Inflammatory Bowel Diseases

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Inflammatory Bowel Diseases:
doi: 10.1097/MIB.0000000000000026
Clinical Review Articles

Systematic Review of Cuff and Pouch Cancer in Patients with Ileal Pelvic Pouch for Ulcerative Colitis

Selvaggi, Francesco MD, EBSQ colo; Pellino, Gianluca MD; Canonico, Silvestro MD; Sciaudone, Guido MD, PhD

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Unit of General Surgery, Second University of Naples, Naples, Italy.

Reprints: Francesco Selvaggi, MD, EBSQ colo, Unit of General Surgery, Second University of Naples, Via F. Giordani, 42, 80122 Naples, Italy (e-mail: fselvaggi@hotmail.com).

The authors have no conflicts of interest to disclose.

Received January 21, 2014

Accepted February 12, 2014

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Abstract

Background: Ileal pouch–anal anastomosis (IPAA) is the procedure of choice for refractory or complicated ulcerative colitis (UC). Since 1990, pouch-related adenocarcinomas have been described. The aim of this study was to review the literature to evaluate the burden of this complication, seeking for risk factors, prevention, and ideal management.

Methods: We performed a systematic review of the literature to identify all described pouch-related adenocarcinoma in patients operated on with IPAA for UC. Studies were thoroughly evaluated to select authentic de novo pouch carcinomas. Some authors were contacted for additional information. Data of patients were pooled. Meta-analyses of suitable studies were attempted to identify risk factors.

Results: Thirty-four articles reported on 49 patients (2:1, male:female) who developed unequivocal pouch-related adenocarcinoma, 14 (28.6%) and 33 (67.3%) arising from the pouch and anorectal mucosa, respectively. Origin was not reported in 2 (4%). Pooled cumulative incidence of pouch-related adenocarcinoma was 0.33% (95% confidence interval [CI], 0.31–0.34) 50 years after the diagnosis and 0.35% (95% CI, 0.34–0.36) 20 years after IPAA. Primary pouch cancer incidence was below 0.02% 20 years after IPAA. Neoplasia on colectomy specimen was the strongest risk factor (odds ratio, 8.8; 95% CI, 4.61–16.80). Mucosectomy did not abolish the risk of subsequent cancer but avoiding it increased 8 times the risk of cancer arising from the residual anorectal mucosa (odds ratio, 8; 95% CI, 1.3–48.7; P = 0.02). Surveillance is currently performed yearly starting 10 years since diagnosis, but cancers escaping this pathway are reported. In patients receiving mucosectomy, a 5-year delay for surveillance could be proposed.

Conclusions: Pouch-related adenocarcinomas are rare. Diagnosis of Crohn's disease in the long term may further decrease the rates in UC. Presumed evolution from dysplasia might offer a time window for cancer prevention. Abdominoperineal excision should be recommended for pouch-related adenocarcinomas.

Restorative proctocolectomy, consisting of total proctocolectomy with ileal pouch–anal anastomosis (IPAA), is the procedure of choice for the treatment of ulcerative colitis (UC) refractory to medical treatment or when dysplasia or cancer occurs. IPAA has been historically performed with a hand-sewn anastomosis after transanal mucosectomy, aiming to remove all diseased mucosa.

Stapling devices have simplified IPAA and improved functional results. Their use determines the retention of a “cuff” of rectal mucosa, which brings about the risk of neoplastic change. However, recent reports also pinpointed the risk of malignancies even after mucosectomy.1,2

Although limited, some data also suggested that the mucosa of the ileal pouch may be at the risk of cancer development. Due to the rarity of the observed events, incidence,3–5 risk factors,3–7 and prevention8–11 of pouch and cuff cancer in patients with pelvic pouch remain unclear and controversial.

The aim of our study was to systematically review the literature to evaluate epidemiology, risk factors, diagnosis, and preventing surveillance protocols concerning pouch-related malignancies after IPAA for UC.

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MATERIALS AND METHODS

Inclusion Criteria

Case report, case series, and cohort studies were included if they clearly reported on patients receiving IPAA for UC with adenocarcinoma arising from the ileal pouch or from the anorectal residual mucosa (rectal cuff, anal transitional zone [ATZ]). Studies mentioning patients with UC, familial adenomatous polyposis, indeterminate colitis, and Crohn's disease were evaluated and only included if UC patients were identifiable. Studies were evaluated for potential replication of data. In the case of duplicate publication or similar data from same institutions, studies were matched, and data were merged. Das et al5 suggested that several equivocal pouch-related carcinomas are reported in the literature. Patients with cancer developing pouch-related carcinoma within few months were considered local recurrences or disease persistence and were excluded unless pathological descriptions of primary and pouch-related cancer were reported in the literature. Patients receiving incomplete mucosectomy and those with residual tumor or dysplasia on the distal part of resected specimen were excluded from evaluation. Information were collected from description of the operative procedure and by means of contacting the corresponding authors in dubious cases.

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Data Search

Available data of all patients operated on with IPAA between 1978 and 2013 were evaluated for inclusion. The literature searches were performed on PubMed, Scopus, U.S. National Library of Medicine database (MEDLINE), the Excerpta Medica database (EMBASE), the Cochrane Database of Systematic Reviews. Also Google search engine was searched. Keywords and medical subjects headings (MeSH) used were as follows: “restorative proctocolectomy,” “ulcerative colitis,” “carcinoma,” “adenocarcinoma,” and “neoplasms.” Free-text words were as follows: “inflammatory bowel diseases,” “IBD cancer,” “IBD malignancy,” “ulcerative colitis colorectal cancer,” “ulcerative colitis,” “restorative proctocolectomy,” “colectomy,” “ileoanal anastomosis,” “ileal pouch,” “ileal pouch anal anastomosis,” “IPAA,” “mucosectomy,” “adenocarcinoma,” “dysplasia,” “pouch cancer,” “pouch adenocarcinoma,” “pouch malignancy,” and “pouch neoplasia.” Limits: publication date between 1978 and 2014. Cross-referencing and related articles were also reviewed. Searches were repeated periodically until January 2014. We excluded experimental articles. Article published in English, French, Spanish, Dutch, or Italian was included.

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Quality Assessment

Two authors separately reviewed each selected article thoroughly. Quality assessment was based on a score obtained through the sum of the following variables: number of patients (0–2 points), study nature (prospective versus retrospective, 1 versus 0 points), patient assessment (0–2 points), disease and IPAA assessment (0–3 points), pouch-related malignancy assessment (0–1 points), and follow-up and outcome description (0–1 points). Article scored below 2 were excluded from evaluation. When available, full text of articles that were candidate for being included were collected; for articles published in national-based journals or without an on-line full-text access, abstracts were collected and reviewed in a similar fashion. Congress proceedings abstracts that were not published as full article were not included.

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Data Extraction

Selected publications were read thoroughly, and all needed information gathered. Missing data were collected by means of contacting the corresponding authors of each publication. Data from case series were collected and merged. Prospective and retrospective cohort studies reporting on larger sample of patients were used to attempt meta-analyses and to extract a pooled cumulative incidence of pouch-related adenocarcinoma.

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Statistical Analysis

Data of patients were pooled. Results are expressed as mean ± SD unless otherwise indicated. Differences in means between subgroups were compared using t test. Comparisons between categorical variables were analyzed using the Fisher’s exact test. Meta-analysis of the cumulative incidence of pouch-related adenocarcinoma was performed, and results are reported as pooled cumulative incidence. Potential risk factors were evaluated by means of odds ratio (OR) with 95% confidence interval (CI). P < 0.05 was considered statistically significant.

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RESULTS

Characteristics of all studies found in the literature reporting on pouch-related cancer are depicted in Table 1. Systematic study selection flowchart for analysis is reported in Figure 1.

TABLE 1-a Neoplasia ...
TABLE 1-a Neoplasia ...
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Figure 1
Figure 1
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Study and Patient Selection and Characteristics
TABLE 1-b Neoplasia ...
TABLE 1-b Neoplasia ...
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TABLE 1-c Neoplasia ...
TABLE 1-c Neoplasia ...
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Only unequivocal de novo carcinoma of the cuff or ileal pouch was included in the present analysis. The initial search yielded 1346 studies. Of these, 1204 did not fit to inclusion criteria. The full texts of 142 articles were read. Articles only dealing with dysplasia and routine surveillance, without mention of carcinoma, were excluded. Studies reporting on patients receiving IPAA subsequently diagnosed with Crohn's disease or for indeterminate colitis were excluded. Four articles only reporting on squamocellular carcinoma (SCC),12,29,45,46 1 on pouch lymphoma,16 and 1 on pouch carcinoid53 were excluded from evaluation. Data from one study13 were replicated in another one,44 and hence, the former was removed. Another article was removed35 because the authors performed an inadequate mucosectomy due to scarring from previous hemorrhoidectomy on a patient with rectal low-grade dysplasia (LGD). An additional article was removed because the pouch-related cancer was presumably a local recurrence of the previous mucinous rectal adenocarcinoma, showing the same pathological patterns.37 Pedersen et al40 reported that a patient developed a severe stenosis at the site of ileostomy closure, suspect for Crohn's disease, and the pouch was excised 11 years before cancer development in the residual anorectal mucosa. Four corresponding authors18,47,51,55 out of 718,41,44,47,51,54,55 contacted replied and provided additional data. This allowed exclusion of another study (one patient) because of the late diagnosis of Crohn's disease, unknown at the time of publication.47 Thirty-six articles (62 patients) were included in quality assessment, and 2 articles (2 patients) were removed5,36 (Table 2). Three studies were merged as reporting on the same population with data needing to be matched and for good quality of each one.3,4,51 Thirty-four studies reporting on 60 patients were further evaluated. Two patients from the study by Lee et al30 were not included in the analysis because evolution from rectal dysplasia (case 1) and local recurrence of rectal cancer (case 2) could not be ruled out.5 One patient with pouch lymphoma and 3 with SCC in the reports from the Cleveland Clinic,3,4,51 and 4 patients with frank local recurrences in the study by Derikx et al55 (cases 11–14) were excluded. Another patient in the study by Al-Sukhni et al44 with pouch lymphoma was excluded (case 3). Thirty-four studies reporting on 49 patients were hence included. Included studies were from the following countries: the United States (10, 29.4%),3,4,21,23,26,30,38,41,48,51 Italy (6, 17.6%),24,27,34,42,49,50 Germany (3, 8.8%),18,20,31 the United Kingdom (3),32,33,39 Canada (2, 5.6%),44,52 India (2),14,28 Czech Republic (1, 2.9%),17 Greece (1),22 Israel (1),43 Japan (1),19 the Netherlands (1),55 New Zealand (1),25 Spain (1),15 and Sweden (1).54

Table 2
Table 2
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Epidemiology

At the time of drafting the manuscript, we were able to identify 49 cases of pouch adenocarcinoma, of which 14 (28.6%)18,20,26,27,31,33,38,39,41,49,51,55 and 33 (67.3%)14,15,17,19,21–25,28,30,32,34,42–44,48,50–52,54,55 arose from the pouch and anorectal mucosa, respectively. In 2 cases, the cancer was found in the pouch but presumably originated from islets of rectal mucosa.14,15 In 2 patients (4%)52,55 origin was not reported. Besides adenocarcinoma, other pouch-related cancers have been reported, which are not included in the analysis: 7 SCC,3,4,12,29,45,46 3 pouch lymphoma,3,4,16,44 and 1 pouch carcinoid.53 Derikx et al55 also found in the Dutch Pathology Registry (PALGA) a case of pouch lymphoma, which is not described in details.

Mean age at IPAA was 39.1 ± 13.3 years. Male to female ratio was 2 to 1. Raw data of 5136 patients3,4,51,54,55 receiving IPAA were available for cumulative incidence evaluation. Pooled cumulative incidences3,4,51,54,55 of pouch-related adenocarcinoma at 5, 10, 15, 20, 25, 30, 40, and 50 years since UC diagnosis were 0, 0, 0.04 (95% CI, 0.035–0.045), 0.12 (95% CI, 0.11–0.13), 0.21 (95% CI, 0.19–0.22), 0.27 (95% CI, 0.26–0.28), 0.31 (95% CI, 0.29–0.32), and 0.35 (95% CI, 0.34–0.36), respectively. When only considering cancer arising from the ileal mucosa, pooled cumulative incidence was 0% up to 15 years after UC diagnosis, reaching 0.04% (95% CI, 0.034–0.045) at 20 years, remained unmodified up to 50 years.

Pooled cumulative incidences3,4,51,54,55 of pouch-related adenocarcinoma after IPAA were 0.12 (95% CI, 0.11–0.13), 0.19 (95% CI, 0.18–0.20), 0.29 (95% CI, 0.28–0.3), and 0.33% (95% CI, 0.31–0.34), 5, 10, 15, and 20 years, respectively. Primary pouch cancer cumulative incidences did not exceed 0.02% (95% CI, 0.01–0.12) 20 years after IPAA.

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Dysplasia or Cancer in the Resected Colon

Of 49 patients diagnosed with pouch-related carcinoma, 28 (57.1%) had dysplasia (14, 28.6%) or cancer (14, 28.6%) on the resected specimen. The stage of pouch-related cancer at presentation did not significantly differ between patients with or without previous dysplasia or cancer (≥stage III, 67.9% versus 42.8%; P = 0.18). Patients with previous dysplasia or cancer on the specimen had shorter pouch duration before cancer diagnosis (7.9 ± 5.8 versus 14.7 ± 7.3 years; P = 0.0012).

We attempted a meta-analysis to assess the risk of developing pouch-related cancer in patients with or without cancer or dysplasia on the specimen. The analysis included 4860 patients.4,43,54,55 Those with previous colorectal cancer or dysplasia were at higher risk of developing pouch-related adenocarcinoma (OR, 8.8; 95% CI, 4.61–16.80). Data seemed homogeneous (τ2 = 0; χ2 = 2.58; P = 0.46; I2 = 0%) (Fig. 2).

Figure 2
Figure 2
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Disease and Pouch Duration

Mean pouch duration before cancer was 10.8 ± 7.3 years, shorter duration being 1 year.17 No differences were observed according to cancer origin (pouch versus anorectal mucosa 11.9 ± 9 versus 10.9 ± 7 years; P = 0.74). Mean interval between UC diagnosis and pouch-related cancer was 25.3 ± 9.7 years. IPAA cancer was diagnosed 4 years after UC diagnosis at the earliest.41 Patients with at least 10-year history of UC had shorter pouch duration (9.3 ± 7.3 versus 14.5 ± 6.6 years; P = 0.03), but pouch adenocarcinoma developed within 1 year after IPAA even with shorter disease duration.17

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Backwash Ileitis, Pouchitis, Mucosal Changes, and Extraintestinal Manifestations

Four patients (8.2%) had backwash ileitis (BWI),18,28,51 of whom 1 developed cancer arising from the pouch.18 Pouchitis was reported in 20 patients (40.8%). Surveillance protocols, and endoscopic and pathological features of the pouch are poorly described in the studies. Pouchitis was defined as “severe” in 2 (4%),20,21 pouch dysplasia was found in 1 (2%),22 whereas chronic atrophic pouchitis (CAP) was clearly described in 4 (8.2%).27,31,39,49 Cancers arising from ileal pouch mucosa were found in 35% of patients with pouchitis and in 20.7% without (P = 0.33). In 100% of patients with CAP, the cancer originated from the pouch versus 22.2% of those without or with inflammation other than CAP pouchitis (P = 0.005).

Extraintestinal manifestations (EIMs) were reported in 4 patients (8.2%) and mainly consisted of primary sclerosing cholangitis (PSC) (75%).24,33,41,52 Again, these are poorly assessed in the studies.

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Hand-sewn Plus Mucosectomy Versus Stapled Anastomosis

Fifteen patients (30.6%) received mucosectomy,15,18,19,20,24,26–28,30,33,39,44,49,52,55 19 (38.8.4%) did not,17,21–23,25,31,32,34,38,42,43,50,52,55 whereas in 15 (30.6%), it was not reported14,41,48,51,54 or not available.55 A meta-analysis of 3245 North American patients4,44 showed that mucosectomy was associated with higher incidence of subsequent pouch-related carcinoma (OR, 4.36; 95% CI, 1.62–11.72) (Fig. 3). Patients with adenocarcinoma arising from the ileal pouch more frequently received mucosectomy18,20,26,27,33,39,49 than stapled IPAA31,38 (77.8% versus 30.4%; P = 0.02). Stapled IPAA was associated with a higher risk of developing cancer from the anorectal mucosa (OR, 8; 95% CI, 1.3–48.7). Three patients who received mucosectomy developed cancer that was described as arising from the ileoanal anastomosis.19,24,44

Figure 3
Figure 3
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A geographical variability was observed. In European countries and Israel, adenocarcinoma occurred after stapled IPAA in 14 patients (60.9%)17,22,31,32,34,42,43,50,55 and after mucosectomy with hand-sewn IPAA in 9 (39.1%)15,18,20,27,33,39,49,55; conversely, in studies from Northern America, it occurred in 4 patients with mucosectomy26,30,44,52 and in 4 without21,23,38,52 (50%). Two patients (66.7%) received mucosectomy19,28 and 1 (33.3%) did not25 in studies from other countries.

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Treatment and Survival

Thirty-six patients (73.5%) were fit to surgical treatment. Surgical procedure was often complicated by adhesions and disease extension and required urinary14,39,41,50 and pelvic19,41 floor reconstruction. Posterior adhesions to the sacrum further complicated the surgical procedure.26,30 Only 1 patient (2%) operated on died in the perioperative period due to pelvic hemorrhage.33 Abdominoperineal excision of the pouch was performed in 25 patients (51%), which included resection of adjacent soft tissues and organs in 2 (8%).30,41,50 One patient (2.7%) received exenteration pelvis.41 In 2 patients, the pouch was diverted.21,34 Neoadjuvant and adjuvant treatments were advocated in 16 patients (32.6%). In 1 patient (2%), brachytherapy tubes were placed during surgical procedure.41 Four patients (8.2%) were not amenable to surgical treatment and received radiotherapy alone or with chemotherapy. In 9 patients (19.1%), no surgical details were available. Length of follow-up after surgical treatment was inadequate to allow conclusions on survival. Palliative surgery was effective in reducing cancer-related symptoms.

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DISCUSSION

Studies included in the present review mainly consist of case reports and case series, and patient characteristics are succinctly described, making it difficult to draw definitive conclusions. It should be noted that several reviews on the topic are reported in the literature, but the research and study selection methods are not clearly stated in most of these. Also, several inconsistencies between reviews can be found.1,2,5

The first pouch procedure is dated 1978,56 and the first report of a “true,” de novo pouch-related adenocarcinoma was published in 1992.14 Stern et al13 in 1990 published the first description of a “cancer in an ileal pouch”, but this observation was probably flawed, as cancer occurred early after IPAA (4 years) in a patient who had “severe dysplasia” in the rectum of the surgical specimen. A study from the St. Mark’s Hospital in London5 already found that several cases of pouch-related carcinoma were to be ruled out from further evaluation, as cancers were not an “authentic” carcinomas in the pouch or anorectal mucosa. Similarly, we found 49 unequivocal pouch-related adenocarcinomas.3,4,14,15,17–28,30–34,38,39,41–44,48–52,54,55 Recent articles reported a cumulative incidence of pouch-related cancer and dysplasia reaching 5.1% 25 years after IPAA3,4; these alarming data were not confirmed by others, reporting incidence below 0.002% with a mean follow-up of 13.4 years.52 Although an increased rate of pouch-related cancer can be predicted in the next years, we observed a pooled cumulative incidence of 0.35% and 0.33% 50 years after UC diagnosis and 20 years after IPAA, respectively. One should also consider that the initial diagnosis of UC in patients with pouchitis or pouch-related malignancies may have been shifted to Crohn's disease in the long-term follow-up, this not being clearly stated in the article.47 Additionally, 3 articles report on patients developing primary ileal pouch carcinoma found with a perineal abscess41 and pouch/cutaneous fistula,18,22 questioning the diagnosis of UC. Patients with Crohn's disease have been recently reported to be at the higher risk of malignancies than general population and those with UC,57 and small bowel adenocarcinoma is a feature of long-standing Crohn's disease arising from severely inflamed ileal segments.58

The cumulative risk of developing colorectal cancer from birth to 75 years in the general population is reported to be as high as 1.96% worldwide by GLOBOCAN 2008.59 The risk of primary pouch-related cancers arising from anorectal residual mucosa derived from pooled analysis of the United States–based and Europe-based studies3,4,51,54,55 does not exceed 0.4% at 80 years. It could be speculated that IPAA is safe and almost abolish the risk of cancer of colorectal origin. The benefits of IPAA over conservative treatment in patients with long-standing remitting-relapsing UC is evident,60 although recent reports suggest lower rates of UC-related colorectal cancer,61,62 explained by methodological aspects of studies and by a true decrease in the risk due to better disease control and surveillance.63

Debate exists as to the benefits of performing mucosectomy in pouch surgery. Based on the reported experiences, mucosectomy does not seem to abolish the risk of subsequent pouch-related cancer.1–4 Stapled IPAA is easier to perform and is associated with better functional outcomes, whereas residual microscopic islets of rectal mucosa have been reported in 20% of patients receiving mucosectomy,64 so that a cancer can develop between the pouch and the muscle layers. Tsunoda et al6 found dysplasia in 3 patients within the anal strip, but 2 had a carcinoma in large bowel. Remzi et al7 studied dysplasia of ATZ performing several biopsies in 289 patients receiving IPAA for a minimum follow-up of 10 years. Eight patients developed ATZ dysplasia in 4 to 123 months. By analyzing data of the United States–based and Canada-based studies,4,44 we found a higher rate of pouch adenocarcinoma in patients receiving mucosectomy (Fig. 2), but patients are poorly described in details. Mucosectomy has been performed a long before the introduction of staplers and observed cancers developed in patients operated on many years ago. We observed geographical disparity between the type of IPAA and the development of pouch-related cancer. Patients with adenocarcinoma in reports from North America received mucosectomy more frequently than those operated on in European countries. It could be speculated that differences in the surgical technique and the extent of mucosectomy may account for this. The complete excision of the anorectal mucosa may prevent dysplasia arising from residual diseased tissue, with optimal oncological results.8 Physiological changes occur in the ileal pouch mucosa, irrespective of the type of anastomosis. High expression of cyclooxygenase 2 (COX-2) and vascular endothelial growth factor was found in patients receiving mucosectomy developing pouchitis or those who are not developing pouchitis,8,65 and the phenomenon has been attributed to colonic metaplasia in the ileal mucosa rather than dysplasia, which is independent from the anastomotic technique. In the present series, most cancer arising primarily from the ileal pouch mucosa affected patients who received mucosectomy, whereas those originating from ATZ were more common in patients with stapled IPAA (OR, 8; 95% CI, 1.3–48.7; P = 0.02), but up to 30% of patients receiving mucosectomy had cancer arising from the residual diseased mucosa. Of 6 cancers not clearly arising from pouch mucosa in the mucosectomy group,19,24,28,30,44,55 319,24,44 were described as originating from the anastomosis, suggesting that an ileal origin cannot be ruled out. Notably, pouch-related cancer in patients receiving mucosectomy arose in 2 cases19,49 from diverted pouch, and hence, an immune-mediated cancerogenesis rather than evolution from residual islets of rectal mucosa can be hypothesized. Another facet to consider is the mucosectomy being performed inadequately15 or in centers without expertise in IPAA surgery, with patients being referred once pouch-related cancers have developed.18,41 Also, mucosectomy is often performed in patients at the high risk of developing pouch-related cancer. Figure 4 shows the number of reported pouch-related cancer according to the origin and type of anastomosis. A subgroup analysis of patients in the present series with at least 1 preoperative risk factor (EIMs, disease duration >10 years, colorectal cancer or dysplasia, BWI) and/or dysplasia or cancer on colectomy specimen showed that those receiving mucosectomy developed pouch-related adenocarcinoma after a longer interval from UC diagnosis than those who did not (29.9 ± 10 versus 19.5 ± 6.3 years; P = 0.012). Patients receiving mucosectomy developed pouch-related carcinoma 18 years after IPAA at the earliest versus 10 years in those receiving stapled IPAA (range, 18–47 versus 10–30 years). This should be considered when planning surveillance.

Figure 4
Figure 4
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Several risk factors for the development of pouch-related cancer have been proposed.3–7,9,55 Dysplasia or cancer in the resected colon increases the likelihood of subsequent dysplasia.6–8,55 Tsunoda et al6 and Remzi et al7 found an association between dysplasia in the ATZ and cancer or dysplasia in the postoperative specimen, concluding that the carcinoma poses at high risk the anal mucosa. Approximately 54% to 70% of patients developing pouch-related cancer had a dysplasia or cancer in the operative specimen.5,8 Patients in our analysis found with cancer or dysplasia on the specimen had shorter interval between IPAA and pouch-related cancer diagnosis. By analyzing data of 4860 patients,4,43,54,55 this conferred a significant increase in the likeliness of developing pouch-related adenocarcinomas (OR, 8.8; 95% CI, 4.61–16.80).

The pathway leading to cancerogenesis in UC is different from that of colorectal cancer in general population.51,62,58,66 Inflammation plays a pivotal role in cancer development in inflammatory bowel diseases, and evidences support the inflammation–dysplasia–carcinoma sequence.58,66 Setti-Carraro et al67 and Veress et al68,69 studied the pouch mucosal inflammation through biopsies and classified pouchitis accordingly. They identified a subset of patients with severe pouchitis and constant villous atrophy, suggesting that they may be at the risk of developing dysplasia and should be followed up closely. Gullberg et al70 studied 7 patients with severe atrophy (type C) and 14 control subjects (type A) with flexible endoscopy and multiple biopsies: dysplasia was found in 71% versus 0%, respectively (P < 0.001). In a group of 276 IPAA patients, Banasiewicz et al71 found that pouchitis significantly increased the risk of LGD (OR, 13.48; 95% CI, 1.48–122.86; P = 0.021), progressing to high-grade dysplasia (HGD) in 6 to 8 years. This observation points out the importance of long-term follow-up, as dysplasia may occur many years after IPAA. Because cumulative incidence of pouch-related cancer is low and evolution from dysplasia (prevalence 1.13%)72 may be gradual, this might offer a reasonable time window for intervention.36,58,73 Levesque et al73 were able to reverse dysplasia with medical therapy. However, the ideal treatment of pouchitis and dysplasia remains unclear, also considering that most patients in the present series were diagnosed with pouchitis years before the development of pouch-related cancer, suggesting a suboptimal management. Das et al74 reported that UC patients with indefinitely diverted pouch develop atrophy with distortions of the ileal pouch mucosa and of the ATZ in those receiving a stapled IPAA, but they did not find any case of dysplasia or cancer.74 However, fecal stream may exert a protective effect over dysplasia,49 as 2 patients in the present series who had failure with definitive ileostomy but retained their pouch developed pouch-related carcinoma with marked alterations of the ileal pouch mucosa.19,49 In 1 included patient52 and in another suspect for Crohn's disease,40 cancer developed from the residual anorectal mucosa after pouch resection. Patients with definitive diversion reluctant to follow-up should be offered abdominoperineal pouch excision, extended to the perineal skin surrounding the anus, particularly in case of a stapled IPAA.

However, EIMs seem to increase the risk of developing pouch-related malignancies. EIMs are associated with higher rates of pouchitis and type C changes of the pouch,75–77 due to an immunological imbalance. Patients with PSC show even 20% higher risk of colorectal carcinoma78 and may develop pouchitis and dysplasia more frequently.9 In the present series, only 3 patients were diagnosed with PSC, and the association with pouch neoplasia has been questioned by more recent reports.4,55

The risk of pouch cancer, as well as that of colorectal cancer in UC, increases with time, probably in a similar fashion.1,71,79 Cancer are reported to occur at least 10 years after UC diagnosis.1,5 UC onset is more important than interval from IPAA when considering surveillance, but disease duration itself may not adequately predict the risk of developing pouch-related cancer. Irrespective of disease duration, patients in the present series, with at least another 1 preoperative risk factor (EIMs, colorectal cancer or dysplasia, BWI), had shorter pouch duration before adenocarcinoma than those without (7.8 ± 5.6 versus 17.7 ± 6 years; P < 0.001). Shorter intervals were 117 and 441 years, respectively. The shortest interval since diagnosis was 10 years.17

Surveillance protocols are debated. Aiming to identify reliable biomarkers and immunohistological markers of pouchitis, which may lead to cancer development, Coull et al80 found that p53 was not useful in routine surveillance of cuff biopsies, up to 12 years after IPAA. This was confirmed in some patients from the present series.39 Several markers of inflammation are overexpressed in ileal pouch, even without the endoscopic evidence of pouchitis.8,65 Vento et al8 studied 42 patients with chronic pouchitis who underwent endoscopy with biopsies and found that COX-2 expression (P < 0.01) positively correlated with mucosal atrophy; Ki-67 immunostaining was increased only in patients with chronic pouchitis (P < 0.002). Obusez et al48 suggested that fecal methylated DNA markers could precede endoscopic/histological anomalies in the pouch. Biomarkers are poorly addressed in the most reported articles, with few exceptions39,48,49,52 and conflicting results,39,52 which do not allow drawing conclusions.

Surveillance is costly, and hence, identifying patients at the higher risk of developing malignancies is crucial to select them for close follow-up. Routine endoscopy is recommended starting from 10 years since diagnosis5; however, we identified several cases “escaping” the conventional protocol, and even developing cancer without dysplasia during accurate follow-ups.32,48 This advocate the need of developing new strategies to identify patients at the risk of developing pouch-related adenocarcinoma.8–11,48,61,65 It would seem prudent to recommend strict surveillance in patients with at least 1 risk factor, according to the type of IPAA. In patients who received a stapled IPAA, it should be started within 10 years after diagnosis,5 whereas in those who received mucosectomy, it could be delayed of 5 years. Subsequently, a pouchoscopy should be performed at least yearly. The protocol should be modulated on evolution, seeking for ileal pouch mucosa anomalies, and potentially intensified accordingly. Irrespective of the type of anastomosis, patients should receive long-term follow-ups, as changes in the pouch may still occur many years after IPAA.8,65,71,79

It is widely accepted that cancers arising from pouch and from anorectal mucosa after IPAA for UC should not be rigidly considered as 2 different entities, but distinguishing between the 2 may guide the surveillance protocols. Polypoid lesions arising from the pouch are often inflammatory polyps, and they should be removed by means of endoscopic polypectomy.36 Data on the management of pouch and cuff dysplasia are scanty. Patients with LGD diagnosed early in the pouch may benefit from cautious wait-and-see policy and managed with medical treatment,58,71–73 on the condition that the patients adhere to annual follow-ups. Adenoma-like LGD may be treated by means of polypectomy or endoscopic mucosal resection and strict follow-ups.71,72 Foci of HGD should be managed with medical and topical treatment,58 followed by 3- to 6-month controls. Persisting HGD should be resected.72 Dysplasia-associated lesion or mass should be considered as an indication for pouch excision.20 In patients with LGD arising from the residual anorectal mucosa after a stapled IPAA or an inadequate mucosectomy, a mucosectomy and advancement of the IPAA,7,42 followed by strict surveillance, is advisable. The management of HGD arising from the residual anorectal mucosa is less clear. Although some investigators suggested to remove the residual mucosa and advance the pouch,81 others recommend pouch excision, should HGD persist after 3 to 6 months.7 Endoscopy and biopsies of the pouch and ATZ should be performed according to the already described modalities.5,10 At least 2 expert pathologists should assess dysplasia and pouchitis.5 Excision of the pouch is recommended for pouch-related adenocarcinoma, and it must be performed in centers with extensive expertise. Multispecialist operative teams are desirable.14,19,39,41,50 Whether preoperative and/or postoperative chemotherapy or radiotherapy should be administered remain controversial.

New technologies may help preventing islets of rectal mucosa to be left in site during mucosectomy and diagnosing at an early stage dysplasia, warranting active treatment during surveillance.11,82

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CONCLUSIONS

Pouch-related adenocarcinoma is a rare eventuality after IPAA for UC. Forty-nine unequivocal cases of adenocarcinoma arising from the pouch or anorectal residual mucosa are sufficiently described in the literature.

Cumulative incidence does not exceed 0.4% 20 years after IPAA. A shift to diagnosis of Crohn's disease in the long term may further decrease the rates of pouch cancer in UC. The strongest risk factor for pouch adenocarcinoma is the presence of dysplasia or cancer on the proctocolectomy specimen (OR, 8.8; 95% CI, 4.61–16.80). Mucosectomy does not abolish the risk of subsequent cancer, but the technique is surgeon dependent. Avoiding mucosectomy in this series significantly increased the risk of cancer arising from the residual mucosa (OR, 8; 95% CI, 1.3–48.7; P = 0.02).

Surveillance is often performed yearly starting 10 years since diagnosis, but a 5-year delay in patients who received a mucosectomy could be considered. Patients with HGD of the ATZ and pouch-related adenocarcinoma should be offered abdominoperineal excision of the pouch.

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Keywords:

restorative proctocolectomy; ulcerative colitis; carcinoma; adenocarcinoma; neoplasms; IPAA

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