Q J Med 2003; 96: 345-353
© 2003 Association of Physicians
Primary small-bowel malignancy in the UK and its association with coeliac disease
From the 1 Academic Unit of Medicine, Clinical Sciences Building, St. James's University Hospital, Leeds, 2 Department of Medicine, Derbyshire Royal Infirmary, Derby, and 3 Section of Cancer Genetics, Institute of Cancer Research, Sutton, UK
Received 17 September 2002 and in revised form 25 February 2003
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Summary |
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Background: Malignancies of the small intestine are rare, accounting for <2% of all cancers of the gastrointestinal tract. There is little information about the presentation and prognosis of these tumours, and the frequency of established risk factors.
Aim: To estimate the frequency of small-bowel malignancy in the UK, and its relationship to the presence of coeliac disease.
Design: Survey of clinicians registered with the British Society of Gastroenterology.
Methods: Data were collected monthly from June 1998 to May 2000. Clinicians (n=1327) were asked by post to report newly diagnosed cases of primary small-bowel malignancy. A form was sent to reporting clinicians, requesting an anonymous identifier, type of malignancy, and whether coeliac disease was present. A detailed questionnaire followed, requesting further clinical and pathological details.
Results: Clinico-pathological data were ascertained for 395 cases, including 175 adenocarcinomas, 107 lymphomas and 79 carcinoid tumours. In 13% of adenocarcinoma cases and in 39% of lymphomas, there was a diagnosis of coeliac disease. Survival rates at 30 months for adenocarcinomas, lymphomas and carcinoid tumours were 58%, 45% and 78%, respectively. Prognosis of all tumours was inversely related to stage at presentation, and lymphomas associated with coeliac disease were associated with a poorer prognosis.
Discussion: This study provides additional evidence that coeliac disease confers susceptibility to adenocarcinoma of the small bowel, as well as lymphoma. The long time from the onset of symptoms to diagnosis of small bowel tumours is of concern, as this delay is reflected in the high proportion that presented with metastatic disease. Although the absolute risk of malignancy is small, coeliac disease complicated by malignancy appears to be poorly controlled.
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Introduction |
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The small intestine constitutes 90% of the mucosal surface area of the gastrointestinal tract, but is the site of <5% of all gastrointestinal malignancies.1 Because of the rarity of small-bowel cancers, most reported series are from individual centres and few population-based studies have been reported.
Small-bowel lymphoma and adenocarcinoma are recognized complications of coeliac disease.2,3 There are several reports of the risk of malignancy from follow-up studies, most from specialist coeliac centres.4–7 Estimates for all cancers range from 3% to 11% and for lymphoma, from 0% to 7%.8–10 The 1983 UK collaborative study collected data on a large number of coeliac patients with malignancy, but was based on selected clinics.11 No study reported to date has examined the incidence of coeliac-associated malignancy in the general population.
It is now accepted that the prevalence of coeliac disease is much greater than previously thought, because the diagnosis of symptomatic cases only represents the tip of the iceberg.12–15 A recent study in England showed a prevalence of undiagnosed coeliac disease of 1.3%.16 Despite the higher prevalence of coeliac disease, a proportional increase in the frequency of associated lymphoma has not been reported. It seems likely that the increasing number of coeliac patients encountered nowadays, who are treated quickly, are at less risk of lymphoma than those who present with classical symptoms.
From a long-term follow-up study of coeliac patients in Derby, it has been estimated that in the coeliac population of the UK, only approximately 28 small-bowel lymphomas would occur each year (Holmes 2002, personal communication). However, the magnitude of the prevalence of coeliac-associated malignancy in Britain has never been established through a national audit. To address this, we have carried out a national survey of the incidence of primary small-bowel malignancy and of the proportion associated with coeliac disease.
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Methods |
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Data collection
A four-step data collection procedure was adopted under the auspices of the British Society of Gastroenterology Research Unit (BSGRU), and data were collected prospectively over a 24-month period (June 1998 to May 2000). A card was posted every month to all UK clinicians registered with the British Society of Gastroenterology (BSG). At the outset of the study there were 1327 clinicians registered, including 663 gastrointestinal surgeons (50%), 559 medical gastroenterologists (42%), 77 gastrointestinal pathologists (6%) and 28 paediatric gastroenterologists (2%). These numbers did not vary significantly during the two years of reporting. The card asked the clinicians to report newly diagnosed cases of primary small-bowel malignancy. Following notification of a case, a preliminary form was sent to the reporting clinician requesting an anonymous identifier, the type of small-bowel malignancy, and whether there was a diagnosis of coeliac disease. A detailed questionnaire was then sent to responding clinicians, requesting further clinical and pathological details. Telephone contact with the clinician was made for prompt return of the questionnaire or to obtain clarification of details. Malignancies diagnosed before June 1998 were excluded from the study.
Derby coeliac clinic
To gauge the accuracy of our national survey, we compared our findings with those seen in the city of Derby, England. Derby has a stable population of 
360 000 adults and a dedicated coeliac clinic. Data on the occurrence of malignancy in coeliac disease patients have been collected over the last 28 years.
Statistical analyses
These were performed using the software program STATA Version 6 (Stata Corporation, [http://www.stata.com]). The association between categorical variables was made using either the Fisher exact test or the 
2 test. For analysis of survival data, Kaplan-Meier curves were constructed and the log-rank test performed. Multivariate analysis was performed using Cox's proportional hazards model. A p value of <0.05 was considered statistically significant.
Tumour staging
Adenocarcinoma and carcinoid tumours were staged according to the TNM clarification.17 Lymphomas were staged using the Ann Arbor Staging System.18
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Results |
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Around 1400 cards (range 1317–1428) were mailed to clinicians each month. On average, 613 were returned each month (44%). Over 24 months, we were notified of 560 probable small-bowel malignancies (on average 23 per month; range 10–36). Of these, 473 (84%) primary small-bowel malignancies were preliminarily confirmed by the reporting consultant, but 78 cases were subsequently excluded due to incorrect diagnosis on histology, duplication in reporting or a diagnosis before June 1998. The remaining 395 cases had a definite diagnosis of small-intestinal malignancy. There were 175 (44%) adenocarcinomas, 107 (27%) lymphomas, 79 (20%) carcinoid tumours and 34 (9%) leiomyosarcoma or stromal cell tumours.
Table 1
shows the number of confirmed cases each year, and also those associated with coeliac disease and inflammatory bowel disease. The detailed questionnaire was sent to clinicians reporting cases of adenocarcinoma, lymphoma or carcinoid tumours, and 288 were returned. These provided data on 134 adenocarcinomas, 86 lymphomas and 68 carcinoids. Data were obtained on 37 of the 42 cases of lymphoma and on 19 of the 23 cases of adenocarcinoma associated with coeliac disease.
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Demographic data
Age at diagnosis was similar in patients with adenocarcinomas, lymphomas and carcinoid tumours (Table 2
). There was no significant sex difference in patients with lymphoma, but there was a male preponderance for adenocarcinomas in coeliac disease (2:1) and among carcinoid tumour cases (3:2). All of the patients reported were White Caucasians, with the exception of three; two with non-coeliac adenocarcinomas were Afro-Caribbeans and one with non-coeliac lymphoma was Oriental.
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Site of occurrence and clinical presentation
Table 2
also shows the sites of the tumours by histology. Overall, 41% of adenocarcinomas were duodenal, 34% jejunal and 25% in the ileum. Adenocarcinomas associated with coeliac disease were more likely to be proximal, 94% compared to 72% (p<0.04). Overall, 10% of lymphomas were duodenal, 50% jejunal and 40% in the ileum. Lymphomas associated with coeliac disease were more likely to be proximal, 80% compared to 45% (p<0.001). The majority of carcinoids were in the ileum (83%).
Laparotomy was required to establish the diagnosis in 66% adenocarcinomas, in 73% and 80% lymphomas with or without coeliac disease, respectively, and in 93% of carcinoid cases.
The mean interval between the onset of symptoms and diagnosis of adenocarcinoma with or without coeliac disease was 14 months (9–25 months). It was 11 months (0–60 months) in lymphoma unrelated to coeliac disease, 7 months (0–26 months) in lymphoma with coeliac disease and 11 months (1–102 months) in carcinoids.
Table 3 shows details of the presenting symptoms. In adenocarcinoma cases, 55% presented acutely, the majority having intestinal obstruction (77%). There was no difference between those with and those without coeliac disease. In lymphoma patients, 48% presented acutely, 49% had obstruction and 37% perforation. Coeliac disease was present in 7/20 with obstruction and 8/15 with perforation, but in none with haemorrhage. In carcinoid patients, 38% presented acutely, almost all with obstruction. Six of these had a history of chronic intestinal symptoms.
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Chronic problems, i.e. anaemia, abdominal pain and weight loss were common in adenocarcinomas with and without coeliac disease. Abdominal pain and weight loss were commonly associated with lymphomas and, to a lesser extent, with carcinoid tumours. An abdominal mass or malabsorption was more common in lymphoma than with the other malignancies. As regards the lymphoma patients, coeliac disease was present in 12/19 with chronic anaemia, in 25/47 with chronic abdominal pain, 30/44 with weight loss, 6/14 with an abdominal mass and 12/14 with evidence of malabsorption.
Past history of malignancy
In adenocarcinoma patients 16 (12%) had a history of another primary malignancy (8 colorectal, 2 uterine, 2 lung, 1 prostate, 1 bladder, 1 pharyngeal and 1 renal). None had associated coeliac disease. In 14 (21%) carcinoid cases, there was a past history of another primary (7 colorectal, 1 prostate, 1 bladder, 2 renal, 1 chronic myeloid leukaemia and 2 Hodgkin's). Two (4%) lymphoma patients without coeliac disease had a past history of another primary (1 breast, 1 colon), and one (3%) with coeliac disease had a past history of breast cancer.
Family history of malignancy
In the adenocarcinoma patients, 13 (10%) had a family history of cancer, including one familial adenomatous polyposis, one hereditary non-polyposis colorectal cancer and four with a first-degree relative with colon cancer. Three (4%) carcinoid patients had a family history of cancer, one colon and two breast in first-degree relatives. A family history of cancer was seen in three (8%) of the lymphoma patients with coeliac disease (one brother with gastric cancer) and in three (6%) of the lymphoma patients without coeliac disease (one colon and one gastric cancer in first-degree relatives).
Metastatic disease
At the time of diagnosis, 40% (54/134) of adenocarcinoma patients, 31% (27/86) lymphoma patients and 54% (37/68) carcinoid patients had metastatic disease.
Histology of coeliac-disease-associated lymphomas
Thirty-three (89%) of the patients with coeliac-associated lymphomas had enteropathy-associated T-cell lymphoma. Two had B-cell lymphomas (5%), one had a T- and B-cell type lymphoma (3%) and one had a mesangiocentric T-cell lymphoma (3%). In contrast the majority (32 cases) of non-coeliac lymphomas were B-cell tumours (65%), the commonest being high-grade diffuse large-cell lymphoma. Three patients had Burkitt's lymphoma.
Coeliac disease, gluten-free diet and lymphoma
Coeliac disease had been diagnosed before lymphoma in 59% (22/37), the mean duration being 7.6 years (range 6 months to 60 years). Compliance with a gluten-free diet (GFD) was reported to be good in all patients, and a good clinical response was achieved in 14, but eight had had a poor clinical response. However, histologically, 16 (73%) had poor mucosal recovery and only three had good improvement of villous architecture. In three patients, repeat biopsy had not been carried out. In the remaining 15 (41%) patients, the coeliac mucosal abnormality was only established at the time of diagnosis of the lymphoma.
Coeliac disease, gluten-free diet and adenocarcinoma
Nineteen patients with adenocarcinoma had coeliac disease, 12 (63%) had been diagnosed with coeliac disease prior to the diagnosis of cancer. The mean time before diagnosis of cancer was 8.2 years (range 10 months to 36 years). Dietary compliance with a GFD was reported to be good in 11, and a good clinical response had been achieved in nine. Seven had had good histological recoveries to a GFD, two a poor response, and in three a follow-up biopsy had not been obtained. There was a good correlation between clinical response and histological response. In the remaining seven (37%) patients, the coeliac mucosal abnormality was only established at the time of diagnosis of the adenocarcinoma.
Comparison with incidence data in the Derby coeliac clinic
In Derby, 665 individuals from a population of 360 000 have been diagnosed with coeliac disease in 28 years (Holmes 2002, personal communication). During this time, five patients developed small-bowel lymphomas and two adenocarcinomas. Using these data, 55 lymphomas and 22 adenocarcinomas would be expected in the UK during the two years of our survey. Given that we ascertained 42 lymphomas and 23 adenocarcinomas, this suggests that the reporting system in our survey generally reflects the national expected incidence rate of small-bowel malignancy associated with coeliac disease.
Treatment
In the majority of adenocarcinoma and carcinoid patients, complete resection was possible, and this is reflected in the survival data. Lymphomas were frequently widespread at presentation, and the majority of patients underwent partial resection and/or chemotherapy.
Survival data
The overall survival associated with adenocarcinomas at 30-months was 58% (95%CI 48–67%). Figure 1 shows that the 30-month survival associated with stage T1–T3 disease was 77% (95%CI 55–94%) compared to 35% (95%CI 21–48%) in cases with T4 disease (p<0.001). There was no evidence that age at diagnosis or presence of coeliac disease was associated with a poorer prognosis.
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The overall survival associated with carcinoid tumours at 30 months was 78% (95%CI 64–88%) (Figure 2
). The only deaths were observed in patients with T4 stage disease, and in this group, survival at 30 months was 71% (95% CI 52–83%). Within this group, younger patients tended to have a more favourable prognosis (p<0.01), 95% in those diagnosed before age 65 (95%CI 68–99%) compared to 50% in those who were older than 65-years at diagnosis (95%CI 68–99%).
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The prognosis associated with lymphoma was poor. Overall, the survival at 30 months was 45% (95%CI 33–56%). However, this largely reflects the fact that most patients had advanced disease, as all deaths were confined to those with stage T4, and 30-month survival was 30% (95%CI 17–44%) in this group. There was a significant difference in survival at 30 months from lymphoma between those with or without coeliac disease (p=0.04). Survival was 52% (95%CI 29–71%) in patients without coeliac disease, but only 13% (95%CI 4–27%) in those with coeliac disease (Figure 3
).
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Discussion |
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This national survey is one of the first such carried out under the auspices of the BSG. There are clearly advantages to ascertaining cases of a rare disease through a central database rather than relying on specialist centres. However, certain disadvantages are inherent, principally under-reporting, particularly of elderly cases, since clinicians managing such individuals may not be routinely registered with the BSG. This presumed under-reporting is supported by comparison with the annual incidence rate of 9.9 per million people predicted by the SEER program in the US.19 Our annual incidence is approximately 5.1 per million people which is, however, of a similar order of magnitude. Nevertheless, the number of tumours reported in our study was similar to that predicted by the data from the Derby Coeliac Clinic, indicating that clinicians tended only to report positive cases.
Our study is the largest survey of small-intestinal malignancies reported to date in one series. The distribution of tumour types is similar to other reports, although our special reference to coeliac disease no doubt encouraged the reporting of lymphomas due to this known association. Table 4 summarizes published reports of various series of small-intestinal malignancies. The variations are presumably due to many factors. Most of the reports are from single institutions over many years, and there will undoubtedly be an inherent case selection bias.
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The ages at presentation in our series, and sites of occurrence, were similar to those in other series.20–24 Coeliac-associated lymphomas were more proximal than those in non-coeliac patients, concordant with other reports21,25,26 and to be expected, given the site of mucosal pathology in coeliac disease. Coeliac disease was associated with lymphoma in 39% and adenocarcinoma in 13% of cases, confirming previous reports.11,27,28 Clinical presentation was also similar to that reported in other series.21,25,29
The length of time from the onset of symptoms to diagnosis, while not unexpected,22,29–31 is of concern, as delay is reflected in the high proportion with metastatic disease.
As expected, most lymphomas associated with coeliac disease were enteropathy-associated T-cell lymphomas (EATL), the entity first described by O'Farrelly and colleagues.32 Non-coeliac-associated lymphomas, as expected, were predominantly B-cell lymphomas.33
Several series have reported that coeliac disease had been diagnosed prior to the presentation of malignancy. In our series, this was the case in 59% of lymphomas and 63% of adenocarcinomas, which is similar to other series.7,11,34 In the lymphoma patients, there was generally a poor mucosal response to a GFD. Although this could have been due to poor dietary compliance, it could also represent the neoplastic process, which is described as progressing from refractory coeliac disease through to T-cell lymphoma.35–38 There is very little information available concerning adenocarcinoma development, mucosal response and gluten withdrawal, but adenocarcinoma appears to develop irrespective of the grade of mucosal damage.
Unfortunately, in the UK there is currently incomplete ascertainment of all cases of small-intestinal malignancy in the cancer registries, and the prevalence of coeliac disease in the general population is not known. Thus an estimate of the risk of malignancy in coeliac disease cannot be accurately computed. Our observation that 13% of small-bowel adenocarcinomas and 39% of small-bowel lymphomas are associated with coeliac disease, implies that the risk of these cancers in coeliac disease is very high. Such increases, however, translate into very small absolute lifetime risks of less than 1% since these tumours are rare and coeliac disease is common.16
Five-year survival figures for adenocarcinomas range from 59%24 to 40–50%39 to 25%40 and 33%.23 Survival rates at 30 months for patients in our series with adenocarcinoma, lymphoma and carcinoid tumours were 58%, 45% and 78%, respectively. For those with lymphoma and coeliac disease, the outlook was particularly poor; only 13% survived for 30 months, compared with 54% for those without coeliac disease. Swinson et al.11 reported a 10% five-year survival for coeliac lymphoma. Gale et al.34 reported survival figures of 39% at one year and 20% at five years for EATL, while Egan et al.7 found an overall one-year survival of 31% and a five-year survival of 11%. Carcinoids have a good prognosis, with 83% five-year survival.40
Compliance with a GFD was reported to be good in all 22 patients with coeliac disease prior to the diagnosis of lymphoma in our survey. Histological assessment, however, did not support this evaluation, for improvement in villous architecture was only demonstrated in three patients. These observations are in keeping with the evidence that those who do not adhere to a strict GFD are more likely to develop lymphoma.41 It is interesting that of 12 patients with coeliac disease diagnosed and treated with a GFD before the development of adenocarcinoma, compliance was said to be good in 11 and of these nine showed a good histological response. It is not known whether taking a strict GFD protects against adenocarcinoma, as is the case for lymphoma, and because this malignancy is so rare, an answer to this question may never be obtained.
Currently, there are no recommendations for screening for small-intestinal malignancy nor specific protocols for the follow-up of patients with coeliac disease. In view of our findings, we would certainly recommend upper gastrointestinal endoscopy with duodenal biopsy and EMA/tTG serology in any patient being investigated for symptoms suggestive of small-bowel disease, in view of the association of coeliac disease with malignancy. In patients with known coeliac disease, particularly in those with a poor mucosal response, there should be a high index of suspicion for small-bowel malignancy, especially of the proximal small intestine. There is no good evidence that particular symptoms distinguish malignant from benign small-intestinal disease. Small-bowel radiology, enteroscopy and CT scanning are suitable investigations. The role of capsule endoscopy has still to be assessed. Laparotomy may ultimately be necessary in difficult cases.
This survey provides evidence that primary small-intestinal tumours are rare in the UK population. The process of data collection, although involving potential methodological problems, has provided a summary of the clinical features of small-bowel malignancies and current practice in the UK. The number of cases reported appears to be of a similar order to that expected in diagnosed coeliac patients, and the marked increase in serological prevalence of coeliac disease has not been reflected by an increase in malignancy. The risk to coeliac patients of developing malignancy is very low.
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Acknowledgments |
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We are grateful to the BSG Research Unit, and in particular Dr S. Mian, for collating the initial notification of these cases. We thank the hundreds of members of the BSG who reported cases and who willingly completed the questionnaires. We are grateful to Mrs E. Tasker for extensive clerical assistance in this project. Financial support was provided from departmental funds.
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Notes |
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Address correspondence to Professor P.D. Howdle, Academic Unit of Medicine, Clinical Sciences Building, St. James's University Hospital, Leeds LS9 7TF. e-mail: P.D.Howdle{at}leeds.ac.uk
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References |
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