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The risk of gastrointestinal malignancies in cystic fibrosis Case report of a patient with a near obstructing villous adenoma found on colon cancer screening and Barrett's esophagus ⁎ C.L. Alexander, S.J. Urbanski, R. Hilsden, H. Rabin, W.K. MacNaughton, P.L. Beck

Gastrointestinal Research Group and Inflammation Research Network, Institute of Infection, Immunity and Inflammation, University of Calgary, Calgary, AB, Canada Received 13 February 2007; received in revised form 4 July 2007; accepted 7 July 2007 Available online 4 September 2007

Abstract

The life expectancy for cystic fibrosis (CF) patients has increased dramatically over the last 30 years. Although the overall cancer risk for CF patients does not appear to be increased there is a marked increased risk of gastrointestinal malignancies especially in the post lung transplant population. CF patients that do develop gastrointestinal malignancies do so at an earlier age and there is often a lag in the diagnosis and management of these individuals. We present a 39 year old male CF patient that underwent a colonoscopy for colon cancer screening and a large, near obstructing, villous adenoma of his ileum was found. The polyp was removed successfully via endoscopy without incident and there was no evidence of malignancy. An upper endoscopy revealed a long segment of Barrett's esophagus with no evidence of dysplasia. We present this case as well as a detailed review of the literature on cancer risk in CF and a discussion of the mechanisms that may be involved. We also present the risk of GI malignancies in non-CF patients as a guide on how to assess and manage the risk of GI malignancies in this ever-changing patient population. © 2007 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Keywords: Cystic fibrosis; Adenoma; Colon cancer; Small bowel cancer; Barrett's esophagus; Esophageal cancer; Screening

Contents

1. Introduction...... 1 2. Case report ...... 2 3. Discussion ...... 3 3.1. Risks and mechanisms of GI Cancer in CF patients ...... 3 3.2. Cancer risk in non-CF patients ...... 4 3.3. Comparing cancer risks in CF and non-CF patients...... 5 References ...... 5

1. Introduction ⁎ Corresponding author. Division of Gastroenterology, Faculty of Medicine, University of Calgary Health Sciences Center, 3330 Hospital Drive N.W., Calgary, Alberta, Canada, T2N 4N1. Tel.: +1 403 220 4500; Approximately 1 in every 2500 Caucasian newborns will fax: +1 403 270 0995. have cystic fibrosis (CF) resulting from a genetic mutation E-mail address: [email protected] (P.L. Beck). in the cystic fibrosis transmembrane conductance regulator

1569-1993/$ - see front matter © 2007 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jcf.2007.07.005 2 C.L. Alexander et al. / Journal of Cystic Fibrosis 7 (2008) 1–6

(CFTR), making this the most common inherited disease of diet and inadequate pancreatic enzyme replacement) as a that population. This recessive disease has a carrier rate of child. He also had common bile duct stones and subsequently approximately 4% in the Caucasian population with the most a cholecystectomy as well as mild gastro-esophageal reflux common mutation of CFTR being a deletion of the phenyla- for greater than 5 years which was effectively managed with lanine residue at position 508 (ΔF508) which accounts for 20 mg of omeprazole per day. He denied dysphagia, ody- about 67% of CF-causing gene mutations worldwide [1]. nophagia, early satiety, nausea, , change in weight or Improved therapy over the past three decades has allowed bowel habit, GI blood loss, or and bloating. for increased longevity in CF patients, increasing the like- His family history was significant in that his mother was lihood that the health of CF patients will be affected by recently diagnosed with rectal cancer at the age of 61, a disease states other than CF. In the past, screening of CF maternal grandmother with Crohn's disease and a brother patients for other disease states was limited due to the severity who is deceased due to complications of CF. His abdominal of the CF symptoms, the inability of many patients to tolerate exam was unremarkable. His medications included omepra- screening procedures and the associated risks when subse- zole, salbutamol, Gluconorm (repaglinide), Pulmnozyme quent interventions were required. Over the last few decades it has become apparent that those with CF have an increased risk of certain types of cancer. Although the overall cancer risk in the CF population has been shown to be approximately the same as in the general population, they do have an increased risk of developing certain forms of malignancies of the gastrointes- tinal (GI) tract. The most common GI malignancies in the CF population include both colorectal cancer and adenocarcino- ma of the small intestine [2]. Not only do CF patients have a higher risk of developing GI malignancies, they also present at an earlier age and there is often a delay in making the diagnosis. The average age of onset of GI malignancies among North American and European CF patients was found to be 32.2±12.6 years of age, compared to 58.2±14.3 years of age in non-Hispanic whites [1]. The present case report highlights an asymptomatic 39 year old CF patient who was screened for colon cancer due to positive family history of colorectal cancer (CRC) and although a few small adenomas were noted in the colon, the main finding was a near obstructing villous adenoma of the ileum. To rule out polyps elsewhere in the GI tract an upper endoscopy was performed and the patient was found to have Barrett's esophagus without any biopsy evidence of dyspla- sia. The patient had a normal small bowel follow through but refused capsule endoscopy. In this report we review the case in detail, discuss the increased incidence of GI malignancies in CF and then review the possible factors that may be involved in this increased risk of neoplasia in CF. We also discuss an approach to GI screening and follow up of this patient as well as others with CF.

2. Case report

A 39 year old male with CF (ΔF508 homozygous, pancreatic insufficiency and chronic colonization with Pseu- domonas aeruginosa) presented to the Outpatient Gastroen- terology Clinic at the University of Calgary Medical Centre inquiring about colon cancer screening. His past history was significant for numerous complica- tions of CF including recurrent pneumonias, pneumothoraces Fig. 1. Ileal polyp; A) endoscopic view of the near obstructing polyp prior to and a pleurectomy. His only gastrointestinal problems in- polypectomy, B) histopathological assessment revealed a villous adenoma cluded a history of diarrhea (thought to be due to a high fat with no evidence of high grade dysplasia or malignancy. C.L. Alexander et al. / Journal of Cystic Fibrosis 7 (2008) 1–6 3

ulation. However, a few large studies have identified that CF patients have an increased risk for developing GI malignan- cies (see Table 1). In a 10-year study by Maisonneuve et al. [2], CF patients developed significantly more GI cancers than expected with a standardized incidence ratio (SIR) of 5.1 [2] (see Table 1). More specifically there was an increased risk of cancers of the small intestine (SIR; 24.8), colon (SIR;7.4), biliary tract (SIR;39.0), liver (SIR;4.1), esophagus (SIR;5.4) and pancreas (SIR;2.6) [2] (see Table 1). In a study from 1995, Neglia et al. [1] reported on approximately 25,000 CF

Table 1 Cancer risk in CF and non-CF patients SIR or RR (with CI) CF patients (non-transplanted) All sites [2] SIR; 1.1 (0.8–1.4) – Fig. 2. Barrett's esophagus; note the tongue like projections of the Barrett's Digestive SIR; 5.1 (3.2 7.6) [2], – epithelium (arrows) and surrounding squamous epithelium. 6.4 (2.9 14.0) [1] Non-digestive [2] SIR; 0.8 (0.6–1.0) Esophagus [2] SIR; 5.4 (0.1–30.3) Esophagus [1] SIR; 14.3 (1.4–148) (dornase alpha), Cotazyme ECS-20 ostoforte (ergocalciferol) Stomach [2] SIR; 0.0 (0.0–8.9) and a CF-specific multiple vitamin preparation (ADEKs). Small bowel [2] SIR; 24.8 (6.8–63.6) The various modalities of colon cancer screening were Colon [2] SIR; 7.4 (3.7–13.2) discussed with the patient in detail and after the risks and Liver [2] SIR; 4.1 (0.5–14.6) – benefits of each approach were reviewed the patient decided to Biliary tract/gallbladder [2] SIR; 39.0 (8.0 114.0) CF patients (post transplanted) pursue colonoscopy. Colonoscopy revealed a normal looking All sites [2] SIR; 6.3 (3.4–10.8) colon with a tiny 2–3 mm polyp in the ascending colon which Digestive [2] SIR; 21.0 (5.8–54.2) was removed by biopsy forceps. Approximately 15 cm up the Small bowel [2] SIR; 143 (3.6–796.0) terminal ileum from the ileocecal valve, a large, near ob- Colon [2] SIR; 30.3 (3.7–109.0) – structing mass was encountered. This polypoid lesion was Liver [2] SIR; 76.9 (2.0 429.0) Non-CF patients approximately 2 cm wide and 3.5 cm in length and was Risk in 1st degree relative of SIR; colon cancer 2.24 removed via endoscopic polypectomy without complications colon cancer patient [42] (2.06–2.43) (Fig. 1). The diminutive polyp was an adenoma without evi- Risk of colon cancer if sibling SIR; 2.03 (1.76–2.33) dence of high grade dysplasia. The polyp from the ileum was a diagnosed with colon cancer [42] – villous adenoma also with no evidence of high grade dysplasia. Peutz Jeghers [43] RR; small intestine 520 (220–1306), Three months later a repeat colonoscopy was performed colon 84 (47–137) and a small piece of remaining ileal polyp was removed Lynch family cancer syndrome/ SIR; 3.20 (2.39–4.19) without incident. The histology was identical to the previous hereditary non-polyposis for cancers of the colon assessment. An upper endoscopy was performed to assess the colorectal cancer (HNPCC) [34] and rectum – stomach and duodenum for polyps and none were identified. [35] SIR; 4.1 (2.7 5.8) for colon cancer However, 6 cm of Barrett's esophagus was noted (Fig. 2) with Crohn's disease [37] Pooled SIR; 2.5 (1.7–3.5) no histological evidence of dysplasia. A small bowel follow for colon cancer through was performed and was completely normal. The Pooled SIR; 27.1 (14.9–49.2) patient refused a capsule endoscopy. A follow up colonoscopy for small bowel cancer – has been booked for 6 months and a repeat upper endoscopy Celiac disease [38] SIR; 40.51 (1.03 225.68) for small bowel lymphoma has been booked for 2 years from the last endoscopy for re- SIR; 1.58 (0.72–2.99) assessment of the Barrett's esophagus. The patient refused for all GI malignancies further genetic testing for genes associated with colon cancer. Esophagitis SIR; 5.38 (3.01–8.87) [39], 6.0 (1.9–14) [40] for 3. Discussion adenocarcinoma of the esophagus. Barrett's esophagus SIR; 39.1 (20.2–68.3) 3.1. Risks and mechanisms of GI Cancer in CF patients adenocarcinoma of the esophagus [40] The overall cancer risk in the CF population has been SIR; standardized incidence ratio, CI; 95% confidence intervals, RR; relative shown to be approximately the same as in the general pop- risk ratio. 4 C.L. Alexander et al. / Journal of Cystic Fibrosis 7 (2008) 1–6 patients in the United States and 24,500 CF patients in Europe of these genes has been noted in colorectal carcinomas [15,16]. and again a significantly increased risk of developing GI Altered mucin expression has been well described in CF with malignancies was observed (see Table 1). CF patients also an increased expression of MUC 5 in the lungs of CF patients develop GI malignancies at an earlier age (mean age [17] and increased MUC 1, 2 and 3 expression by intestinal 32.2 years [1]) and there is a marked increased risk in CF epithelial cells in a mouse model of CF [18–20]. Interestingly, patients between the age of 20 and 29 years (odds ratio; 20.2) treatment of bacterial overgrowth in this mouse model of CF [1]. Since the average age of onset of GI malignancies in markedly reduced mucus, and MUC 2 and 3, production [21]. North American and European non-Hispanic Caucasian It has been postulated that altered mucin production (both populations is approximately 58.2 years clearly those with increases in certain forms as well as decreases in certain MUC) CF have earlier onset of GI malignancies [3]. may be involved in the increased risk of GI inflammation and Not only do CF patients have an increased risk of de- malignancies seen in patients; however clear evidence for this veloping GI malignancies and are affected at an earlier age is lacking [2]. Interestingly the tumor markers CA 19-9 and but often there can be a delay in diagnosing these malig- CA 125, which are also mucin-associated antigens, as well as nancies [4]. This delay in diagnosis has not been thoroughly carcinoembryonic antigen (CEA), can be over expressed in CF studied and has been most often reported in case report patients [22,23]. In addition, deficiencies in the omega-3 fatty format. The cause of this delay has been attributed to the acid docosahexaenoic acid, selenium and vitamin E in CF numerous symptomatic GI problems that can also affect pa- patients may also increase the risk as this essential fatty acid tients with CF. Furthermore, it appears that malignancies are and some of these antioxidants have been theorized to protect not high on the differential diagnosis due to the fact that most against cancer [1,2]. of the patients are of a young age; and also likely due to the Disease states of chronic GI inflammation, such as inflam- limited knowledge that exists of their increased potential to matory bowel disease, Celiac disease and Helicobacter pylori develop malignancies. gastritis, are associated with an increased risk of GI malig- More specifically, in the present case, our patient had a nancies. Several studies have shown that patients with CF very high risk ileal polyp (based on polyp size and villous may have ongoing intestinal inflammation affecting both the changes), a small, low risk polyp of the colon and Barrett's small and large intestine [24–29]. At present it is unclear if esophagus. Although over 50% of GI malignancies affect the this chronic inflammation is due to pancreatic enzyme re- colon in CF patients, small bowel cancers are not uncom- placement, intestinal damage due to distal intestinal ob- mon in the patient population as noted above [1,2]. CF has struction syndrome (DIOS), or other factors. Gut bacterial been clearly recognized as a risk factor for developing small load may also play a part; however, there appears to be bowel cancer [5]. There have been some reports specifically intestinal inflammation present prior to increased bacteria of ileal cancers in CF patients and unfortunately in these cases counts [24,25]. High dose pancreatic enzyme replacement in the lesion was not noted until autopsy or late in the disease children, and more recently in adults, can be associated with process [6–8]. intestinal inflammation and in some settings can lead to Those with CF have long been known to have increased fibrosing colonopathy and/or strictures in the right colon problems with gastro-esophageal reflux [9–12]. Longstand- [24,25,30,31]. The exact cause of this inflammation is unclear ing GERD is associated with Barrett's esophagus and an but some have proposed that it may, in part, be due to an increased risk of esophageal cancer. Although the incidence impaired intestinal barrier allowing leakage of pancreatic of Barrett's in the CF population has not been fully studied, enzymes into the surrounding tissues leading to diffuse tissue there have been case reports of Barrett's esophagus in CF injury and inflammation [32]. [13,14]. It is likely that this marked increase in GERD leads to the increased risk of esophageal neoplasia in CF [1,2] (see 3.2. Cancer risk in non-CF patients Table 1). The pathophysiology involved in the increased risk of The cumulative lifetime risk of colon cancer in average GI malignancies in CF patients is unclear. Since CFTR is risk individuals in North America is about 6% and the risk of expressed in much higher levels along the GI tract than in colon cancer among first-degree relatives and siblings is adult lung epithelial cells and other tissues, a correlation increased (SIR 1.47, 2.24, respectively) (see Table 1) [33]. between levels of the mutated CFTR protein and an increased Clearly some polyp syndromes have a very high risk of risk of gastrointestinal malignancies has been postulated. developing cancer with some syndromes having an 80 to Mutations in the CFTR gene may lead to altered expression of 100% risk. In Lynch family cancer syndrome/hereditary non- other genes including the mucin genes MUC 3, MUC 11 and polyposis colorectal cancer (HNPCC) the increased risk re- MUC 12 that are located adjacent to CFTR in the same sults in a SIR of 3.20 for cancers of the colon and rectum [34] chromosome band 7q31 [2]. These mucins, which are (see Table 1). Inflammatory bowel disease also increases the normally produced and excreted by the epithelial cell surface, risk of developing GI malignancies (ulcerative colitis; SIR serve to protect the GI tract from injury, modulate bacterial 4.1 for CRC [35] (a meta-analysis noted a prevalence rate of and cell adhesion, and mediate wound repair as well as other 3.7% and a cumulative probability of 2% with disease dura- processes critical in intestinal homeostasis. Altered regulation tion up to 10 years to 18% with disease up to 30 years [36]) C.L. Alexander et al. / Journal of Cystic Fibrosis 7 (2008) 1–6 5 and Crohn's disease pooled SIR, 2.5 for CRC and pooled Neglia et al. study [1] of approximately 53,000 patients 76 SIR 27.1 for small intestinal cancer [37] (see Table 1). Celiac developed cancer (24 digestive tract cancers). disease has been found to be associated with an increased Colon cancer screening of those with CF should clearly risk of lymphoma in the small bowel (SIR 40.5) and all GI be considered on an individual basis in that screening ap- malignancies (SIR 1.58) [38] (see Table 1). proaches have their inherent risks. Routine screening for fecal In two studies assessing the risk of adenocarcinoma of the occult blood is reasonable for those with no added risk other esophagus in patients with esophagitis, the SIR was 5.38 and than CF, but due to the false positives inherent with this test it 6.0 [39,40] (see Table 1). The SIR for adenocarcinoma of the would lead to increased numbers of colonoscopies being esophagus in Barrett's is 39.1 [40]. Even with these risk performed on these individuals. Sigmoidoscopy and air factors there is debate over the cost effectiveness of screening contrast barium enema are of lower risk but have a higher Barrett's patients and those with longstanding reflux. At miss rate than colonoscopy. Stool DNA testing and CT present there are no current guidelines for screening patients colonography are still in the development stages as far as with esophagitis. screening tests, but at some point may well offer lower risk options for these patients. 3.3. Comparing cancer risks in CF and non-CF patients In summary, we have presented a 39 year old male patient with CF with a family history of colon cancer. Upon screening To date there are no clear guidelines if or how patients with he was found to have small adenomas in his colon and a large, CF should be screened with respect to their risk of developing near obstructing, villous adenoma of his ileum. Upper en- a colorectal or small intestinal malignancy compared to doscopy revealed no further polyps, but he did have a long other at risk groups. It is difficult to directly compare different segment of Barrett's esophagus. Several reports have disease states since earlier intestinal cancer studies did not shown that patients with CF have a markedly increased risk report SIR as did the main CF malignancy studies. Thus, in of developing cancers of the esophagus, small bowel and colon the CF population with a SIR for the development of which generally develops at younger age and there is often a esophageal cancer of 5.1 (3.2 to 7.6) (nearly identical to delay in the diagnosis. Furthermore, the risk appears to drama- those with esophagitis noted above) it would be appropriate tically increase in the post lung transplant population. We feel to screen these patients as one would those with known that this case and evidence in the literature highlights the need esophagitis. Those with CF have a risk of developing small to consider screening for GI malignancies in CF patients. intestinal cancer that appears to be lower than those with Celiac disease (SIR 40.5) and similar to those with Crohn's References disease (CF; SIR=24.8, versus Crohn's SIR=27.1). At present there are no guidelines for screening Celiac or [1] Neglia JP, FitzSimmons SC, Maisonneuve P, Schoni MH, Schoni- Crohn's disease patients for small intestinal malignancies. Affolter F, Corey M, et al. The risk of cancer among patients with These guidelines may change with the increased accuracy of, cystic fibrosis. Cystic Fibrosis and Cancer Study Group. 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Delayed diagnosis of colon who are at increased risk for HNPCC is that they should have carcinoma in cystic fibrosis. Clin Radiol Mar 2000;55(3): 240–2. a colonoscopy every 1–2 years beginning at age 20–25 years, [5] Neugut AI, Jacobson JS, Suh S, Mukherjee R, Arber N. The epidemiology of cancer of the small bowel. Cancer Epidemiol or 10 years earlier than the youngest age of colon cancer Biomarkers Prev Mar 1998;7(3): 243–51. diagnosis in the family—whichever comes first [41].It [6] Redington AN, Spring R, Batten JC. Adenocarcinoma of the ileum should be noted in Table 1 that the risk of GI malignancies presenting as non-traumatic clostridial myonecrosis in cystic fibrosis. increases dramatically in the post lung transplant population Br Med J (Clin Res Ed) Jun 22 1985;290(6485): 1871–2. (SIR for all digestive cancers, 21.0; small bowel, 143; colon, [7] Siraganian PA, Miller RW, Swender PT. Cystic fibrosis and ileal carcinoma. 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