ORIGINAL CONTRIBUTIONS

nature publishing group

1869

Cancer Risk in Inflammatory Bowel Disease According

to Patient Phenotype and Treatment: A Danish
Population-Based Cohort Study
Tine Jess, MD, DrSci1, Erzsbet Horvth-Puh, MSc, PhD2, Jan Fallingborg, MD, DrSci3, Henrik H. Rasmussen, MD, PhD3,4 and
Bent A. Jacobsen, MD3
OBJECTIVES:

Population-based studies of site-specific cancer risk in patients with inflammatory bowel disease
(IBD) according to IBD phenotype and treatment are lacking. We studied cancer risk in a
well-characterized population-based IBD cohort from North Jutland County, Denmark.

METHODS:

A total of 1,515 patients were diagnosed with ulcerative colitis (UC) and 810 with Crohns disease
(CD) during 19782002. Patients were followed until 31 December 2010 for occurrence of incident
cancer, identified in the Danish Cancer Registry. Observed numbers of cancer were compared with
expected numbers (based on age- and sex-specific background rates) and presented as standardized
incidence ratios (SIRs) with 95% confidence intervals (CIs).

RESULTS:

Patients with UC were not at increased risk of cancer overall (SIR, 1.12; 95% CI, 0.971.28)
despite increased risk of prostate cancer (SIR, 1.82; 95% CI, 1.172.71). Patients with CD had a
55% increased risk of cancer overall (SIR, 1.55; 95% CI, 1.291.84) related to young age, colonic
disease, smoking, and thiopurine exposure. Patients were at increased risk of small bowel cancer
(SIR, 15.18; 95% CI, 1.8454.78), lung cancer (SIR, 2.13; 95% CI, 1.193.52 (associated with
female gender and smoking)), colorectal cancer in males (SIR, 2.43; 95% CI, 1.054.78), cervical
dysplasia (SIR, 1.65; 95% CI, 1.102.37 (associated with young age at diagnosis, smoking,
5-aminosalicylic acid, and thiopurine exposure)), and non-Hodgkin lymphoma (SIR, 3.43; 95% CI,
1.387.07 (unrelated to thiopurine exposure)).

CONCLUSIONS: Patients with CD, but not UC, have an overall excess risk of cancer. Clinical characteristics of IBD

patients at excess risk differ by cancer subtype.

Am J Gastroenterol 2013; 108:18691876; doi:10.1038/ajg.2013.249; published online 27 August 2013

INTRODUCTION
Inflammatory bowel disease (IBD) may be complicated by intestinal and extra-intestinal cancer (14), potentially because of local
and systemic inflammation (5,6). Risk of cancer in IBD patients
ideally should be studied in population-based cohorts representing a broad and unselected spectrum of disease activity. This
allows risk estimates to be applied to average IBD patients and
can be used to counsel patients.
However, there is a lack of population-based studies that
yields overall estimates of cancer risk and also examines this
risk according to patient phenotype and type of IBD treatment. For these reasons, available population-based results are

difficult to translate into clinical guidelines. Age at diagnosis,

disease extent, and type of treatment vary markedly among
IBD patients and may help to define subsets of patients at
particularly high risk of cancer. Treatment of IBD in Denmark
primarily consists of 5-aminosalicylic acids (5-ASAs), corticosteroids, thiopurines, and tumor necrosis factor- antagonists
(7). In particular, 5-ASA (8,9) and thiopurines (1013) are
thought to decrease or increase the risk for cancer development
in IBD patients.
The aims of this study were to examine a prospectively followed population-based IBD cohort from North Jutland County,
Denmark, in order to investigate both overall risk of cancer and

1
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark; 2Department of Clinical Epidemiology, Aarhus University Hospital,
Aarhus, Denmark; 3Department of Medical Gastroenterology, Aalborg University Hospital, Aalborg, Denmark; 4Faculty of Health, Aalborg University, Aalborg,
Denmark. Correspondence: Tine Jess, MD, DrSci, Department of Epidemiology Research; Statens Serum Institut, National Health Surveillance and Research, 5
Artillerivej, DK-2300 Copenhagen, Denmark. E-mail: tjs@ssi.dk
Received 25 January 2013; accepted 4 June 2013

2013 by the American College of Gastroenterology

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INFLAMMATORY BOWEL DISEASE

see related editorial on page x

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Jess et al.

INFLAMMATORY BOWEL DISEASE

risk of specific cancer subtypes (intestinal and extra-intestinal cancer) according to IBD phenotype and treatment type.

METHODS
Study population

North Jutland County is a rural area with a large urban center,

the city of Aalborg, located in the western part of Denmark. The
regional population encompassed 477,001 inhabitants in 1978
and increased to 495,548 inhabitants in the year 2002 (approximately 9% of the Danish population). All citizens in the region
have free access to medical care at seven public county hospitals.
During the 19782002 period, 1,515 inhabitants (50% women)
were diagnosed with ulcerative colitis (UC) and 811 (57%
women) with Crohns disease (CD; according to strict diagnostic
criteria (14)), representing a population-based inception cohort
of 2,326 IBD patients (14). During the study period, disease
extent at time of diagnosis was determined by ileocolonoscopy,
small bowel X-ray, and/or MR-scan of the small bowel. Capsule
endoscopy was not yet available.
Patient follow-up

After an IBD diagnosis, patients were followed by a gastroenterologist at one of the seven local hospitals with at least annual visits.
Approximately 80% of the patients were seen at Aalborg University Hospital, the main hospital in the region. All patients were
able to consult their gastroenterologist between scheduled visits,
without restrictions. Treatment was carried out according to algorithms agreed upon by the gastroenterologists of North Jutland
County.
During the study period, patients with mild-to-moderate UC
were treated with topical and/or peroral 5-ASA as maintenance
therapy. In cases of treatment failure or severe disease activity, oral
corticosteroids were added. If repeated flares occurred and if more
than two courses of oral corticosteroids per year were needed,
thiopurines were added (primarily azathioprine). Exposure to
these medications is shown in Table 1. Since 2005, tumor necrosis factor- antagonists have been used in patients with otherwise
treatment refractory chronic active UC. When medical treatment
failed, colectomies were performed. The cumulative probability of
colectomy among patients with UC was 5.8%, 10.8%, 14.2%, and
17.7% 1, 5, 10, and 20 years after diagnosis, respectively.
Patients with mild-to-moderate CD also were treated with
5-ASA, especially early in the study period. Since 1999, an increasing number of patients have received tumor necrosis factor-
antagonists instead of oral corticosteroids during flares, especially
for perianal disease. Also, thiopurines and/or tumor necrosis
factor- antagonists have been used as maintenance treatment
in patients with repeated flares and/or perianal disease. Exposure to these medications is shown Table 1. Like UC, surgery was
performed on CD patients when medical treatment failed.

Danish Cancer Registry (DCR), which contains comprehensive,

valid information on all incident cancers diagnosed in Denmark since 1943 (15). Cancers are coded in the DCR according to the International Classification of Diseases, 10th revision
(ICD-10). DCR is continuously updated and all cancer codes
recorded between 1977 and the introduction of ICD-10 in the
1990s have later been converted to ICD-10 codes. We identified all incident cases of cancer occurring among members of
the cohort before or after a diagnosis of IBD. We then excluded
patients with a prior history of cancer (n = 92) or missing personal identification number or born outside Denmark (n = 23),
leaving 1,437 UC patients and 774 CD patients available for
analyses.
Statistical analysis

Patients were followed from date of IBD diagnosis to date of

first cancer diagnosis, emigration (1%), death (21%), or the
end of the study (31 December 2010), whichever occurred first.
Information on vital status was obtained from the Danish Civil
Registration System (16), which has maintained demographic
information, including gender, date of birth, and daily changes
in vital status, for all individuals residing in Denmark since 1968.
Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) for overall and site-specific cancer occurrence were
calculated as a measure of relative risk. The SIRs compared the
number of cases observed in the cohort with expected numbers
based on the entire North Jutland County population. Expected
numbers were estimated using age- and sex-specific incidence
rates of cancer from the background population multiplied by
person-years of follow-up in the study cohort. For estimation of
colorectal cancer risk, person-years of follow-up were censored
at time of proctocolectomy. Ninety-five percent CIs were calculated, assuming a Poisson distribution of observed numbers of
cases. Exact 95% CIs were calculated for SIRs when the number
of observed cases was < 10, and the Byar approximation (Breslow) was used when the number of observed cases exceeded
10. In a sensitivity analysis, we used the Bonferroni correction to adjust for multiple comparisons (new significance level:
100-p/n). Results of this analysis are only shown when turning
insignificant after adjustment. We stratified both overall and sitespecific cancer analyses by sex, age at IBD diagnosis, extent of
disease at diagnosis, smoking status at time of diagnosis (yes/no/
unknown), treatment with 5-ASA (ever/never), and treatment
with thiopurines (ever/never). Analyses were performed using
SAS software 9.2 (SAS Institute, Cary, NC).
Ethics

This registry-based study followed the regulations and instructions established by the Danish Data Protection Agency (record
no. 2008-54-0472).

Cancer follow-up

RESULTS

The unique 10-digit personal identification number provided

to all Danish citizens at birth was used to link the cohort to the

The 1,437 UC patients were followed for 22,582 person-years

(median follow-up time, 15 years; range, 033 years) and the

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Cancer Risk by Phenotype and Treatment of IBD

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Table 1. Demographic and clinical characteristics of the IBD cohort, North Jutland County, Denmark, 19782002

Total

Crohns disease

N (%)

Person-years

N (%)

Person-years

1,437

22,582

774

11,261

Women

707 (49%)

11,373

441 (57%)

6,502

Men

730 (51%)

11,253

333 (43%)

4,771

Age at diagnosis of inflammatory bowel disease

019 Years

153 (11%)

2,865

115 (15%)

1,872

2039 Years

653 (45%)

11,705

363 (47%)

5,997

4049 Years

194 (14%)

3,167

87 (11%)

1,279

5059 Years

162 (11%)

2,360

77 (10%)

992

6069 Years

141 (10%)

1,576

62 (8%)

690

7079 Years

108 (8%)

814

59 (8%)

387

80 + Years

26 (2%)

139

11 (1%)

56

Proctitis

771 (54%)

12,528

Left sided

335 (23%)

5,114

Extensive

277 (19%)

4,110
223 (29%)

3,596

Disease extent at diagnosis

Small bowel
Small bowel and colon

205 (26%)

3,237

Colon

316 (41%)

4,015

Unknown

54 (4%)

874

30 (4%)

425

Yes

473 (33%)

7,076

383 (49%)

5,715

No

586 (41%)

9,815

237 (31%)

3,503

Unknown

378 (26%)

5,735

154 (20%)

2,055

Yes

1,245 (87%)

19,392

584 (75%)

8,592

No

192 (13%)

3,234

190 (25%)

2,681

Yes

257 (18%)

3,962

345 (45%)

5,190

No

1,180 (82%)

18,664

429 (55%)

6,083

Smoking at time of diagnosis

5-ASA ever use

Thiopurines ever use

5-ASA, 5-aminosalicylic acid; IBD, inflammatory bowel disease.

774 CD patients were followed for 11,261 person-years (median,

14 years; range, 033 years). Demographic and clinical characteristics of the cohort are presented in Table 1.
Overall cancer risk

Ulcerative colitis. Among patients with UC, 207 cancers were

observed vs. 185.1 expected (SIR, 1.12; 95% CI, 0.971.28;
Table 2). Estimates were similar for women and men, across
age groups, across categories of disease localization, among
smokers and non-smokers, and among ever users and never users
of 5-ASA and thiopurines (Table 2).
2013 by the American College of Gastroenterology

Crohns disease. Patients with CD were at increased overall risk

of cancer (SIR, 1.55; 95% CI, 1.291.84) with no gender differences (Table 2). The highest risk estimates were observed
among patients diagnosed with CD at a young age, among those
with colonic disease alone or combined small bowel and colonic
disease, among smokers, and among ever users of thiopurines
(Table 2).
Intestinal cancer risk

Ulcerative colitis. Fifteen patients with UC developed colorectal cancer vs. 17.58 expected (SIR, 0.85; 95% CI, 0.481.41;
The American Journal of GASTROENTEROLOGY

INFLAMMATORY BOWEL DISEASE

Ulcerative colitis

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Jess et al.

INFLAMMATORY BOWEL DISEASE

Table 2. Overall SIRs of cancer in patients with ulcerative colitis or Crohns disease, by patient characteristics and treatment, North
Jutland County, Denmark, 19782010
Ulcerative colitis

Total

Crohns disease

Observed, n

Expected, n

SIR (95% CI)

Observed, n

Expected, n

SIR (95% CI)

207

185.12

1.12 (0.971.28)

129

83.29

1.55 (1.291.84)

Women

105

98.31

1.07 (0.871.29)

83

54.55

1.52 (1.211.89)

Men

102

86.81

1.17 (0.961.43)

46

28.73

1.60 (1.172.14)

Age at diagnosis of inflammatory bowel disease

019 Years

7.73

1.16 (0.532.21)

13

6.00

2.17 (1.153.71)

2039 Years

56

53.72

1.04 (0.791.35)

47

26.85

1.75 (1.292.33)

4049 Years

30

27.65

1.08 (0.731.55)

18

10.94

1.65 (0.972.60)

5059 Years

36

35.81

1.01 (0.701.39)

22

13.81

1.59 (1.002.41)

6069 Years

40

34.83

1.15 (0.821.56)

16

14.03

1.14 (0.651.85)

7079 Years

30

21.56

1.39 (0.941.99)

11

9.94

1.11 (0.551.98)

80 + Years

3.81

1.57 (0.583.43)

1.73

1.16 (0.144.18)

Proctitis

38

44.93

0.85 (0.601.16)

Left sided

122

100.96

1.21 (1.001.44)

Extensive

37

32.53

1.14 (0.801.57)
36

28.08

1.28 (0.901.78)

Disease extent at diagnosis

Small bowel
Small bowel and colon

34

18.95

1.79 (1.242.51)

Colon

52

32.62

1.59 (1.192.09)

Unknown

10

6.70

1.49 (0.712.75)

3.64

1.92 (0.773.96)

Yes

77

70.15

1.10 (0.871.37)

79

46.60

1.70 (1.342.11)

No

76

67.01

1.13 (0.891.42)

23

19.94

1.15 (0.731.73)

Unknown

54

47.97

1.13 (0.851.47)

27

16.74

1.61 (1.062.35)

Yes

173

155.99

1.11 (0.951.29)

95

62.78

1.51 (1.221.85)

No

34

29.13

1.17 (0.811.63)

34

20.51

1.66 (1.152.32)

Yes

34

30.54

1.11 (0.771.56)

58

31.39

1.85 (1.402.39)

No

173

154.58

1.12 (0.961.30)

71

51.90

1.37 (1.071.73)

Smoking at time of diagnosis

5-ASA ever use

Thiopurines ever use

5-ASA, 5-aminosalicylic acid; CI, confidence interval; SIR, standardized incidence ratio.
Bold text in this table reflects statistically significant results.

Table 3), with similar risks in females and males (Table 4). The
risk of colorectal cancer was highest in patients diagnosed with
UC at a young age (SIR, 17.09; 95% CI, 0.4395.19) and among
patients with extensive colitis (Table 4). UC patients who were
smokers tended to have a lower risk of colorectal cancer than nonsmokers (Table 4). The risk of colorectal cancer was similar in
users and non-users of 5-ASA and thiopurines (Table 4).
Crohns disease. Twelve patients with CD developed colorectal
cancer vs. 6.99 expected (SIR, 1.72; 95% CI, 0.893.00; Table 5).
The risk was highest in men (SIR, 2.43; 95% CI, 1.054.78) and
The American Journal of GASTROENTEROLOGY

in patients with colonic involvement (Table 4). Also, a tendency

toward higher risk of colorectal cancer was observed in CD
patients who were smokers (Table 4). Age at CD diagnosis
and use of 5-ASA or thiopurines was not associated with risk of
colorectal cancer (Table 4).
Two cases of small bowel cancer were observed vs. 0.13 expected (SIR, 15.18; 95% CI, 1.8454.78; Table 5). One case occurred
in a 70-year-old female with CD restricted to the small bowel,
and the other occurred in a 34-year-old male with combined
small bowel and colonic disease. Both were smokers and had
been treated with 5-ASA and thiopurines (Table 4).
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Cancer Risk by Phenotype and Treatment of IBD

Cancer (ICD-10)
All

Observed, n

Expected, n

Table 4. SIRs of intestinal cancer in patients with inflammatory

bowel disease, by patient characteristics and treatment, North
Jutland County, Denmark, 19782010

SIR (95% CI)

Ulcerative colitis

Crohns disease

Colorectal
cancer SIR
(95% CI)

Colorectal
cancer SIR
(95% CI)

Small bowel
cancer SIR
(95% CI)

1.72 (0.893.00)

15.18 (1.8454.78)

207

185.12

1.12 (0.971.28)

Upper GI (C00C17)

7.46

1.21 (0.552.29)

Colorectal (C18C20)

15

17.28

0.85 (0.481.41)

Total

0.85 (0.481.41)

Liver, bile ducts,

pancreas (C22C25)

5.47

1.65 (0.753.13)

Women

0.82 (0.301.79)

1.08 (0.292.78)

14.52 (0.3780.90)

Men

0.88 (0.401.66)

2.43 (1.054.78)

15.89 (0.4088.49)

Lung (C30C39,
C45)

16

18.22

0.88 (0.501.43)

Malignant melanoma
and other skin
cancer excluding
basal cell carcinoma
(C43C44)

9.15

0.98 (0.451.87)

Breast (C50)

17

16.83

1.01 (0.591.62)

Female organs
(C51C58)

7.92

1.01 (0.441.99)

Cervical dysplasia
including carcinoma
in situ (N87, D06)

19

26.69

0.71 (0.431.11)

Male organs
(C60C63)

25

14.94

1.67 (1.082.47)

Urinary tract
(C64C68)

12

11.09

Lymphoma
(C81C90)

Leukemia (C91C96)

Age at diagnosis of inflammatory bowel disease

019 Years

17.09 (0.4395.19)

2039 Years

1.74 (0.474.46)

1.13 (0.036.28)

41.00 (1.04228.38)

4049 Years

1.20 (0.253.49)

2.12 (0.267.67)

5059 Years

0.50 (0.061.79)

1.91 (0.395.58)

6069 Years

0.41 (0.051.50)

1.56 (0.324.56)

7079 Years

0.93 (0.192.71)

2.13 (0.446.23)

44.69 (1.13248.95)

80 + Years

Disease extent at diagnosis

Proctitis/
small bowel

0.43 (0.051.56)

0.83 (0.103.00)

22.04 (0.56122.76)

0.82 (0.351.62)

3.15 (0.868.08)

41.14 (1.04229.17)

1.08 (0.561.89)

Left-sided/
small bowel
and colon

1.96 (0.724.28)

1.41 (0.612.78)

Extensive/
colon

1.85 (0.604.32)

5.66

Unknown

3.05

1.64 (0.533.82)
Smoking at time of diagnosis

Other (remaining
cancer codes)

55

41.04

1.34 (1.011.74)

CI, confidence interval; ICD-10, International Classification of Diseases, 10th

revision; SIR, standardized incidence ratio.
Bold text in this table reflects statistically significant results.

Extra-intestinal cancer risk

Ulcerative colitis. Among patients with UC, an excess risk of

male genital cancers was observed (SIR, 1.67; 95% CI, 1.082.47;
Bonferroni-adjusted, SIR 1.67; 95% CI, 0.962.70; Table 3),
because of an excess risk of prostate cancer (SIR, 1.82; 95% CI,
1.172.71). Although the risk of male genital cancers was not
related to UC phenotype or smoking habits, a higher risk was
observed among ever users of 5-ASA (SIR, 1.84; 95% CI,
1.162.76) than among never users of this drug (SIR, 0.83; 95%
CI, 0.102.98). Opposite estimates were obtained for users of
thiopurines (SIR, 0.82; 95% CI, 0.102.96) and never users of
thiopurines (SIR, 1.84; 95% CI, 1.172.76).
Crohns disease. In patients with CD (Table 5), the risk of
pulmonary cancer was increased (SIR, 2.13; 95% CI, 1.193.52)
and was associated with female gender (SIR, 3.40; 95% CI,
1.696.08), age 5059 years at CD diagnosis (SIR, 3.83; 95% CI,
1.547.90), CD restricted to the small bowel (SIR, 3.60; 95% CI,
2013 by the American College of Gastroenterology

Yes

0.94 (0.381.94)

1.44 (0.533.14)

24.97 (3.0290.13)

No

1.29 (0.522.66)

0.72 (0.024.01)

Unknown

0.21 (0.011.18)

3.48 (1.138.11)

Yes

0.85 (0.451.46)

1.56 (0.673.08)

21.03 (2.5575.93)

No

0.85 (0.103.06)

2.14 (0.585.48)

5-ASA ever use

Thiopurines ever use

Yes

0.82 (0.102.95)

1.41 (0.294.13)

46.09 (5.58166.40)

No

0.86 (0.461.47)

1.85 (0.853.51)

5-ASA, 5-aminosalicylic acid; CI, confidence interval; SIR, standardized incidence ratio.
Bold text in this table reflects statistically significant results.

1.656.85), smoking (SIR, 3.02; 95% CI, 1.615.16), and ever use
of 5-ASA (SIR, 2.31; 95% CI, 1.194.03).
The risk of cervical dysplasia (including carcinoma in situ) also
was increased (SIR, 1.65; 95% CI, 1.102.37; Bonferroni-adjusted,
SIR, 1.65; 95% CI, 0.992.58; Table 5), and the risk was
particularly high in patients diagnosed with CD at age 019
years (SIR, 2.52; 95% CI, 1.264.51), smokers (SIR, 2.15; 95% CI,
1.273.40), and in patients treated with 5-ASA (SIR, 1.69; 95% CI,
1.082.51) or thiopurines (SIR, 2.47; 95% CI, 1.543.73).
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INFLAMMATORY BOWEL DISEASE

Table 3. SIRs of site-specific cancers in 1,437 patients with

ulcerative colitis, compared with the general population, North
Jutland County, Denmark, 19782010

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Jess et al.

Table 5. SIRs of site-specific cancers in 774 patients with

Crohns disease, compared with the general population, North
Jutland County, Denmark, 19782010
Cancer (ICD-10
code)
All
Upper GI (C00C16)

Observed, n

Expected, n

SIR (95% CI)

129

83.29

1.55 (1.291.84)

2.81

1.78 (0.584.14)

Small intestine (C17)

0.13

15.18 (1.8454.8)

Colorectal (C18C20)

12

6.99

1.72 (0.893.00)

Liver, bile ducts,

pancreas (C22C25)

2.18

0.46 (0.012.56)

Lung (C3039, C45)

15

7.04

2.13 (1.193.52)

Malignant melanoma
and other skin
cancer (excluding
basal cell carcinoma
(C43C44))

4.02

1.74 (0.703.59)

Breast (C50)

13

8.34

1.56 (0.832.66)

Female organs
(C51C58)

4.14

1.21 (0.392.81)

Cervical dysplasia
including carcinoma
in situ (N87, D06)

29

17.61

1.65 (1.102.37)

Male organs
(C60C63)

4.96

0.81 (0.222.06)

Urinary tract
(C64C68)

4.13

1.69 (0.683.49)

Lymphoma
(C81C90)

2.32

3.01 (1.216.19)

Leukemia (C91C96)

1.20

0.83 (0.024.63)

Other (remaining
cancer codes)

21

17.41

1.21 (0.751.84)

CI, confidence interval; ICD-10, International Classification of Diseases, 10th

revision; SIR, standardized incidence ratio.
Bold text in this table reflects statistically significant results.

Finally, we observed an increased risk of lymphoma in patients

with CD (SIR, 3.01; 95% CI, 1.216.19; Bonferroni-adjusted, SIR,
3.01; 95% CI, 0.987.08; Table 5) with no impact from gender or
smoking habits. The risk was particularly high for non-Hodgkin
lymphoma (SIR, 3.43; 95% CI, 1.387.07) and was related to
young age at CD diagnosis (2039 years; SIR, 7.05; 95% CI,
1.4520.58), combined small bowel and colonic disease (SIR,
7.33; 95% CI, 1.5121.41), and never use of 5-ASA (SIR, 9.33;
95% CI, 3.0221.74). Patients exposed to thiopurines (SIR,
2.85; 95% CI, 0.3510.30) were not at higher risk of lymphoma
compared with never users of thiopurines (SIR, 3.73; 95% CI,
1.218.70).

DISCUSSION
The present population-based cohort study, which included
2,211 incident IBD cases, with 33,843 person-years of follow-up,
The American Journal of GASTROENTEROLOGY

from Denmark showed no substantial overall increased risk of

cancer among patients with UC, but a 50% increased risk among
patients with CD. This increased risk was related to young age
at diagnosis, colonic involvement, smoking, and treatment with
thiopurines.
Among patients with UC, the risk of colorectal cancer was
not increased, and no clear protective or harmful effect of
5-ASA or thiopurines was observed. In contrast, male patients
with CD had a twofold increased risk of colorectal cancer,
with no influence from medication use, but a potential effect
from smoking and disease location. CD patients also had a
15-fold increased risk of small bowel cancer. Concerning
extra-intestinal cancers, UC patients had an excess risk of
prostate cancer, whereas CD patients had an increased risk
of pulmonary cancer (related to smoking), cervical dysplasia (related to young age, smoking, 5-ASA, and use of thiopurines), and non-Hodgkin lymphoma (related to young age
but not to use of thiopurines).
The primary strength of the study is its comprehensive
detailed assessment of cancer risk in a contemporary IBD
cohort, accounting for patient characteristics and treatment
with 5-ASA and thiopurines. The study population represents a complete population-based inception cohort carefully
identified during the 1978 2002 period by a limited group
of clinicians (hence assuring uniform recording of data) in
a well-defined geographic area of Denmark; North Jutland
County ( 14 ). Of importance, the region provides free and
easily accessible health care to all citizens, and the completeness of the study is guaranteed by the fact that all patients
were diagnosed in public hospital settings. The two private
gastroenterologists practicing in the area referred all IBD
cases to hospital. In contrast to earlier studies, particularly
on extra-intestinal cancer risk in IBD patients ( 17 20 ), we
were able to define subgroups of patients at excess risk of
specific cancer subtypes. The high quality, completeness, and
validity of the Danish Cancer Register have previously been
described ( 15 ).
Potential limitations apply to the population-based and wellcharacterized cohort setting. Although the sample size was
large enough to allow stratification by patient characteristics
and treatment, power was limited for conducting more detailed
pharmaco-epidemiological analyses. Still, this study provides
a degree of detail typically not available in larger registry
studies. Inclusion of cervical dysplasia as an outcome resulted
in an apparently high incidence of cancer in our study population. However, since focus was on relative risk rather than on
incidence of cancer, inclusion of an additional outcome should
not influence results.
Our finding of an increased risk of cancer in CD patients
but not in UC patients accords with an earlier Canadian
study ( 17 ). In contrast, a recent cross-European study with
15 years of follow-up suggested no overall increased risk of
cancer among patients with IBD ( 21 ) and a recent review
of the burden of IBD in Europe also suggested that the risk
of cancer in IBD is of limited magnitude ( 22 ). Our study
VOLUME 108 | DECEMBER 2013 www.amjgastro.com

was able to show that the increased risk of cancer among

CD patients was associated with young age at diagnosis
(potentially because of left truncation), colonic involvement,
smoking, and treatment with thiopurines. Smoking is known
to cause cancer and in a recent nationwide Danish study
thiopurines have been shown to increase the overall cancer
risk in IBD patients ( 23 ).
The risk of colorectal cancer was not elevated among
patients with UC in this study. This is in agreement with a
recent nationwide Danish study (24), but contrasts with a
recent meta-analysis of eight population-based studies that
reported a pooled SIR of 2.4 (95% CI: 2.12.7) (3). However,
this estimate was based on relatively old cohorts with low
absolute numbers, with cumulative incidence of colorectal
cancer of < 1% at 10 years, 0.42.0% at 15 years, and 1.12.5%
at 20 years (in studies with sufficiently long follow-up) (3).
The lack of an association between UC and colorectal cancer
in the present population may partly be explained by a colectomy rate of 18% at 20 years, although this is not particularly
high. Also, we cannot exclude an increased risk of colorectal
cancer in patients diagnosed at young age, although this did
not reach statistical significance. In contrast, we observed a
twofold increased risk of colorectal cancer in men with CD,
but not in women. This is in accordance with a recent study
from Hungary reporting no overall increased risk of colorectal
cancer in CD but a tendency toward increased risk in men
(SIR: 1.95, 95% CI: 0.814.70) (25). A meta-analysis of population-based studies from the same time period also showed
an almost twofold increased risk of colorectal cancer among
CD patients (4). We observed no protective effect of 5-ASA
or thiopurines on risk of colorectal cancer, which accords
with recent studies of 5-ASA (9,26) and some (23), but not
all, studies of thiopurines (11). Our observation of a 15-fold
increased relative risk of small bowel cancer, but a low absolute risk, corresponds well with previous observations (4).
A meta-analysis from 2010 focusing on extra-intestinal
malignancies in eight population-based IBD cohorts revealed
that the overall risk of extra-intestinal cancer was not increased
(SIR, 1.10; 95% CI, 0.961.27) (2). However, in site-specific
analyses, UC patients were found to be at increased risk of
leukemia and liver-biliary cancer, but at decreased risk of pulmonary cancer. CD patients were at increased risk of cancer of
the upper gastrointestinal tract, lung, skin, and urinary tract
(2). In this study, we could not confirm an increased risk of
leukemia or liver-biliary cancer in UC patients, but did find
an increased risk of prostate cancer. Whether a causal relation exists is uncertain, as this finding could reflect enhanced
screening in this patient group, including rectal examination.
This speculation is somewhat supported by the observed association with 5-ASA treatment, if this treatment is considered a
proxy for close follow-up and regular examination of patients.
Among patients with CD, we found an increased risk of
pulmonary cancer, likely explained by smoking habits. This

2013 by the American College of Gastroenterology

observation is in accordance with the former meta-analysis

of all population-based studies on extra-intestinal cancer
in IBD ( 2 ). Patients were also at increased risk of cervical
dysplasia (including carcinoma in situ ) related to young age,
smoking, and use of 5-ASA and thiopurines. The relation
between IBD and human papilloma virus-related cervical
dysplasia and the impact of especially immunosuppressive
therapy on this risk is still debated ( 27,28 ). Also, investigation into the impact of detection bias through enhanced
screening is needed.
Finally, we observed an increased risk of non-Hodgkin
lymphoma among patients with CD, a risk not related to
treatment with thiopurines. A number of studies have
suggested an increased risk of lymphoma in IBD patients
treated with thiopurines compared with unexposed IBD
patients ( 13,23,29 ). However, not all of these studies
accounted for likelihood of receiving treatment. Our study s
findings add to the ongoing discussion of ways of differentiating between baseline and treatment-induced cancer risk
in IBD patients ( 30 ).
In conclusion, this population-based cohort study with
long-term follow-up of 2,211 well-characterized IBD patients
showed that the overall risk of cancer was increased in CD
patients, but not in UC patients. However, the risk of certain subtypes of cancer was significantly higher than in the
general population. The association between cancer risk and
patient characteristics, smoking, and exposure to medical
treatment differed by cancer subtype. Of note, the increased
risk of lymphoma in CD patients was not related to thiopurine exposure.

ACKNOWLEDGMENTS

We thank Professor Dr Henrik Toft Srensen for his valuable

input to the study design and for his useful comments on the
manuscript.

CONFLICT OF INTEREST

Guarantor of the article: Tine Jess, MD, DrSci.

Specific author contributions: The study was conceived and
designed by T.J., E.H.P., and B.A.J. Data were collected by
B.A.J., J.F., and H.H.R. Statistical analyses were performed by
E.H.P. All authors were involved in the interpretation of data.
T.J. drafted the manuscript, which was critically revised by
all authors, who also approved the final version of the
manuscript.
Financial support: Tine Jess is supported by a Female
Research Leader grant (no. 09-066323) from the Danish Council
of Independent Research and by the Danish Cancer Society
(grant no. R40-A1737-11-S2). The funding sources had no role
in this study.
Potential competing interests: None.

The American Journal of GASTROENTEROLOGY

1875

INFLAMMATORY BOWEL DISEASE

Cancer Risk by Phenotype and Treatment of IBD

1876

Jess et al.

Study Highlights

INFLAMMATORY BOWEL DISEASE

WHAT IS CURRENT KNOWLEDGE

3According to older population-based studies, patients with

inflammatory bowel disease (IBD) may be at increased risk
of both intestinal and extra-intestinal cancer.

3Updated population-based cohort studies of cancer risk in

patients with IBD overall and according to clinical characteristics are lacking.

WHAT IS NEW HERE

3This population-based study following IBD patients until

year 2010 showed no excess overall risk of cancer in UC,
despite increased risk of prostate cancer.

3Patients with CD had a 55% increased overall risk of cancer

related to young age at diagnosis, colonic disease, smoking, and exposure to thiopurines.

3In particular, CD patients were at excess risk of lung cancer

(in females and smokers), colorectal cancer (in males), cervical dysplasia (in young females, smokers, and 5-ASA and
thiopurine users), and non-Hodgkin lymphoma (not related
to thiopurine exposure).

3The study provides initial evidence of the possibility for

clinical characterization of IBD patients at particular risk

of cancer.

REFERENCES
1. Herrinton LJ, Liu L, Levin TR et al. Incidence and mortality of colorectal
adenocarcinoma in persons with inflammatory bowel disease from 1998 to
2010. Gastroenterology 2012;143:3829.
2. Pedersen N, Duricova D, Elkjaer M et al. Risk of extra-intestinal cancer
in inflammatory bowel disease: meta-analysis of population-based cohort
studies. Am J Gastroenterol 2010;105:14807.
3. Jess T, Rungoe C, Peyrin-Biroulet L. Risk of colorectal cancer in patients
with ulcerative colitis: a meta-analysis of population-based cohort studies.
Clin Gastroenterol Hepatol 2012;10:63945.
4. Jess T, Gamborg M, Matzen P et al. Increased risk of intestinal cancer in
Crohns disease: a meta-analysis of population-based cohort studies.
Am J Gastroenterol 2005;100:27249.
5. Ullman TA, Itzkowitz SH. Intestinal inflammation and cancer. Gastroenterology 2011;140:180716.
6. Hotamisligil GS. Inflammation and metabolic disorders. Nature
2006;444:8607.
7. Jess T, Riis L, Vind I et al. Changes in clinical characteristics, course, and
prognosis of inflammatory bowel disease during the last 5 decades: a
population-based study from Copenhagen, Denmark. Inflamm Bowel Dis
2007;13:4819.
8. Velayos FS, Terdiman JP, Walsh JM. Effect of 5-aminosalicylate use on
colorectal cancer and dysplasia risk: a systematic review and metaanalysis
of observational studies. Am J Gastroenterol 2005;100:134553.

The American Journal of GASTROENTEROLOGY

9. Nguyen GC, Gulamhusein A, Bernstein CN. 5-Aminosalicylic acid is

not protective against colorectal cancer in inflammatory bowel disease:
a meta-analysis of non-referral populations. Am J Gastroenterol 2012;107:
1298304.
10. Singh H, Nugent Z, Demers AA et al. Increased risk of nonmelanoma skin
cancers among individuals with inflammatory bowel disease. Gastroenterology 2011;141:161220.
11. van Schaik FD, van Oijen MG, Smeets HM et al. Thiopurines prevent
advanced colorectal neoplasia in patients with inflammatory bowel disease.
Gut 2012;61:23540.
12. Peyrin-Biroulet L, Khosrotehrani K, Carrat F et al. Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease. Gastroenterology 2011;141:16218.
13. Beaugerie L, Brousse N, Bouvier AM et al. Lymphoproliferative disorders in
patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study. Lancet 2009;374:161725.
14. Jacobsen BA, Fallingborg J, Rasmussen HH et al. Increase in incidence and
prevalence of inflammatory bowel disease in northern Denmark: a population-based study, 19782002. Eur J Gastroenterol Hepatol 2006;18:6016.
15. Storm HH, Michelsen EV, Clemmensen IH et al. The Danish Cancer Registryhistory, content, quality and use. Dan Med Bull 1997;44:5359.
16. Pedersen CB, Gotzsche H, Moller JO et al. The Danish Civil Registration
System. A cohort of eight million persons. Dan Med Bull 2006;53:4419.
17. Bernstein CN, Blanchard JF, Kliewer E et al. Cancer risk in patients with
inflammatory bowel disease: a population-based study. Cancer 2001;91:
85462.
18. Jess T, Winther KV, Munkholm P et al. Intestinal and extra-intestinal
cancer in Crohns disease: follow-up of a population-based cohort in
Copenhagen County, Denmark. Aliment Pharmacol Ther 2004;19:28793.
19. Ekbom A, Helmick C, Zack M et al. Extracolonic malignancies in
inflammatory bowel disease. Cancer 1991;67:20159.
20. Persson PG, Karlen P, Bernell O et al. Crohns disease and cancer:
a population-based cohort study. Gastroenterology 1994;107:16759.
21. Katsanos KH, Tatsioni A, Pedersen N et al. Cancer in inflammatory
bowel disease 15 years after diagnosis in a population-based European
Collaborative follow-up study. J Crohns Colitis 2011;5:43042.
22. Burisch J, Jess T, Martinato M et al. The burden of inflammatory bowel
disease in Europe. J Crohns Colitis 2013;7:32237.
23. Pasternak B, Svanstrom H, Schmiegelow K et al. Use of azathioprine
and the risk of cancer in inflammatory bowel disease. Am J Epidemiol
2013;177:1296305.
24. Jess T, Simonsen J, Jorgensen KT et al. Decreasing risk of colorectal cancer
in patients with inflammatory bowel disease over 30 years. Gastroenterology 2012;143:37581.
25. Lakatos PL, David G, Pandur T et al. Risk of colorectal cancer and small
bowel adenocarcinoma in Crohns disease: a population-based study from
western Hungary 19772008. J Crohns Colitis 2011;5:1228.
26. Bernstein CN, Nugent Z, Blanchard JF. 5-Aminosalicylate is not chemoprophylactic for colorectal cancer in IBD: a population based study.
Am J Gastroenterol 2011;106:7316.
27. Mahadevan U. Cervical neoplasia risk in IBD: truth or hysteria? Inflamm
Bowel Dis 2009;15:161920.
28. Beaugerie L. Immunosuppression-related lymphomas and cancers in IBD:
how can they be prevented? Dig Dis 2012;30:4159.
29. Armstrong RG, West J, Card TR. Risk of cancer in inflammatory bowel disease treated with azathioprine: a UK population-based case-control study.
Am J Gastroenterol 2010;105:16049.
30. Jess T. Thiopurines for inflammatory bowel disease: time to engage with
dermatologists? Gastroenterology 2011;141:154951.

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