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






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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


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


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

Approximately 1 in every 2500 Caucasian newborns will have cystic fibrosis (CF) resulting from a genetic mutation in the cystic fibrosis transmembrane conductance regulator

⁎ 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; fax: +1 403 270 0995.

E-mail Beck).

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


(CFTR), making this the most common inherited disease of that population. This recessive disease has a carrier rate of approximately 4% in the Caucasian population with the most common mutation of CFTR being a deletion of the phenyla-lanine residue at position 508 (ΔF508) which accounts for about 67% of CF-causing gene mutations worldwide[1].

Improved therapy over the past three decades has allowed for increased longevity in CF patients, increasing the like-lihood that the health of CF patients will be affected by disease states other than CF. In the past, screening of CF patients for other disease states was limited due to the severity of the CF symptoms, the inability of many patients to tolerate screening procedures and the associated risks when subse-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 sadenocarcino-mall 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 and a pleurectomy. His only gastrointestinal problems in-cluded a history of diarrhea (thought to be due to a high fat

diet and inadequate pancreatic enzyme replacement) as a child. He also had common bile duct stones and subsequently a cholecystectomy as well as mild gastro-esophageal reflux for greater than 5 years which was effectively managed with 20 mg of omeprazole per day. He denied dysphagia, ody-nophagia, early satiety, nausea, vomiting, change in weight or bowel habit, GI blood loss, or abdominal pain and bloating. His family history was significant in that his mother was recently diagnosed with rectal cancer at the age of 61, a maternal grandmother with Crohn's disease and a brother who is deceased due to complications of CF. His abdominal exam was unremarkable. His medications included omepra-zole, salbutamol, Gluconorm (repaglinide), Pulmnozyme

Fig. 1. Ileal polyp; A) endoscopic view of the near obstructing polyp prior to polypectomy, B) histopathological assessment revealed a villous adenoma with no evidence of high grade dysplasia or malignancy.


(dornase alpha), Cotazyme ECS-20 ostoforte (ergocalciferol) and a CF-specific multiple vitamin preparation (ADEKs).

The various modalities of colon cancer screening were discussed with the patient in detail and after the risks and benefits of each approach were reviewed the patient decided to pursue colonoscopy. Colonoscopy revealed a normal looking colon with a tiny 2–3 mm polyp in the ascending colon which was removed by biopsy forceps. Approximately 15 cm up the terminal ileum from the ileocecal valve, a large, near ob-structing mass was encountered. This polypoid lesion was approximately 2 cm wide and 3.5 cm in length and was removed via endoscopic polypectomy without complications (Fig. 1). The diminutive polyp was an adenoma without evi-dence of high grade dysplasia. The polyp from the ileum was a villous adenoma also with no evidence of high grade dysplasia. Three months later a repeat colonoscopy was performed and a small piece of remaining ileal polyp was removed without incident. The histology was identical to the previous assessment. An upper endoscopy was performed to assess the stomach and duodenum for polyps and none were identified. However, 6 cm of Barrett's esophagus was noted (Fig. 2) with no histological evidence of dysplasia. A small bowel follow through was performed and was completely normal. The patient refused a capsule endoscopy. A follow up colonoscopy has been booked for 6 months and a repeat upper endoscopy has been booked for 2 years from the last endoscopy for re-assessment of the Barrett's esophagus. The patient refused further genetic testing for genes associated with colon cancer. 3. Discussion

3.1. Risks and mechanisms of GI Cancer in CF patients The overall cancer risk in the CF population has been shown to be approximately the same as in the general

pop-ulation. However, a few large studies have identified that CF patients have an increased risk for developing GI malignan-cies (seeTable 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]

(seeTable 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

Fig. 2. Barrett's esophagus; note the tongue like projections of the Barrett's epithelium (arrows) and surrounding squamous epithelium.

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) Digestive SIR; 5.1 (3.2–7.6)[2], 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) Stomach[2] SIR; 0.0 (0.0–8.9) Small bowel[2] SIR; 24.8 (6.8–63.6)

Colon[2] SIR; 7.4 (3.7–13.2)

Liver[2] SIR; 4.1 (0.5–14.6)

Biliary tract/gallbladder[2] SIR; 39.0 (8.0–114.0) CF patients (post transplanted)

All sites[2] SIR; 6.3 (3.4–10.8) Digestive[2] SIR; 21.0 (5.8–54.2) Small bowel[2] SIR; 143 (3.6–796.0)

Colon[2] SIR; 30.3 (3.7–109.0)

Liver[2] SIR; 76.9 (2.0–429.0)

Non-CF patients

Risk in 1st degree relative of colon cancer patient[42]

SIR; colon cancer 2.24 (2.06–2.43)

Risk of colon cancer if sibling diagnosed with colon cancer[42]

SIR; 2.03 (1.76–2.33) Peutz–Jeghers[43] RR; small intestine

520 (220–1306), colon 84 (47–137) Lynch family cancer syndrome/

hereditary non-polyposis colorectal cancer (HNPCC)[34]

SIR; 3.20 (2.39–4.19) for cancers of the colon and rectum

Ulcerative colitis[35] SIR; 4.1 (2.7–5.8) for colon cancer

Crohn's disease[37] Pooled SIR; 2.5 (1.7–3.5) for colon cancer

Pooled SIR; 27.1 (14.9–49.2) for small bowel cancer Celiac disease[38] SIR; 40.51 (1.03–225.68)

for small bowel lymphoma SIR; 1.58 (0.72–2.99) for all GI malignancies Esophagitis SIR; 5.38 (3.01–8.87)[39],

6.0 (1.9–14)[40]for adenocarcinoma of the esophagus. Barrett's esophagus SIR; 39.1 (20.2–68.3)

adenocarcinoma of the esophagus[40]

SIR; standardized incidence ratio, CI; 95% confidence intervals, RR; relative risk ratio.


patients in the United States and 24,500 CF patients in Europe and again a significantly increased risk of developing GI malignancies was observed (seeTable 1). CF patients also develop GI malignancies at an earlier age (mean age 32.2 years[1]) and there is a marked increased risk in CF patients between the age of 20 and 29 years (odds ratio; 20.2)

[1]. Since the average age of onset of GI malignancies in North American and European non-Hispanic Caucasian populations is approximately 58.2 years clearly those with CF have earlier onset of GI malignancies[3].

Not only do CF patients have an increased risk of de-veloping GI malignancies and are affected at an earlier age but often there can be a delay in diagnosing these malig-nancies[4]. This delay in diagnosis has not been thoroughly studied and has been most often reported in case report format. The cause of this delay has been attributed to the numerous symptomatic GI problems that can also affect pa-tients with CF. Furthermore, it appears that malignancies are not high on the differential diagnosis due to the fact that most of the patients are of a young age; and also likely due to the limited knowledge that exists of their increased potential to develop malignancies.

More specifically, in the present case, our patient had a very high risk ileal polyp (based on polyp size and villous changes), a small, low risk polyp of the colon and Barrett's esophagus. Although over 50% of GI malignancies affect the colon in CF patients, small bowel cancers are not uncom-mon in the patient population as noted above[1,2]. CF has been clearly recognized as a risk factor for developing small bowel cancer[5]. There have been some reports specifically of ileal cancers in CF patients and unfortunately in these cases the lesion was not noted until autopsy or late in the disease process[6–8].

Those with CF have long been known to have increased problems with gastro-esophageal reflux[9–12]. Longstand-ing GERD is associated with Barrett's esophagus and an increased risk of esophageal cancer. Although the incidence of Barrett's in the CF population has not been fully studied, there have been case reports of Barrett's esophagus in CF

[13,14]. It is likely that this marked increase in GERD leads to the increased risk of esophageal neoplasia in CF[1,2](see

Table 1).

The pathophysiology involved in the increased risk of GI malignancies in CF patients is unclear. Since CFTR is expressed in much higher levels along the GI tract than in adult lung epithelial cells and other tissues, a correlation between levels of the mutated CFTR protein and an increased risk of gastrointestinal malignancies has been postulated. Mutations in the CFTR gene may lead to altered expression of other genes including the mucin genes MUC 3, MUC 11 and MUC 12 that are located adjacent to CFTR in the same chromosome band 7q31 [2]. These mucins, which are normally produced and excreted by the epithelial cell surface, serve to protect the GI tract from injury, modulate bacterial and cell adhesion, and mediate wound repair as well as other processes critical in intestinal homeostasis. Altered regulation

of these genes has been noted in colorectal carcinomas[15,16]. Altered mucin expression has been well described in CF with an increased expression of MUC 5 in the lungs of CF patients

[17]and increased MUC 1, 2 and 3 expression by intestinal epithelial cells in a mouse model of CF[18–20]. Interestingly, treatment of bacterial overgrowth in this mouse model of CF markedly reduced mucus, and MUC 2 and 3, production[21]. It has been postulated that altered mucin production (both increases in certain forms as well as decreases in certain MUC) may be involved in the increased risk of GI inflammation and malignancies seen in patients; however clear evidence for this is lacking[2]. Interestingly the tumor markers CA 19-9 and CA 125, which are also mucin-associated antigens, as well as carcinoembryonic antigen (CEA), can be over expressed in CF patients[22,23]. In addition, deficiencies in the omega-3 fatty acid docosahexaenoic acid, selenium and vitamin E in CF patients may also increase the risk as this essential fatty acid and some of these antioxidants have been theorized to protect against cancer[1,2].

Disease states of chronic GI inflammation, such as inflam-matory bowel disease, Celiac disease and Helicobacter pylori gastritis, are associated with an increased risk of GI malig-nancies. Several studies have shown that patients with CF may have ongoing intestinal inflammation affecting both the small and large intestine[24–29]. At present it is unclear if this chronic inflammation is due to pancreatic enzyme re-placement, intestinal damage due to distal intestinal ob-struction syndrome (DIOS), or other factors. Gut bacterial load may also play a part; however, there appears to be intestinal inflammation present prior to increased bacteria counts[24,25]. High dose pancreatic enzyme replacement in children, and more recently in adults, can be associated with intestinal inflammation and in some settings can lead to fibrosing colonopathy and/or strictures in the right colon

[24,25,30,31]. The exact cause of this inflammation is unclear but some have proposed that it may, in part, be due to an impaired intestinal barrier allowing leakage of pancreatic enzymes into the surrounding tissues leading to diffuse tissue injury and inflammation[32].

3.2. Cancer risk in non-CF patients

The cumulative lifetime risk of colon cancer in average risk individuals in North America is about 6% and the risk of colon cancer among first-degree relatives and siblings is increased (SIR 1.47, 2.24, respectively) (seeTable 1)[33]. Clearly some polyp syndromes have a very high risk of developing cancer with some syndromes having an 80 to 100% risk. In Lynch family cancer syndrome/hereditary non-polyposis colorectal cancer (HNPCC) the increased risk re-sults in a SIR of 3.20 for cancers of the colon and rectum[34]

(seeTable 1). Inflammatory bowel disease also increases the risk of developing GI malignancies (ulcerative colitis; SIR 4.1 for CRC[35](a meta-analysis noted a prevalence rate of 3.7% and a cumulative probability of 2% with disease dura-tion up to 10 years to 18% with disease up to 30 years[36])


and Crohn's disease pooled SIR, 2.5 for CRC and pooled SIR 27.1 for small intestinal cancer[37](seeTable 1). Celiac disease has been found to be associated with an increased risk of lymphoma in the small bowel (SIR 40.5) and all GI malignancies (SIR 1.58)[38](seeTable 1).

In two studies assessing the risk of adenocarcinoma of the esophagus in patients with esophagitis, the SIR was 5.38 and 6.0[39,40](seeTable 1). The SIR for adenocarcinoma of the esophagus in Barrett's is 39.1 [40]. Even with these risk factors there is debate over the cost effectiveness of screening Barrett's patients and those with longstanding reflux. At present there are no current guidelines for screening patients with esophagitis.

3.3. Comparing cancer risks in CF and non-CF patients To date there are no clear guidelines if or how patients with CF should be screened with respect to their risk of developing a colorectal or small intestinal malignancy compared to other at risk groups. It is difficult to directly compare different disease states since earlier intestinal cancer studies did not report SIR as did the main CF malignancy studies. Thus, in the CF population with a SIR for the development of esophageal cancer of 5.1 (3.2 to 7.6) (nearly identical to those with esophagitis noted above) it would be appropriate to screen these patients as one would those with known esophagitis. Those with CF have a risk of developing small intestinal cancer that appears to be lower than those with Celiac disease (SIR 40.5) and similar to those with Crohn's disease (CF; SIR = 24.8, versus Crohn's SIR = 27.1). At present there are no guidelines for screening Celiac or Crohn's disease patients for small intestinal malignancies. These guidelines may change with the increased accuracy of, and minimal invasiveness of, capsule endoscopy.

The SIR for CF patients for colon cancer was 7.4 and this is markedly higher than the SIR for a first degree relative of a patient that has colon cancer (SIR 1.47–2.03) and also higher than Lynch/HNPCC syndrome (SIR 3.20), but markedly lower than familial polyposis syndromes and likely lower than UC. The current guidelines for colon cancer screening for those with a genetic or clinical diagnosis of HNPCC or who are at increased risk for HNPCC is that they should have a colonoscopy every 1–2 years beginning at age 20–25 years, or 10 years earlier than the youngest age of colon cancer diagnosis in the family—whichever comes first [41]. It should be noted inTable 1that the risk of GI malignancies increases dramatically in the post lung transplant population (SIR for all digestive cancers, 21.0; small bowel, 143; colon, 30.3 and liver, 76.9) (based on a single report[2]). It should be noted, that although some of the CF cancer risk studies are very large and there are marked increased risks in cancer development outlined inTable 1, these still translate into a small number of cancers. In the largest study to date (Maisonneuve et al.[2]) which followed 28,858 CF patients, 75 cancers were observed (versus 69.7 expected) including 23 digestive tract cancers (versus 4.5 expected) and in the

Neglia et al. study[1]of approximately 53,000 patients 76 developed cancer (24 digestive tract cancers).

Colon cancer screening of those with CF should clearly be considered on an individual basis in that screening ap-proaches have their inherent risks. Routine screening for fecal occult blood is reasonable for those with no added risk other than CF, but due to the false positives inherent with this test it would lead to increased numbers of colonoscopies being performed on these individuals. Sigmoidoscopy and air contrast barium enema are of lower risk but have a higher miss rate than colonoscopy. Stool DNA testing and CT colonography are still in the development stages as far as screening tests, but at some point may well offer lower risk options for these patients.

In summary, we have presented a 39 year old male patient with CF with a family history of colon cancer. Upon screening he was found to have small adenomas in his colon and a large, near obstructing, villous adenoma of his ileum. Upper en-doscopy revealed no further polyps, but he did have a long segment of Barrett's esophagus. Several reports have shown that patients with CF have a markedly increased risk of developing cancers of the esophagus, small bowel and colon which generally develops at younger age and there is often a delay in the diagnosis. Furthermore, the risk appears to drama-tically increase in the post lung transplant population. We feel that this case and evidence in the literature highlights the need to consider screening for GI malignancies in CF patients. References

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