Background
Prophylactic surgery and intensive endoscopic surveillance has decreased the risk of colorectal cancer (CRC) in patients with familial adenomatous polyposis (FAP) and has improved life expectancy [
1,
2]. Consequently, new challenges in the management of FAP arise in this aging population, which are mostly related to extra-colonic manifestations of the disease. Nowadays, one of the most common FAP-related causes of death are desmoid tumours (DT) [
3,
4], occurring in 12% of patients [
5]. Desmoid tumours are benign myofibroblastic proliferations, arising most often in the small bowel mesentery or abdominal wall. Intra-abdominal DT are a major source of morbidity, as they might cause compression and even perforation of hollow viscera, blood vessels or ureters. Reported risk factors for the development of DT are female sex, a positive family history for DT, a germline mutation in the
APC gene on the 3’ end of codon 1399, and a history of abdominal surgery [
5].
Nearly all patients with FAP undergo a prophylactic colectomy to prevent CRC. Among known risk factors, colectomy might be the only modifiable determinant of DT formation. A different timing, surgical approach, type of colectomy, and reconstruction of continuity may result in differences in DT risk. Up to 85% of DT develop after abdominal surgery [
6]. DT also tend to arise shortly after surgery, with a median interval of 3.2 years, highlighting the potential influence of surgical trauma [
5]. Most FAP patients undergo total colectomy with ileorectal anastomosis (IRA) or proctocolectomy with ileal pouch-anal anastomosis (IPAA) [
7]. The severity of rectal polyp burden is widely used to guide the choice between IRA and IPAA. Some authors advice to perform IRA in patients at high risk of DT, hypothesizing that stretching of the small bowel mesentery and lengthening manoeuvres at the index surgery may trigger DT development when constructing an IPAA [
8,
9].
The reported cumulative DT incidence after colectomy varies substantially, with proportions ranging from 1.6 to 17.2% [
10‐
18]. To guide decision-making and to improve the consent process for prophylactic surgery in FAP patients, it would be helpful to review the current evidence for the risk of DT in relation to type, approach, and timing of colectomy. The aim of this study was to systematically review the literature, to calculate summary estimates of the relative risks for DT related to colectomy, and to explore source of heterogeneity in reported results between studies.
Methods
This systematic review and meta-analysis is summarized in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [
19]. The protocol of this review was included in the PROSPERO international register of systematic reviews (CRD42020161424).
Search strategy
A systematic search was conducted with assistance of a clinical librarian using MEDLINE, EMBASE and the Cochrane Library to identify studies from inception up to 2021. The search (reported in full in Supplementary Material 1) included the following Medical Subject Heading (MeSH) and entry terms: Adenomatous Polyposis Coli (Mesh), APC Genes (Mesh), Adenomatous Polyposis Coli Protein (Mesh), adenomatous polyposis, FAP, familial polyposis, hereditary polyposis, polyposis coli, Aggressive Fibromatosis (Mesh), desmoid, aggressive fibromatosis, fibrous tissue neoplasms, mesenteric fibromatosis. The search was last updated on June 4, 2021. No restrictions were applied on publication date or language. By cross-referencing relevant articles, potential additional studies of interest were identified.
Study selection
Studies were considered eligible when the corresponding article included estimates of the incidence of DT. Studies were excluded when it was impossible to calculate incidence estimates, for example, when studies only reported on patients with desmoid tumours (DT) and not on the whole study group of FAP patients, or when no comparison between treatment groups was made.
Two reviewers (A.S.A. and D.S.) independently screened all titles and abstracts of identified studies. Subsequently, studies considered potentially eligible were included or excluded based on the corresponding full text report. Disagreements between reviewers were discussed and resolved in consensus meetings.
Two reviewers (A.S.A. and D.S.) independently extracted data from the reports of included studies using a standardized data extraction form, focussing on the following study characteristics: author, year of publication, country, study design, total number of FAP patients, total number of patients with DT, location of DT, and duration of follow-up. Additionally, the number of patients in each treatment group and number of patients with DT were collected for each comparison, for calculating incidence estimates. Authors were contacted by email to collect additional data from all studies with missing data. Disagreements between reviewers in data extraction were resolved in consensus meetings.
Risk of bias assessment
The same two reviewers also critically appraised included studies with the Cochrane risk-of-bias tool for non-randomized studies of interventions (ROBINS-I) [
20]. This tool evaluates the risk of bias based on seven domains: confounding, selection of participants into the study, classification of interventions, deviations from intended interventions, missing data, measurement of outcomes, and selection of the reported results.
Statistical analysis
The primary aim was to compare the cumulative incidence of DT after ileorectal anastomosis (IRA) versus proctocolectomy with ileal pouch-anal anastomosis (IPAA). Secondary aims were to make a comparison between open or a laparoscopic colectomy, early versus late colectomy, and between patients with a history of abdominal surgery and those without.
Comparisons of the DT incidence between treatment groups were expressed as odds ratios (OR). Summary estimates of the OR were calculated for comparisons including five or more studies using a random-effects model. OR were considered statistically significant when the 95% confidence interval did not include 1.
Publication bias was assessed by inspection of the constructed funnel plot. Heterogeneity between included studies was evaluated by calculating tau and I2 statistics.
All statistical analyses were performed using Review Manager version 5.4 (The Nordic-Cochrane Center, The Cochrane Collaboration, Copenhagen, Denmark).
Discussion
This systematic review summarizes the available evidence on the effects of type, approach, and timing of colectomy in FAP patients on the risk of developing desmoid tumours.
Based on a meta-analysis of available studies, no significant difference in DT risk was observed between patients who underwent total colectomy and IRA and those who underwent proctocolectomy and IPAA. Similarly, no significant difference was observed comparing patients who underwent open versus laparoscopic colectomy. In comparing laparoscopic IRA with laparoscopic IPAA, all three existing studies reported a higher incidence of DT in patients who underwent laparoscopic IPAA, but a similar difference was not observed in those undergoing open procedures.
Although being labelled as a laparoscopic procedure, a laparoscopic IPAA entails partly open surgery including creation of the pouch and lengthening manoeuvres that cannot be safely performed laparoscopically. In addition to trauma related to proctectomy and stretching of the small bowel mesentery, this open segment of the surgery may attribute to DT formation as well. Some of the procedures in the IPAA group might be two-stage procedures with temporary ileostomy. Reversal of the ileostomy results in additional surgical trauma and might thereby contribute to a higher DT risk.
No significant differences were observed between those undergoing colectomy early and those operated later in life. More patients with a history of abdominal surgery developed DT compared to patients without a history of abdominal surgery, as was also observed in a meta-analysis performed by Sinha et al. [
5]. However, none of the included studies documented the median age of both groups and patients with a history of abdominal surgery might be older, which potentially contributes to an increased risk of DT. Nevertheless, Nieuwenhuis et al. [
6] did not find age to be a risk factor for DT in multivariable analysis.
One more systematic review, by Xie et al. [
25], addressed the risk of DT after IRA and IPAA. Similar to the present review, no difference in DT incidence was observed after the different types of colectomy. The review presented here provides additional relevant data and has several strengths. Firstly, 20 studies were included including 6452 FAP patients, of which 804 patients had one or more DT; significantly higher numbers compared to the systematic review performed by Xie et al. (18). More studies were included since multiple comparisons were assessed. For some studies data were initially incomplete but these could be included after authors were contacted. Since the majority of studies on desmoids are performed in a small group of expert centers, the risk of overlapping data was closely assessed and only the most recent study on each outcome from each center was included. Xie et al. [
25] included two studies at high risk of overlapping data and some included studies concerned centers that have published on this subject more recently. The present study is the only systematic review investigating the influence of the surgical approach (open or laparoscopic colectomy) on DT risk.
The largest study on DT in FAP patients comprises data from five European registries. It showed that the first diagnosis of DT is made at a young median age of 31, thus potentially affecting a great part of the life of a patient with FAP [
6]. 72% of DT developed after colorectal surgery, with a median time between surgery and DT diagnosis of 3 years, highlighting the potential influence of surgical trauma in tumour development.
A major difficulty in studying DT lies in the multifactorial etiology. Before drawing conclusions on the influence of types, approaches, and timing of colectomy on DT development, information on other abdominal operations and all known risk factors is needed: sex, DT family history and mutation site on the
APC gene [
5].
No randomized trials were identified and the available evidence largely stems from historical cohort studies, with limited attempts to correct for confounding. Most of the included studies provided insufficient data on other risk factors for DT development and how these differed between treatment groups. As a result, most studies had serious risk of confounding as shown in the risk-of-bias assessment (Table
1).
Patients could be stratified by their risk of DT based on previously reported risk factors before undergoing colectomy. In patients at risk, some authors recommend performing a less extensive IRA [
8,
9] whereas others advice to perform IPAA [
6] arguing that DT formation might prevent a future proctectomy for patients with IRA and advanced rectal polyposis or cancer [
26]. This was refuted by Church et al. [
27], showing proctectomy was possible in all 26 patients with IRA and DT. Policy differences between centers might introduce selection bias in the included studies in this review, resulting in treatment groups with an overall higher or lower risk of DT at time of colectomy.
Another limitation regards the duration of follow-up, which differed amongst studies and, sometimes, between treatment groups within studies. In six studies, no information on duration of follow-up was available even after contacting the authors. As stated before, DT occur shortly after colorectal surgery in most patients and a longer duration of follow-up might therefore not result in a considerable higher cumulative incidence, as shown in Fig.
4, which included 6 studies with a different duration of follow-up.
Although representing a small part of the total number of DT, patients with extra-abdominal DT were also included in some studies (Table
1). Only DT located in the mesentery or abdominal wall were extracted for construction of forest plots when possible. Studies were not excluded when it was not possible to rule out extra-abdominal desmoids. This is a potential limitation of this review, since formation of these DT are presumably not related to colorectal surgery.
The goal of this systematic review was to assess the risk of DT for guiding surgical decision-making in polyposis patients. Unfortunately, these results do not allow us to state with full confidence that any of the modifiable elements regarding type, approach and timing of colectomy affects the subsequent risk of DT development. A lower incidence after laparoscopic IRA was observed, presumably due to the relatively limited extent of surgical trauma, yet without being able to correct for bias due to confounding and without reaching statistical significance.
Though the initiation of large randomized trials, comparing type and timing of colectomy in patients with FAP over a sufficient duration of follow-up, is desirable, randomization might be challenging, as many other factors also play a role in decision-making. A large multi-center cohort study, with extensive data collection on type and approach of colectomy and all known risk factors, could also add further evidence for deciding whether DT risk should play a role in decision-making for colorectal surgery in FAP.
Since DT most often develop after colorectal surgery in FAP patients, patients at high risk of DT formation based on known risk factors may benefit from postponing colectomy, if feasible considering the severity of the colonic polyposis. As shown in this review, this will presumably not lead to an overall lower risk of DT but could result in DT formation at an older age. DT are less often diagnosed in older patients [
5] and a peak incidence is observed in patients in their 20’s-30’s. This peak might be caused by the fact most patients undergo colectomy in this time of their life more than their age itself. Pregnancy in this period might also elicit DT formation in women [
28], although Nieuwenhuis et al. [
26] did not find pregnancy to be a risk factor for DT development.
When a clear indication for colectomy is set, robust evidence-based recommendations on the preferred type and approach of colectomy to reduce post-operative desmoid risk cannot be given. Based on current literature, decision-making on type and timing of colectomy should primarily be guided by rectal polyp burden [
7,
9]. This should always be a shared-decision process with the patient, respecting social factors and potential pregnancy wish in women. In this era of minimal invasive surgery a laparoscopic IRA, when feasible in terms of rectal polyp burden, might be the procedure of choice, possibly resulting in the lowest risk of desmoid formation.
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