia is infrequent but potentially lethal adverse sequelae after IPAA for patients with underlying IBD.10,17,18 Most published studies in this field have focused on the prevalence rate and risk factors associated with the development of pouch neoplasia, with limited data available assessing the long-term natural history. Interestingly, this study of the 44 cases with pouch neoplasia showed pouch LGD either persisted or progressed in 6 (27.3%) of the 22 patients and family history of CRC seemed to be associated with LGD persistence or progression. We also found that 41.7% of the patients with pouch HGD and 85.7% of those with pouch adenocarcinoma had a history of or synchronous dysplasia. We proposed an algorithm for the management of pouch neoplasia in 2011.16 This study with real data showed that disease course of LGD was highly variable, supporting the notion in the algorithm that patients with LGD should be further stratified into a high-risk group (i.e., those with persistent or progressive LGD) and low-risk group (i.e., those without LGD detection during subsequent surveillance). Similar to LGD seen in patients with UC before colectomy, the management of pouch LGD is controversial.16 Although the efficacy of surveillance in LGD is not clear, it may be reasonable to biopsy these patients at intervals of 3 to 6 months. If apparent regression of dysplasia is seen, yearly biopsies are recommended thereafter. Otherwise, surgical interventions, such as completion proctectomy, may be needed, particularly for the patients with risk factors for neoplastic progression, such as those with a preoperative diagnosis of rectal neoplasia or a family history of CRC.12 Of the 22 patients with initial diagnosis of pouch LGD in our study, surveillance pouchoscopy was performed to all as the initial management. Six patients (27.3%) with pouch LGD either persisted or progressed after a median follow-up of 9.5 (4.1–17.6) years. All of the 6 patients underwent completion proctectomy with a redo pouch for the persistence or progression of dysplasia. Interestingly, our study for the first time showed that family history of CRC might be a risk factor associated with persistence or progression of pouch LGD. The management of pouch-associated HGD might not be as controversial as LGD, although some investigators supported mucosectomy and pouch advancement procedure while others advocated pouch excision.12,19,20 Of the 12 patients who had pouch HGD, 4 (33.3%) underwent completion proctectomy with redo pouch. The other procedures used included pouch advanced flap (1, 8.3%), transanal excision (1, 8.3%), continuing
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Disease Course of Pouch Neoplasia
TABLE 4. Comparisons of Patient Characteristics Between Pouch Adenocarcinoma and Pouch Dysplasia Characteristics No. patients Age at diagnosis of IBD, yr Age at pouch construction, yr Age at diagnosis of pouch neoplasia, yr Duration from IBD diagnosis to pouch construction, yr Duration from IBD diagnosis to pouch neoplasia, yr Duration from pouch construction to pouch neoplasia, yr Body mass index, kg/m2 Male patients Caucasian patients Smoking Ever Never Drinking alcohol Ever Never Significant comorbidities Autoimmune disorders Family history of IBD Family history of CRC Extent of colitis Extensive colitis Left-sided colitis Toxic megacolon Primary sclerosing cholangitis Extraintestinal manifestations Underlying diseases Ulcerative colitis Indeterminate colitis Crohn’s disease Indication for colectomy Refractory disease Neoplasia Pouch construction stages 1 or 2 3 Pouch configuration J pouch S pouch Type of anastomosis Stapled Handsewn Location of pouch neoplasia ATZ Pouch body Pouch body and ATZ Afferent limb
All Cases
Pouch Dysplasia
Pouch Adenocarcinoma
43 28.2 6 11.9 42.1 6 13.1 48.7 6 14.0 13.3 (5.5–20.7) 18.8 (13.2–29.0) 4.8 (1.7–11.2) 26.6 6 6.8 27 42
29 28.2 6 11.0 40.8 6 11.6 45.6 6 12.9 11.6 (5.0–18.5) 16.0 (11.5–24.4) 3.2 (1.5–7.1) 25.9 6 6.8 17 (58.6%) 29 (100.0%)
14 28.2 6 13.9 44.9 6 16.0 54.9 6 14.5 16.0 (6.6–21.9) 25.6 (18.9–31.0) 10.5 (3.3–16.2) 28.2 6 6.9 10 (71.4%) 13 (92.9%)
14 24
8 (32.0%) 17 (68.0%)
6 (46.2%) 7 (53.8%)
11 27 22 9 4 7
8 (32.0%) 17 (68.0%) 16 (55.2%) 5 (17.2%) 2 (9.1%) 5 (22.7%)
3 (23.1%) 10 (76.9%) 6 (42.9%) 4 (28.6%) 2 (14.3%) 2 (14.3%)
38 5 4 4 8
26 (89.7%) 3 (10.3%) 4 (13.8%) 3 (10.3%) 5 (17.2%)
12 (85.7%) 2 (14.3%) 0 (0%) 1 (7.1%) 3 (21.4%)
35 6 2
24 (82.8%) 4 (13.8%) 1 (3.4%)
11 (78.6%) 2 (14.3%) 1 (7.1%)
21 22
15 (51.7%) 14 (48.3%)
6 (42.9%) 8 (57.1%)
29 14
22 (75.9%) 7 (24.1%)
7 (50.0%) 7 (50.0%)
35 8
21 (72.4%) 8 (27.6%)
14 (100%) 0 (0%)
36 7
28 (96.6%) 1 (3.4%)
8 (57.1%) 6 (42.9%)
35 3 3 1
25 2 1 1
10 (71.4%) 1 (7.1%) 2 (14.3%) 0 (0%)
P
0.99 0.34 0.04 0.21 0.007 0.013 0.33 0.51 0.33 0.49
0.71
0.45 0.44 0.63 0.68 1.0
0.29 1.0 1.0 1.0
0.75
0.16
0.039
0.003
0.38 (86.2%) (6.9%) (3.4%) (3.4%)
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TABLE 4 (Continued) Characteristics Afferent limb and pouch body Any concurrent pouch disorders Concurrent chronic pouchitis Concurrent Crohn’s disease of the pouch Concurrent cuffitis Concurrent pouch sinus or fistula
All Cases
Pouch Dysplasia
Pouch Adenocarcinoma
P
1 24 12 3 13 5
0 (0%) 14 (48.3%) 8 (27.6%) 1 (3.4%) 6 (20.7%) 2 (6.9%)
1 (7.1%) 10 (71.4%) 4 (28.6%) 2 (14.3%) 7 (50.0%) 3 (21.4%)
0.15 1.0 0.24 0.077 0.31
surveillance pouchoscopy (5, 41.7%) and 1 patient (8.3%) was lost to follow-up. After a median follow-up of 5.4 (2.2–9.2) years, 3 patients (25.0%) had persistence or progression, including one who had undergone completion proctectomy with redo pouch, indicating that the risk for persistence or progression for patients with pouch HGD persisted even after undergoing definitive surgical intervention. Pouch excision becomes the treatment of choice should pouch HGD persist.12 Consistent with this, all but 1 patient who was lost to follow-up underwent APR of the ileal pouch for the persistence or progression of pouch HGD. The election of surgical procedure for pouch adenocarcinoma seems to be straightforward, with both IBD specialists and colorectal surgeons advocating APR with end ileostomy or continent ileostomy for patients with pouch adenocarcinoma.16 For the 14 patients with pouch adenocarcinoma in our study, surgical intervention was offered to all the patients, with palliative procedures being done in 3 (21.4%) due to nonresectable tumors. Of the remaining 11 patients (78.6%) who had curative resection, all but 1 patient had APR with end ileostomy or Koch pouch. Surgical management for patients with pouch adenocarcinoma might be technically demanding because the anatomy in the pelvic cavity has been altered after ileal pouch construction. Indeed, our study showed that 3 (27.3%) of the 11 patients with resected tumor were found to have positive margins, and intraoperative or postoperative complications were encountered in 8 patients (57.1%). Prognosis for patients with pouch adenocarcinoma seemed to be poor.10,17 During a median follow-up period of 2.1 (0.6–5.2) years, 5 (45.5%) of the 11 patients who had curative resection of the tumor developed locoregional recurrence or distant metastasis. At the last follow-up, a total of 6 patients (42.9%) died, with a 5-year cumulative survival rate of 49.5%. Of the 43 patients with a final diagnosis of dysplasia or adenocarcinoma, 38 (88.4%) were found to have the involvement at the ATZ, indicating that ATZ is the most common site predisposed to the development of neoplasia.10 Construction of an ileal pouch can be accomplished either with handsewn anastomosis after mucosectomy or with a stapled anastomosis without mucosectomy.21 Although mucosectomy results in a more complete removal of diseased mucosa, this benefit may be at the price of poorer function.9,22 Our study showed that 7 (18.4%) of the 38 patients with ATZ involvement have undergone mucosectomy with a handsewn anastomosis, validating the notion that the risk
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for the occurrence of neoplasia in patients with IPAA is not eliminated by mucosectomy.9,23 Possible explanations include the inability of even the most meticulous mucosectomy to remove all rectal columnar mucosa, as evidenced by one study that stated that macroscopically complete mucosectomy might leave behind islets of rectal mucosa in .20% of cases.24,25 Furthermore, technical difficulty in visualization and biopsy of retained islets of rectal mucosa after mucosectomy with a handsewn anastomosis might also play a role.15,16,18 At the same time, 22 (51.2%) of the 43 patients with pouch dysplasia or adenocarcinoma had a preoperative diagnosis of IBD-associated neoplasia, reflecting that the presence of previous colonic dysplasia or cancer is predictive for the development of pouch neoplasia.7,10,12 Keeping this in mind, it has been the practice at our institution that no patient with a known preoperative diagnosis of carcinoma of the rectum or of dysplasia within 8 cm of the anal verge is considered for stapled IPAA; instead, such patients undergo mucosectomy and a handsewn anastomosis.12 This study included the largest number of patients with pouch adenocarcinoma from a single institution.15,18,20,26–46 Of note, our study indicated that patients with pouch adenocarcinoma were found to be older and have longer durations from IBD diagnosis or pouch construction to the diagnosis than those with pouch dysplasia only. The longer time intervals for patients with pouch adenocarcinoma together with the fact that 78.6% (n ¼ 11) of patients with pouch adenocarcinoma had a history of or synchronous dysplasia might further support the hypothesized carcinogenic pathway: chronic inflammation–LGD–HGD–carcinoma.17 However, a nontraditional carcinogenic pathway might also exist because neither a history of nor synchronous dysplasia was identified in the remaining 2 patients (14.3%) with pouch adenocarcinoma. The findings of this study have several clinical implications. One novel finding from our study was that the family history of CRC was shown to be a risk factor associated with persistence or progression for patients with pouch LGD. This would help us to have a better understanding of the natural history of pouch neoplasia. A more intensified endoscopic surveillance program or a more radical treatment algorithm may be required for patients with pouch LGD with a family history of CRC. Our results also suggest that the majority of pouch adenocarcinoma cases might follow a carcinogenic pathway similar to that of UC-associated
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cancer. The findings of this study support the previously proposed algorithm for surveillance of pouch neoplasia.16 The poor prognosis of pouch adenocarcinoma once diagnosed, further supports our recommendations.10,17 Last but not the least, additional benefits of surveillance pouchoscopy might also be obtained by the detection of endoscopically treatable lesions, such as strictures and polyps, even in asymptomatic patients as shown by a recent study from our group.47 There are limitations to our study. The sample size of the study, although the largest in the literature to date, is still small, which excluded extensive multivariable analyses. For example, the association between family history of CRC and the risk for persistence or progression for patients with LGD was not further evaluated using the multivariate analysis. Although a general strategy of surveillance pouchoscopy has been routinely offered to patients with ileal pouch followed up at our institution,16 patients’ compliance with the surveillance plan was not predicted in the clinical practice. This, along with the suboptimal accuracy of the endoscopic evaluation may compromise our ability to identify all pouch neoplasia, hence potentially underestimating its true frequency.10,11 In summary, the presence of family history of CRC was shown to be a risk factor for persistence or progression on pouch LGD. About 40% of patients with pouch HGD and a majority of patients with pouch adenocarcinoma had a history of or synchronous neoplastic lesions, supporting the hypothesized carcinogenic pathway similar to that of colitis-associated cancer, i.e., chronic inflammation–LGD–HGD–carcinoma. Once diagnosed, the prognosis of patients with pouch adenocarcinoma seemed to be poor.
ACKNOWLEDGMENTS Author contributions: Study concept and design: X-R. Wu, F. H. Remzi, X-L. Liu, L. Lian, L. Stocchi, J. Ashburn, B. Shen; analysis and interpretation of data: X-R. Wu, F. H. Remzi, X-L. Liu, L. Lian, L. Stocchi, J. Ashburn, B. Shen; acquisition: X-R. Wu; drafting of the manuscript: X-R. Wu; critical revision of the manuscript for important intellectual content: F. H. Remzi, X-L. Liu, L. Lian, L. Stocchi, J. Ashburn, B. Shen; supervision of the whole project: B. Shen. All authors read and approved the final manuscript.
REFERENCES 1. Delaney CP, Fazio VW, Remzi FH, et al. Prospective, age-related analysis of surgical results, functional outcome, and quality of life after ileal pouch-anal anastomosis. Ann Surg. 2003;238:221–228. 2. Fazio VW, Kiran RP, Remzi FH, et al. Ileal pouch anal anastomosis: analysis of outcome and quality of life in 3707 patients. Ann Surg. 2013;257:679–685. 3. Delaney CP, Remzi FH, Gramlich T, et al. Equivalent function, quality of life and pouch survival rates after ileal pouch-anal anastomosis for indeterminate and ulcerative colitis. Ann Surg. 2002;236:43–48. 4. Scarpa M, van Koperen PJ, Ubbink DT, et al. Systematic review of dysplasia after restorative proctocolectomy for ulcerative colitis. Br J Surg. 2007;94:534–545. 5. O’Riordain MG, Fazio VW, Lavery IC, et al. Incidence and natural history of dysplasia of the anal transitional zone after ileal pouch-anal
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anastomosis: results of a five-year to ten-year follow-up. Dis Colon Rectum 2000;43:1660–1665. Shepherd NA, Jass JR, Duval I, et al. Restorative proctocolectomy with ileal reservoir: pathological and histochemical study of mucosal biopsy specimens. J Clin Pathol. 1987;40:601–607. Ziv Y, Fazio VW, Sirimarco MT, et al. Incidence, risk factors, and treatment of dysplasia in the anal transitional zone after ileal pouch-anal anastomosis. Dis Colon Rectum. 1994;37:1281–1285. Banasiewicz T, Marciniak R, Paszkowski J, et al. Pouchitis may increase the risk of dysplasia after restorative proctocolectomy in patients with ulcerative colitis. Colorectal Dis. 2012;14:92–97. Chambers WM, Mc CMNJ. Should ileal pouch-anal anastomosis include mucosectomy? Colorectal Dis. 2007;9:384–392. Kariv R, Remzi FH, Lian L, et al. Preoperative colorectal neoplasia increases risk for pouch neoplasia in patients with restorative proctocolectomy. Gastroenterology. 2010;139:806–812. Derikx LA, Kievit W, Drenth JP, et al. Prior colorectal neoplasia is associated with Increased risk of ileoanal pouch neoplasia in patients with inflammatory bowel disease. Gastroenterology. 2014;146:119–128. Remzi FH, Fazio VW, Delaney CP, et al. Dysplasia of the anal transitional zone after ileal pouch-anal anastomosis: results of prospective evaluation after a minimum of ten years. Dis Colon Rectum. 2003;46: 6–13. Veress B, Reinholt FP, Lindquist K, et al. Different types of mucosal adaptation in the ileal reservoir after restorative proctocolectomy. A two-year follow-up study. APMIS. 1990;98:786–796. Stahlberg D, Veress B, Tribukait B, et al. Atrophy and neoplastic transformation of the ileal pouch mucosa in patients with ulcerative colitis and primary sclerosing cholangitis: a case control study. Dis Colon Rectum. 2003;46:770–778. Lee SW, Sonoda T, Milsom JW. Three cases of adenocarcinoma following restorative proctocolectomy with hand-sewn anastomosis for ulcerative colitis: a review of reported cases in the literature. Colorectal Dis. 2005;7:591–597. Liu ZX, Kiran RP, Bennett AE, et al. Diagnosis and management of dysplasia and cancer of the ileal pouch in patients with underlying inflammatory bowel disease. Cancer. 2011;117:3081–3092. Jiang W, Shadrach B, Carver P, et al. Histomorphologic and molecular features of pouch and peripouch adenocarcinoma: a comparison with ulcerative colitis-associated adenocarcinoma. Am J Surg Pathol. 2012; 36:1385–1394. Branco BC, Sachar DB, Heimann TM, et al. Adenocarcinoma following ileal pouch-anal anastomosis for ulcerative colitis: review of 26 cases. Inflamm Bowel Dis. 2009;15:295–299. Coull DB, Lee FD, Henderson AP, et al. Risk of dysplasia in the columnar cuff after stapled restorative proctocolectomy. Br J Surg. 2003;90:72–75. Heuschen UA, Heuschen G, Autschbach F, et al. Adenocarcinoma in the ileal pouch: late risk of cancer after restorative proctocolectomy. Int J Colorectal Dis. 2001;16:126–130. Heald RJ, Allen DR. Stapled ileo-anal anastomosis: a technique to avoid mucosal proctectomy in the ileal pouch operation. Br J Surg. 1986;73: 571–572. Tuckson W, Lavery I, Fazio V, et al. Manometric and functional comparison of ileal pouch anal anastomosis with and without anal manipulation. Am J Surg 1991;161:90–95; discussion 95–96. Lovegrove RE, Constantinides VA, Heriot AG, et al. A comparison of hand-sewn versus stapled ileal pouch anal anastomosis (IPAA) following proctocolectomy: a meta-analysis of 4183 patients. Ann Surg. 2006;244: 18–26. Heppell J, Weiland LH, Perrault J, et al. Fate of the rectal mucosa after rectal mucosectomy and ileoanal anastomosis. Dis Colon Rectum. 1983; 26:768–771. O’Connell PR, Pemberton JH, Weiland LH, et al. Does rectal mucosa regenerate after ileoanal anastomosis? Dis Colon Rectum. 1987;30:1–5. Negi SS, Chaudhary A, Gondal R. Carcinoma of pelvic pouch following restorative proctocolectomy: report of a case and review of the literature. Dig Surg. 2003;20:63–65. Bell SW, Parry B, Neill M. Adenocarcinoma in the anal transitional zone after ileal pouch for ulcerative colitis: report of a case. Dis Colon Rectum. 2003;46:1134–1137. www.ibdjournal.org |
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28. Kotanagi H, Kon H, Iida M, et al. Adenocarcinoma at the site of ileoanal anastomosis in Crohn’s disease: report of a case. Dis Colon Rectum. 2001; 44:1210–1213. 29. Sequens R. Cancer in the anal canal (transitional zone) after restorative proctocolectomy with stapled ileal pouch-anal anastomosis. Int J Colorectal Dis. 1997;12:254–255. 30. Puthu D, Rajan N, Rao R, et al. Carcinoma of the rectal pouch following restorative proctocolectomy. Report of a case. Dis Colon Rectum. 1992; 35:257–260. 31. Iwama T, Kamikawa J, Higuchi T, et al. Development of invasive adenocarcinoma in a long-standing diverted ileal J-pouch for ulcerative colitis: report of a case. Dis Colon Rectum. 2000;43:101–104. 32. Botterill ID, Sagar PM. Adenocarcinoma in the residual outflow tract after incomplete excision of a failed ileoanal pouch: a late complication of unrecognized Crohn’s colitis: report of a case. Dis Colon Rectum. 2002; 45:1112–1115. 33. Laureti S, Ugolini F, D’Errico A, et al. Adenocarcinoma below ileoanal anastomosis for ulcerative colitis: report of a case and review of the literature. Dis Colon Rectum. 2002;45:418–421. 34. Vieth M, Grunewald M, Niemeyer C, et al. Adenocarcinoma in an ileal pouch after prior proctocolectomy for carcinoma in a patient with ulcerative pancolitis. Virchows Arch. 1998;433:281–284. 35. Baratsis S, Hadjidimitriou F, Christodoulou M, et al. Adenocarcinoma in the anal canal after ileal pouch-anal anastomosis for ulcerative colitis using a double stapling technique: report of a case. Dis Colon Rectum. 2002;45:687–691; discussion 691–692. 36. Rotholtz NA, Pikarsky AJ, Singh JJ, et al. Adenocarcinoma arising from along the rectal stump after double-stapled ileorectal J-pouch in a patient with ulcerative colitis: the need to perform a distal anastomosis. Report of a case. Dis Colon Rectum. 2001;44:1214–1217. 37. Pedersen ME, Rahr HB, Fenger C, et al. Adenocarcinoma arising from the rectal stump eleven years after excision of an ileal J-pouch in
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a patient with ulcerative colitis: report of a case. Dis Colon Rectum. 2008;51:1146–1148. Ota H, Yamazaki K, Endoh W, et al. Adenocarcinoma arising below an ileoanal anastomosis after restorative proctocolectomy for ulcerative colitis: report of a case. Surg Today. 2007;37:596–599. Chia CS, Chew MH, Chau YP, et al. Adenocarcinoma of the anal transitional zone after double stapled ileal pouch-anal anastomosis for ulcerative colitis. Colorectal Dis. 2008;10:621–623. Rodriguez-Sanjuan JC, Polavieja MG, Naranjo A, et al. Adenocarcinoma in an ileal pouch for ulcerative colitis. Dis Colon Rectum. 1995;38:779– 780. Knupper N, Straub E, Terpe HJ, et al. Adenocarcinoma of the ileoanal pouch for ulcerative colitis: a complication of severe chronic atrophic pouchitis? Int J Colorectal Dis. 2006;21:478–482. Walker M, Radley S. Adenocarcinoma in an ileoanal pouch formed for ulcerative colitis in a patient with primary sclerosing cholangitis and a liver transplant: report of a case and review of the literature. Dis Colon Rectum. 2006;49:909–912. Bentrem DJ, Wang KL, Stryker SJ. Adenocarcinoma in an ileal pouch occurring 14 years after restorative proctocolectomy: report of a case. Dis Colon Rectum. 2003;46:544–546. Sagar P. Adenocarcinoma in a pouch without a preceeding history of dysplasia. Colorectal Dis. 2006;8:526–527. Ault GT, Nunoo-Mensah JW, Johnson L, et al. Adenocarcinoma arising in the middle of ileoanal pouches: report of five cases. Dis Colon Rectum. 2009;52:538–541. Vento P, Lepisto A, Karkkainen P, et al. Risk of cancer in patients with chronic pouchitis after restorative proctocolectomy for ulcerative colitis. Colorectal Dis. 2011;13:58–66. Zhu H, Wu XR, Queener E, et al. Clinical value of surveillance pouchoscopy in asymptomatic ileal pouch patients with underlying inflammatory bowel disease. Surg Endosc. 2013;27:4325–4332.
Disease Course and Management Strategy of Pouch Neoplasia in Patients with Underlying Inflammatory Bowel Diseases Xian-Rui Wu, MD, PhD,* Feza H. Remzi, MD,* Xiu-Li Liu, MD, PhD,† Lei Lian, MD, PhD,* Luca Stocchi, MD,* Jean Ashburn, MD,* and Bo Shen, MD‡
Background: To evaluate the disease course and management strategy for pouch neoplasia. Methods: Patients undergoing ileal pouch surgery for underlying ulcerative colitis who developed low-grade dysplasia (LGD), high-grade dysplasia, or adenocarcinoma in the pouch were identified.
Results: All eligible 44 patients were evaluated. Of the 22 patients with initial diagnosis of pouch LGD, 6 (27.3%) had persistence or progression after a median follow-up of 9.5 (4.1–17.6) years. Family history of colorectal cancer was shown to be a risk factor associated with persistence or progression of LGD (P ¼ 0.03). Of the 12 patients with pouch high-grade dysplasia, 5 (41.7%) had a history of (n ¼ 2, 16.7%) or synchronous (n ¼ 4, 33.3%) pouch LGD. Pouch high-grade dysplasia either persisted or progressed in 3 patients (25.0%) after the initial management, during a median time interval of 5.4 (2.2–9.2) years. Of the 14 patients with pouch adenocarcinoma, 12 (85.7%) had a history of (n ¼ 2, 14.3%) or synchronous dysplasia (n ¼ 12, 85.7%). After a median follow-up of 2.1 (0.6–5.2) years, 6 patients with pouch cancer (42.9%) died. Comparison of patients with a final diagnosis of pouch adenocarcinoma (14, 32.6%), and those with dysplasia (29, 67.4%) showed that patients with adenocarcinoma were older (P ¼ 0.04) and had a longer duration from IBD diagnosis or pouch construction to the detection of pouch neoplasia (P ¼ 0.007 and P ¼ 0.0013).
Conclusions: The risk for progression of pouch dysplasia can be stratified. The presence of family history of colorectal cancer seemed to increase the risk for persistence or progression for patients with pouch LGD. The prognosis for pouch adenocarcinoma was poor. (Inflamm Bowel Dis 2014;20:2073–2082) Key Words: ileal pouch, inflammatory bowel disease, pouch adenocarcinoma, pouch dysplasia
R
estorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) has been widely considered as the surgical treatment of choice for the majority of patients with medically refractory ulcerative colitis (UC) or colitis-associated neoplasia. IPAA significantly improves patients’ health-related quality of life (QOL) by preserving the natural route of defecation and by avoiding the need for permanent ileostomy. Good functional outcomes of IPAA have been reported in long-term follow-up studies.1–3 However, the risk for inflammatory bowel diseases (IBD)–associated neoplastic transformation in the anal transitional zone (ATZ) or pouch body per se may still persist, despite removal of the diseased colon.
Received for publication May 12, 2014; Accepted June 23, 2014. From the Departments of *Colorectal Surgery, †Anatomic Pathology, and ‡ Gastroenterology & Hepatology, Cleveland Clinic Foundation, Cleveland, Ohio. Supported in part by a grant from the Crohn’s and Colitis Foundation of America and the Ed and Joey Story Endowed Chair (B.S.). X-R. Wu is a research fellow from the Department of Colorectal Surgery, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. The remaining authors have no conflicts of interest to disclose. Reprints: Bo Shen, MD, Department of Gastroenterology & Hepatology, Desk A31, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195 (e-mail: [email protected]). Copyright © 2014 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000152 Published online 18 August 2014.
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The reported cumulative prevalence of pouch neoplasia ranges from 0% to 18.5%.4–9 Our recent study of 3203 patients with ileal pouches showed that the cumulative incidence for pouch neoplasia at 5, 10, 15, 20, and 25 years after pouch construction were 0.9%, 1.3%, 1.9%, 4.2%, and 5.1%, respectively.10 Reported risk factors for the development of pouch neoplasia after IPAA surgery for patients with underlying UC include diagnosis of UC-associated dysplasia or cancer based on either preoperative biopsies or surgical specimen,10,11 the presence of type C mucosa of the pouch, concurrent primary sclerosing cholangitis, a family history of colorectal cancer (CRC), and a long duration of underlying UC.7,10–15 There has been no consensus on how to manage pouch patients with LGD, either continuous close surveillance or surgical intervention. There are scant data in the literature on the natural history of pouch neoplasia, which would provide some guidance. Therefore, the aims of our study were to evaluate the disease course of pouch neoplasia, including low-grade dysplasia (LGD), high-grade dysplasia (HGD), and adenocarcinoma and to identify risk factors associated with the persistence or progression of LGD after the initial diagnosis.
PATIENTS AND METHODS Patients This study was approved by the Cleveland Clinic Institutional Review Board. Patients with pouch neoplasia were identified www.ibdjournal.org |
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using the Institutional Review Board–approved Pouchitis Registry at the Center for Ileal Pouch Disorders and Pouch Database at Department of Colorectal Surgery. Demographics and clinical data were all prospectively maintained in the Registry or Database. Both paper charts and electronic medical records would be carefully reviewed when necessary.
Inclusion and Exclusion Criteria Inclusion criteria were: (1) ileal pouches; (2) diagnosis of neoplasia in the ileal pouches, including LGD, HGD, or adenocarcinoma; and (3) underlying IBD. Patients with IPAA with a preoperative diagnosis of familial adenomatous polyposis or other colonic pathologies were excluded.
Diagnostic Criteria Neoplasia was documented and graded as LGD, HGD, or adenocarcinoma based on histology. Pouch neoplasia was defined as the presence of neoplasia at the ATZ, pouch body, and/or afferent limb. The patient (n ¼ 1) with HGD at the ATZ, which later on progressed to squamous cell carcinoma (SCC) was also evaluated in this study. As a part of our routine clinical practice, all the diagnoses of pouch dysplasia were confirmed with at least 2 expert gastrointestinal pathologists with a special interest in IBD.
Definition of Variables Demographic and clinicopathological variables were defined as follows: active smoking: consumption of more than 7 cigarettes per week for at least 6 months before the data entry; ex-smoking: cessation of smoking 6 months before data entry; family history of IBD: one or more of the first-degree (parents, offspring, or siblings of the index patients) or second-degree relatives who had IBD; family history of CRC: one or more of the first-degree (parents, offspring, or siblings of the index patients) or second-degree relatives who had CRC; history of pouch neoplasia: the presence of pouch neoplasia at least 3 months before the diagnosis of the current neoplasia; synchronous neoplasia: the presence of neoplasia within 3 months of the current neoplasia; persistent neoplasia: the diagnosis of dysplasia of the same grade at least 3 months after its initial diagnosis; extensive colitis: endoscopic, macroscopic, or microscopic disease extending proximal to the splenic flexure; extraintestinal manifestations: including the presence of arthralgia or arthropathy, primary sclerosing cholangitis, pyoderma gangrenosum, erythema nodosum, IBD-related ocular lesions, thromboembolic events; Significant comorbidities: congestive heart failure, coronary bypass surgery, chronic obstructive pulmonary diseases, renal stone or insufficiency, nongastrointestinal cancer, stroke, and liver failure; chronic pouchitis: a modified Pouchitis Disease Activity Index $5 points and symptoms lasting 4 weeks or more and failed to respond to a 4-week course of single antibiotic therapy (ciprofloxacin, metronidazole, or tinidazole); cuffitis: endoscopic and histologic inflammation of the rectal cuff; Crohn’s disease of the pouch: diagnosed based on our previously published criteria, i.e., the presence of non-surgery-related perianal
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fistula or inflammation or ulcerations at the prepouch neoterminal ileum or small bowel in the absence of non-steroidal anti-inflammatory drug use, or granulomas on histology.
Clinical Practice Pattern For patients with ileal pouch seen and followed up at our institution, surveillance pouchoscopy was routinely offered once every 1 to 3 years at the discretion of the IBD specialist (B.S.) or colorectal surgeons, largely based on the algorithm previous published by our group.16 Patients were given 1 to 2 Fleet (CB Fleet, Lynchburg, VA) enemas or oral PEG before the procedure. Sedated or unsedated pouchoscopy procedures included careful inspection of the ATZ, pouch body, and afferent limb. During the diagnostic and/or surveillance pouchoscopy, 2 to 6 pieces of biopsy were taken randomly from each of the 3 aforementioned areas. In addition, any abnormal or suspicious areas, such as polyps and deep ulcers, were sampled. The biopsy specimens were separately labeled and submitted for pathologists’ evaluation. The management strategy for the patients with pouch neoplasia also largely followed the treatment algorithm, which was previous proposed by our group.16
Outcome Measurement The primary outcomes of this study were the progression or “regression” of pouch neoplasia and risk factors associated with the persistence or progression of LGD after the initial diagnosis.
Statistical Analysis Descriptive statistics were computed for all variables. These included mean and SDs or medians and interquartile ranges (IQRs) for continuous factors, and frequencies for categorical factors. Comparisons between 2 groups were made by using the 2-tailed t test (or Wilcoxon rank sum test as appropriate) for continuous variables and chi-square test (or the Fisher’s exact test as appropriate) for categorical variables. Patient survival analysis and the impact of family history of CRC on the persistence or progression for patients with LGD was depicted with Kaplan– Meier curves with log-rank test. All statistical analyses were performed with the SPSS software version 16 (SPSS, Chicago, IL). P , 0.05 was considered statistically significant.
RESULTS A total of 44 patients with LGD, HGD, or adenocarcinoma in the ileal pouch were identified. The diagnosis at the first detection of the neoplasia was LGD in 22 patients (50.0%), HGD in 10 (22.7%) and adenocarcinoma in 12 (27.3%). The final diagnosis (the highest grade of dysplasia) of neoplasia was LGD in 19 patients (43.2%), HGD in 10 (22.7%), adenocarcinoma in 14 (31.8%) and SCC in 1 (2.3%) patient.
Disease Course of Pouch LGD A total of 22 patients were initially diagnosed with LGD in the ileal pouches. Male accounted for 68.2% (n ¼ 15), with a mean age at diagnosis of 48.0 6 15.9 years. The location of the pouch
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LGD was at the ATZ in 19 patients (86.4%), pouch body in 2 (9.1%), and ATZ and pouch body in 1 (4.5%) patient. Of the 22 patients, 1 (4.5%) had synchronous indefinite dysplasia. All of the 22 patients (100%) continued surveillance pouchoscopy as the primary management at the time of the diagnosis. After a median of 6.0 (IQR, 2.0–9.0) follow-up pouchoscopies during a time period of 9.5 (IQR, 4.1–17.6) years, pouch LGD either persisted or progressed in 6 patients (27.3%): 3 had persistence only, 1 had persistence then progressed to HGD, 1 progressed to HGD, and 1 had persistence then progressed to adenocarcinoma (Fig. 1). All the 6 patients (27.3%) underwent completion proctectomy with redo pouch as the management for persistence or progression (Table 1). Other clinicopathological features of pouch LGD were shown in Table 2.
Risk Factors for Persistence or Progression of Pouch LGD The 22 patients were further evaluated to identify risk factors associated with the persistence or progression of LGD in the ileal pouches. Comparison analyses between patients with persistence or progression (n ¼ 6, 27.3%) and those without (n ¼ 16, 72.7%) showed that patients with persistence or progression were more likely to have a family history of CRC (P ¼ 0.029) (Table 2). This was further confirmed by using the Kaplan–Meier survival analysis (log-rank test, P ¼ 0.03) (Fig. 2). No other demographics or clinical data were found to be significantly associated with dysplasia persistence or progression once pouch LGD was diagnosed (P . 0.05) (Table 2).
Disease Course of Pouch HGD A total of 12 patients were diagnosed with HGD in the ileal pouch, including 2 patients (16.7%) who progressed from pouch LGD and another 10 (83.3%) who were initially diagnosed with pouch HGD. Six patients (50%) were men, with a mean age at diagnosis of 43.9 6 7.4 years. The location of the pouch HGD was at the ATZ in 11 patients (91.7%) and afferent limb in 1 (8.3%). Of the 12 patients, 6 (50.0%) had synchronous pouch neoplasia, including 1 patient who had a history of pouch LGD. The synchronous lesions were indefinite dysplasia in 2 (16.7%), LGD in 3 (25.0%), and both indefinite dysplasia and LGD in 1
FIGURE 1. Flow chart for patients with LGD in the ileal pouches.
Disease Course of Pouch Neoplasia
TABLE 1. Management and Outcomes for Pouch Dysplasia Characteristics History of LGD (.3 mo from the diagnosis of index pouch neoplasia) Synchronous neoplasia (,3 mo from the diagnosis of index pouch neoplasia) LGD IND LGD and IND Management of index pouch neoplasia Completion proctectomy with redo pouch Pouch advancement flap Transanal excision Surveillance pouchoscopy Unclear Persistence or progression Adenocarcinoma Squamous cell cancer HGD LGD Management for recurrence or progression APR with end ileostomy APR with K pouch Completion proctectomy with redo pouch Unclear No. follow-up scopes Duration of follow-up, yr
LGD (N ¼ 22) (%)
HGD (N ¼ 12) (%)
NA
2 (16.7)
1 (4.5)
6 (50.0)
NA 1 (4.5) NA
3 (25.0) 2 (16.7) 1 (8.3)
0 (0)
4 (33.3)
0 (0) 0 (0) 22 (100) 0 (0) 6 (27.3) 1 (4.5) 0 (0) 3 (13.6) 5 (22.7) n¼6
1 (8.3) 1 (8.3) 5 (41.7) 1 (8.3) 3 (25.0) 1 (8.3) 1 (8.3) 2 (20.0) 0 (0) n¼3
0 (0) 0 (0) 6 (100)
1 (33.3) 1 (33.3) 0 (0)
0 (0) 6.0 (2.0–9.0) 9.5 (4.1–17.6)
1 (33.3) 3.0 (2.0–4.0) 5.4 (2.2–9.2)
IND, indeterminate for dysplasia.
(8.3%) patient. The primary management for the 12 patients included completion proctectomy with redo pouch (4, 33.3%), pouch advanced flap (1, 8.3%), transanal excision (1, 8.3%), ongoing surveillance pouchoscopy (5, 41.7%), and 1 patient (8.3%) was lost to follow-up (Table 1). Continued surveillance pouchoscopy without surgical treatment in 5 patients (41.7%) with pouch HGD was due to unifocal lesion with subsequently negative follow-up pouchoscopy (n ¼ 3, 25.0%), HGD contained in an inflammatory polyp (n ¼ 1, 8.3%) and patient refusal of surgical management (n ¼ 1, 8.3%). After a median of 3.0 (2.0– 4.0) follow-up pouchoscopies during a time period of 5.4 (2.2– 9.2) years, 3 patients (25.0%) had either persistence or progression of the pouch HGD (1 persisted only, 1 progressed to SCC, and 1 progressed to adenocarcinoma), including one who had undergone completion proctectomy with redo pouch after the initial diagnosis of pouch HGD, one who had underwent transanal www.ibdjournal.org |
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TABLE 2. Risk Factors Associated with Persistence or Progression for Patients with Ileal Pouch with LGD Persistence or Progression Characteristics No. patients Age at diagnosis of IBD, yr Age at pouch construction, yr Age at diagnosis of pouch LGD, yr Duration from IBD diagnosis to pouch construction, yr Duration from IBD diagnosis to pouch LGD, yr Duration from pouch construction to pouch LGD, yrs Body mass index, kg/m2 Male patients Smoking Ever Never Drinking alcohol Ever Never Significant comorbidities Autoimmune disorders Family history of IBD Family history of CRC Extent of colitis Extensive colitis Left-sided colitis Toxic megacolon Primary sclerosing cholangitis Extraintestinal manifestations Underlying diseases UC Indeterminate colitis CD Indication for colectomy Refractory disease Neoplasia Stage of pouch construction 1 or 2 3 Configuration of the pouch J pouch S pouch Location of pouch neoplasia ATZ Pouch body Pouch body and ATZ Any concurrent pouch disorders Concurrent chronic pouchitis Concurrent CD of the pouch Concurrent cuffitis No. follow-up scopes Duration of follow-up, yr CD, Crohn’s disease; IND, indeterminate for dysplasia.
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All Cases
No
Yes
22 29.3 6 10.3 43.5 6 13.6 48.0 6 15.9 13.8 (5.2–21.0) 15.3 (10.9–27.8) 2.7 (1.1–6.3) 26.5 6 5.3 15
16 29.0 6 10.7 42.2 6 13.6 47.0 6 15.8 12.8 (2.6–20.7) 16.3 (5.4–29.1) 2.8 (1.4–6.1) 25.9 6 5.2 10 (62.5%)
6 30.2 6 10.1 47.2 6 14.0 50.5 6 17.1 13.8 (5.8–26.2) 14.3 (10.9–29.0) 2.0 (0.5–7.1) 27.8 6 5.9 5 (83.3%)
6 13
4 (30.8%) 9 (69.2%)
2 (33.3%) 4 (66.7%)
8 11 14 5 2 3
5 8 9 3
3 3 5 2 2 3
19 3 3 1 5
15 (93.8%) 1 (6.2%) 3 (18.8%) 1 (6.2%) 4 (25.0%)
4 (66.7%) 2 (33.3%) 0 (0%) 0 (0%) 1 (16.7%)
17 4 1
12 (75.0%) 3 (18.8%) 1 (6.2%)
5 (83.3%) 1 (16.7%) 0 (0%)
11 11
9 (56.2%) 7 (43.8%)
2 (33.3%) 4 (66.7%)
15 7
9 (56.2%) 7 (43.8%)
6 (100%) 0 (0%)
16 6
11 (68.8%) 5 (31.2%)
5 (83.3%) 1 (16.7%)
19 2 1 10 7 1 4 6.0 (2.0–9.0) 9.5 (4.1–17.6)
13 (81.2%) 2 (12.5%) 1 (6.2%) 7 (43.8%) 4 (25.0%) 1 (6.2%) 3 (18.8%) 6.0 (3.0–10.5) 11.6 (5.3–17.1)
6 (100%) 0 (0%) 0 (0%) 3 (50.0%) 3 (50.0%) 0 (0%) 1 (16.7%) 4.0 (2.0–8.0) 5.4 (2.4–19.1)
P
0.81 0.45 0.66 0.61 1.0 0.46 0.49 0.62 1.0
1.0 (38.5%) (61.5%) (56.2%) (18.8%) 0 (0%) 0 (0%)
(50.0%) (50.0%) (83.3%) (33.3%) (33.3%) (50.0%)
0.35 0.59 0.11 0.029 0.17
0.53 1.0 1.0 1.0
0.64
0.12
0.63
1.0
1.0 0.33 1.0 1.0 0.57 0.61
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Disease Course of Pouch Neoplasia
TABLE 3. Management and Outcomes for Pouch Adenocarcinoma Characteristics
FIGURE 2. The impact of family history of CRC on the persistence or progression of LGD in the ileal pouches.
excision, and one who continued surveillance pouchoscopy without surgical intervention (Fig. 3). The management for the 3 patients with pouch HGD who either persisted or progressed included abdominoperineal resection (APR) with end ileostomy in 1 (33.3%) patient, APR with a K pouch in 1 (33.3%), and 1 (33.3%) was lost to follow-up (Table 1).
Disease Course of Pouch Adenocarcinoma A total of 14 patients were diagnosed with adenocarcinoma in the ileal pouch, including 2 (14.3%) had a history of pouch dysplasia (diagnosed at least 3 mo before the diagnosis of pouch adenocarcinoma) (Table 3). Ten patients (71.4%) were men, with a mean age at diagnosis of 54.9 6 14.5 years. The location of the pouch adenocarcinoma was at the ATZ in 10 patients (71.4%), ATZ and pouch body in 2 (14.3%), pouch body in 1 (7.1%), and afferent limb and pouch body in 1 (7.1%). Of the 14 patients, 3 (21.4%) had stage I diseases, 6 (42.9%) had stage II, 3 (21.4%) had stage III, and 2 (14.3%) had stage IV diseases. Twelve patients (85.7%), including the 2 patients who had a history of
FIGURE 3. Flow chart for patients with HGD in the ileal pouches.
Number (%)
History of neoplasia (.3 mo from the diagnosis of pouch adenocarcinoma) LGD LGD and HGD Synchronous neoplasia (#3 mo from the diagnosis of pouch adenocarcinoma) LGD and HGD HGD LGD Management APR with end ileostomy APR with K pouch Palliative resection with end ileostomy Loop ileostomy Completion proctectomy with redo J pouch Positive margin (patients with curative resection, n ¼ 11) Any complication Pelvic bleeding Pelvic abscess Deep vein thrombosis Urinary tract infection Ileus Wound infection Recurrence or metastasis (patients with curative resection, n ¼ 11) Local (presacral) recurrence Liver and omentum Bone Unclear site Death Duration of follow-up, yr
2 (14.3) 1 (7.1) 1 (7.1) 12 (85.7) 8 (57.1) 3 (21.4) 1 (7.1) 8 2 1 2 1 3
(57.1) (14.3) (7.1) (14.3) (7.1) (27.3)
8 3 2 2 1 1 1 5
(57.1) (21.4) (14.3) (14.3) (7.1) (7.1) (7.1) (45.5)
2 1 1 1 6 2.1
(18.2) (9.1) (9.1) (9.1) (42.9) (0.6–5.2)
pouch dysplasia, had synchronous dysplasia, which was defined as the presence of dysplasia within 3 months of the pouch adenocarcinoma diagnosis. The synchronous lesion was LGD in 1 patient (7.1%), HGD in 3 (21.4%), and both LGD and HGD in 8 (57.1%) patients. Regarding the primary management for the 14 patients with pouch adenocarcinoma, 8 (57.1%) underwent APR with end ileostomy, 2 (14.3) underwent APR with a Kock pouch, 1 (7.1%) underwent completion proctectomy with a redo J pouch, 2 (14.3) underwent loop ileostomy, and 1 (7.1%) underwent palliative resection with end ileostomy (Table 3). A detailed history review of the patient who underwent completion proctectomy with redo J pouch demonstrated that the patient only had a preoperative diagnosis of HGD at ATZ but the invasive stage I adenocarcinoma was confirmed based on the surgical specimen postoperatively. Eight patients (57.1%) experienced perioperative complications, including pelvic bleeding (n ¼ 3, 21.4%), pelvic www.ibdjournal.org |
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abscess (n ¼ 2, 14.3%), deep vein thrombosis (n ¼ 2, 14.3%), urinary tract infection (n ¼ 1, 7.1%), ileus (n ¼ 1, 7.1%), and wound infection (n ¼ 1, 7.1%). Of the 11 patients who underwent resection with curative intent, 3 (27.3%) were found to have microscopically positive radial margins. After a median followup of 2.1 (0.6–5.2) years, 2 patients (18.2%) had locoregional recurrence and another 3 (27.3%) developed distant metastasis. At the last follow-up, a total of 6 patients (42.9%) died, with a 5-year cumulative overall survival rate of 49.5% (Table 3 and Fig. 4). Other clinicopathological features of pouch adenocarcinoma were shown in Table 4.
Comparisons of Clinicopathological Features Between Pouch Adenocarcinoma and Dysplasia To further evaluate the natural history of pouch neoplasia, we compared the clinicopathological features between patients who had a final diagnosis of pouch adenocarcinoma (n ¼ 14, 32.6%) and those with pouch dysplasia (n ¼ 29, 67.4%). The patient with pouch HGD who progressed to SCC was not included in this analysis. The mean age at diagnosis of pouch adenocarcinoma was 54.9 6 14.5 years versus 45.6 6 12.9 years at the diagnosis of pouch dysplasia (P ¼ 0.04). Both median intervals from IBD diagnosis to the detection of pouch neoplasia (25.6 [IQR, 18.9–31.0] versus 16.0 [IQR: 11.5–24.4] yr, P ¼ 0.007) and duration from pouch construction to the detection of pouch neoplasia (10.5 [IQR, 3.3–16.2] versus 3.2 [IQR: 1.5–7.1] yr, P ¼ 0.013) were found to be significantly longer in patients with pouch adenocarcinoma than those with pouch dysplasia (Table 4). More patients with pouch adenocarcinoma had undergone mucosectomy with handsewn anastomosis than those with pouch dysplasia (42.9% versus 3.4%, P ¼ 0.003). All patients (100%, n ¼ 24) with pouch adenocarcinoma had a J pouch configuration, whereas only 72.4% (n ¼ 21) for patients with pouch dysplasia (P ¼ 0.039). The location of the ileal pouch neoplasia was at the ATZ in 35 patients (81.4%),
FIGURE 4. Survival curve of 14 patients with pouch adenocarcinoma.
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pouch body in 3 (7.0%), ATZ and pouch body in 3 (7.0%), afferent limb in 1 (2.3%), and afferent limb and pouch body in 1 (2.3%). There was no statistical difference in the location of pouch neoplasia between patients with a final diagnosis of pouch dysplasia and those with pouch adenocarcinoma (P ¼ 0.38). There was also no significant difference between the 2 groups in other variables (P . 0.05) (Table 4).
DISCUSSION Pouch neoplasia is infrequent but potentially lethal adverse sequelae after IPAA for patients with underlying IBD.10,17,18 Most published studies in this field have focused on the prevalence rate and risk factors associated with the development of pouch neoplasia, with limited data available assessing the long-term natural history. Interestingly, this study of the 44 cases with pouch neoplasia showed pouch LGD either persisted or progressed in 6 (27.3%) of the 22 patients and family history of CRC seemed to be associated with LGD persistence or progression. We also found that 41.7% of the patients with pouch HGD and 85.7% of those with pouch adenocarcinoma had a history of or synchronous dysplasia. We proposed an algorithm for the management of pouch neoplasia in 2011.16 This study with real data showed that disease course of LGD was highly variable, supporting the notion in the algorithm that patients with LGD should be further stratified into a high-risk group (i.e., those with persistent or progressive LGD) and low-risk group (i.e., those without LGD detection during subsequent surveillance). Similar to LGD seen in patients with UC before colectomy, the management of pouch LGD is controversial.16 Although the efficacy of surveillance in LGD is not clear, it may be reasonable to biopsy these patients at intervals of 3 to 6 months. If apparent regression of dysplasia is seen, yearly biopsies are recommended thereafter. Otherwise, surgical interventions, such as completion proctectomy, may be needed, particularly for the patients with risk factors for neoplastic progression, such as those with a preoperative diagnosis of rectal neoplasia or a family history of CRC.12 Of the 22 patients with initial diagnosis of pouch LGD in our study, surveillance pouchoscopy was performed to all as the initial management. Six patients (27.3%) with pouch LGD either persisted or progressed after a median follow-up of 9.5 (4.1–17.6) years. All of the 6 patients underwent completion proctectomy with a redo pouch for the persistence or progression of dysplasia. Interestingly, our study for the first time showed that family history of CRC might be a risk factor associated with persistence or progression of pouch LGD. The management of pouch-associated HGD might not be as controversial as LGD, although some investigators supported mucosectomy and pouch advancement procedure while others advocated pouch excision.12,19,20 Of the 12 patients who had pouch HGD, 4 (33.3%) underwent completion proctectomy with redo pouch. The other procedures used included pouch advanced flap (1, 8.3%), transanal excision (1, 8.3%), continuing
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Disease Course of Pouch Neoplasia
TABLE 4. Comparisons of Patient Characteristics Between Pouch Adenocarcinoma and Pouch Dysplasia Characteristics No. patients Age at diagnosis of IBD, yr Age at pouch construction, yr Age at diagnosis of pouch neoplasia, yr Duration from IBD diagnosis to pouch construction, yr Duration from IBD diagnosis to pouch neoplasia, yr Duration from pouch construction to pouch neoplasia, yr Body mass index, kg/m2 Male patients Caucasian patients Smoking Ever Never Drinking alcohol Ever Never Significant comorbidities Autoimmune disorders Family history of IBD Family history of CRC Extent of colitis Extensive colitis Left-sided colitis Toxic megacolon Primary sclerosing cholangitis Extraintestinal manifestations Underlying diseases Ulcerative colitis Indeterminate colitis Crohn’s disease Indication for colectomy Refractory disease Neoplasia Pouch construction stages 1 or 2 3 Pouch configuration J pouch S pouch Type of anastomosis Stapled Handsewn Location of pouch neoplasia ATZ Pouch body Pouch body and ATZ Afferent limb
All Cases
Pouch Dysplasia
Pouch Adenocarcinoma
43 28.2 6 11.9 42.1 6 13.1 48.7 6 14.0 13.3 (5.5–20.7) 18.8 (13.2–29.0) 4.8 (1.7–11.2) 26.6 6 6.8 27 42
29 28.2 6 11.0 40.8 6 11.6 45.6 6 12.9 11.6 (5.0–18.5) 16.0 (11.5–24.4) 3.2 (1.5–7.1) 25.9 6 6.8 17 (58.6%) 29 (100.0%)
14 28.2 6 13.9 44.9 6 16.0 54.9 6 14.5 16.0 (6.6–21.9) 25.6 (18.9–31.0) 10.5 (3.3–16.2) 28.2 6 6.9 10 (71.4%) 13 (92.9%)
14 24
8 (32.0%) 17 (68.0%)
6 (46.2%) 7 (53.8%)
11 27 22 9 4 7
8 (32.0%) 17 (68.0%) 16 (55.2%) 5 (17.2%) 2 (9.1%) 5 (22.7%)
3 (23.1%) 10 (76.9%) 6 (42.9%) 4 (28.6%) 2 (14.3%) 2 (14.3%)
38 5 4 4 8
26 (89.7%) 3 (10.3%) 4 (13.8%) 3 (10.3%) 5 (17.2%)
12 (85.7%) 2 (14.3%) 0 (0%) 1 (7.1%) 3 (21.4%)
35 6 2
24 (82.8%) 4 (13.8%) 1 (3.4%)
11 (78.6%) 2 (14.3%) 1 (7.1%)
21 22
15 (51.7%) 14 (48.3%)
6 (42.9%) 8 (57.1%)
29 14
22 (75.9%) 7 (24.1%)
7 (50.0%) 7 (50.0%)
35 8
21 (72.4%) 8 (27.6%)
14 (100%) 0 (0%)
36 7
28 (96.6%) 1 (3.4%)
8 (57.1%) 6 (42.9%)
35 3 3 1
25 2 1 1
10 (71.4%) 1 (7.1%) 2 (14.3%) 0 (0%)
P
0.99 0.34 0.04 0.21 0.007 0.013 0.33 0.51 0.33 0.49
0.71
0.45 0.44 0.63 0.68 1.0
0.29 1.0 1.0 1.0
0.75
0.16
0.039
0.003
0.38 (86.2%) (6.9%) (3.4%) (3.4%)
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TABLE 4 (Continued) Characteristics Afferent limb and pouch body Any concurrent pouch disorders Concurrent chronic pouchitis Concurrent Crohn’s disease of the pouch Concurrent cuffitis Concurrent pouch sinus or fistula
All Cases
Pouch Dysplasia
Pouch Adenocarcinoma
P
1 24 12 3 13 5
0 (0%) 14 (48.3%) 8 (27.6%) 1 (3.4%) 6 (20.7%) 2 (6.9%)
1 (7.1%) 10 (71.4%) 4 (28.6%) 2 (14.3%) 7 (50.0%) 3 (21.4%)
0.15 1.0 0.24 0.077 0.31
surveillance pouchoscopy (5, 41.7%) and 1 patient (8.3%) was lost to follow-up. After a median follow-up of 5.4 (2.2–9.2) years, 3 patients (25.0%) had persistence or progression, including one who had undergone completion proctectomy with redo pouch, indicating that the risk for persistence or progression for patients with pouch HGD persisted even after undergoing definitive surgical intervention. Pouch excision becomes the treatment of choice should pouch HGD persist.12 Consistent with this, all but 1 patient who was lost to follow-up underwent APR of the ileal pouch for the persistence or progression of pouch HGD. The election of surgical procedure for pouch adenocarcinoma seems to be straightforward, with both IBD specialists and colorectal surgeons advocating APR with end ileostomy or continent ileostomy for patients with pouch adenocarcinoma.16 For the 14 patients with pouch adenocarcinoma in our study, surgical intervention was offered to all the patients, with palliative procedures being done in 3 (21.4%) due to nonresectable tumors. Of the remaining 11 patients (78.6%) who had curative resection, all but 1 patient had APR with end ileostomy or Koch pouch. Surgical management for patients with pouch adenocarcinoma might be technically demanding because the anatomy in the pelvic cavity has been altered after ileal pouch construction. Indeed, our study showed that 3 (27.3%) of the 11 patients with resected tumor were found to have positive margins, and intraoperative or postoperative complications were encountered in 8 patients (57.1%). Prognosis for patients with pouch adenocarcinoma seemed to be poor.10,17 During a median follow-up period of 2.1 (0.6–5.2) years, 5 (45.5%) of the 11 patients who had curative resection of the tumor developed locoregional recurrence or distant metastasis. At the last follow-up, a total of 6 patients (42.9%) died, with a 5-year cumulative survival rate of 49.5%. Of the 43 patients with a final diagnosis of dysplasia or adenocarcinoma, 38 (88.4%) were found to have the involvement at the ATZ, indicating that ATZ is the most common site predisposed to the development of neoplasia.10 Construction of an ileal pouch can be accomplished either with handsewn anastomosis after mucosectomy or with a stapled anastomosis without mucosectomy.21 Although mucosectomy results in a more complete removal of diseased mucosa, this benefit may be at the price of poorer function.9,22 Our study showed that 7 (18.4%) of the 38 patients with ATZ involvement have undergone mucosectomy with a handsewn anastomosis, validating the notion that the risk
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for the occurrence of neoplasia in patients with IPAA is not eliminated by mucosectomy.9,23 Possible explanations include the inability of even the most meticulous mucosectomy to remove all rectal columnar mucosa, as evidenced by one study that stated that macroscopically complete mucosectomy might leave behind islets of rectal mucosa in .20% of cases.24,25 Furthermore, technical difficulty in visualization and biopsy of retained islets of rectal mucosa after mucosectomy with a handsewn anastomosis might also play a role.15,16,18 At the same time, 22 (51.2%) of the 43 patients with pouch dysplasia or adenocarcinoma had a preoperative diagnosis of IBD-associated neoplasia, reflecting that the presence of previous colonic dysplasia or cancer is predictive for the development of pouch neoplasia.7,10,12 Keeping this in mind, it has been the practice at our institution that no patient with a known preoperative diagnosis of carcinoma of the rectum or of dysplasia within 8 cm of the anal verge is considered for stapled IPAA; instead, such patients undergo mucosectomy and a handsewn anastomosis.12 This study included the largest number of patients with pouch adenocarcinoma from a single institution.15,18,20,26–46 Of note, our study indicated that patients with pouch adenocarcinoma were found to be older and have longer durations from IBD diagnosis or pouch construction to the diagnosis than those with pouch dysplasia only. The longer time intervals for patients with pouch adenocarcinoma together with the fact that 78.6% (n ¼ 11) of patients with pouch adenocarcinoma had a history of or synchronous dysplasia might further support the hypothesized carcinogenic pathway: chronic inflammation–LGD–HGD–carcinoma.17 However, a nontraditional carcinogenic pathway might also exist because neither a history of nor synchronous dysplasia was identified in the remaining 2 patients (14.3%) with pouch adenocarcinoma. The findings of this study have several clinical implications. One novel finding from our study was that the family history of CRC was shown to be a risk factor associated with persistence or progression for patients with pouch LGD. This would help us to have a better understanding of the natural history of pouch neoplasia. A more intensified endoscopic surveillance program or a more radical treatment algorithm may be required for patients with pouch LGD with a family history of CRC. Our results also suggest that the majority of pouch adenocarcinoma cases might follow a carcinogenic pathway similar to that of UC-associated
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cancer. The findings of this study support the previously proposed algorithm for surveillance of pouch neoplasia.16 The poor prognosis of pouch adenocarcinoma once diagnosed, further supports our recommendations.10,17 Last but not the least, additional benefits of surveillance pouchoscopy might also be obtained by the detection of endoscopically treatable lesions, such as strictures and polyps, even in asymptomatic patients as shown by a recent study from our group.47 There are limitations to our study. The sample size of the study, although the largest in the literature to date, is still small, which excluded extensive multivariable analyses. For example, the association between family history of CRC and the risk for persistence or progression for patients with LGD was not further evaluated using the multivariate analysis. Although a general strategy of surveillance pouchoscopy has been routinely offered to patients with ileal pouch followed up at our institution,16 patients’ compliance with the surveillance plan was not predicted in the clinical practice. This, along with the suboptimal accuracy of the endoscopic evaluation may compromise our ability to identify all pouch neoplasia, hence potentially underestimating its true frequency.10,11 In summary, the presence of family history of CRC was shown to be a risk factor for persistence or progression on pouch LGD. About 40% of patients with pouch HGD and a majority of patients with pouch adenocarcinoma had a history of or synchronous neoplastic lesions, supporting the hypothesized carcinogenic pathway similar to that of colitis-associated cancer, i.e., chronic inflammation–LGD–HGD–carcinoma. Once diagnosed, the prognosis of patients with pouch adenocarcinoma seemed to be poor.
ACKNOWLEDGMENTS Author contributions: Study concept and design: X-R. Wu, F. H. Remzi, X-L. Liu, L. Lian, L. Stocchi, J. Ashburn, B. Shen; analysis and interpretation of data: X-R. Wu, F. H. Remzi, X-L. Liu, L. Lian, L. Stocchi, J. Ashburn, B. Shen; acquisition: X-R. Wu; drafting of the manuscript: X-R. Wu; critical revision of the manuscript for important intellectual content: F. H. Remzi, X-L. Liu, L. Lian, L. Stocchi, J. Ashburn, B. Shen; supervision of the whole project: B. Shen. All authors read and approved the final manuscript.
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