The longterm risk of malignancy following a diagnosis

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The long-term risk of malignancy following a diagnosis of coeliac disease or dermatitis herpetiformis: A cohort study Article in Alimentary Pharmacology & Therapeutics · March 2012 DOI: 10.1111/j.1365-2036.2012.04998.x · Source: PubMed

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Nottingham University Hospitals NHS Trust



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Alimentary Pharmacology and Therapeutics

The long-term risk of malignancy following a diagnosis of coeliac disease or dermatitis herpetiformis: a cohort study M. J. Grainge*, J. West*,†, M. Solaymani-Dodaran*,‡, T. R. Card*,† & R. F. A. Logan*,†

*Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK. † NIHR Biomedical Research Unit, Nottingham Digestive Diseases Centre, Queen’s Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK. ‡ Minimally Invasive Surgery Research Centre, Tehran University of Medical Sciences, Tehran, Iran.

Correspondence to: Dr M. J. Grainge, Division of Epidemiology and Public Health, School of Community Health Sciences, University of Nottingham, Clinical Sciences Building 2, Nottingham City Hospital, Hucknall Road, Nottingham, NG5 1PB, UK. E-mail: matthew.grainge@nottingham. ac.uk

Publication data Submitted 14 October 2011 First decision 6 November 2011 Resubmitted 9 December 2011 Accepted 5 January 2012 EV Pub Online 30 January 2012

SUMMARY Background People with coeliac disease are known to be at increased risk of malignancy; however, long-term risks of malignancy beyond 10–15 years are largely unstudied. Aim To estimate how long an increased risk of malignancy among coeliac disease patients persists following diagnosis and treatment, using data from a cohort with an average follow-up of 25 years. Methods People with coeliac disease diagnosed in the Lothian region of Scotland, United Kingdom, were followed up from January 1970 or the date of coeliac disease diagnosis (whichever was later) until the first occurrence of death, emigration, cancer diagnosis or the end of 2004. Standardised incidence ratios were calculated to compare the cancer incidence rates among this group with those from the population of Scotland. Results Overall, the risk of any malignancy in coeliac disease patients compared with the general population was increased 40% [standardised incidence ratio (SIR) = 1.41; 95% CI 1.09–1.78]. An increased risk for cancer overall persisted for up to 15 years, beyond which no overall increase in malignancy risk was observed, although the risk of non-Hodgkin’s lymphoma remained raised beyond 15 years (SIR = 5.15; 95% CI 1.40–13.2). In total, there were 14 non-Hodgkin’s lymphomas in the cohort, providing an overall incidence of 1.3 per 1000 person-years. Conclusions The overall risk of malignancy in coeliac patients declines with time after diagnosis and is not significantly increased after 15 years. Most of the increased risk can be attributed to the development of haematological malignancies, despite their very low absolute rate of occurrence. Aliment Pharmacol Ther 2012; 35: 730–739

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ª 2012 Blackwell Publishing Ltd doi:10.1111/j.1365-2036.2012.04998.x

Malignancy in coeliac disease INTRODUCTION Coeliac disease is an auto immune disorder, which affects approximately 1% of the population of Western countries. Studies have proved beyond doubt that patients with diagnosed coeliac disease have an increased risk of malignancy and in particular of non-Hodgkin’s lymphoma.1–11 The risks of malignancy in long-term follow-up, however, are almost entirely unstudied with cohort studies with beyond 10–15 years of follow-up particularly lacking. Knowledge of these long-term risks would inform current practice guidelines, which, whilst generally advising long-term follow-up of people with coeliac disease, contain specific recommendations, which vary considerably in nature and are seldom evidencebased.12 We are aware of one study, which has previously provided data on malignancy risks over a 10- to 15-year time frame, yet curiously its finding that this risk ceases after prolonged follow-up has received little attention.2 As we believe that the loss of the malignant risk with time after diagnosis is potentially supportive evidence of the effect of gluten-free diet, we feel that this finding is of great importance and have therefore endeavoured to discover whether it is reproducible. MATERIAL AND METHODS Study population Our cohort comprised patients diagnosed with coeliac disease and dermatitis herpetiformis in the Lothian region of Scotland whose population predominantly resides in the City of Edinburgh. The cohort was assembled in 1979, and included new cases diagnosed up until 1983. Cases were identified from multiple sources, including the gastrointestinal units of the Edinburgh Royal Infirmary and Western General Hospital, existing histopathology records, a postal survey of general practitioners in the Lothian region in 1979 and the local branch of the Coeliac Society. Further details on the identification of cohort members can be found elsewhere.13–16 For coeliac disease, all study participants had to have at least one abnormal small bowel biopsy, and two pathologists reviewed all the specimens at the time of recruitment to the study. For a case to be included in the cohort, the findings from the histopathological review had to be typical of coeliac disease. Cases of dermatitis herpetiformis (DH) were identified from the dermatitis herpetiformis clinic of the Edinburgh Royal Infirmary, although case ascertainment may have been incomplete prior to the mid 1970s as a jejunal biopsy Aliment Pharmacol Ther 2012; 35: 730-739 ª 2012 Blackwell Publishing Ltd

was sometimes not performed in cases of dermatitis herpetiformis identified before then.13,14

Follow-up and outcomes Follow-up of study participants commenced on the date of diagnosis of coeliac disease/dermatitis herpetiformis or 1 January 1970, whichever was later. The Information Services Division (ISD), NHS Scotland was responsible for flagging members of the study cohort with the Scottish Cancer Registry. All cancer diagnoses since 1958 in Scotland were obtained from the Scottish Open Cancer Registration and Tumour Enumeration System (SOCRATES). Prior to 1980 details of cancers were obtained directly from SOCRATES. After 1980, details of cancer registrations were obtained from a central prelinked dataset maintained by ISD (Scottish Record Linkage System), where cancer registry data are linked to a number of different sources including hospital discharge records and death registrations. We used ICD codes (versions 9 and 10) assigned at the time of cancer diagnosis to determine site of cancer. For haematological malignancies, death certificates were obtained to help with further classification of the tumours. Patients who had a cancer diagnosed prior to the diagnosis of coeliac disease/dermatitis herpetiformis were also excluded. Follow-up ended at the time of death, emigration from the United Kingdom, first cancer diagnosis or the 31 December 2004, whichever was earliest. Our cohort therefore contained a mixture of retrospective (until 1979) and prospective (from 1979) follow-up. Linkage of cohort with cancer registry data A probability matching algorithm was developed by the ISD, NHS Scotland, to link people in the cohort with cancer registration data. This was necessary because for core items of identifying information used to link the records (surname, initial, year, month and day of birth), there may be a discrepancy rate of up to 5% in pairs of records belonging to the same person. Identifiable variables used for matching where available included first initial (or first name), gender, date of birth, maiden name, postcode, NHS number and hospital case reference number. Using this algorithm, 446 of 653 people (68%) were successfully linked. The percentage of females was similar among those linked compared with those not linked (61% vs. 57%). Also, the groups were comparable with respect to mean age (SD) at coeliac disease diagnosis [27.2 years (24.0) in linked patients compared with 23.5 years (24.0) in nonlinked patients], and median 731

M. J. Grainge et al. (IQR) year of diagnosis [1972 (1967, 1977) vs. 1969 (1963, 1974)]. The mean (SD) duration of follow-up (until either death, emigration or study end) was slightly longer for those who were linked [27.2 (11.9) vs. 23.9 (15.1); t-test, P = 0.004]. Finally, there was no difference in the respective standardised mortality ratios (as we have previously reported16) between patients who were successfully linked and those who were not (SMR = 1.75 vs. SMR = 2.05; test for heterogeneity of SMRs, P = 0.80).

diagnosed after 1970, to assess whether retrospective diagnosis of coeliac disease affected the comparison of results between time periods. We also re-ran analyses including only follow-up from 1980 onwards, the period from which all outcome data were obtained from the Scottish Record Linkage System. On both occasions, these restrictions had a negligible effect on the overall findings; hence, the results presented here are from the entire study sample. All analyses were carried out using Stata v. 11.0.

Statistical analysis We estimated the expected number of cancers occurring among our cohort of coeliac and dermatitis herpetiformis patients, using information on cancer registrations and population data from the whole of Scotland. Cancer incidence rates were calculated stratified by calendar year (from 1970 to 2004), age (5-year bands) and gender and applied to the corresponding person-years of follow-up within our study cohort. Standardised incidence ratios (SIR) were then calculated (observed divided by expected numbers of cancers), along with 95% confidence intervals assuming a Poisson distribution for the observed number of events. SIRs were produced both for cancer overall, and specifically for the following cancer types: all gastro intestinal cancer (ICD10; C15–C26), oesophageal cancer (C15), colorectal cancer (C18–C20), small intestine cancer (C17), breast cancer (C50), lung cancer (C33–C34), all haematological malignancies (C81–C96), Hodgkin’s lymphoma (C81) and non-Hodgkin’s lymphoma (C82–C85). To examine time trends, we divided follow-up into four periods based on time following coeliac disease diagnosis (first year; 1–4; 5–14; and over 15 years). In a sensitivity analysis, we restricted the analysis to patients who were

RESULTS Patient characteristics Our cohort comprised 435 patients with coeliac disease (after exclusion of 11 people with malignancy diagnosed before the diagnosis of coeliac disease) and 84 patients with dermatitis herpetiformis. The earliest diagnosis of coeliac disease was in 1942 and the most recent was in 1983 (median year of diagnosis = 1972). DH patients were diagnosed between 1948 and 1982 (median = 1971). The mean age at baseline of coeliac patients was 26.3 years (SD = 23.7; range 0–81 years) and 39% of the cohort were male (Table 1). DH patients, in contrast, were older on average (mean = 40.2 years, SD = 15.8; range 7–69 years) and more likely to be male (64%). A total of 69 coeliac patients developed cancer in 10 942 person-years of follow-up, whilst among DH patients, there were 27 cancers among 1806 person-years of follow-up (Table 1). Coeliac patients were followed up for a mean 25.2 years (SD = 10.1 years) and DH patients for a mean of 21.5 years (SD = 6.0 years). Among coeliac patients, more than half of all follow-up (5821 person-years) took place more than 15 years after the date of initial diagnosis.

Table 1 | Comparison of people with coeliac disease and dermatitis herpetiformis from Lothian, UK

No. patients No. patients with cancer Mean age at diagnosis (s.d.) Median year of diagnosis (IQR) Mean age at start of follow-up (s.d.) N (%) male Total person-years of follow-up Mean follow-up per person (years) (s.d.) Mean time until cancer diagnosis – years (range) Mean age at cancer diagnosis (range)

Coeliac disease

Dermatitis herpetiformis

435 69 26.3 (23.7) 1972 (1967–1977) 28.5 (23.3) 170 (39.1) 10 942 25.2 (10.1) 15.3 (0.2–54.6) 62.9 (10.5–91.4)

84 27 40.2 (15.8) 1971 (1966–1976) 49.5 (15.0) 54 (64.3) 1806 21.5 (6.0) 25.5 (6.1–50.0) 72.6 (48.8–90.6)

s.d., standard deviation; IQR, inter-quartile range. 732

Aliment Pharmacol Ther 2012; 35: 730-739 ª 2012 Blackwell Publishing Ltd

Malignancy in coeliac disease Overall malignancy risk in coeliac disease and dermatitis herpetiformis Overall, coeliac patients had a significantly raised risk of malignancy compared with the general population, both for all malignancies (SIR = 1.41; 95% CI 1.09–1.78) and after exclusion of nonmelanoma skin cancer (Table 2). For gastrointestinal malignancies specifically, the increase in risk was similar (SIR = 1.62; 95% CI, 0.93–2.63). Although the risk of malignancy was raised for a number of cancer types, only for non-Hodgkin’s lymphoma was this increase in risk statistically significant (SIR = 12.0; 95% CI 6.55–20.1). Patients with dermatitis herpetiformis were found to have a similar risk of malignancy to the

general population for cancer overall (SIR = 0.99; 95% CI, 0.65–1.44), although they were also found to have a significantly raised risk of non-Hodgkin’s lymphoma specifically (SIR = 5.14; 95% CI, 1.05–15.0) (Table 3). Due to the lack of an overall effect and the reduced total amount of follow-up among the DH group, further analyses focused solely on patients with coeliac disease.

Risk of malignancy by time since diagnosis Of the 69 cancers in coeliac patients, four occurred within 1 year of coeliac diagnosis (SIR = 4.70; 95% CI, 1.28–12.0) of which one was a non-Hodgkin’s lymphomas (SIR = 68.1 95% CI, 1.72–380). After exclusion of

Table 2 | Observed and expected numbers of cancers in the Lothian region stratified by cancer type among patients with coeliac disease – all periods (total person-years = 10 942) Observed events

Expected events

Incidence per 1000 p-ys

69 59

49.03 41.80

6.3 5.4

1.41 (1.09–1.78) 1.41 (1.07–1.82)

16 3 6 1 5 6 17 15 1 14

9.87 1.05 5.14 0.09 7.04 7.71 2.92 1.51 0.30 1.17

1.5 0.3 0.5 0.1 0.5 0.5 1.6 1.4 0.1 1.3

1.62 (0.93–2.63) 2.86 (0.59–8.37) 1.17 (0.43–2.54) 11.1 (0.28–61.6) 0.71 (0.23–1.66) 0.78 (0.29–1.69) 5.82 (3.39–9.31) 9.91 (5.54–16.3) 3.37 (0.09–18.8) 12.0 (6.55–20.1)

Any cancer All cancers excluding nonmelanoma skin cancer GI cancer Oesophageal Colorectal Small bowel Breast cancer Lung cancer Lymphoproliferative malignancy All lymphoma Hodgkin’s disease Non-Hodgkin’s lymphoma

SIR (95% CI)

SIR, standardised incidence ratio; p-ys, person-years.

Table 3 | Observed and expected numbers of cancers in the Lothian region stratified by cancer type among patients with dermatitis herpetiformis – all periods (total person-years = 1806)

Any cancer All cancers excluding NMSC GI cancer Oesophageal Colorectal Small bowel Breast cancer Lung cancer Lymphoproliferative malignancy All lymphoma Hodgkin’s disease Non-Hodgkin’s lymphoma

Observed events

Expected events

Incidence per 1000 p-ys

27 25 3 0 2 0 2 8 3 3 0 3

27.30 22.25 5.88 0.67 3.17 0.05 1.40 5.00 1.49 0.67 0.06 0.58

15.0 13.8 1.7 0.0 1.1 0.0 1.1 4.4 1.7 1.7 0.0 1.7

SIR (95% CI) 0.99 (0.65–1.44) 1.12 (0.73–1.66) 0.51 (0.11–1.49) 0.00 (0.00–5.51) 0.62 (0.08–2.22) 0.00 (0.00–80.2) 1.43 (0.17–5.15) 1.60 (0.69–3.15) 2.02 (0.42–5.90 4.50 (0.93–13.2) 0.00 (0.00–61.5) 5.14 (1.06–15.0)

SIR, standardised incidence ratio; NMSC, nonmelanoma skin cancer; p-ys person-years.

Aliment Pharmacol Ther 2012; 35: 730-739 ª 2012 Blackwell Publishing Ltd

733

734

5.15 (1.40–13.2) 0.78 4 23.3 (9.38–48.0) 0.30 NMSC, nonmelanoma skin cancer; SIR, standardised incidence ratio.

7 0.08 2

26.6 (3.22–91.2)

0.92 (0.61–1.33) 0.95 (0.61–1.41) 1.03 (0.38–2.24) 0.65 (0.08–2.34) 0.88 (0.24–2.25) 0.46 (0.06–1.68) 2.17 (0.59–5.56) 30.52 25.35 5.83 3.09 4.55 4.31 1.84 28 24 6 2 4 2 4 2.07 (1.38–2.99) 1.93 (1.22–2.89) 2.38 (0.96–4.91) 2.68 (0.73–6.87) 0.53 (0.01–2.95) 0.84 (0.10–3.02) 10.1 (4.36–19.9) 13.52 11.94 2.94 1.49 1.89 2.40 0.79 28 23 7 4 1 2 8 2.26 (1.03–4.29) 2.23 (0.96–4.39) 3.43 (0.71–10.0) 0.00 (0.00–8.04) 0.00 (0.00–7.12) 1.27 (0.03–7.10) 8.66 (1.05–31.3) 3.98 3.59 0.88 0.46 0.52 0.78 0.23 9 8 3 0 0 1 2

Any cancer All cancers excluding NMSC GI cancer Colorectal Breast cancer Lung cancer Lymphoproliferative malignancy Non-Hodgkin’s lymphoma

SIR (95% CI) Expected Observed SIR (95% CI) Expected

SIR (95% CI)

Expected Observed

15+ years post-diagnosis (total personyears = 5820.5)

Observed

Risk of haematological malignancies in people with coeliac disease Haematological malignancies accounted for 25% of all registered cancers among people with coeliac disease (compared with 6% expected). When we excluded this type of malignancy, the increase in overall risk compared with the general population was no longer significant (SIR = 1.13; 95% CI, 0.84–1.48). Of these 17 lesions, 15 were lymphomas of which all but one were non-Hodgkin’s lymphomas, resulting in an absolute risk of non-Hodgkin’s lymphoma in coeliac patients of 1.3 per 1000 person-years. Details on site of the lymphoma were not available from cancer registry data except for one patient who was diagnosed with a cutaneous T-cell lymphoma in 1995. All of the 14 patients who developed non-Hodgkin’s lymphoma had died by the end of 1996 and there have been no new registrations of non-Hodgkin’s lymphoma since 1995

5–14 years post-diagnosis (total personyears = 3553.4)

Risk of malignancy by age at diagnosis When results were stratified according to age of diagnosis (