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1 Systematic review of cuff and pouch cancer in patients with ileal pelvic pouch for ulcerative colitis Francesco Selvaggi, MD, EBDQ colo; Gianluca Pellino, MD; Silvestro Canonico, MD; Guido Sciaudone, MD, PhD Unit of General Surgery, Second University of Naples, Naples, Italy Running title: pouch-related cancer after IPAA Correspondence to: Francesco Selvaggi, MD, EBSQ colo Associate Professor of General Surgery Unit of General Surgery Second University of Naples Via F. Giordani, 42 80122 Naples, Italy Mob +393358419132 Phone/fax +39815667919 E-mail [email protected] Conflicts of Interest and Source of Funding: none
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Systematic Review of Cuff and Pouch Cancer in Patients with Ileal Pelvic Pouch for Ulcerative Colitis

Apr 28, 2023

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Page 1: Systematic Review of Cuff and Pouch Cancer in Patients with Ileal Pelvic Pouch for Ulcerative Colitis

1

Systematic review of cuff and pouch cancer in patients with ileal pelvic pouch for

ulcerative colitis

Francesco Selvaggi, MD, EBDQ colo; Gianluca Pellino, MD; Silvestro Canonico, MD;

Guido Sciaudone, MD, PhD

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

Running title: pouch-related cancer after IPAA

Correspondence to:

Francesco Selvaggi, MD, EBSQ colo

Associate Professor of General Surgery

Unit of General Surgery

Second University of Naples

Via F. Giordani, 42

80122

Naples, Italy

Mob +393358419132 Phone/fax +39815667919

E-mail [email protected]

Conflicts of Interest and Source of Funding: none

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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.Aim of this study was to review 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 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 papers reported on 49 patients(2:1,male:female) developing

unequivocal pouch-related adenocarcinoma, 14(28.6%) and 33(67.3%) arising from the

pouch and anorectal mucosa,respectively. Origin was not reported in two(4%). Pooled

cumulative incidence of pouch-related adenocarcinoma was 0.33%(95%CI 0.31-0.34) 50

years after diagnosis and 0.35%(95%CI 0.34-0.36) 20years after IPAA. Primary pouch

cancer incidence was below0.02% 20 years after IPAA. Neoplasia on colectomy specimen

was the strongest risk factor(OR 8.8,95%CI 4.61-16.80).Mucosectomy did not abolish the

risk of subsequent cancer,but avoiding it increased eight times the risk of cancer arising

from the residual anorectal mucosa(OR 8,CI95% 1.3-48.7,p=0.02). Surveillance is

currently performed yearly starting ten 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

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might offer a time window for cancer prevention. Abdominoperineal excision cures pouch-

related adenocarcinomas.

Key-words: restorative proctocolectomy; ulcerative colitis; carcinoma; adenocarcinoma;

neoplasms; IPAA

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Introduction

Restorative proctocolectomy, consisting of total proctocolectomy with ileal pouch-anal

anastomosis (IPAA), is the procedure of choice for the treatment of and Ulcerative Colitis

(UC) refractory to medical treatment or when dysplasia or cancer occur. IPAA has been

historically performed with an hand-sewn anastomosis after trans-anal 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 suggested also that the mucosa of the ileal pouch may be at

risk of cancer development. Due to the rarity of the observed events, incidence[3,4,5], risk

factors[3-7] and prevention[8-11] of pouch and cuff cancer in patients with pelvic pouch

remain unclear and controversial.

The aim of our study was to systematically review 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.

Authors[5] 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 excluded unless

pathological descriptions of primary and pouch-related cancer were reported in the paper.

Patients receiving incomplete mucosectomy and those with residual tumour or dysplasia

on the distal part of resected specimen were excluded from evaluation. Information were

collected from description of the operative procedure as well as by contacting the

corresponding authors in dubious cases.

Data Search

Available data of all patients operated on with IPAA between 1978 and 2013 were

evaluated for inclusion. The literature searches were carried out on PubMed, Scopus, US

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: “restorative

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proctocolectomy”, “ulcerative colitis”, “carcinoma”, “adenocarcinoma”, and “neoplasms”.

Free text words were: “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 were included.

Quality assessment

Each selected article was thoroughly reviewed separately by two authors. Quality

assessment was based on a score obtained by the sum of the following variables: number

of patients (0-2 points), study nature (prospective vs retrospective 1 vs 0 points), patient

assessment (0-2 points), disease and IPAA assessment (0-3 points), pouch-related

malignancy assessment (0-1 points), follow-up and outcome description (0-1 points).

Article scored below 2 were excluded from evaluation. When available, full-text of articles

candidate for being included were collected; for papers 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 which were not published as full paper

were not included.

Data extraction

Selected publications were read thoroughly and all needed information gathered. Missing

data were collected by contacting the corresponding authors of each publication. Data

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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.

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 analysed using the Fisher’s exact test.

Meta-analysis of the cumulative incidence of pouch 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 <.05 was considered

statistically significant.

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Results

Characteristics of all studies found in literature reporting on pouch-related cancer are

depicted in Table 1. Systematic study selection flow-chart for analysis is reported in Figure

1.

Study and patient selection and characteristics

Only unequivocal de novo carcinoma of the cuff or ileal pouch were included in the present

analysis. The initial search yielded 1346 studies. Out of these, 1204 did not fit to inclusion

criteria. The full-texts of 142 papers were read. Papers 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 papers only reporting on squamocellular carcinoma (SCC)

[12,29,45,46], one on pouch lymphoma[16], and one on pouch carcinoid[53] were

excluded from evaluation. Data from a study[13] were replicated in another one[44]: the

former was removed. Another paper was removed[35] because the authors performed an

inadequate mucosectomy due to scarring from previous haemorrhoidectomy on a patient

with rectal low-grade dysplasia(LGD). An additional paper was removed as the pouch-

related cancer was presumably a local recurrence of the previous mucinous rectal

adenocarcinoma, showing the same pathological patterns[37]. Pedersen et al[40] 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 authors[18,47,51,55] out of

7[18,41,44,47,51,54,55] contacted replied and provided additional data. This allowed

exclusion of another study (one patient) because of late diagnosis of Crohn’s disease,

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unknown at the time of publication[47]. Thirty-six papers (62 patients) were included in

quality assessment, and two papers (two patients) were removed[5,36](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 al[30] were not

included into 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 three with SCC in the reports from the Cleveland Clinic[3,4,51], and four

patients with frank local recurrences in the study by Derikx et al.[55] (no. 11 to 14) were

excluded. Another patient in the study from Al-Sukhni[44] with pouch lymphoma was

excluded (case 3). Thirty-four studies reporting on 49 patients were hence included.

Included studies were from the following Countries: US (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], UK (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 Nederlands (1)[55], New

Zealand (1)[25], Spain (1)[15], and Sweden (1)[54].

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 two cases the cancer was found in the pouch but

presumably originated from islets of rectal mucosa[14,15]. In two patients (4%)[52,55]

origin was not reported. Besides adenocarcinoma, other pouch-related cancers have been

reported, not included in the analysis: 7 SCC[3,4,12,29,45,46]; 3 pouch

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lymphoma[3,4,16,44]; and 1 pouch carcinoid[53]. Derikx et al.[55] also found in the PALGA

registry 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 2:1. Raw data of 5136

patients[3,4,51,54,55] receiving IPAA were available for cumulative incidence evaluation.

Pooled cumulative incidences[3,4,51,54,55] 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, unmodified up to 50 years.

Pooled cumulative incidences[3,4,51,54,55] 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.

Dysplasia or cancer in the resected colon

Out 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. Pouch-related cancer stage at

presentation did not significantly differ between patients with or without previous dysplasia

or cancer (≥III stage 67.9% vs 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 vs 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

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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%)(Figure 2).

Disease and pouch duration

Mean pouch duration before cancer was 10.8±7.3 years, shorter duration being one

year[17]. No differences were observed according to cancer origin (pouch vs anorectal

mucosa 11.9±9 vs 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 vs 14.5±6.6 years, p=0.03), but pouch adenocarcinoma developed within

one year after IPAA even with shorter disease duration[17].

Backwash ileitis, pouchitis and mucosal changes, extra-intestinal manifestations

Four patients (8.2%) had backwash ileitis (BWI)[18,28,51], of whom one 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 two (4%)[20,21], pouch dysplasia was

found in one (2%)[22], while chronic atrophic pouchitis (CAP) was clearly described in

four(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 other-than-CAP

pouchitis (p=0.005).

Extra-intestinal manifestations (EIMs) were reported in four 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 received a mucosectomy (30.6%) [15,18,19,20,24,26-

28,30,33,39,44,49,52,55], 19 did not (38.8.4%) [17,21-23,25,31,32,34,38,42,43,50,52,55],

while in 15 it was not reported[14,41,48,51,54] or not available[55] (30.6%). A meta-

analysis of 3245 North American patients [4,44] showed that mucosectomy was

associated with higher incidence of subsequent pouch-related carcinoma (OR=4.36,

95%CI 1.62-11.72)(Figure 3). Patients with adenocarcinoma arising from the ileal pouch

more frequently received mucosectomy [18,20,26,27,33,39,49] than stapled IPAA

[31,38](77.8% vs 30.4%, p=0.02). Stapled IPAA was associated with an higher risk of

developing cancer from the anorectal mucosa (OR 8 CI95% 1.3-48.7). Three patients with

mucosectomy developed cancer described as arising from the ileo-anal

anastomosis[19,24,44].

A geographical variability was observed. In Europe Countries and Israel adenocarcinoma

occurred after 14 stapled IPAA[17,22,31,32,34,42,43,50,55] (60.9%) and after 9

mucosectomy with hand-sewn IPAA[15,18,20,27,33,39,49,55] (39.1%); conversely, in

studies from Northern America, it occurred in 4 patients with mucosectomy[26,30,44,52]

and in 4 without[21,23,38,52] (50%). Two patients received mucosectomy (66.7%)[19,28]

and one did not (33.3%)[25] in studies from other Countries.

Treatment and survival

Thirty-six patients were fit to surgery(73.5%). Surgery was often complicated by adhesions

and disease extension, and required urinary[14,39,41,50] and pelvic floor

reconstruction[19,41]. Posterior adhesions to the sacrum further complicated

surgery[26,30]. Only one patients operated on died in the perioperative period due to a

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pelvic haemorrhage(2%)[33]. Abdomino-perineal excision of the pouch was performed in

25 patients (51%), which included resection of adjacent soft tissues and organs in

two(8%)[30,41,50]. One patient received exenteratio pelvis (2.7%)[41]. In two patients the

pouch was diverted[21,34]. Neo-adjuvant and adjuvant treatments were advocated in 16

patients (32.6%). In one patient brachytherapy tubes were placed during surgery(2%)[41].

Four patients(8.2%) were not amenable to surgery, and received radiotherapy alone or

with chemotherapy. In nine patients (19.1%), no surgical details were available. Length of

follow-up after surgery 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

patients 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]. The first description of a “cancer in an

ileal pouch” was published by Stern et al[13] in 1990, 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

London[5] 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 papers reported a cumulative

incidence of pouch-related cancer and dysplasia reaching 5.1% 25 years after IPAA[3,4];

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 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 paper[47]. Additionally, three papers report on patients

developing primary ileal pouch carcinoma found with a perineal abscess [41] and pouch-

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cutaneous fistula [18,22], questioning the diagnosis of UC. Patients with Crohn’s disease

have been recently reported to be at higher risk of malignancies than general population

and 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 of age 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 US and Europe based studies[3,4,51,54,55] does

not exceed 0.4% at 80 years of age. 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], though

recent reports suggest lower rates of UC-related colorectal cancer [61,62] explained by

methodological aspects of studies and by a true decrease in 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[1,2,3,4]. Stapled IPAA is easier to perform and is associated with

better functional outcomes, while 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 al.[6] found dysplasia in 3 patients

within the anal strip, but 2 had a carcinoma in large bowel. Remzi et al.[7] studied

dysplasia of ATZ performing several biopsies in 289 pouch patients for a minimum follow-

up of 10 years. Eight patients developed ATZ dysplasia in 4-123 months. By analysing

data of US and Canada based studies[4,44] we found a higher rate of pouch

adenocarcinoma in patients receiving mucosectomy (Figure 2), but patients are poorly

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described in details. Mucosectomy has been performed a long before the introduction of

staplers, and observed cancers developed in patients operated on many years before. We

observed geographical disparity between type of IPAA and development of pouch-related

cancer. Patients with adenocarcinoma in reports from North America received a

mucosectomy more frequently than those operated on in Europe Countries. It could be

speculated that differences in surgical technique and 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

cycloxigenase 2 (COX-2) and vascular endothelial growth factor (VEGF) expression was

found in both patients receiving mucosectomy developing or not 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 primary from the ileal pouch mucosa affected patients who received

mucosectomy, while those originating from ATZ were more common in patients with

stapled IPAA (OR 8, CI95% 1.3-48.7,p=0.02), but up to 30% of patients receiving

mucosectomy had cancer arising from the residual diseased mucosa. Out of 6 cancers not

clearly arising from pouch mucosa in the mucosectomy group[19,24,28,30,44,55],

three[19,24,44] 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 cases[19,49] from diverted pouch, and 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

inadequately[15] or in Centres without expertise in IPAA surgery, with patients being

referred once pouch-related cancers have developed[18,41]. Also, mucosectomy is often

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performed in patients at high risk of developing pouch-related cancer. Figure 4 shows the

number of reported pouch-related cancer according to origin and type of anastomosis. A

subgroup analysis of patients in the present series with at least one 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 vs 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 vs 10-30 years). This should be considered

when planning surveillance.

Several risk factors for the development of pouch-related cancer have been proposed[3-

7,9,55].

Dysplasia or cancer in the resected colon increase the likelihood of subsequent

dysplasia[6,7,8,55]. Tsunoda et al.[6] and Remzi et al.[7] 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 54-70% 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 cancer diagnosis. By analysing data of 4860

patients[4,43,54,55], this conferred a significant increase in 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 al.[67] and Veress et al. [68,69] studied the

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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 risk of developing dysplasia and should followed-up

closely. Gullberg et al.[70] studied 7 patients with severe atrophy (Type C) and 14 controls

(Type A) with flexible endoscopy and multiple biopsies: dysplasia was in found in 71% vs

0%, respectively (p<0.001). In a group of 276 IPAA patients Banasiewicz et al.[71] found

that pouchitis significantly increased the risk of low grade dysplasia (OR 13.48, 1.48-

122.86 95%CI, p= 0.021), progressing to high-grade dysplasia(HGD) in 6-8 years. This

observation points out the importance of long-term follow-up, as dysplasia may occur

many years after IPAA. Since 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 al reported[73] 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 cancer, suggesting a

suboptimal management. Das et al.[74] 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, faecal stream may exert a protective effect over dysplasia[49], as two 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 one included patient[52] 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 abdomino-perineal pouch

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excision, extended to the perineal skin surrounding the anus, particularly in case of a

stapled IPAA.

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 [75,76,77], due

to an immunological imbalance. Patients with PSC show even 20% higher risk of

colorectal carcinoma[78] 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 one preoperative risk factor (EIMs, colorectal cancer or dysplasia,

backwash ileitis) had shorter pouch duration before adenocarcinoma than those without

(7.8±5.6 vs 17.7±6 years, p<0.001). Shorter interval were 1[17] and 4 [41] 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

al.[80] 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 al.[8] studied 42 patients with chronic pouchitis by

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

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pouchitis (p<0.002). Obusez et al.[48] suggested that faecal methylated DNA markers

could precede endoscopic/histologic anomalies in the pouch. Biomarkers are poorly

addressed in most reported papers, with few exceptions[39,48,49,52] and conflicting

results[39,52], which do not allow drawing conclusions.

Surveillance is costly, hence identifying patients at higher risk of developing malignancies

is crucial to select them for close follow-up. Routine endoscopy is recommended starting

from ten years since diagnosis[5], 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 risk of developing pouch-related adenocarcinoma[8-11,48,61,65]. It would seem prudent

to recommend strict surveillance in patients with at least one risk factor, according to type

of IPAA. In patients who received a stapled IPAA it should be started within ten years

after diagnosis[5], while those who received mucosectomy it could be delayed of 5 years.

Subsequently, a pouchoscopy should 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 two different entities, but distinguishing

between the two may guide the surveillance protocols. Polypoid lesions arising from the

pouch are often inflammatory polyps, and 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 condition that the patients

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21

adhere to annual follow-ups. Adenoma-like LGD may be treated by polypectomy or

endoscopic mucosal resection and strict follow-ups[71,72]. Foci of HGD should be treated

by medical and topical treatment[58], followed by 3- to 6-month controls. Persisting HGD

should be resected[72]. DALM 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. While some investigators suggested to

remove the residual mucosa and advance the pouch[81], other recommend pouch

excision, should HGD persist after 3- to 6-month[7]. Endoscopy and biopsies of the pouch

and ATZ should be performed according to already described modalities[5,10]. Dysplasia

and pouchitis should be assessed by at least two expert pathologists[5]. Excision of the

pouch is recommended for pouch-related adenocarcinoma, and must be performed in

Centres with extensive expertise. Multi-specialist operative teams are desirable

[14,19,39,41,50]. Whether pre- and/or post-operative chemo- 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 CI95% 1.3-48.7, p=0.02).

Surveillance is often performed yearly starting ten years since diagnosis, but a five-year

delay in patients who received a mucosectomy could be considered.

Patients with HGD of the ATZ and pouch-related adenocarcinoma should be offered

abdomino-perineal excision of the pouch.

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Legends to Figures

Figure 1. Flow-chart of study selection for inclusion in the analysis

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Page 25: Systematic Review of Cuff and Pouch Cancer in Patients with Ileal Pelvic Pouch for Ulcerative Colitis

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Figure 2. Forest plot of the outcomes (pouch-related adenocarcinoma) of patients with or

without cancer or dysplasia on proctocolectomy specimen from a prospective study from

Europe[54], and three retrospective studies from Europe[55], US [4] and Israel[43], which

gave sufficient information. Patients with previous dysplasia had an OR 8.8 (95%CI 4.61-

16.8) of developing pouch related cancer than those without (Mantel-Haenszel random

effect). Results are to be balanced with the limited number of events. CRC: colorectal

cancer

Figure 3. Forest plot of the outcomes (pouch-related adenocarcinoma) of patients

receiving or not mucosectomy from two retrospective studies from US[4] and Canada[44].

Mucosectomy was associated with higher rates of pouch-related adenocarcinoma (OR

4.36 95%CI 1.62-11.72). Only 16 cases were observed.

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Figure 4. Adenocarcinoma reported in the literature with adequate description according

to type of anastomosis (stapled vs mucosectomy and hand-sewn) and origin of

adenocarcinoma (ileal pouch mucosa vs anorectal mucosa). Mucosectomy does not

abolish the risk of subsequent cancer but avoiding mucosectomy in this series significantly

increased the risk of cancer arising from the residual mucosa (OR 8 CI95% 1.3-48.7,

p=0.02).

ATZ: anal transitional zone; SCC: squamocellular carcinoma

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Referefences

1. M'Koma AE, Moses HL, Adunyah SE. Inflammatory bowel disease-associated

colorectal cancer: proctocolectomy and mucosectomy do not necessarily eliminate

pouch-related cancer incidences. Int J Colorectal Dis. 2011;26:533-552.

2. Um JW, M'Koma AE. Pouch-related dysplasia and adenocarcinoma following

restorative proctocolectomy for ulcerative colitis. Tech Coloproctol. 2011;15:7-16.

3. 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.

4. 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.

5. Das P, Johnson MW, Tekkis PP, et al. Risk of dysplasia and adenocarcinoma

following restorative proctocolectomy for ulcerative colitis. Colorectal Dis.

2007;9:15-27.

6. Tsunoda A, Talbot IC, Nicholls RJ. Incidence of dysplasia in the anorectal mucosa

in patients having restorative proctocolectomy. Br J Surg. 1990;77:506-508.

7. 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.

8. Vento P, Lepistö A, Kärkkäinen P, et al. Risk of cancer in patients with chronic

pouchitis after restorative proctocolectomy for ulcerative colitis. Colorectal Dis.

2011;13:58-66.

Page 28: Systematic Review of Cuff and Pouch Cancer in Patients with Ileal Pelvic Pouch for Ulcerative Colitis

28

9. Ståhlberg 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.

10.McLaughlin SD, Clark SK, Thomas-Gibson S, et al. Guide to endoscopy of the ileo-

anal pouch following restorative proctocolectomy with ileal pouch-anal anastomosis;

indications, technique, and management of common findings. Inflamm Bowel Dis.

2009;15:1256-1263.

11.Hurlstone DP, Shorthouse AJ, Cross SS, et al. High-magnification chromoscopic

pouchoscopy: a novel in vivo technique for surveillance of the anal transition zone

and columnar cuff following ileal pouch-anal anastomosis. Tech Coloproctol.

2004;8:173-178; discussion 178.

12. Ravitch MM. The reception of new operations. Ann Surg. 1984;200:231–246.

13.Stern H, Walfisch S, Mullen B, et al. Cancer in an ileoanal reservoir: a new late

complication? Gut. 1990;31:473-475.

14.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.

15.Rodriguez-Sanjuan JC, Polavieja MG, Naranjo A, et al. Adenocarcinoma in an ileal

pouch for ulcerative colitis. Dis Colon Rectum. 1995;38:779-780.

16.Nyam DC, Pemberton JH, Sandborn WJ, et al. Lymphoma of the pouch after ileal

pouch-anal anastomosis: report of a case. Dis Colon Rectum. 1997;40:971-972.

17.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.

Page 29: Systematic Review of Cuff and Pouch Cancer in Patients with Ileal Pelvic Pouch for Ulcerative Colitis

29

18.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.

19.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.

20.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.

21.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.

22.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.

23.Hyman N. Rectal cancer as a complication of stapled IPAA. Inflamm Bowel Dis.

2002;8:43-45.

24.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.

25.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.

Page 30: Systematic Review of Cuff and Pouch Cancer in Patients with Ileal Pelvic Pouch for Ulcerative Colitis

30

26.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.

27.Hassan C, Zullo A, Speziale G, et al. Adenocarcinoma of the ileoanal pouch

anastomosis: an emerging complication? Int J Colorectal Dis. 2003;18:276-278.

28.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.

29.Schaffzin DM, Smith LE. Squamous-cell carcinoma developing after an ileoanal

pouch procedure: report of a case. Dis Colon Rectum. 2005;48:1086-1089.

30.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.

31.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.

32.Sagar P. Adenocarcinoma in a pouch without a preceeding history of dysplasia.

Colorectal Dis. 2006;8:526-527.

33.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.

34.Candioli S, Manigrasso A, Arcieri S, Caruso F, Tarroni D, Mascagni D, Palazzini G,

Filippini A. Adenocarcinoma following restorative proctocolectomy for ulcerative

colitis: a case report and review of the literature. G Chir. 2007;28:371-376.

Page 31: Systematic Review of Cuff and Pouch Cancer in Patients with Ileal Pelvic Pouch for Ulcerative Colitis

31

35.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.

36.Schaus BJ, Fazio VW, Remzi FH, et al. Clinical features of ileal pouch polyps in

patients with underlying ulcerative colitis. Dis Colon Rectum. 2007;50:832-838.

37.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.

38.Koh PK, Doumit J, Downs-Kelly E, et al. Ileo-anal j-pouch cancer: an unusual case

in an unusual location. Tech Coloproctol. 2008;12:341-345.

39.Naik VS, Patil SB, Scholefield J, et al. Adenocarcinoma arising in a background of

chronic atrophic pouchitis in an ileoanal pouch for ulcerative colitis. Histopathology.

2008;53:354-358.

40.Pedersen ME, Rahr HB, Fenger C, et al. Adenocarcinoma arising from the rectal

stump eleven years after excision of an ileal J-pouch in a patient with ulcerative

colitis: report of a case. Dis Colon Rectum. 2008;51:1146-1148.

41.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.

42.Panier-Suffat L, Marracino M, Resegotti A, et al. Anal transitional zone

adenocarcinoma following restorative proctocolectomy for ulcerative colitis: case

report and review of literature. Acta Gastroenterol Belg. 2009;72:441-443.

43.Zmora O, Spector D, Dotan I, et al. Is stapled ileal pouch anal anastomosis a safe

option in ulcerative colitis patients with dysplasia or cancer? Int J Colorectal Dis.

2009;24:1181-1186.

Page 32: Systematic Review of Cuff and Pouch Cancer in Patients with Ileal Pelvic Pouch for Ulcerative Colitis

32

44.Al-Sukhni W, McLeod RS, MacRae H, et al. Oncologic outcome in patients with

ulcerative colitis associated with dyplasia or cancer who underwent stapled or

handsewn ileal pouch-anal anastomosis. Dis Colon Rectum. 2010;53:1495-1500.

45.D'Souza FR, Lim M, Hainsworth A, et al. A case of squamous cell carcinoma in an

ileoanal pouch. Colorectal Dis. 2011;13:e314-315.

46.Macdonald E, Gee C, Kerr K, et al. Squamous cell carcinoma of an ileo-anal pouch.

Colorectal Dis. 2010;12:945-946.

47.Gerich ME, McManus MC, McCarter M, et al. Multifocal pouch body

adenocarcinoma following ileal pouch-anal anastomosis (IPAA) for ulcerative colitis.

Inflamm Bowel Dis. 2011;17:E96-98.

48.Obusez EC, Liu Y, Bennett AE, et al. Adenocarcinoma in the ileal pouch: early

detection and potential role of fecal DNA methylated markers in surveillance. Int J

Colorectal Dis. 2011;26:951-953.

49.Marmorale C, Stortoni P, Siquini W, et al. Adenocarcinoma arising from ileoanal J-

pouch mucosa: an announced event? Inflamm Bowel Dis. 2011;17:E57-58.

50.Alessandroni L, Kohn A, Capaldi M, et al. Adenocarcinoma below stapled ileoanal

anastomosis after restorative proctocolectomy for ulcerative colitis. Updates Surg.

2012;64:149-152.

51.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

52.O'Riordan JM, Kirsch R, Mohseni M, et al. Long-term risk of adenocarcinoma post-

ileal pouch-anal anastomosis for ulcerative colitis: report of two cases and review of

the literature. Int J Colorectal Dis. 2012;27:405-410.

Page 33: Systematic Review of Cuff and Pouch Cancer in Patients with Ileal Pelvic Pouch for Ulcerative Colitis

33

53.Al-Khyatt W, Abercrombie JF. Carcinoid tumour complicating a restorative ileo-anal

pouch for ulcerative colitis. Colorectal Dis. 2013;15:e62-63.

54.Andersson P, Norblad R, Söderholm JD, et al. Ileorectal anastomosis in comparison

with ileal pouch anal anastomosis in reconstructive surgery for ulcerative colitis - a

single institution experience. J Crohns Colitis. 2013 Dec 4. pii: S1873-

9946(13)00403-0.

55.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.e1.

56.Parks AG, Nicholls RJ. Proctocolectomy without ileostomy for ulcerative colitis.

BMJ. 1978;2:85–88.

57.Pedersen N, Duricova D, Elkjaer M, et al. Risk of extra-intestinal cancer in

inflammatory bowel disease: meta-analysis of population-based cohort studies. Am

J Gastroenterol. 2010;105:1480-1487.

58.Egan L, D'Inca R, Jess T, et al. Non-colorectal intestinal tract carcinomas in

inflammatory bowel disease: Results of the 3rd ECCO Pathogenesis Scientific

Workshop (II). J Crohns Colitis. 2014;8:19-30.

59.GLOBOCAN 2008 v1.2 [database online]. Ferlay J, Shin HR, Bray F, et al: Cancer

Incidence and Mortality Worldwide: IARC CancerBase No. 10. International Agency

for Research on Cancer, Lyon (France) 2010. Available from WWW:

http://globocan.iarc.fr

60.Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative

colitis: a meta-analysis. Gut. 2001;48:526–535.

Page 34: Systematic Review of Cuff and Pouch Cancer in Patients with Ileal Pelvic Pouch for Ulcerative Colitis

34

61.Jess T, Horváth-Puhó E, Fallingborg J, et al. Cancer risk in inflammatory bowel

disease according to patient phenotype and treatment: a danish population-based

cohort study. Am J Gastroenterol. 2013;108:1869-1876.

62.Sebastian S, Hernández V, Myrelid P, et al. Colorectal cancer in inflammatory

bowel disease: Results of the 3rd ECCO pathogenesis scientific workshop (I). J

Crohns Colitis. 2014;8:5-18.

63.Lakatos PL, Lakatos L. Challenges in calculating the risk for colorectal cancer in

patients with ulcerative colitis. Clin Gastroenterol Hepatol. 2012;10:1179–1180.

64.O'Connell PR, Pemberton JH, Weiland LH, et al. Does rectal mucosa regenerate

after ileoanal anastomosis? Dis Colon Rectum. 1987;30:1-5.

65.Romano M, Cuomo A, Tuccillo C, et al. Vascular endothelial growth factor and

cyclooxygenase-2 are overexpressed in ileal pouch-anal anastomosis. Dis Colon

Rectum. 2007;50:650-659.

66.Rubin DT, Cruz-Correa MR, Gasche C, et al. Colorectal cancer prevention in

inflammatory bowel disease and the role of 5-aminosalicylic acid: a clinical review

and update. Inflamm Bowel Dis. 2008;14:265–274.

67.Setti Carraro P, Talbot IC, Nicholls RJ. Longterm appraisal of the histological

appearances of the ileal reservoir mucosa after restorative proctocolectomy for

ulcerative colitis. Gut. 1994;35:1721-1727.

68.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.

69.Veress B, Reinholt FP, Lindquist K, et al. Long-term histomorphological surveillance

of the pelvic ileal pouch: dysplasia develops in a subgroup of patients.

Gastroenterology. 1995;109:1090-1097.

Page 35: Systematic Review of Cuff and Pouch Cancer in Patients with Ileal Pelvic Pouch for Ulcerative Colitis

35

70.Gullberg K, Ståhlberg D, Liljeqvist L, et al. Neoplastic transformation of the pelvic

pouch mucosa in patients with ulcerative colitis. Gastroenterology. 1997;112:1487-

1492.

71.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.

72.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.

73.Levesque BG, Hanson KA, Sandborn WJ. Reversal of multifocal low- and high-

grade dysplasia in patients with an ileoanal pouch. Gastroenterology.

2011;140:1107-1108

74.Das P, Smith JJ, Lyons AP, et al. Assessment of the mucosa of the indefinitely

diverted ileo-anal pouch. Colorectal Dis. 2008;10:512-517.

75.Lohmuller JL, Pemberton JH, Dozois RR, et al. Pouchitis and extraintestinal

manifestations of inflammatory bowel disease after ileal pouch-anal anastomosis.

Ann Surg. 1990;211:622-627; discussion 627-629.

76.Löfberg R, Leijonmarck CE, Broström O, et al. Mucosal dysplasia and DNA content

in ulcerative colitis patients with ileorectal anastomosis. Follow-up study in a defined

patient group. Dis Colon Rectum. 1991;34:566-571.

77.Löfberg R, Liljeqvist L, Lindquist K, et al. Dysplasia and DNA aneuploidy in a pelvic

pouch. Report of a case. Dis Colon Rectum. 1991;34:280-283; discussion 283-284.

78.Shetty K, Rybicki L, Brzezinski A, et al. The risk for cancer or dysplasia in ulcerative

colitis patients with primary sclerosing cholangitis. Am J Gastroenterol.

1999;94:1643-1649.

Page 36: Systematic Review of Cuff and Pouch Cancer in Patients with Ileal Pelvic Pouch for Ulcerative Colitis

36

79.Haboubi N. Dysplasia in the ileal pouch revisited: what does it mean and what does

it imply? Colorectal Dis. 2012;14:1-2.

80.Coull DB, Lee FD, Anderson JH, et al. Long-term cancer risk of the anorectal cuff

following restorative proctocolectomy assessed by p53 expression and cuff

dysplasia. Colorectal Dis. 2007;9:321-327.

81.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.

82.Trovato C, Sonzogni A, Fiori G, et al. Confocal laser endomicroscopy for the

detection of mucosal changes in ileal pouch after restorative proctocolectomy. Dig

Liver Dis. 2009;41:578-585.

Page 37: Systematic Review of Cuff and Pouch Cancer in Patients with Ileal Pelvic Pouch for Ulcerative Colitis

37

The final version of the article can be accessed at LWW via doi

10.1097/MIB.0000000000000026

Inflamm Bowel Dis. 2014 Jul;20(7):1296-308.