Familial adenomatous polyposis (FAP) is an autosomal

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2008;6: Risk of Developing Adenomas and Carcinomas in the Ileal Pouch in Patients With Familial Adenomatous Polyposis PIETER FRIEDERICH,* ANDREA E. DE JONG,, LISBETH M. MATHUS VLIEGEN, EVELINE DEKKER, HAN H. KRIEKEN, JAN DEES, # FOKKO M. NAGENGAST,* and HANS F. A. VASEN, *Department of Gastroenterology & Hepatology, Radboud University, Nijmegen Medical Centre, Nijmegen; The Netherlands Foundation for the Detection of Hereditary Tumours, Leiden; Department of Gastroenterology & Hepatology, Leiden University Medical Center, Leiden; Department of Gastroenterology & Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam; # Department of Gastroenterology & Hepatology, Erasmus University Medical Center, Rotterdam; and Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Background & Aims: At present, more than half of patients with familial adenomatous polyposis (FAP) are treated with a proctocolectomy and an ileal pouch anal anastomosis (IPAA). Originally it was thought that this procedure would eliminate the risk of developing rectal cancer. However, an increasing number of studies reported development of adenoma and carcinoma in the pouch. The aim of this study was to evaluate the long-term risk of developing adenomas and carcinomas in the pouch in a large cohort of Dutch FAP patients. Methods: A total of 254 patients with FAP who underwent an IPAA were selected from the Dutch Polyposis Registry. The results of the surveillance examinations and the pathology reports were analyzed. Surveillance with chromoendoscopy was offered to a subgroup of patients. Results: Full information on follow-up was available in 212 (84%) patients. These patients (56% male) underwent a total of 761 endoscopies. The mean follow-up was 7.9 years (range, years). The cumulative risk of developing an adenoma in the pouch at 10-year follow-up was 45%. Twenty-five patients (11.8%) developed an adenoma with advanced pathology, and 4 (1.9%) developed a carcinoma. The cumulative risk of developing a pouch carcinoma at 10-year follow-up was 1%. A very high prevalence (75.7%) of adenomas was found in a subgroup of patients who were examined with chromoendoscopy. Conclusions: This study demonstrated that although the risk of developing adenomas in the pouch after an IPAA is high, the risk of malignant degeneration appears to be low. The use of chromoendoscopy improves the detection of small adenomas. Familial adenomatous polyposis (FAP) is an autosomal dominant disease characterized by the development of numerous adenomas in the colorectum and various other extracolonic manifestations, with an estimated prevalence of 1 in 5000 to 1 in 7500 births. 1 Virtually all patients will develop colorectal cancer if left untreated. Ileal pouch anal anastomosis (IPAA) is 1 of the 2 main options for surgical treatment of these patients. Originally it was thought that this procedure would eliminate the risk of rectal cancer. However, an increasing number of studies reported the development of adenomas and even carcinomas in the pouch. The reported incidence of pouch adenomas after a follow-up of at least 5 years is 8% 60%, increasing to 75% in certain subgroups. 2 7 However, the malignant potential of pouch adenomas, especially those located in the ileal mucosa, is unclear. At present, 14 cases of pouch carcinoma in patients with FAP have been reported, including 3 that were localized in the pouch itself The other cases were either localized in the rectal cuff or at the anastomosis, demonstrating the malignant potential of the remnant rectal cuff. The IPAA procedure was introduced about 20 years ago. Because the adenoma-carcinoma sequence in the colorectum of FAP patients takes approximately 20 years, it might be expected that the incidence of pouch carcinoma will increase during the forthcoming years. Although the reported cases demonstrated the risk of pouch carcinoma, the number of cases is small. Therefore, the aim of the present study was to evaluate the long-term risk of developing an adenoma or carcinoma in the pouch in a large cohort of Dutch FAP patients. Moreover, we evaluated the value of chromoendoscopy in the detection of adenomas in a subgroup of the patients. Patients and Methods Dutch Polyposis Registry In 1985, the Netherlands Foundation for the Detection of Hereditary Tumours (NFDHT) established a registry of patients with FAP. The main objective of the registry is to promote the early detection of cancer in high-risk families. The approach and the regulations of the registry have been described elsewhere. 19 In short, families with FAP are referred to the national registry by clinical geneticists, surgeons, or gastroenterologists. During the early years, social workers and genetic field workers associated with the registry performed extensive genealogic studies and counselling. Nowadays, genealogic studies, genetic counselling, and mutation analysis are performed in clinical genetic centers, and the registry focuses on coordination of lifelong surveillance of these families. At the time of registration, written informed consent was obtained for collecting personal and medical data. The data collected by the registry include the mode of diagnosis, age at diagnosis, age at surgery, type of surgery, results of endoscopic surveillance, results of pathology examination, age at death, and causes of death. To ensure the continuity of the follow-up, the registry uses a Abbreviations used in this paper: AAP, adenoma with advanced pathology; FAP, familial adenomatous polyposis; IPAA, ileal pouch anal anastomosis; NFDHT, Netherlands Foundation for the Detection of Hereditary Tumours by the AGA Institute /08/$34.00 doi: /j.cgh

2 1238 FRIEDERICH ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 11 Table 1. Characteristics of FAP Patients Total cohort 254 (56% male) After exclusion 212 (56% male) Type of anastomosis 70 HS, 115 DS, and 27 unknown Mean age at time of IPAA (y) 30.0 (range, ) Mean interval pouch, first surveillance (y) 3.8 (range, ) Mean follow-up time since IPAA (y) 7.9 (range, ) No. of surveillance endoscopies 761 (range, 1-19) No. of patients with pouch removal 13, after a mean of 7.5 y (range, ) Abbreviations: HS, hand-sewn; DS, double-stapled. reminder system. A few months before the proposed date of the next endoscopy, the treating physician receives a reminder from the registry that an endoscopy should be scheduled. By March 2005, the registry had collected medical and pathologic data on 327 families. A total of 254 FAP patients were identified who had undergone an IPAA. This surgical procedure was introduced in FAP patients in various medical centers in the Netherlands in In 1998, it was recommended to have a pouch endoscopy every 1 3 years. In 2001, the protocol was revised; from then on, pouch endoscopy was recommended every year. Chromoendoscopy Study To evaluate the accuracy of the regularly performed endoscopies, a subgroup of 33 patients from the region of the Radboud University Nijmegen Medical Centre were offered a different, more extensive surveillance protocol with chromoendoscopy. The endoscopy was performed with an Olympus GIF- 1T140 (Tokyo, Japan) video endoscope, and a 3.0-mm diameter biopsy forceps (B102-C ; MedWork/Treier Endoscopie GA, Beromünster, Switzerland) was used. The mucosa was sprayed with 1% indigo carmine dye (Laboratoires SERB, Paris, France) at 1:1 dilution with water. Photographs before and after chromoendoscopy were taken to evaluate number and size of polyps if present. Minimally 4 biopsies were taken from polyps or normal-appearing mucosa. An expert pathologist examined all biopsy specimens. The biopsies were scored for dysplasia. Adenomas with high-grade dysplasia or adenomas larger than 1 cm were considered as adenomas with advanced pathology (AAPs). Statistical Analysis Data were analyzed by using SPSS 11.0 for Windows (SPSS Inc, Chicago, IL). Survival analysis with the Cox relative hazard model was used to determine the significance of sex, follow-up time, and carrier status in a multivariate model. Observation time was measured from birth, either until the date of diagnosis of the first incident adenoma or carcinoma or until the last endoscopic screening when no adenoma was detected in a patient. Results Between 1984 and 2005, 327 families with FAP were registered at the NFDHT. A total of 254 FAP patients (141 male, 113 female) with an IPAA were identified within these families. In 40 patients, 15.7% of the total cohort, no endoscopy surveillance was performed, or the endoscopy or pathology reports could not be obtained. In 2 patients, a pouch carcinoma was diagnosed 5 years after reconstructive proctocolectomy for a primary rectal cancer. Because we could not exclude that the pouch carcinoma was a locoregional recurrence, these patients were excluded. Full information on follow-up was available in 212 patients (84%). Table 1 outlines characteristics of these patients. There were 119 male and 93 female patients, with a median age at last contact of 37.4 years (range, years) and a median age at time of the IPAA procedure of 29.2 years (range, years). Of the 212 patients, 71 had a hand-sewn anastomosis with mucosectomy, and 115 patients had a double-stapled anastomosis. In 27 patients we could not obtain certainty about the type of anastomosis. The median follow-up time since the IPAA was 6.8 years (range, years). The number of control endoscopies varied among the patients. During the observed time period, a total of 767 surveillance endoscopies were performed. Seventy-four (35%) patients developed an adenoma, with a cumulative risk of 16% at 5 years and 42.2% at 10-year followup. The cumulative proportion of patients free of adenomas is presented in Figure 1. Twenty-five patients (11.8%) developed an AAP. The cumulative risk of developing an AAP was 12.8% at 10-year follow-up. The cumulative proportion of patients free of AAP or carcinoma is shown in Figure 1. After stratification for type of operation, the cumulative risk for developing an adenoma was 64% at 10 years for the doublestapled anastomosis versus 29% for the hand-sewn anastomosis (P.0004) (Figure 2). The cumulative risk for AAP after a double-stapled and hand-sewn anastomosis was 16% and 9%, respectively (P.078). The more extensive chromoendoscopy surveillance cohort consisted of 33 patients, 20 men and 13 women with a median age of 33 years (range, years) and a median time after IPAA of 8 years (range, 2 19 years). A single endoscopy was performed to obtain a cross-sectional adenoma prevalence. Table 2 outlines the patient characteristics of this cohort. With conventional colonoscopy, adenomas were detected in 19 patients. After chromoendoscopy in almost all patients (93.9%), very small polypoid lesions were visualized. These lesions consisted mainly of nodular lymphoid hyperplasia (Figure 3). In 6 patients adenomas, all smaller than 5 mm, were identified only after chromoendoscopy (Figure 4). Thus, the combined use of conventional and chromoendoscopy led to the detection of adenomas in 25 of the 33 patients (75.7%), including one with high-grade dysplasia. This proportion of patients with adenomas is much higher than that observed in the total cohort of 212 patients.

3 November 2008 RISK OF DEVELOPING ADENOMAS AND CARCINOMAS IN ILEAL POUCH IN PATIENTS WITH FAP 1239 Figure 1. Cumulative proportion of patients free of adenoma or adenoma with AAP after IPAA. In 13 patients (6.1%) the pouch was resected during follow-up after a median of 7.9 years (range, years), in 4 cases (1.9% of the total cohort) because of a carcinoma. The characteristics of the patients with a pouch carcinoma are shown in Table 3. The median interval between the detection of cancer and the previous surveillance endoscopy was 25 months (range, 6 54 months). In 2 patients no adenomas were found in the endoscopy before the diagnosis of pouch carcinoma. In 1 patient, a tubulovillous adenoma with high-grade dysplasia was resected 6 months before pouch carcinoma was detected. The fourth patient was not under surveillance and presented with symptoms. The cumulative risk of developing a pouch carcinoma was 1% at 10-year follow-up. Pouch excision occurred in another 2 patients (0.9%) because of severe patient concern. This decision was made during the Figure 2. Cumulative proportion of subjects free of adenoma stratified for double-stapled or hand-sewn anastomosis.

4 1240 FRIEDERICH ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 11 Table 2. Characteristics of the Chromoendoscopy Subgroup Total cohort 33 (60.6% male) Median age (y) 33 (range, 18 76) Median follow-up time after IPAA (y) 8 (range, 2 19) No. of patients with adenomas 25 (75.7%) Low-grade dysplasia 32 (96.9%) High-grade dysplasia 1 (0.3%) last endoscopy in which multiple low-grade adenomas were found in both patients. Because of stenosis of the anal anastomosis the pouch was removed in 1 patient and in 6 patients because of severe functional problems. Overall, the presence of (pre)malignancy led to a pouch resection in 6 patients (2.8%). Discussion The present study provides for the first time an estimate of the cumulative risk of developing a pouch carcinoma in patients with FAP. In this cohort of 212 patients with FAP prospectively followed by the Dutch FAP polyposis registry, the cumulative risk for adenoma development in the pouch after 5- and 10-year follow-up was 16.0% and 42.2%, respectively. In contrast, the risk of developing a carcinoma in the pouch was only 1% at 10-year follow-up. We also demonstrated that the use of chromoendoscopy improved the detection of small adenomas. The strengths of this study are its large size, the prospective collection of data by the registry, and the long time of followup. The study also has some limitations. The endoscopic examinations have been performed in various medical centers in the Netherlands, and no standardized scoring system was used. However, most endoscopies have been performed by experienced gastroenterologists. Another limitation was that the follow-up of the pouch was started only in the mid-1990s, when physicians became aware that FAP patients with an IPAA harbored a risk for developing adenomas and cancer. For approximately 10 years there has been an increasing number of reports in the literature about the development of adenomas in the pouch of FAP patients who had an IPAA. These adenomas were located not only in the remnant rectal Figure 4. Before (A) and after chromoendoscopy (B). Notice the small polypoid lesions after chromoendoscopy. Figure 3. Microadenoma and follicular lymphoid hyperplasia; hematoxylin-eosin stain, original magnification 100. cuff but also in the ileal mucosa of the pouch itself. In the present study, we found a cumulative risk for adenoma in the pouch of 16.0% and 42.2% after 5 and 10 years, respectively. These figures are similar to the findings in the study of Wu but higher than those reported by Parc. 4,7 In the study by van Duijvendijk et al, consecutive patients with an IPAA from various national polyposis registries were analyzed. Endoscopy reports were available in 97 patients with a median follow-up of 66 months. The incidence of adenoma at the anastomotic site was 10%. This relatively low percentage might be explained by the fact that the authors focused on adenomas localized at the

5 November 2008 RISK OF DEVELOPING ADENOMAS AND CARCINOMAS IN ILEAL POUCH IN PATIENTS WITH FAP 1241 Table 3. Characteristics of Subjects With Pouch Carcinoma Subject Sex Age at IPAA (y) Findings in resected rectum Type of anastomosis Rectum mucosa left? Age at diagnosis of pouch carcinoma (y) Dukes stage of tumor Interval since last endoscopy (y) 1 M 21.3 Several adenomas, mild dysplasia 2 M 26.7 Several adenomas, mild dysplasia 3 M 16.0 No adenomas in rectum 4 F 29.6 Several adenomas, mild dysplasia Hand-sewn 1 cm 35.3 C 4.4, no polyps Stapled Linea dentata 36.9 B 2.1, no polyps Hand-sewn 1.5 cm 32.4 B No control Stapled Linea dentata 35.8 B 0.6; adenoma, resection and argon anastomosis. Although in the present study we were not able to differentiate between pouch adenomas located in the anal transitional zone or pouch, a significant difference in prevalence of pouch adenomas between subjects with a double-stapled or hand-sewn anastomosis was found (64% vs 29% after 10 years, respectively; P.0004). Also, in the study by van Duijvendijk et al, a 3 times higher risk for developing adenomas was found in patients with a double-stapled anastomosis compared with those with a hand-sewn anastomosis (31% vs 10%, respectively). Remzi et al 21 reported the incidence of adenomas in a group of 77 patients with an IPAA with a double-stapled anastomosis and 42 with a hand-sewn anastomosis with a follow-up of 3.6 and 5.8 years, respectively. They observed an incidence of adenomas at the anal transitional zone of 28% in patients with a double-stapled anastomosis versus 14% in those with a handsewn anastomosis. Our studies and other studies showed that patients with a double-stapled anastomosis are at increased risk of developing adenomas in the pouch. This increased risk of adenomas after a double-stapled anastomosis should be balanced with the relatively better functional outcome reported after this procedure. The present study also demonstrated that the use of chromoendocopy significantly increased the detection of pouch adenomas compared with standard endoscopic surveillance. With this technique, adenomas were identified in up to three fourths of the patients. If future studies confirm this high prevalence of pouch adenomas, the question should not be whether patients with FAP develop pouch adenomas, but whether these adenomas harbor a clinically relevant malignant potential. So far, a total of 14 cases of pouch carcinoma have been published in the literature In the present cohort of 212 patients, 4 cases of pouch carcinoma were identified, with a cumulative risk of 1% after 10 years. The median interval between the prior endoscopy and the detection of cancer was 25 months, indicating that surveillance endoscopy should be performed with shorter intervals than 2 years. Unfortunately, the time that rectal cuff adenomas and true pouch adenomas need to become malignant (adenoma-carcinoma sequence) is unknown. If this sequence is equal to that observed in the colon in patients with FAP, ie, approximately 20 years, then an increase in pouch cancer could be expected in the forthcoming years. In conclusion, this study demonstrated a very high cumulative risk of developing adenomas in the pouch especially after double-stapled anastomosis. In contrast, the risk of pouch cancer seems to be low. Because pouch cancer might be diagnosed shortly after a previous endocopy, an interval of 1 year between examinations might be appropriate. References 1. Bussey HJ, Veale AM, Morson BC. Genetics of gastrointestinal polyposis. Gastroenterology 1978;74: Nugent KP, Spigelman AD, Nicholls RJ, et al. Pouch adenomas in patients with familial adenomatous polyposis. Br J Surg 1993; 80: Parc Y, Piquard A, Dozois RR, et al. Long-term outcome of familial adenomatous polyposis patients after restorative coloproctectomy. Ann Surg 2004;239: Parc YR, Olschwang S, Desaint B, et al. Familial adenomatous polyposis: prevalence of adenomas in the ileal pouch after restorative proctocolectomy. Ann Surg 2001;233: Polese L, Keighley MR. Adenomas at resection margins do not influence the long-term development of pouch polyps after restorative proctocolectomy for familial adenomatous polyposis. Am J Surg 2003;186: Shepherd NA, Jass JR, Duval I, et al. Restorative proctocolectomy with ileal reservoir: pathological and histochemical study of mucosal biopsy specimens. J Clin Pathol 1987;40: Wu JS, McGannon EA, Church JM. Incidence of neoplastic polyps in the ileal pouch of patients with familial adenomatous polyposis after restorative proctocolectomy. Dis Colon Rectum 1998;41: Campos FG, Habr-Gama A, Kiss DR, et al. Adenocarcinoma after ileoanal anastomosis for familial adenomatous polyposis: review of risk factors and current surveillance apropos of a case. J Gastrointest Surg 2005;9: Ulas M, Nessar G, Bostanoglu A, et al. Development of two cancers in the same patient after ileorectal and ileal pouch anal anastomosis for familial adenomatous polyposis. Med Princ Pract 2006;15: Bassuini MM, Billings PJ. Carcinoma in an ileoanal pouch after restorative proctocolectomy for familial adenomatous polyposis. Br J Surg 1996;83: Brown SR, Donati D, Seow-Choen F. Rectal cancer after mucosectomy for ileoanal pouch in familial adenomatous polyposis: report of a case. Dis Colon Rectum 2001;44: Cherki S, Glehen O, Moutardier V, et al. Pouch adenocarcinoma after restorative proctocolectomy for familial adenomatous polyposis. Colorectal Dis 2003;5: Hoehner JC, Metcalf AM. Development of invasive adenocarcinoma following colectomy with ileoanal anastomosis for familial polyposis coli: report of a case. Dis Colon Rectum 1994;37:

6 1242 FRIEDERICH ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No Ooi BS, Remzi FH, Gramlich T, et al. Anal transitional zone cancer after restorative proctocolectomy and ileoanal anastomosis in familial adenomatous polyposis: report of two cases. Dis Colon Rectum 2003;46: Palkar VM, desouza LJ, Jagannath P, et al. Adenocarcinoma arising in J pouch after total proctocolectomy for familial polyposis coli. Indian J Cancer 1997;34: von HA, Stern J, Herfarth C. Pouch-anal cancer after restorative proctocolectomy for familial adenomatous polyposis. Am J Surg Pathol 1996;20: Vrouenraets BC, van DP, Bemelman WA, et al. Adenocarcinoma in the anal canal after ileal pouch-anal anastomosis for familial adenomatous polyposis using a double-stapled technique: report of two cases. Dis Colon Rectum 2004;47: Vuilleumier H, Halkic N, Ksontini R, et al. Columnar cuff cancer after restorative proctocolectomy for familial adenomatous polyposis. Gut 2000;47: Vasen HF, den Hartog Jager FC, Menko FH, et al. Screening for hereditary non-polyposis colorectal cancer: a study of 22 kindreds in The Netherlands. Am J Med 1989;86: van Duivendijk P, Vasen HF, Bertario L, et al. Cumulative risk of developing polyps or malignancy at the ileal pouch-anal anastomosis in patients with familial adenomatous polyposis. J Gastrointest Surg 1999;3: Remzi FH, Church JM, Bast J, et al. Mucosectomy vs stapled ileal pouch-anal anastomosis in patients with familial adenomatous polyposis: functional outcome and neoplasia control. Dis Colon Rectum 2001;144: Address requests for reprints to Dr Hans F. A. Vasen, Netherlands Foundation for the Detection of Hereditary Tumours, Department of Gastroenterology, Rijnsburgerweg 10, Poortgebouw Zuid, 2333 AA Leiden, Netherlands. hfavasen@stoet.nl; fax: The authors disclose no financial conflicts of interest.