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Corresponding author at: Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania “Luigi Vanvitelli”, Naples, Italy/Vall d'Hebron University Hospital, Barcelona, Spain.
Affiliations
Department of Advanced Medical and Surgical Sciences, Universitá degli Studi della Campania "Luigi Vanvitelli", Naples, ItalyColorectal Surgery, Vall d'Hebron University Hospital, Barcelona, Spain
Department of Gastroenterology, Northern Hospital, Epping, Melbourne, AustraliaDepartment of Medicine, University of Melbourne, Parkville, Melbourne, Australia
Restorative proctocolectomy results in the formation of a pouch that adapts to a more colonic phenotype. The incidence of cancer of the pouch is thought to be low with most societal guidelines differing on their recommendations for surveillance.
Aims
We conducted a systematic review with meta-analysis to report the incidence of cancer in all pouch patients.
Methods
The Embase, Embase classic and PubMed databases were searched between June 1979– June 2021. A random effects model was performed to find the pooled incidence of pouch cancer. In addition, we also looked for risk factors for pouch cancers.
Results
Forty-six studies were included. In 19,964 patients with Ulcerative Colitis (UC) the pooled incidence of pouch cancer was 0.0030 (95% CI: 0.0016 -0.0055). In 3741 patients with Familial Adenomatous Polyposis (FAP) the pooled incidence of pouch cancer was 0.01 (95% CI: 0.01 – 0.02). In UC most pouch cancers were found to occur in the pouch body (0.59 (95% CI: 0.29–0.84)).
Conclusions
The findings suggest that the pooled incidence of pouch cancer in UC is similar to that which was previously published, and this is the first meta-analysis to report a pooled incidence for pouch cancer in FAP.
Restorative proctocolectomy (RPC) refers to the operation where the diseased large bowel is removed, and the patient's own small bowel is constructed into a reservoir where defaecation can occur. The procedure is most commonly carried out in patient with ulcerative colitis (UC), Familal adenomatous polyposis (FAP), and Crohn's disease (CD). The pouch is well known to adapt to a more colonic phenotype, but the incidence of pouch cancers is thought to be low [
]. Despite this, most societal guidelines suggest ongoing surveillance of the pouch at different time intervals dependent on risk factors such as coexistence of primary sclerosing cholangitis (PSC), type C pouch mucosa, and pre-existence of dysplasia or cancer in the colectomy specimen [
]. Pouch cancer has been reported as being rare with a systematic review in 2014 by Selvaggi et al. highlighting a pooled cumulative incidence of pouch-related adenocarcinoma of 0.35% after 20 years after RPC for UC [
Incidence and risk factors of cancer in the anal transitional zone and ileal pouch following surgery for ulcerative colitis and familial adenomatous polyposis.
Understanding the incidence of pouch cancers can aid the optimisation of surveillance strategies and help uniform guidelines to help reduce the risk of pouch cancers. Importantly, pouch cancers are associated with significant morbidity and mortality, hence early detection and optimal screening is vital to improve outcomes.
This systematic review with meta-analysis therefore aims to update the systematic review from 2014, exploring the pooled cumulative incidence of all types of pouch cancers after RPC for UC, FAP, and CD.
2. Methods
We searched Embase and Embase classic and PubMed from June 1979 to June 2021 to identify cross sectional studies that reported the incidence of pouch cancers in adults. To identify published abstracts, we hand searched conference proceedings from United European Gastroenterology Week, European Crohn's and Colitis Organisation congress, British Society of Gastroenterology and Digestive Disease Week) up to June 2021.
We searched the medical literature using the terms in Supplementary Table 1 using both as medical subject headings [MeSH] and free-text terms. No language restrictions were applied. We hand searched references from eligible studies for any further studies to be included. For studies that appeared potentially eligible but did not have the required data, we emailed the authors for clarification. The eligibility of studies was independently assessed by two authors (DS and DV). All disagreements went to a third reviewer (JPS) for a consensus.
2.1 Inclusion and exclusion criteria
Cross sectional and population-based studies where the majority (>90%) of the patients were 18 years of age or older were included. The studies had to have reported an incidence of pouch cancer in their cohort of patient with those patients having a diagnosis of UC, FAP, or CD. In addition, studies conducted using registries involving UC, FAP, or CD patients to calculate a incidence of pouch cancers were included. Case reports and cohort studies with less than 5 patients were excluded.
2.2 Data analysis
We collected data on: country, type of pouch, median/mean age of pouch, years of disease before RPC, years between RCP and cancer, presence of dysplasia in pre-colectomy sample, prior rectal cancers, presence of pouchitis, presence of PSC, tumour location, outcome of tumour treatment (alive/ died), months of follow-up post diagnosis of tumour, number of male or female patients. We assessed the quality of studies using the Joanna Briggs Institute (JBI) Prevalence Critical Appraisal Checklist for studies reporting prevalence and incidence data, with studies scoring less than 6/9 being excluded [
We combined the proportion of patients with pouch cancer in each study to give a pooled incidence for each study. We then performed a random effects model in order to pool the data to provide an estimate of incidence of pouch cancer. Heterogeneity was assessed using the I2 statistic. Potential risk factors were evaluated by means of odds ratio (OR) with 95% confidence intervals (CI). P < 0.05 was considered statistically significant.
Sensitivity analysis was performed using one-study remove method to detect the impact of each study on the combined effect. Publication bias was assessed by funnel plot inspection, Egger's test, and Begg's test. All statistics were performed using R with the package “meta”.
The systematic review followed a prior defined protocol with comprehensive search of multiple electronic databases including conference proceedings, and followed steps as recommended in the PRISMA guidelines for reporting systematic reviews [
]. The protocol was assigned a registration number of CRD42021267496 by Prospero.
3. Results
The search revealed 4531 studies. After abstract screening there were 53 studies remaining and after full text screening, 46 studies were analysed (Fig. 1). The 46 studies reported on 23,705 patients with an average follow up of 109 months. Due to a lack of published data for Crohn's disease analysis was not possible, thus only findings for UC and FAP have been reported. The characteristics of the studies are displayed in Table 1.
Oncologic outcome in patients with ulcerative colitis associated with dyplasia or cancer who underwent stapled or handsewn ileal pouch-anal anastomosis.
The prognosis of clinical course and the analysis of the frequency of the inflammation and dysplasia in the intestinal J-pouch at the patients after restorative proctocolectomy due to FAP.
Large bowel mucosal neoplasia in the original specimen may increase the risk of ileal pouch neoplasia in patients following restorative proctocolectomy for ulcerative colitis.
Long-term surgical outcomes following laparoscopic ileal pouch-anal anastomosis in patients with chronic ulcerative colitis: 5-year follow-up of a case-matched study.
Diseases of the Colon and Rectum.2013; : e194-e195
The risk of dysplasia and cancer in the ileal pouch mucosa after restorative proctocolectomy for ulcerative proctocolitis is low: a long-term term follow-up study.
Dysplasia following stapled restorative procto-colectomy for ulcerative colitis: is there a correlation between pre-op colorectal dysplasia and development of post-op dysplasia in the rectal cuff mucosa?.
Incidence of neoplasias and effectiveness of postoperative surveillance endoscopy for patients with ulcerative colitis: comparison of ileorectal anastomosis and ileal pouch-anal anastomosis.
Surgical outcomes of ileal pouch anal anastomosis (IPAA) in a community based hospital.
Scientific session of the society of American gastrointestinal and endoscopic surgeons. Surgical Endoscopy and Other Interventional Techniques,
Salt Lake City2014
Total proctocolectomy with ileal pouch-anal anastomosis in the management of familial adenomatous polyposis and ulcerative colitis: relevance of endoanal mucosectomy and long-term functional outcomes.
in: Total proctocolectomy with ileal pouch-anal anastomosis in the management of familial adenomatous polyposis and ulcerative colitis: relevance of endoanal mucosectomy and long-term functional outcomes. Louvain Medical,
2016: 399-400
Impact of desmoid disease and anal transitional zone neoplasia on quality of life after ileal pouch anal anastomosis in patients with familial adenomatous polyposis.
Diseases of the Colon and Rectum.2019; (e337–e337)
Anal transitional zone neoplasia in patients with familial adenomatous polyposis after restorative proctocolectomy and IPAA: incidence, management, and oncologic and functional outcomes.
Patel R., Anele C., von Roon A., Clark S.K., Latchford A. Indications and outcomes for pouch excision in patients withfamilial adenomatous polyposis (FAP. The 13th Scientific and Annual meeting of the European society of coloproctology. Nice: Colorectal Disease; 2018. p. 117–117.
Prevalence and risk factors for adenomas in the ileal pouch and the afferent loop after restorative proctocolectomy for patients with familial adenomatous polyposis.
Twenty-eight studies reported on 19,964 patients with 73 cases of pouch cancer being found. This produced a pooled incidence of 0.0030 (95% CI: 0.0016 −0.0055) (Fig. 2a) with a significant heterogeneity (I2= 80%, p <0.01). Eggers' test indicated the presence of funnel plot asymmetry suggesting publication bias (P = 0.02) (Supplementary Figure 1).
Fig. 2(a): Forest plot of studies reporting pouch cancer in patients with UC. (b): Forest plot of studies reporting pouch cancer in patients with FAP.
Twenty-two studies reported on 3741 patients with 68 cases of pouch cancer being found. This produced a pooled incidence of 0.01 (95% CI: 0.01 – 0.02) (Fig. 2b) with a significant heterogeneity (I2= 66%, p <0.01). Eggers’ test indicated the presence of funnel plot asymmetry suggesting publication bias (P = 0.001) (Supplementary Figure 2).
3.3 Mixed effects regression
With the incidence data for both UC and FAP pooled; mixed effects regression (Fig. 3) did not suggest an association between the year of publication of the study and the size of effect (14.9 95% CI: 158.3–188.2) (P = 0.86).
Fig. 3Bubble plot of all the studies reporting pouch cancer.
Three studies reported on the number of patients with UC who developed pouchitis and the incidence of cancer. This included 2236 patients with 132 having at least one of episode of pouchitis. Of the patients with pouchitis, three developed pouch cancer compared to none in those without pouchitis. Due to the rarity of the cases and large heterogeneity further analysis was not carried out.
3.5 Effect of hand-sewn procedure vs stapled on pouch cancer
For patients with UC, four studies reported the type of procedure used to create the ileal pouch-anal anastomosis (IPAA) and the incidence of cancer. This included 2141 patients with 147 patients undergoing stapled and 1994 undergoing hand-sewn IPAA. Two patients with stapled anastomosis went on to develop pouch cancer and four with hand-sewn anastomosis. Due to the rarity of the cases and large heterogeneity further analysis was not carried out.
3.6 Location of cancer in the pouch
Twenty-eight studies reported on the location of the cancer in the pouch in patients with UC. There were 53 cases in the pouch body, 17 in the anal transition zone (ATZ) and 3 in the rectal pouch. In the pouch body there is a reported pooled incidence of 0.59 (95% CI: 0.29–0.84) without significant heterogeneity (I2=0% P = 1) (Fig. 4a). Eggers’ test did not indicate the presence of funnel plot asymmetry suggesting absence of publication bias (P = 0.19) (Supplementary Figure 3). At the ATZ there is a reported pooled incidence of 0.24 (95% CI: 0.10–0.49) without significant heterogeneity (I2=0% P = 1) (Fig. 4b). Eggers’ test did not indicate the presence of funnel plot asymmetry suggesting absence of publication bias (P = 0.53) (Supplementary Figure 4). In the rectal pouch there is a reported pooled incidence of 0.00 (95% CI: 0.00 −1.00) (Fig. 4c) without significant heterogeneity (I2=0% P = 1). Eggers’ test did not indicate the presence of funnel plot asymmetry suggesting absence of publication bias (P = 0.85) (Supplementary Figure 5). An absence of sufficient data in patient with FAP meant that an analysis could not be performed. However, the extracted data is available to be viewed in Supplementary Table 4.
Fig. 4(a): Forest plot of studies reporting pouch cancer in the pouch body in patients with UC. (b): Forest plot of studies reporting pouch cancer in the ATZ in patients with UC. (c): Forest plot of studies reporting pouch cancer in the rectal pouch in patients with UC.
] in 2014 and reports on 12 more studies with 97 (198%) more cases of pouch cancer identified. It demonstrates that cancer of the pouch has a pooled incidence of 0.3% in UC and 1% in FAP. In terms of location of pouch cancers our study has found that in UC 59% are found in the pouch body and 24% at the ATZ and again there was insufficient data for patients with FAP.
The incidence of pouch cancer in UC reported by this meta-analysis is congruent to the incidence of 0.35% reported by Selvaggi et al. in 2014. With this meta-analysis including a significantly larger number of patients this will provide clinicians with more confidence when counselling patients prior to RPC as well as helping clinicians who are drafting future guidelines. This meta-analysis is also significant as it is the first to suggest a pooled incidence of pouch cancer in FAP. This is useful as it can help power future studies into the area as well as helping clinicians to make recommendations of surveillance when writing future guidelines.
Surveillance represents the main strategy to prevent and reduce the risk of pouch cancers; it is important to identify high risk patients in order to optimise surveillance protocols and create uniform guidelines with clear indications. There is a lack of consensus in the guidelines produced internationally with regards to surveillance in UC. The British Society of Gastroenterology (BSG) [
] make no specific recommendation on the indication to and frequency of endoscopy in these patients. However, all three organisations do agree that in patients deemed high risk, yearly surveillance is warranted. Comparing the differences between the organisations is beyond the scope of this meta-analysis but is well documented by Derikx et al. [
]. Our results also add further weight to the current guidelines for FAP which recommend earlier and more frequent surveillance than in UC. For example, the American Society for Gastrointestinal Endoscopy suggesting a first endoscopy 1 year after the procedure with regular surveillance 1–2 yearly in all patients with FAP [
Our findings also suggest that cancer is more commonly found in the pouch body which agrees with most of the current discussions on whether pouch cancer arises from dysplasia of the ileal mucosa itself or from residual viable rectal mucosa islets. It has been demonstrated, through clinical studies, the mucosal capability to regenerate and the possibility for the neoplasia to origin from the colonized ileal mucosa or the residual mucosa. The theory of the colonized ileal mucosa is supported by the finding of ileal pouch mucosal dysplasia and aneuploidy that have been reported; even though most of the studies have detected inflammatory changes or villous atrophy with hyperplasia, without any colonic metaplasia [
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.
]. These findings can help endoscopists better target surveillance.
There are several limitations to this study, many of which are inherent to meta-analyses, meaning that the results should be interpreted with caution. Due to the relative rarity of malignancy of the pouch and the limited research in the area there was a small number of patients included. Also, the studies included were all observational cohort studies with significant heterogeneity in the data. This may lead to result selection bias. The heterogeneity is accounted for in the wide range of risk factors that can contribute to the development of malignancies and the inability to separate these adequately when studying a cohort.
This meta-analysis has shown that the incidence of pouch cancers in UC appears to have been stable over the last 7 years. It is also the first to suggest a pooled incidence rate for FAP which while is higher than for UC is lower than rates quoted in the literature. The findings should be considered when counselling patients prior to an RPC as well as when new guidelines into the surveillance of pouch cancers are developed. However, national and international co-operation is required to pool multicentre data sets which will improve granularity in the data.
CRediT authorship contribution statement
Danujan Sriranganathan: Data curation, Writing – original draft. Danilo Vinci: Data curation, Writing – original draft. Gianluca Pellino: Conceptualization, Writing – review & editing. Jonathan P. Segal: Conceptualization, Formal analysis, Writing – original draft.
Conflict of interest
J.P.S. has received speaker fees for Janssen, Abbvie and Takeda; D.S., D.V. and G.P. have no conflict of interest to disclose.
Funding
None to declare.
Data Availability Statement
The data underlying this article are available in the article and in its online supplementary material.
Incidence and risk factors of cancer in the anal transitional zone and ileal pouch following surgery for ulcerative colitis and familial adenomatous polyposis.
Oncologic outcome in patients with ulcerative colitis associated with dyplasia or cancer who underwent stapled or handsewn ileal pouch-anal anastomosis.
The prognosis of clinical course and the analysis of the frequency of the inflammation and dysplasia in the intestinal J-pouch at the patients after restorative proctocolectomy due to FAP.
Large bowel mucosal neoplasia in the original specimen may increase the risk of ileal pouch neoplasia in patients following restorative proctocolectomy for ulcerative colitis.
Long-term surgical outcomes following laparoscopic ileal pouch-anal anastomosis in patients with chronic ulcerative colitis: 5-year follow-up of a case-matched study.
Diseases of the Colon and Rectum.2013; : e194-e195
The risk of dysplasia and cancer in the ileal pouch mucosa after restorative proctocolectomy for ulcerative proctocolitis is low: a long-term term follow-up study.
Dysplasia following stapled restorative procto-colectomy for ulcerative colitis: is there a correlation between pre-op colorectal dysplasia and development of post-op dysplasia in the rectal cuff mucosa?.
Incidence of neoplasias and effectiveness of postoperative surveillance endoscopy for patients with ulcerative colitis: comparison of ileorectal anastomosis and ileal pouch-anal anastomosis.
Surgical outcomes of ileal pouch anal anastomosis (IPAA) in a community based hospital.
Scientific session of the society of American gastrointestinal and endoscopic surgeons. Surgical Endoscopy and Other Interventional Techniques,
Salt Lake City2014 (p313–p313)
Total proctocolectomy with ileal pouch-anal anastomosis in the management of familial adenomatous polyposis and ulcerative colitis: relevance of endoanal mucosectomy and long-term functional outcomes.
in: Total proctocolectomy with ileal pouch-anal anastomosis in the management of familial adenomatous polyposis and ulcerative colitis: relevance of endoanal mucosectomy and long-term functional outcomes. Louvain Medical,
2016: 399-400
Impact of desmoid disease and anal transitional zone neoplasia on quality of life after ileal pouch anal anastomosis in patients with familial adenomatous polyposis.
Diseases of the Colon and Rectum.2019; (e337–e337)
Anal transitional zone neoplasia in patients with familial adenomatous polyposis after restorative proctocolectomy and IPAA: incidence, management, and oncologic and functional outcomes.
Patel R., Anele C., von Roon A., Clark S.K., Latchford A. Indications and outcomes for pouch excision in patients withfamilial adenomatous polyposis (FAP. The 13th Scientific and Annual meeting of the European society of coloproctology. Nice: Colorectal Disease; 2018. p. 117–117.
Prevalence and risk factors for adenomas in the ileal pouch and the afferent loop after restorative proctocolectomy for patients with familial adenomatous polyposis.
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.
Conference presentation: The abstract is under consideration for presentation at BSG LIVE Birmingham, UK, 20th – 23rd of June 2022 and ESCP 2022, Dublin UK 21st – 23rd of September 2022.
Ulcerative colitis (UC) and familial adenomatous polyposis (FAP) are two conditions favouring the occurrence of colorectal cancer (CRC) [1,2]. While CRC arising in the context of UC is basically the result of longstanding inflammatory pathways which lead to cancer, FAP-associated CRC is related to genetic features, mainly APC mutations [3,4].
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