Familial adenomatous polyposis (FAP) is an autosomal dominant inherited disease caused by pathogenic variants in the adenomatous polyposis coli (APC) gene1 with reported incidence of one in 8,000 to 12,000 live births.2 The main hallmark of the disease is the presence of multiple colorectal adenomas, leading to a 100% lifetime risk of developing cancer if the colon remains in situ.3 To prevent the development of cancer, prophylactic colectomy or proctocolectomy is performed when the adenoma burden cannot be managed endoscopically or at the age of 18–25 years old. The following types of surgery are available4: total colectomy with ileorectal anastomosis (IRA) or ileosigmoid anastomosis (ISA); proctocolectomy with/without mucosectomy and stapled ileal pouch-anal anastomosis (IPAA) or hand-sewn IPAA; and total proctocolectomy with end ileostomy. Until restorative proctocolectomy with IPAA and pouch reconstruction was described in the 1970s, colectomy with IRA or end ileostomy was the only surgical prophylactic procedure available and was associated to a considerable high CRC incidence and mortality.5 After this, proctocolectomy with pouch reconstruction (IPAA) was the technique of choice in patients with a high adenoma burden and was sought to eliminate the risk of CRC in FAP patients. However, since the first report of pouch cancer in 19946, there has been a substantial increase in published literature reporting rates of adenoma and cancer development after primary IPAA. The development of adenomas along life in remnant rectal mucosa is a natural phenomenon in this population. Long live periodical surveillance with rectoscopies is widely recommended in international guidelines as shown in Table 1.4,7,8,9,10 As there are no randomised trials comparing endoscopic surveillance and management strategies for FAP patients with IRA and IPAA, we aimed to systematically evaluate adenoma and cancer development after prophylactic surgery, define potential risk factors and to summarise endoscopic practices from published series.
Summary of recommendations from the international guidelines
Vasen et al., 20087 | Every 3 to 6 months | Multiple large adenomas (> 5 mm) Adenomas with dysplasia | Every 6 to 12 months |
Balmaña et al., 2013, ESMO8 | Every 12 months | No recommendations | Every 12 months |
Stoffel et al., 2015, ASCO9 | Every 6 to 12 months | No recommendations | Every 6 months to 5 years (Intervals should be determined on a case-by-case basis and may be even shorter than 1 year for some individuals) |
Sygnal et al., 2015, ACG10 | Every 12 months | No recommendations | Every 12 months |
Herzig et al., 2017, ASCRS4 | Every 12 months | No recommendations | Every 12 months |
Van Leerdam ME et al., 2019, ESGE53 | Every 12 to 24 months | No recommendations | Every 12 to 24 months |
Yang J et al., 2020, ASGE54 | 6 months after surgery with 6 to 12 months further surveillance interval | 12 months after surgery with 12 to 24 months further surveillance interval. 6 months if advance adenoma |
ACG = American College of Gastroenterology; ASCO = American Society of Clinical Oncology; ASCRS = American Society of Colon and Rectal Surgeons; ASGE = American Society for Gastrointestinal Endoscopy; ESGE = European Society of Gastrointestinal Endoscopy; ESMO = European Society for Medical Oncology; IPAA = ileal pouch anal anastomosis; IRA = ileorectal anastomosis
Our review is reported according to the PRISMA guidelines.11
We searched PUBMED from inception to June 2023 to identify studies evaluating long-term adenoma and cancer development in patients with FAP after prophylactic surgery. Deduplication was performed using Zotero software.12 Reference lists of included studies were hand-searched for additional relevant studies. The search was limited to studies, published in English. We used the following keywords: “FAP”, “IRA”, “IPAA”, “familial adenomatous polyposis” and “proctocolectomy”.
We included single-or multicentre retrospective cohort studies, prospective cohort studies and retrospective analyses of polyposis registries. Due to the rarity of the events, we only considered case reports for inclusion when summarising reports on cancers after primary IPAA. Only the most recent series from the same institution or polyposis registry were included in the analysis, as some research groups regularly publish retrospective analyses of their cohorts or polyposis registries. Full-text screening and data extraction were performed by a single researcher (AG). Manuscripts of three case reports could not be obtained, data were summarised from the two review articles.13,14
Of 97 full-text articles screened for eligibility (Figure 1), 46 met our inclusion criteria. A further 8 articles were identified by hand searching the reference lists of the included studies (6 case reports, 1 retrospective cohort, 1 polyposis registry analysis). We included 22 retrospective analyses, 14 case reports (carcinoma development after primary IPAA), 15 retrospective analyses of prospectively maintained polyposis registries and 3 prospective cohort studies. Only 5 studies were multicentre and 1 was bi-centre. The studies were published between 1994 and 2023. The studies included between 1 and 925 patients. A total of 5010 patients were included in the review. Summary characteristics of the included studies are shown in Table 2.
Flowchart of the systematic review according to the Preferred Reporting Items for Systematic Reviews (PRISMA) schema.
Characteristics of included studies
Aelvoet |
144 (111 IPAA, 33 ileostomy) | The Netherlands | Single | Cohort/Retrospective | / | IPAA, ileostomy |
Tatsuta |
65 (22 IRA, 20 IPAA) | Japan | Single | Cohort/Retrospective | 1976–2022 | IRA, IPAA |
Anele |
199 (199 IRA) | United Kingdom | Single | Cohort/Retrospective | 1990–2017 | IRA |
Colletti |
715 (715 IRA) | Italy | Multicentre | Retrospective analysis of the Registry | 1977–2021 | IRA |
Pasquer |
289 (197 IRA, 92 IPAA) | France | Multicentre | Retrospective analysis of the Registry | 1965–2015 | IRA, IPAA |
Ardoino |
925 (585 IRA, 340 IPAA) | Italy | Multicenter | Retrospective analysis of the Registry | 1947–2015 | IRA, IPAA |
Tajika |
47 (14 IRA, 25 IPAA, 8 ileostomy) | Japan | Single | Cohort/Retrospective | 1965–2017 | IRA, IPAA and ileostomy |
Ganschow |
192 | Germany | Singe | Cohort/Prospective and retrospective analysis of Polyposis Registry | Endoscopy data collected during 2010–2013 | IPAA |
Kariv |
45 | Israel | Single | Cohort/Retrospective | 1986–2013 | IPAA |
Patel |
21 (6 IRA, 5 IPAA, 10 intact colon) | Indianapolis, USA | Single | Cohort/Retrospective | Endoscopies performed between 2004–2016 | IRA, IPAA and intact colon |
Walsh |
1 | Ireland | Single | Case report | 1987 | IPAA - cancer |
Maehata |
27 | Japan | Single | Cohort/Retrospective | 1990–2004 | IRA |
Ganschow |
100; 50 hand-sewn and 50 stapled anastomoses | Germany | Single | Cohort/Prospective | ? | Hand-sewn |
Goldstein |
59 | Israel | Single | Cohort/Retrospective | 1986–2013 | IPAA |
Zahid |
27 | Australia | Single | Cohort/Retrospective | 1984–2011 | IPAA |
Kennedy |
95; 85 hand-sewn and 1 stapled anastomosis | Rochester, Mayo Clinic, USA | Single | Cohort/Retrospective | 1987–2011 | IPAA |
Koskenvuo |
140 | Finland | Single | Cohort/Retrospective | 1963–2012 | IRA |
Pommaret |
118 | France | Single | Cohort/Retrospective | / | IPAA and IRA |
Boostrom |
117 | Rochester, Mayo Clinic, USA | Single | Cohort/Retrospective | 1972–2007 | IPAA |
Ozdemir |
260; 86 hand-sewn and 175 stapled anastomoses | Cleveland, USA | Single | Analysis of polyposis registry | 1983–2010 | Hand-sewn |
Wasmuth |
61; 39 hand-sewn with mucosectomy and 22 without of which 15 were stapled and 7 hand-sewn anastomoses | Norway | Multicenter | Analysis of polyposis registry | 1986–2008 | IPAA (mucosectomy |
Yan |
42 (33 IPAA; 6 IRA ?) | China | Single | Cohort/Retrospective | 1988–2008 | IPAA and IRA |
Makni |
1 | Tunisia | Single | Case report | 1996 | IPAA - cancer |
Tonelli |
69 | Italy | Single | Cohort/Prospective data collection | 1984–2008 | IPAA |
von Roon |
140; 44 hand-sewn and 76 stapled anastomoses | UK | Single | Retrospective analysis of St. Mark’s Hospital Polyposis Registry | 1978–2007 | Hand-sewn |
Banasiewicz |
165 | Poland | Bicenter | Bicenter/Retrospective analysis | 1985–2009 operated, Clinical data from endoscopy FUP between 2004–2009 | IPAA |
Booij |
43 (34 IRA) | The Netherlands | Single | Cohort/Retrospective | 1977–2005 | IRA and IPAA |
Sinha |
427 | UK | Single | Retrospective analysis of St. Mark’s Hospital Polyposis Registry | 1990–2008 | IRA |
Ault |
2 | Los Angeles, USA | Single | Case series | 1990, 1993 | IPAA - cancer |
Nieuwenhuis |
475 | Denmark, Finland, Sweden, Netherlands | Multicenter | Analysis of polyposis registry | / | IRA |
Yamaguchi |
59 | Japan | Single | Cohort/Retrospective | 1962–2007 | IRA |
Friederich |
212; 71 hand-sewn with mucosectomy and 115 stapled anastomoses | The Netherlands | Single | Analysis of National Polyposis Registry | 1985–2005 | IPAA |
Campos |
36 | Brasil | Single | Cohort/Retrospective | 1977–2006 | IRA and IPAA |
Bullow |
776; 576 operated in pre-pouch period and 200 in pouch period starting in 1990 | Denmark, Finland, Sweden, Netherlands | Multicenter | Analysis of polyposis registry | 1950–2006 | IRA |
Gleeson |
16 | Rochester, Mayo Clinic, USA | Single | Cohort/Retrospective analysis | 1964–2003(Analysis of endoscopies between 1992–2006) | IPAA and IRA |
Lee |
1 | Korea | Single | Case report | 1998 | IPAA - cancer |
Linehan |
1 | Ireland | Single | Case report | 1997 | IPAA - cancer |
Valanzano |
25 | Italy | Single | Cohort/Prospective | 1986–2004 | IRA |
Moussata |
21 | France | Single | Cohort/Retrospective | / | IPAA and IRA |
Ulas |
1 | Turkey | Single | Case report | 1993 | IPAA - cancer |
Campos |
1 | Brazil | Single | Case report | / | IPAA - cancer |
Groves |
60 | UK | Single | Retrospective analysis of St. Mark’s Hospital Polyposis Registry | / | IPAA |
Vroueraets |
2 | The Netherlands | Single | Case report | 1990, 1991 | IPAA – cancer |
Ooi |
2 | Cleveland, USA | Single | Case report | / | IPAA – cancer |
Church |
197; 62 operated in pre-pouch period and 135 in pouch period starting in 1983 | Cleveland, USA | Single | Analysis of polyposis registry | 1950–1999 | IRA |
Cherki |
1 | France | Single | Case report | / | IPAA - cancer |
Thompson-Fawcett |
33 | Canada | Single | Cohort/Prospective | / | IPAA |
Church |
213 (165 IRA) | Cleveland, USA | Single | Analysis of polyposis registry | / | IRA and IPAA |
Brown |
1 | Singapore | Single | Case report | / | IPAA - cancer |
Bertario |
371 | Italy | Multicenter | Retrospective analysis of Hereditary tumor registry | 1955–1997 | IRA |
Vuilleumier |
1 | UK | Single | Case report | 1990 | IPAA - cancer |
Jenner |
55 | Australia | Single | Analysis of polyposis registry | ?–1994 | IRA |
Bassuini |
1 | UK | Single | Case report | 1991 | IPAA - cancer |
Hoehner |
1 | Iowa, USA | Single | Case report | / | IPAA - cancer |
FUP = follow up; IPAA = ileal pouch anal anastomosis; IRA = ileorectal anastomosis
Five studies described the rate of adenoma development in the residual rectum (Supplementary Table 1). In 8 studies that analysed the frequency of secondary proctectomy due to endoscopically unmanageable polyposis, the rate of proctectomy ranged from 3.7% to 35%.15 Five studies described adenoma evaluated in the neoterminal ileum (Table 3), with a high variance in reported rates from 0%16 to 47.6% in patients followed-up for median of > 20 years17 in one study including a paediatric cohort18, 2 patients required resection of the terminal ileum and construction of a new IRA, one due to low grade dysplasia (LGD) and one due to high grade dysplasia (HGD) adenoma.
Rate of adenoma development in the neoterminal ileum in patients after ileorectal anastomosis (IRA) and ileal pouch anal anastomosis (IPAA)
Tajika |
4/24 (16.7) | 4.4% at 20 years and 36% at 30 years after primary surgery | 23.1 ± 5.8 | 0/14 (0.0) | ||
Boostrom |
4/33 polyps (12.0) | |||||
Pommaretet |
9/118 (6.5) | Presence of pouch adenomas (OR, 2.16, |
||||
Booij |
5/34 (14.7) 2 patients had resection of neo-terminal ileum, one due to LGD and other due to HGD adenoma. | |||||
Gleeson |
3/13 (23.1) | Median 6.5 (0–15) | 4/16 (25.0) | Median 12 (1–29) | ||
Moussata |
Mean 17.6 +-7.8(6–35) Mean from colectomy to diagnosis: 16.4+-8.5 (5–30) | 10/21 (47.6) of which 2 were advanced adenomas. | ||||
Groves |
2/20 (10.0) | 6 (1–14) | 1/47 (2.0%) | 12 (0–39) | ||
Thompson-Fawcett |
1/24 (4.2) | Median 7 (1–19) |
HGD = high grade dysplasia; LGD = low grade dysplasia
The reported rate of cancer in the rectal remnant (Table 4) after primary IRA is 8.8%18 to 16.7%19 with a median follow-up from surgery19 of 91.1 months (3–557 months). However, studies from Japan report higher rates of up to 37%20, but this is due to the inclusion of
Patient characteristics and rate of rectal remnant cancer rate in patients after ileorectal anastomosis (IRA)
Colletti |
57.4% | 93.6% / | / | Median of 13 years | / | / | 47 / 715 (6.57) | / | 14/47 (29.8%) at median follow up of 13 years. |
Pasquer |
95 (48.2) | / | / | / | / | / | 12 / (6.1); 1 was metastatic, 2 were resected endoscopically, 10 surgically | / | / |
Maehata |
16 (59.3) |
21 (77.8) 14 (66.7) |
21.1 (3–35) | / | Median 27 years (9–66) | / | 10/27 (37.0); 6/10 cancers were TisN0M0 | 8% at 10 years; 19% at 20 years; 57% at 30 years | 3/27 (11.1) |
Koskenvuo |
59 (42.1) | / | Median 15 years (0–44) | / | Mean 36 years (18–71) | Cumulative risk 2% at 40 years age; 7% at 50; 13% at 60 years age and 16 % at 70 years age. | 18/140 (13%) | 3% at 5 years; 4% at 10 years; 11% at 20 years; 24% at 30 years after IRA | 10/140 (7%); 5-year survival 55%. Cumulative risk for death due to rectal cancer after IRA: 2% at 5 years, 3% at 10 years and 9% at 30 years. |
Booij |
19 (44.2) | / | / | / | Median 16 (7–25) | / | 3/34 (8.8) | / | 2/34 (5.8) |
Sinha |
232 (54.3) |
/ 311/427 (72.8) |
Median 15 years (7–25) | / | Median 21 years (11–67) | / | 48/427 (11.2%) | / | / |
Yamaguchi |
35 (59.3) | / | Median 8.9 years | / | Median 30 years (13–65) | / | 17/59 (30%) | / | 5-year survival 94%; 10-year survival 94%. |
Nieuwenhuis |
/ | / | / | / | / | / | / | 3.7% for group 1; 9.3% for group 2; 8.3% for group 3.% | / |
Campos |
/ | / | 91.1 (3–557) | / | Mean 45.8 years | Mean 50.6 years | 6/36 (16.7) | 17.2% at 5 years; 24.1% at 10 years; 43.1% after 15 years | / |
Gleeson et al., 200830 | / | / | FUP initiated median 12 (1–29) years after surgery | / | / | 40 and 59 years. | 2/16 (12.5) | / | / |
Bullow |
401 (51.7) | / | Median 7 years (0–13). Patients were operated between 1950–2006 | Median 27 (7–75) | / | 60/776 (7.7%) (56/576; 10% and 4/200; 2%) | 10-year cumulative risk 4.4% [95% CI 2.6–6.2] in pre-pouch era; 10-year cumulative risk 2.5% [95% CI 0–5.5] in pouch era; | / | |
Moussata |
10 (47.6) |
21/21 (100.0) 14/21 (66.7) |
Mean 8.4 years ± 5 since colectomy | / | / | / | 0/21 (0.0) | / | / |
Church |
92 / (46.7) | / | Pre-pouch era: 212 months (IQR 148 months); Pouch era: 60 months (IQR 80 months) | / | Median age 23 years (IQR 15.5 years pre-pouch and 17 years pouch) | / | 8 (12.9%) in the pre-pouch era and 0 in pouch era. | / | / |
Bertario |
206/371 (55.5) |
297/371 (80.1) 200/297 (67.3) |
Median 81 months | Median 102 months (1–26 years) | Mean 32 years | / | 27/371 (7.3) |
10 years – 7.7% 15 years – 13.1 % 20 years – 23.0% |
6/371 (1.6) |
Jenner |
25/55 (45.0) | 55/(100.0) | Median 10 (1–31) | / | Mean age 30 (13–62) | Median 41 | 7/55 (12.7) | / | / |
Colonic phenotype divided in 3 groups: (Group 1 - <100 polyps and mutation in codons 1–157, 312–412 and 1596–2843; Group 2 Hundred of polyps and mutation in codons 158–311, 413–1249 and 1465–1595; Group 3 Thousand of polyps and mutation in codon 125
APC = adenomatous polyposis coli; FUP = follow up
Eleven studies reported nine risk factors predictive of the progressive rectal residual phenotype (Supplementary Table 2). Four studies analysed the genotype-phenotype relationship; The presence of a pathogenic variant between codons 1250–1464 was an independent risk factor for subsequent cancer development (HR 4.4 [1.3–15.0]23 and for the secondary proctectomy26,27 (HR 3.91 [1.45–10.51],
Seventeen studies (Table 5) reported on the development of adenomas after IPAA, of which eight studies differentiated between the pouch body and the anastomosis, one study only reported the anastomotic adenoma rate, while in the remaining seven studies the authors did not precisely define the anatomical location of the adenomas. The median age of patients at the time of surgery ranged from 15.4 to 34.6 years, with a median follow-up from surgery of 5.4 years to a median of 21.6 years. The reported rate of adenoma in the pouch body ranged from 9.4%29 to 76.9%.30 The proportion of HGD histology among adenomas at the polyp level ranged from 5.9%17 to 53.2%.31 In one study, the proportion of advanced adenomas on a per-patient basis was 11.2%.31 The cumulative risk of adenoma development after primary IPAA was 12% and 58% at 5 and 20 years after the surgery respectively.16 According to the analysis from Poland32, 50% of all patients would develop LGD 15 years after the surgery, while HGD is estimated to be present in half of the patients 17.5 years after the surgery. Six studies analysed the rate of adenoma development in the neo terminal ileum, the proportion of patients with histologically confirmed adenoma varied from 4.2%33 to 23.1%30 with at a median follow-up from surgery of 6.534 to 23.1 years.16 The cumulative risk of developing an adenoma in the neo terminal ileum was 4.4% at 20 years and increased to 36% at 30 years after the surgery as reported in the same study. The presence of pouch body adenomas was the only independent risk factor for the neo terminal ileum adenomas (OR, 2.16,
Patient characteristics and rate of adenomas in patients after primary ileal pouch anal anastomosis (IPAA)
Aelvoet AS |
81 (56) |
101 (91) 96 (86) |
Yes | Median 152 (77–240) | 15% at 5 years; 48% at 10 years; 85% at 20 years. | Median 24 (18–32) | Median 5 (3–15) | Tubular adenomas 31 (28%), Tubulovillous 26 (23%), Villous 5 (5%) | Prepouch ileum 4(2–13), Pouch body 20 (5–50), rectal cuff 6 (3–10) | |
Tajika |
16 (47.1) | / | Yes | Median 21.6 (3.7–8.8) | 32 (35.9) of patients showed progression of pouch adenomas during FUP | Median 34.6 (17–52) | 24/34 (70.6) | 2–40 mm | 6 advanced adenomas (25.0) | 1–300 |
Ganschow |
100 (52.1) |
133 (69.3)) ? / 133 |
No | Median 12.8 (9–17) for patients with pouch adenomas and (2.5–12.2) for patients without pouch adenomas; | 32 (35.9) of patients showed progression of pouch adenomas during FUP | 27.5 years (10.2–58.5) | 90/192 (46.9) at a median of 8.5 years (0.9–25.1) after IPAA. 5 years after IPAA 84.9% patients free of adenoma; 15 years after 40.4% and 20 years after 21.9% patients were free of adenomas. | 53/192 (58.9) ≤ 4 mm; 24/192 (26.7) 5 – 10 mm; 13/192 (14.4) ≥ 10 mm | Tubular adenomas in 69/192 (76.7); tubulovillous adenomas in 16/192 (17.8); villous in 5/192 (5.6) | 46/192 (51.1) had < 4; 14/192 (15.6) 5–10; 30/192 (33.3) > 10 adenomas |
Goldstein |
24 (41.0) | Yes | Mean 11.6 years +-14.6 years | Median adenoma free time interval since surgery; Cuff 10.8 years Pouch 16.9 years | Mean 30.8 years +-10.8 years | 35/59 (59.0);
- 20 isolated in cuff - 4 isolated in pouch body - 11 in pouch and body |
/ | All LGD | / | |
Zahid |
14 (51.8) | No | Mean 9.2 years | Median; 72 months (18–249) | Median 31 years (14–65) | 12/27 (44.0) | / | Only 1 polyp HGD (< 99%) | / | |
Kennedy |
43 (45.0) | Watched only anastomosis | Mean 7.6 (0 – 24) | Mean 15.4 (4–20) | 9/95 (9.4) | |||||
Pommaretet |
110 / 139 92 / 110 (Cohort included IRA, ileostomy and IPAA patients but did not distinguish between). |
/ | Median 15 years | 25 years (9−61 years) | 57/118 (48.3) | > 10 mm:12 | 94% LGD; 6% HGD |
1−4: 22 5−20: 18 > 20: 17 |
||
Boostrom |
52 (44.5) | Yes | 125 months (25–423 months) | 12.4 years (15–405 months) | 26 years (4–60 years) | 30/117 (25.6) | 5.9 mm (2 mm to 20 mm) | 22 LGD, 8 tubulovillous | / | |
Wasmuth |
34 (55.7) | / | Yes (body and anastomosis) | Cumulative rate of adenomas at 28 years 17% for mucosectomy group and 75% at 15 years in a group without mucosectomy (P < 0.0001) | 20 (10–49) |
Anastomosis: 4/39 (10.0) Pouch body: 8/39 |
||||
Tonelli |
/ | 45 (65%) | No | Median 133 months (12–288 months) | Mean 7 years (1–15 years) | 33 years (17–63 years) | 25 (36.0) | Mean 3 mm (1–40) | Adenomas, dysplasia not specified | Mean 8 (1–47) |
Yan |
30 (71.5) | / | Yes | Median 7.2 (2.2–20) | 29 (16–65) | At the anastomosis 6/33 (18.2) | / | / | / | |
Banasiewicz |
79 (47.9) | / | / | Endoscopies performed 2–19 years since surgery. |
Mean 14 months to LGD; Mean 16 months to HGD. Estimated frequency LGD 15 years later 50% and for HGD 17.5 years later 50%. |
21/165 (12.7) | LGD - 21/32 (65.6); HGD - 11/32 (34.4) | |||
Gleeson |
/ | / | Yes | / | FUP began median 6.5 (0–15) after surgery | / | 13/13 (100): 10/13 pouch body; 2/13 anastomosis; 3/13 ileum above anastomosis | < 5 mm | / | 5–30 |
Friederich |
119 (56.0) | / | / | Mean 7.9 (0.4–20.3 years) |
Cumulative risk of 16% at 5-years and 42.4% at 10 years for adenoma development. Cumulative risk of 12.8% at 10 years for advanced adenoma development. |
Mean 30.0 years (10–62.6 years) | 47/212 (35%) | / | / | / |
Campos |
/ | / | No | 50.8 (5–228) | 3/26 (11.5) | |||||
Moussata |
12 (57.1) |
23/23 (100.0) 22/23 (95.7) |
Yes (only polyps in the ileal mucosa of the pouch body are described) | Mean 5.4 +- 2.6 (1–11) | Mean 4.7+-3.3 years (1–14) | 17/23 (74.0) | Mean size 5.2 mm +-3.4 mm; 3 polyps were > 10 mm. | LGD 16/17 (94.1); HGD 1/17 (5.9) | / | |
Groves |
35 (58.3) | / | Between pouch and above anastomosis ileum | 6 years (1–17 years) | / | 32.5 years (13–66 years) | 34/60 (57%) of which 5 were > 10 mm / 11 were advance adenomas | Mean size 5 mm (1–40 mm) | / | Median number 4 |
Thompson-Fawcett |
/ |
20/33 (60.6) 18/20 (90.0) |
Only pouch body | / | / | / | 20/33 (60.0) adenomas | 1–3 mm | / | Median 10 (1–100) Also lymphoid hyperplasia included |
APC = adenomatous polyposis coli; FUP = follow up; HGD = high grade dysplasia; IRA = ileorectal anastomosis; LGD = low grade dysplasia
Since the first case report of cancer arising in the ileal pouch of a FAP patient in 19946, we have identified 45 (Table 6) cancers that have developed in FAP patients after primary IPAA. Of these, 30 were located in the pouch body and 15 in the anastomosis/rectal cuff. The time from surgery to cancer diagnosis was reported for 22 patients and ranged from 2.336 to 33 years.37 The information about the interval since last follow-up was reported for only 15 patients. The shortest interval between normal endoscopic surveillance and cancer diagnosis was 9 months.16 Of the studies that reported the final outcome, 13 (28.9%) patients were alive at the last follow-up (range 8 months to 6 years) after surgical therapy and 9 patients died of disseminated cancer (1 month to 4 years after diagnosis), most despite an initial R0 resection.
Cancer rate after primary ileal pouch anal anastomosis (IPAA)
Aelvoet |
3/111 (2.7%) | / | / | / | / | / | Pouch excision |
Pasquer |
1/92 (1.1) | 30 | / | 1 month | Pouch body | Endoscopic resection | |
Ganschow |
1 | / | 27 | / | / | Pouch body | Resection and reconstruction of a new pouch - alive |
Walsh |
1 | 54 | / | Regular annual surveillance | New endoscopy due to anemia and rectal blood loos | Anastomosis | T3N2Mx, resection and ileostomy, alive during last FUP. |
Wasmuth |
1 | / | 11 | / | / | Rectal cuff | Resection and ileostomy - alive |
Boostrom |
1 | / | 23.7 | / | / | Pouch body | Transanal resection - alive |
Ozdemir |
4 | / |
Mucosectomy group; median 11.3 years (8.3–22) Without mucosecomy; 8 years |
Regular annual surveillance | / | All ATZ |
? 3 underwent APR - alive 1 transanal resection – died 4 years later dissemination |
Makni |
1 | 26 | 10 | 8 months | Polyps, LGD? | Pouch body? | Pouch excision – died 12 months later dissemination |
Tonelli |
2 |
29 58 |
10 |
12 months, normal 6 months, normal |
? IIa + IIc polyp |
Pouch body Pouch body |
Excision with ileostomy, T3N0M0, died 6 months later dissemination/Excision with ileostomy, T2N0M0, alive after 56 month FUP |
voon Roon |
1 | / | 13 | / | / | Pouch body | Excision of a pouch – died 2 years of disseminated disease |
Banasiewicz |
5 | / | / | / | / | Pouch body | / |
Ault |
2 |
61 50 |
11 10 |
6, normal / |
Pain and blood per rectum, 3 cm mass/Sacral pain, bleeding ulcer | Pouch body / Pouch body | T2N1Mx, died of AMI prior treatment / Metastatic disease, chemotherapy |
Tajika |
2 |
55 68 |
8.6 20 |
9 months, normal No FUP |
30×25 mm cancer / Polyposis and 25 × 25 mm polyp | Pouch body/Kock’s pouch body |
T4N2M0 – died 1 year later T3N?M? – died (MDS) |
Lee |
1 | / | 7 | / | Ulcerating tumor | Pouch body | T4N1M0, APR ileostomy. Developed metastases 2 years later. |
Friederich |
4 |
35 37 32 36 |
14 10.2 16.4 6.2 |
4.4 years, normal 2.1 years, normal No control (symptoms) 0.6 years, Tubullovilous HGD |
/ | All pouch body |
Dukes C Dukes B Dukes B Dukes B |
Linehan |
1 | 40 | 10 | / | Pelvic pain, discharge | Pouch body (patient had ileostomy but pouch was left in situ) | Excision. At last FUP patient was well. |
Ulas |
1 | / | 9 | / | / | Anastomosis | Dukes B, APR, metachronous cancer after 1 year |
Campos |
1 | / | 12 | No FUP | Presented with rectal bleeding | Pouch body | T2N0Mx, APR and ileostomy, patient well at 6 years FUP. |
Vroueraets |
2 |
48 36 |
9 10 |
5 years normal, then 2 and 1 years (both multiple LGD adenomas refused surgery) / Regular FUP every 2 years | Presented after 1 year with rectal bleeding /Normal. Routine biopsies at subsequent FUP revealed adenoca. |
Anastomosis Anastomosis |
T2N0M0, APR, alive 1 year later / T4N0M0, APR, alive 8 months later |
Cherki |
1 | 35 | 3.5 | 1.5 years | / | Pouch body | T3N1M1, resection with ileostomy, died 1 month later |
Ooi |
2 |
36 / |
2 years 3 months 8 years |
/ / |
Symptoms of anal bleeding/ / |
Anastomosis Anastomosis |
T3NOMO, APR, ileostomy, died 2.5 years later dissemination / T2N0M0, transanal excision with ileostomy (refused APR), died 4 years later, dissemination |
Brown |
1 | 44 | 7 years 4 months | Under FUP every 6 months | / | Anastomosis | / |
Vuilleumier |
1 | 38 | 7 | No FUP | / | Anastomosis | Resection with ileostomy – died 12 months later dissemination |
Palkar |
1 | 39 | 4.7 | 3 months | ? | Pouch body | T4NOM? - alive |
Kim |
1 | / | / | / | / | Pouch body? | / |
Bassuini |
1 | 31 | 3 | No FUP | / | Pouch body | / |
Von Herbay |
1 | 33 | 8 | Anastomosis | T1N0M0 | ||
Hoehner |
1 | 34 | 20 | / | / | Anastomosis | / |
The data from these cases has been drawn from reviews by Tajika and Smith as full-text of the papers were not accessible.
FUP = follow up; HGD = high grade dysplasia; LGD = low grade dysplasia
Six studies (Supplementary Table 3) compared the rates of adenoma development at the anastomosis between hand-sewn and stapled techniques. The incidence of adenoma was lower for hand-sewn anastomosis, ranging from 0 to 33%, and for stapled anastomosis, ranging from 33.9 to 57%. The 10-year cumulative risk of adenoma development is 20–22.6% for hand-sewn anastomosis and 51.1–64% for stapled anastomosis.
Nine studies analysed risk factors for adenoma development (Supplementary Table 4). None of the seven studies found a genotype-phenotype association. There was no association between colon adenoma burden at the time of surgery and subsequent development of pouch adenomas in three out of four studies. In the only positive study, none of the patients with < 200 colon polyps developed pouch adenomas, whereas almost half of the patients with > 1000 colon polyps later developed later pouch adenomas. Three studies have identified age of the pouch as a risk factor, while three others found no association between time since surgery and the rate of pouch adenomas. An association between the Spigelman score and the development of pouch adenomas was not confirmed. One study identified the presence of gastric adenomas as an independent risk factor for the development of pouch adenomas.
Using a systematic approach, we identified a wide range of reported adenoma and cancer rates in the rectal remnant, pouch body, at IPAA and in the neoterminal ileum. The wide range in adenoma rates is probably partly due to the wide range of included studies in terms of year of publication. The equipment and quality of optical diagnosis has improved considerably in recent years, allowing better detection of adenomas and more precise examination of the pouch and rectal remnants. In addition, the risk stratification of patients at the time of surgery has also improved, allowing patients with a more aggressive phenotype to undergo primary restorative proctocolectomy while primary IRA can still be offered to patients with an attenuated phenotype or low rectal disease burden. Indeed, in the largest study of four European national polyposis registries, the cumulative risk of cancer in the rectal remnant (CRR) was 10% in patients operated in the ‘pre-pouch’ period and only 2% in those who were operated in the ‘pouch period.24 Similar findings have been reported from the USA38 where 8 patients operated before 1983 (12.9%) were diagnosed with CRR compared to none of those operated after 1983 when pouch surgery was introduced at the Cleveland Clinic. Recently published data from two Japanese studies reporting an overall CRR rate of 30%25 – 37%20 must be interpreted with caution as carcinoma
The main obstacle to refining recommendations for endoscopic surveillance is the lack of high-quality, prospective data. Unfortunately, we have not found a single randomised trial that has compared different surveillance strategies or aimed to identify factors that would allow risk stratification. Members of the International Society for Gastrointestinal Hereditary Tumors (InSiGHT)40 proposed a staging system41 and stage-specific interventions for patients with intact colon and those with IRA, but unfortunately no effort has been made to validate this staging system. Data on endoscopic treatment modalities are even more descriptive. In fact, in five international recommendations (Table 1), only Vasen
Improvements in endoscopic resection techniques have also been applied to the treatment of large lesions in the rectal remnant. Recently two reports, both from Japan43,44, have been published of successful endoscopic submucosal dissection (ESD) of 75 mm Is + IIa adenoma and residual adenoma at the IRA. In our endoscopy unit (Hospital Clinic, Barcelona) we also perform advanced endoscopic resection techniques. Figure 2 (A and B) shows a recent endoscopic mucosal resection (EMR) of an 18mm laterally spreading tumour granular type (LST-G) in the rectal remnant of a patient with FAP.
Surveillance endoscopy in a 48-year old patient with FAP after colectomy with IRA revealed 18 m LST-G
There is little data on the use of advanced imaging techniques. The study from St. Mark’s hospital in London45 showed no benefit of dye-based chromoendoscopy to detect additional adenomas in the rectal remnant. The European Society of Gastrointestinal Endoscopy (ESGE) guidelines46 published in 2014 did not recommend the use of advanced endoscopic imaging in patients with FAP, but did not specifically differentiate between the patients with intact colon and those after surgery. On the other hand, the French Society of Endoscopy39 recommended the use of dye-based chromoendoscopy with indigo carmine. We believe that use of dye-based chromoendoscopy in these patients does not increase the detection of clinically relevant lesions and it is not routinely performed in our unit. Considering the data on a cumulative risk of 57% for CRR 30 years after surgery20 and the fact that adenoma development in the rectal remnant is an inevitable event16, regular endoscopic surveillance is mandatory. Our recommendations are in line with other guidelines and our patients are recommended annual endoscopic surveillance, despite alarming data from an early study published in 20015 from four European registries in which 75% of patients with CRR had a negative rectoscopy within 12 months and 35% within 6 months prior to diagnosis of CRR. There was no information on the endoscopy equipment used for surveillance. We believe that the high rates of negative rectoscopies prior to cancer diagnosis may – to some extent - be influenced by the quality of endoscopy, which has been limited by the technical aspects of the equipment used in the past. This problem needs to be addressed again in the light of developments in endoscopic equipment.
When restorative proctocolectomy with IPAA was first described in 197847, it was believed that this operation would eliminate the risk of colorectal cancer in patients with FAP. However, a few years later, as the first pouches began to age, case reports of cancers arising in the pouch began to appear in the literature.6 Since then, reports have become more frequent and we have identified 45 cases of cancer after primary IPAA, of which 26 arose in the ileal mucosa of the pouch body and 15 at the anastomosis. Furthermore, we now know that cancer can develop even after mucosectomy down to the dentate line48, because even after removal of all visible rectal mucosa, some microscopic rectal columnar epithelium remains at the ATZ.49 In the study from the Heidelberg Polyposis Registry with 100 patients50, rectal residual mucosa (defined as visible mucosa or detected by histology from blinded biopsies) was found in 42 (84%) cases after stapled and in 21 (42%) cases after hand-sewn anastomosis.
Researchers from Japan16 found a 70% incidence of adenomas in the pouch body with one of the longest follow-up periods reported to date (> 20 years). Similarly, in a study from France, 74% of patients had at least one adenoma in the pouch, but with a mean follow-up of only 5.4 years. In contrast, one study found that isolated rectal cuff adenomas were more common than isolated pouch adenomas (49.1%
On the other hand, the adenoma rates – at least in the stapled group - seem to be higher in the studies that only looked at the anastomosis and compared hand-sewn with stapled: 0–33%
International guidelines most commonly recommend annual endoscopy examination, whereas ASCO guidelines9 advocate ‘case-by-case’ interval allocation. In 11 of only 12 studies that described a surveillance protocol, an interval of 12 months was recommended except in Brazil where endoscopy of the pouch was recommended every 2 years.
Interestingly, in the Netherlands pouch endoscopy was recommended every 1 to 3 years in the late 1990s but in 2001 the protocol was changed to annual endoscopic surveillance regardless of the anastomotic technique (hand-sewn or stapled).
One of the main concerns is the short interval (< 1 year) between the last normal endoscopy and the cancer diagnosis and the aggressive course of the disease despite an initial R0 resection (Supplementary Table 4). It is not entirely clear whether the adenoma-carcinoma sequence is faster in the ileal mucosa compared with the colon and rectum, or whether “negative” endoscopies prior to cancer diagnosis could be explained by the poor quality of pouch endoscopy. Chromoendoscopy improves the detection of diminutive adenomas31 and lymphoid hyperplastic nodules45, but its use is discouraged33,35 for the same reasons as in the examination of rectal remnants – increased of detection of clinically irrelevant polyps. Endoscopy should be performed with a gastroscope or paediatric colonoscope, as stricture can occur at the anastomosis, especially after hand suturing.
There are no official recommendations for endoscopic management of FAP patients after IPAA. We have found considerable heterogeneity in local practice. Italian authors recommend resection of all adenomas > 3 mm.51 On the contrary, ablation with argon plasma coagulation is the preferred resection technique in a French study.17 Ablative techniques were also supported by the study from the Mayo Clinic.30 In a small descriptive cohort of only 5 patients42, large-scale cold snare polypectomy with a mean of 110.6 (30–342) resected polyps demonstrated the efficacy of cold snare in controlling large polyp burden (> 30 polyps) with no reported polypectomy related complication. In our unit we do not use nor encourage use of argon plasma coagulation. We recommend resection of all polyps > 3 mm. Advanced resection techniques, when performed in the tertiary centres, may be a viable alternative prior to surgical resection. A case report of successful
Surveillance endoscopy in a 49-year old patient with FAP after proctocolectomy with IPAA revealed 25 mm LST-G mixed type lesion in the rectal cuff. Lesion was spreading from the anastomosis to the dentate line. Patient had undergone surgery five years earlier and did not show up for endoscopy follow-up since then
Although there is no randomised trial comparing different endoscopic surveillance intervals, it is unlikely that prospective data will be available in the future. The main reason is ethical issue, as these patients are at increased risk of colorectal cancer. However, with the introduction of high quality colonoscopy and improvements in endoscopy technique, a ‘negative’ endoscopy before cancer diagnosis should become highly unlikely if not impossible.