Risk Factors for Ulcerative Colitis-Associated Colorectal Cancer in a Hungarian Cohort of Patients With Ulcerative Colitis: Results of a Population-based Study

Article (PDF Available)inInflammatory Bowel Diseases 12(3):205-11 · April 2006with98 Reads
DOI: 10.1097/01.MIB.0000217770.21261.ce · Source: PubMed
Abstract
There is an increased risk of colorectal cancer (CRC) in ulcerative colitis (UC). The prevalence of UC-associated CRC is different in various geographic regions. The risk depends primarily on the duration and extent of disease. The aim of this study was to identify the risk factors for and the epidemiology of CRC in Hungarian patients with UC. We retrospectively evaluated the relevant epidemiological and clinical data of all patients with UC in Veszprem province in our 30-year IBD database (723 patients with UC; male/female, 380/343; non-CRC related colectomies, 3.7%). CRC was diagnosed in 13 patients (13/8564 person-year duration) during follow-up. Age at diagnosis of CRC was at a median of 51 (range 27-70) years. Eight patients are still alive, 4 died of CRC, and 1 died of an unrelated cause. Longer disease duration, extensive colitis, primary sclerosing cholangitis, and dysplasia found in the biopsy specimen were identified as risk factors for developing CRC. The cumulative risk of developing CRC after a disease duration of 10 years was 0.6% (95% confidence interval [CI] 0.2%-1.0%); 20 years, 5.4% (95% CI 3.7%-7.1%); and 30 years, 7.5% (95% CI 4.8%-10.2%). CRC diagnosed at surveillance colonoscopy was associated with a tendency for longer survival (P = 0.08). The cumulative risk of CRC was high in our patients with UC; however, it was lower compared with that reported in Western European and North American studies. CRC developed approximately 15 years earlier compared with sporadic CRC patients in Hungary. Longer disease duration, extensive colitis, dysplasia, and primary sclerosing cholangitis were identified as important risk factors for developing CRC.
Copyright @ 2006 Crohn’s & Colitis Foundation of America, Inc. Unauthorized reproduction of this article is prohibited.
Risk Factors for Ulcerative ColitisYAssociated
Colorectal Cancer in a Hungarian Cohort of Patients With
Ulcerative Colitis: Results of a Population-b ased Study
Laszlo Lakatos, MD, PhD,* Gabor Mester, MD,* Zsuzsanna Erdelyi, MD,* Gyula David, MD,*
Tunde Pandur, MD,* Mihaly Balogh, MD,
0
Simon Fischer, MD,
1
Peter Vargha, PhD,
1
and Peter Laszlo Lakatos, MD, PhD
1
Background: There is an increased risk of colorectal cancer
(CRC) in ulcerative colitis (UC). The prevalence of UC-associated
CRC is different in various geographic regions. The risk depends
primarily on the duration and extent of disease. The aim of this
study was to identify the risk factors for and the epidemiology of
CRC in Hungarian patients with UC.
Methods: We retrospectively evaluated the relevant epidemiolog-
ical and clinical data of all patients with UC in Veszprem province in
our 30-year IBD database (723 patients with UC; male/female,
380/343; non-CRC related colectomies, 3.7%).
Results: CRC was diagnosed in 13 patients (13/8564 person-year
duration) during follow-up. Age at diagnosis of CRC was at a median
of 51 (range 27Y70) years. Eight patients are still alive, 4 died of CRC,
and 1 died of an unrelated cause. Longer disease duration, extensive
colitis, primary sclerosing cholangitis, and dysplasia found in the
biopsy specimen were identified as risk factors for developing CRC.
The cumulative risk of developing CRC after a disease duration of
10 years was 0.6% (95% confidence interval [CI] 0.2%Y1.0%); 20
years, 5.4% (95% CI 3.7%Y7.1%); and 30 years, 7.5% (95% CI
4.8%Y10.2%). CRC diagnosed at surveillance colonoscopy was
associated with a tendency for longer survival (P =0.08).
Conclusions: The cumulative risk of CRC was high in our
patients with UC; however, it was lower compared with that
reported in Western European and North American studies. CRC
developed approximately 15 years earlier compared with sporadic
CRC patients in Hungary. Longer disease duration, extensive colitis,
dysplasia, and primary sclerosing cholangitis were identified as
important risk factors for developing CRC.
Key Words: inflammatory bowel disease, ulcerative colitis, colo-
rectal cancer, primary sclerosing cholangitis
(Inflamm Bowel Dis 2006;12:205Y211)
S
ince the first report of an inflammatory bowel disea se
(IBD) case associated with colorectal cancer (CRC) by
Crohn and Rosenberg,
1
significant efforts have been made to
elucidate this presumed association. Nowadays, the associa-
tion between IBD and the increased risk of CRC is widely
accepted. Although CRC, complicating ulcerative colitis
(UC) and Crohn_s disease, only accounts for 1% to 2% of
all cases of CRC in the general population, it is considered a
serious complication of the disease and accounts for approx-
imately 10% to 15% of all deaths in patientswith IBD.
2
In UC, an increased risk of CRC was found in most
studies,
3Y7
yet the extent of the risk varied.
8
The first reports
were published by tertiary gastroenterology centers; thus, the
high risk detected may have been a consequence of referral
bias and overinterpretation caused by the high percentage of
extensive and chronically active cases in these cohorts. The
results of population-based studies are more reliable; how-
ever, several geographic and ethnic differences were noted.
From a practical point of view, it is important to reduce
the risk of CRC in patients with IBD. Furthermore, it is
crucial to diagnose and treat precancerous lesions and CRC
early. Previously, preventive colectomy was the method of
choice, whereas presently surveillance colonoscopy,
9Y13
together with biopsy and chemopr eventi on,
14Y16
offers
further valuable possibilities. However, it is important to
define accurately the magnitude of the risk and to identify
risk factors and patients at higher risk.
Recently, Eaden et al
6
published a meta-analysis on the
prevalence and risk factors of UC-associated CRC. The
cumulative incidence of CRC in UC was 2% at 10-year, 8%
at 20-year, and 18% at 30-year follow-up. Recent figures
suggest that the risk of colon cancer for individuals with IBD
increases b y 0.5% to 1.0% annually, 8 to 10 years after the
ORIGINAL ARTICLE
Inflamm Bowel Dis
&
Volume 12, Number 3, March 2006 205
Received for publication August 22, 2005; accepted December 21, 2005.
From the *1st Department of Medicine, Csolnoky F. County Hospital,
Veszprem, Hungary; 0Department of Medicine, Grof Eszterhazy
Hospital, Papa; and 11st Department of Medicine, Semmelweis
University, Budapest, Hungary.
Reprints: Peter Laszlo Lakatos, MD, PhD, 1st Department of Medicine,
Semmelweis University, H1083 Budapest, Koranyi S 2A, Hungary
(e-mail: kislakpet@bel1.sote.hu)
Copyright * 2006 by Lippincott Williams & Wilkins
Copyright @ 2006 Crohn’s & Colitis Foundation of America, Inc. Unauthorized reproduction of this article is prohibited.
diagnosis. The incide nce was higher in the United States and
the United Kingdom as compared with Scandinavian and
other countries. The important risk factors identified were
disease duration, extent, family history of CRC,
17
and
primary sclerosing cholangitis,
18Y20
whereas the role of other
factors (age at onset,
6,21
frequency of flare ups, severity of
inflammation,
22
backwash ileitis,
23
smoking, and medical-
therapy with 5-aminosalicylic preparations) remains ques-
tionable.
24
Studies inves tigating the role of the severity of
inflammation as a risk fa ctor for CRC also revealed
conflicting results. In a recent study, histological activity
was found to be an independent risk factor for developing
CRC in patients with UC.
25
Because there is only a limited amount of data available
on IBD-associated CRC from Eastern Europe,
26
our aim was
to address t he epidemiology and risk factors for IBD-
associated CRC in a population-based study (in Veszprem
province, having a population of 379,329: 192,867 males and
186,462 females). A well-characterized cohort of patients with
UC was studied for >30 years. Because the mean incidence of
sporadic CRC in Hungary (60 to 65/10
5
inhabitants) is one of
the highest in the world, we initially suspected a high
incidence of CRC in the UC population as well.
27
MATERIALS AND METHODS
A well-characterized cohort of 723 unrelated Hungarian
patients with UC (male/female, 380/343; median age, 49
[lower and upper quartiles, 37Y63] years, median age at
presentation 36 [range 27Y40] years) was investigated.
Patients with UC with a diagnosis and with a follow -up time
of at least 1 year were included. Median disease duration was
10 (range 5Y16) years.
IBD patient data were collected every year from the 7
general hospitals and gastroenterology outpatient units
(internal medicine departments, surgery departments, pedia-
tric departments, and outpatient units), each staffed by at least
1 gastroenterologist or internist with a special interest in
gastroenterology and family physicians. The majority of
patients (76% of patients with UC) were monitored in the
Csolnoky F. Province Hospital in Veszprem. This hospital also
serves as a secondary referral center for patients with IB D in
the province. Data collection was prospective since 1985;
before that, data w ere only collected prospectively in
Veszprem. In other sites throu ghout the province, data for
this period (1974Y1985) were collected retrospectively in
1985. Both inpatients and outpatients permanently residing in
the area studied were included in the study. Most patients
were observed regularly. Diagnoses (based on hospitalization
records; outpatient visits; endoscopic, radiological, and
histological evidence) generated in each hospital and out-
patient unit were reviewed thoroughly, using the Lennard-
Jones criteria.
28
The provincial IBD register data were
centralized in Veszprem. The disease phenotype was assessed
by a questionnaire completed by the clinician at the time of
diagnosis and updated yearly, if necessary. A more detailed
description of our data collection method, case ascertain-
ment, and geographic and socio economic background of the
province and the Veszprem Province IBD G roup was
published in reports of our previous epidemiological
studies.
29,30
Moreover, because of Hungarian health authority
regulations, a follow-up visit is obligatory for patients with
IBD at a specialized gastroenterology center every 6 months.
Otherwise, the conditions of the health insurance change and
patients forfeit their ongoing subsidized therapy. Conse-
quently, the relationship between patients with IBD and
specialists is a close one. Age, age at presentation, familia
lIBD, location, contraceptive use, rate of appendectomies,
presence of extraintestinal manifestations (arthritis, peripheral
and axial; ocular mani festations, conjunctivitis, uveitis,
scleritis; skin lesions, erythema nodosum, pyoderma gangre-
nosum; hepatic manifestations, primary sclerosing cholangitis
[PSC]), therapeutic effectiveness (e.g., acetylsalicylic acid
[ASA], steroid and/or immunosuppressiveuse and resistance),
need for surgery (colectomy), colonoscopic surveillance (at
least 2 colonoscopies/5 years after a disease duration of 10
years), and smoking habits were determined (Table 1). PSC
and small-duct PSC were proven by histology and cholan-
giography.
The study was approved by the Semmelweis University
Regional and Institutional Committee of Science and
Research Ethics (194/2004).
Statistical Methods
Variables were tested for normality by the Shapiro-
Wilks W test. The Wilcoxon rank-sum test, 2
2
test, and 2
2
testwith Yates correction and logistic regression were used to
test differences in disease phenotype between subgroups of
patients with Crohn_s disease. Odds ratios (OR) were
calculated. Kaplan-Meier survival analysis was performed
to determine tumor-free survival. A P G 0.05 was considered
significant. Results are expressed as median (lower and upper
quartiles) unless stated otherwise. For the statistical analysis
SPSS13.0 (SPSS, Chicago, Ill) was used with the help of a
statistician (Dr Peter Vargha).
RESULTS
Of the 723 patients (male/female, 380/343), CRC was
diagnosed in 13 patients (male, 6; female, 7) during follow-
up, equaling an incidence rate of 13/8564 person-year
duration (PYD); 0 to 10 years, 3/2242 PYD; 11 to 20 years,
8/3524 PYD; >20 years, 2/2798 PYD).
The overall duration of UC in patients with UC-
associated CRC was a median of 19.0 years (range 16Y28),
significantly longer as compared with patients with UC
without CRC (P G 0.001; Table 1). The median age of
Lakatos et al Inflamm Bowel Dis
&
Volume 12, Number 3, March 2006
206 * 2006 Lippincott Williams & Wilkins
Copyright @ 2006 Crohn’s & Colitis Foundation of America, Inc. Unauthorized reproduction of this article is prohibited.
patients with UC-CR C at the time of CRC diagnosis was
51 years (range 45Y57), almost 15 years younger than the
average observ ed in the sporadic CRC population in Hungary.
The clinical data for the patients with UC-CRC are
summarized in Tables 1 and 2. The location of UC was the
left side in 5 patients and pancolonic in 8. Six patients were
ex-smokers, 7 were non smokers. The family history of IBD
was 5.2% in our patients with UC, whereas no familial
disease was present in the patients with UC-CRC. The data
on the family history of patients with CRC were insufficient
for analysis. 5-ASA (Q1.5 g/day) maintenance therapy was
prescribed for $17% (n = 95) of patients, whereas sulfasa-
lazine (Q2g/day) was prescribed to $58% (n = 462) continu-
ously. Folate supplementation was given to $35% of patients
receiving sulfasalazine (n = 159). Approximately 5% of
the patients (n = 24) received local 5-ASA suppositories
(1.5 g/week) for maintenance and $20% of patients were
taking either 5-ASA or sulfasalazine only for a short period
(1Y2 months) after the diagnosis but not during follow-up.
PSC was present in 5 of 13 patients with UC-CRC, reflecting
an increased risk of CRC in this subgroup of patients. All but
1 of the patients with PSC received ursodeoxycholic acid
therapy.
Six of the patients with UC-CRC participated in regular
surveillance colonoscopy; 7 refused it because of a symptom-
free disease. All of the patients underwent colon surgery,
whereas 2 patients also underwent met astasectomy. The rate
of colectomy in the patients with UC without CRC was 3.7%
(26/710). The stage of CRC was Duke_s A in 2, B in 3, C in
6, and D in 2 patients.
TABLE 1. Clinical Characteristics of Patients With UC, According to the Presence of Colitis-associated CRC.
Total
(N = 723)
Patients With
UC With
CRC (n = 13)
Patients With
UC With No
CRC (n = 710)
Male/female 380/343 6/7 374/336
Age, yr (range) 49 (37Y63) 60 (50Y64) 49 (36Y63)
Age at onset, yr (range) 36 (26Y48) 30 (27Y40) 36 (26Y48)
Duration, yr (range) 10 (5Y16) 19 (16Y28)* 10 (5Y16)*
Family history of IBD, no. (%) 37 (5.1) 0 37 (5.2)
Smoking habits
No, no. (%) 427 (67.1) 7 (53.8) 420 (67.4)
Yes, no. (%) 92 (14.5) 0 92 (14.7)
Previous, no. (%) 117 (18.4) 6 (46.2) 111 (17.9)
Contraceptive use (in female patients), no. (%) 124/301 (41.2) 3/8 (47.5) 121/294 (41.1)
Maximum extent
Proctitis, no. (%) 183 (25.3) 0* 183 (25.7)*
Left-sided, no. (%) 368 (50.9) 5 (38.5) 363 (51.1)
Extensive, no. (%) 172 (23.8) 8 (61.5) 164 (23.2)
Chronic continuous, no. (%) 50 (6.9) 4 (30.8)0 46 (6.5)0
Extraintestinal manifestations
Arthritis, no. (%) 26 (3.6) 1 (7.7) 25 (3.5)
Ocular, no. (%) 22 (3.1) 0 22 (3.1)
Erythema nodosum/pyoderma, no. (%) 16 (2.2) 1 (7.7) 15 (2.1)
PSC, no. (%) 21 (2.9) 5 (38.5)0 16 (2.3)0
Chronic or iron-deficiency anemia, no. (%) 249 (34.4) 10 (76.9)* 239 (33.7)*
Presence of dysplasia in biopsy
specimen before CRC, no. (%)
20 (2.8) 4 (30.8)0 16 (2.3)0
5-ASA/sulfasalazine use1 95/462 2/9 93/453
Steroid use, no. (%) 273 (37.8) 8 (61.5) 265 (37.3)
Azathioprine, no. (%) 37 (5.1) 1 (7.7) 36 (5.1)
Appendectomy, no. (%) 39/614 (6.3) 1/13 (7.7) 38/601 (6.3)
Note: Values are expressed as median (lower and upper quartiles).
*P G 0.01, between patients with UC with and without CRC by Wilcoxon rank-sum test or Yates-corrected 2
2
.
0P G 0.001, between patients with UC with and without CRC by Wilcoxon rank-sum test or Yates-corrected 2
2
.
1Approximately 35% of patients taking sulfasalazine received additional folate supplementation.
Inflamm Bowel Dis
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Volume 12, Number 3, March 2006 Colitis-associated CRC
* 2006 Lippincott Williams & Wilkins
207
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Eight patients are still alive (median survival, 58.5
months [range 34Y92.5]), 4 patients died of CRC (median
survival 6.5 months), 1 died of an unrelated disease 10 years
after the diagnosis of CRC. Figure 1 shows the Kaplan-Meier
survival curve of our patients with UC-CRC. The probability
of 5- and 10-year survival was 68.4% (95% confidence
interval [CI] 55.3%Y81.5%). The 12-year survival was 34.2%
(95% CI 9.1%Y59.3%); the last patient, however, died of an
unrelated cause. Patients receiving surveillance colonoscopy
had a tendency for increased median survival compared with
patients not receiving surveillance colonoscopy (84 months
[range 48Y121]; 4 of 6 patients were alive versus 20 [range
8Y36] months, 4/7 patients were alive, P = 0.08).
The association between possible clinical factors and
the risk of UC-associated CRC is shown in Tables 3 and 4. In
univariate analysis, disease duration, chronic continuous
disease, extensive colitis, the presence of iron deficiency or
chronic anemia, PSC, and the presence of low-grade
dysplasia in the biopsy sample each increased the risk of
developing CRC. PSC and dysplasia were associated with the
highest risk (OR 27.1; 95% CI 7.98Y92.0 and OR 19.3; 95%
CI 5.4Y69.8, respec tively). The association between the risk
of UC-associated CRC and longer disease duration, PSC,
more extensive colitis, and dysplasia was also significant in a
logistic regression model (Table 4). If we included chronic or
iron-deficiency anemia in this model, then PSC and dysplasia
were still significantly associated with an increased risk of
UC-associated CRC.
Figure 2 illustrates the cumulative probability for
developing CRC in patients with UC. The cumulative risk of
developing CRC was 0.6% (95% CI 0.2%Y1.0%) after a
disease duration of 10 years, 5.4% (95% CI 3.7%Y7.1%) after
20 years, 7.5% (95% CI 4.8%Y10.2%) after 30 years, and
12.6% (95% CI 7.0%Y18.2%) after 32 years.
TABLE 2. Clinical Characteristics of Patients With UC-CRC.
No. Gender Smoking
Age at
Onset of
UC, yr
Age at
Diagnosis of
CRC, yr
Duration of
UC at Diagnosis
CRC, yr PSC
Location at
Diagnosis
Colonoscopic
Surveillance
CRC Stage
(Duke_s)
Survival of
Patients Who
Died During
Follow-up(mo)
Survival of
Patients Still
Alive (mo)
1 M No 40 57 17 j P j C V 86
2 M Ex 31 50 19 j P j A V 163
3 M Ex 56 70 14 j L j C V 69
4 F No 30 39 9 j L j C V 48
5 M No 28 55 27 j P j/j D8V
6 F Ex 61 62 1 j P j C V 32
7 F No 26 41 15 + (small duct) L j B V 10
8 F No 27 45 18 + P + B 121 V
9 F No 20 53 33 + P +/j A V 36
10 F Ex 31 51 20 j P+/j C20V
11 M Ex 56 65 9 j L+ B V 99
12 M Ex 29 47 18 +(small duct) P j D5V
13 F No 13 27 14 + L + C 4 V
Note: M, male; F, female; L, left-sided; P, pancolitis; +, regular colonoscopic surveillance; +/j, irregular or occasional colonoscopic surveillance only; j, no colonoscopic surveillance.
FIGURE 1. Survival of patients with UC-CRC (Kaplan-Meier
product moment method).
Lakatos et al Inflamm Bowel Dis
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Volume 12, Number 3, March 2006
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DISCUSSION
In concordance with the findings of several previous
studies,
3,5Y7
we found an increased prevalence of CRC in our
cohort of Hungarian patients with UC; however, the risk was
lower compared with that reported in Western European and
North American studies. In contrast, in a Danish population-
based study,
3
the risk was not different from that of the
general population and the cumulative incidence of CRC was
not elevated in patients with UC. This may be a consequence
of the high number of colectomies in the Danish study.
Colectomy early in the management of UC, before an
appreciable risk of CRC has increased, is likely to prevent
the development of a significant number of cases of CRC,
and this may have contributed to the low incidence of CRC
observed in this study.
The epidemiology and clinical characteristics of IBD
were observed for >30 years in Veszprem province. Some
decades ago, the incidence and prevalence of UC in Hungary
were low; however, the increasing number of patients in the
past few years resulted in incidence and prevalence rates
comparable with those observed in Western Europe and
North America.
29,30
The incidence of CRC in Hungary is one
of the highest reported, according to the data of the National
Cancer Registry and cancer mortality data.
27
Accordingly, the
number of CRC cases in UC patients was expected to be
high.
The cumulative risk of CRC during the follow-up of
the 723 patients with UC after a disease duration of 10 years
was 0.6%, 5.4% after 20 years, and 7.5% after 30 years, with
an overall incidence of 1.52/1000 PYD. This is much lower
compared with the findings of Western European centers or
the meta-analysis by Eaden et al
6
(overall incidence rate was
3/1000 PYD). We must note that the percentage of patients
with non-CRCYrelated colectomies (3.7%) was far below that
reported in Western European countries, which may have
also been associated with a greatly increased risk of CRC.
How can we explain the relatively low number of UC-
associated CRC cases in Hungarian patients?
A possible explanation is that our study was population
based, concurring with other population-based studies, which
found a lower risk of CRC. In contrast, a high incidence of
CRC was reported from tertiary referral centers,
5,6,8
having a
greater number of patients with severe UC. Another
TABLE 3. Association Between Clinical Factors and Risk of
UC-associated CRC (Univariate Analysis).
Factor 2
2
P Value OR (95% CI)
Female gender 0.218 0.641 1.29 (0.43Y3.90)
Familial disease 0.73 0.393 0.98 (0.95Y1.03)
Smoking 1.93 0.17 0.87 (0.78Y1.09)
Contraceptive use in
female patients
0.13 0.83 0.85 (0.20Y3.64)
Disease duration
(>10 yr vs 10 yr)
11.2 0.001 14.3 (1.85Y110.53)
Chronic continuous disease 11.7 0.001 6.4 (1.9Y21.6)
Extensive colitis (left-sided
vs extensive/pancolitis)
10.3 0.001 5.3 (1.7Y16.4)
Location (each location) 11.6 0.003 Not 2 2 table
Iron deficiency or
chronic anemia
11.1 0.001 6.8 (1.86Y25.0)
PSC 59.3 0.0001 27.1 (7.98Y92.0)
Dysplasia in biopsy sample
before CRC
38.6 0.0001 19.3 (5.4Y69.8)
Appendectomy 0.04 0.84 1.23 (0.15Y9.75)
Azathioprine use 0.189 0.66 1.57 (0.19Y12.4)
TABLE 4. Logistic Regression: Association Between Gender,
Disease Duration, Disease Location, Presence of Frequent
Flare-ups, PSC, and the Presence of UC-associated CRC.
Factor Coefficient* P Value OR (95% CI)
Female gender 0.17 0.79 1.18 (0.34Y4.17)
Longer duration
(>10 yr vs 10 yr)
2.12 0.04 8.33 (1.10Y68.9)
Chronic continuous
disease
1.04 0.19 2.82 (0.59Y13.4)
More extensive colitis
(each location)
0.57 0.04 1.76 (1.011Y3.07)
PSC 2.25 0.002 9.50 (2.23Y40.5)
Dysplasia in biopsy
sample before CRC
1.55 0.05 4.72 (1.00Y22.3)
*The coefficient is equivalent to the natural log of the OR.
FIGURE 2. Cumulative risk of developing CRC in patients with
UC according to disease duration (Kaplan-Meier, 1-tumor free
survival).
Inflamm Bowel Dis
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Volume 12, Number 3, March 2006 Colitis-associated CRC
* 2006 Lippincott Williams & Wilkins
209
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explanation may be that most patients received sulfasalazine
or 5-ASA for maintenance treatment. We do not have exact
data on patient compliance, but these drugs may have
reduced the risk of CRC.
14Y16,31
Patients taking sulfasalazine
were also receiving oral folic acid supplementation, which
may have had an additional risk-lowering effect.
32
Disease duration and extent are frequently identified as
risk factors for CRC in patients with IBD. In the present
study, all of the patients with UC except 1 had a disease
duration of at least 9 years at the diagnosis of CRC (median
19.0 years), and the disease duration was identified as an
independent risk factor for CRC in a logistic regression
model in agreement with previous studies.
6,7
There is some debate as to whether patients with an
early onset of colitis have an increased risk compared with
patients with a later onset. In this study, there was a tendency
for the age at onset to be lower in patients with UC who
developed CRC. Ekbom et al
21
identified the age at onset of
G15 years old as an independent r isk facto r for CRC;
however, other studies, including our own, could not confirm
this finding. In contrast, an age at onset >30 years old was
associated with a higher risk in an American study, compared
with a group of pa tients in which the age at onset was G20
years old.
33
In a study investigating the epidemiological data of
>3000 patients with UC, the risk of CRC was 1.9-fold
elevated in proctitis, 2.8-fold elevated in left-sided colitis,
and 14.8-fold elevated in pancolitis, compared with the
general population.
21
In our study, the location of UC in the
13 patients with UC-CRC was more extensive compared with
the patients with UC with no CRC. Furthermore, disease
extent was identified as an independent risk factor for CRC
(OR 1.76 for each location sequentially), confirming results
of previous studies.
6,12
The CRC developed wi thin the
affected region in each patient. The location of CRC was
more proximal compared with the distribution of sporadic
CRC cases in Hungary.
34
Of significance, 3 of the 13 patients
with UC-CRC had multiple tumors, further confirming
previous findings.
35
The median age of patients with UC at
the time of CRC diagnosis was 51 years, 10 to 15 years
younger compared with the sporadic Hungarian CRC cases
(62.2 years).
34
Several studies have recognized PSC as a risk factor for
CRC in patients with UC
18,20,36
; however, this was not proven
in all of the studies.
37
The percentage of right-sided CRCs
was higher in the subgroup of patients with UC with PSC.
36
It has been hypothesized that alterations in the bile salt pool
and a high concentration of bile acids in the colon may be at
least partially responsible for the increased risk. Based on
results from this study, 3 PSC cases and 2 small-duct PSC
cases were diagnosed in patients with UC-CRC, in contrast to
16 PSC cases in patients with UC with no CRC and PSC was
identified as an independent risk factor. The prognosis of the
patients with UC-CR C with PSC also appeared to be worse:
2 patients died shortly after the diagnosis of CRC.
Familial disease was observed in 5.2% of all patients
with UC, yet it was absent in all UC-CRC cases. In addition,
data on the family history of CRC and backwash ileitis were
limited; thus, we could not investigate the effect of these
possible risk factors.
The role of smoking in the development of UC-
associated CRC has been controversial. Nonetheless, it has
been identified as a risk factor for sporadic CRC.
38
In UC, an
additive protective role may be hypothesized because it may
attenuate the inflammation and prevent relapses. In the present
study, we could not identify a significant difference in smoking
habits between patients with UC with and with no CRC.
Colonoscopic surveillance was performed in all com-
pliant patients. Surveillance at 2-year intervals was initiated
in cases of extensive colitis after a disease duration of 8 years
and in left-sided colitis after 15 years. After a disease duration
of 20 years, we decreased the screening interval to 1 year.
From among the 13 patients with UC-CRC, 1 was operated on
because of high-grade dysplasia and only the final histology
confirmed the diagnosis of CRC. Patients receiving surveil-
lance appeared to have less advanced disease (CRC stage:-
Duke_s A, 1; B, 2; C, 3) compared with patients not receiving
surveillance (CRC stage: Duke_s A, 1; B, 1; C, 3; D, 2). The
overall survival of the patients with UC-CRC seems to be
better in comparison with sporadic CRC cases in Hungary.
27,34
It may be assumed that more careful follow-up and the
detection of CRCs at an earlier stage through surveillance are
responsible for this phenomenon.
The use of immunosuppressant drugs is associated with
an increased risk of certain malignancies, especially lympho-
mas.
39,40
In contras t, IBD itself does not appear to be
associated with such an increased risk.
7,41
Several studies
have addressed the association between the risk of lymphoma
and azathioprin e and 6-mercaptopurine treatment in patients
with IBD; however, results are conflicting.
39,41
A recent
meta-analysis
40
has reported a 4-fold elevated risk of
lymphoma in patients with IBD treated with azathioprine or
6-mercaptopurine. In the present study, azathioprine was
prescribed to only 1 UC-CRC patient and to an additional 36
patients with UC with no CRC. Because lymphoma (diffuse
large B cell non-Hodgkin_s lymphoma) only developed in a
patient with proctosigmoiditis receiving only 5-ASA, aza-
thioprine therapy did not seem to be associated with the
reported increased risk. However, our study may have been
under powered to identify the small absolute risk.
In conclusion, the cumulative risk of CRC was high in
our patients with UC; however, it was lower compared with
that reported in Western European and North American
studies. CRC developed $15 years earlier compared with
the sporadic CRC cases. Long disease duration, extensive
colitis, and the presence of iron deficiency or chronic anemia,
Lakatos et al Inflamm Bowel Dis
&
Volume 12, Number 3, March 2006
210 * 2006 Lippincott Williams & Wilkins
Copyright @ 2006 Crohn’s & Colitis Foundation of America, Inc. Unauthorized reproduction of this article is prohibited.
dysplasia, and PSC seem to be important risk factors. CRC
was diagnosed at an earlier stage in patients taking part in
regular surveillance colonoscopy, which may have also
contributed to the tendency of increased survival observed
in these patients.
ACKNOWLEDGMENTS
The authors thank Dr Zsuzsanna Balogh (Papa), Dr
Agnes Horvath (Veszprem), Dr Gyorgy Kamaras (Ajka), Dr
Erzsbet Komaromi (Veszprem), Dr Pal Kuronya (Ajka),
Dr Sandor Meszaros (Ajka), Dr Csa ba Molnar (Ajka), Dr
Istvan Szipocs (Tapolca), and Dr Arpad Tollas (Varpalota) for
help in data collection, and Gabriella Demenyi for technical
assistance.
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Inflamm Bowel Dis
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Volume 12, Number 3, March 2006 Colitis-associated CRC
* 2006 Lippincott Williams & Wilkins
211
    • "Known risk factors associated with adenomatous polyp development include age, smoking, excessive alcohol consumption, obesity, and chronic inflammatory conditions such as inflammatory bowel disease (IBD)456. Consequently, inflammation has long been suspected to be a major environmental risk factor in CRC development789. Other evidence supporting the link between inflammation and CRC development comes from the effect of non-steroidal anti-inflammatory drugs (NSAIDs), particularly aspirin, which has been shown to reduce CRC incidence and disease progression10111213 . More recently, variations in immune cell populations and changes in the gut microbiome have been linked to CRC induction and progression [3,14151617181920. "
    [Show abstract] [Hide abstract] ABSTRACT: Inflammatory cytokines in the colonic microenvironment have been shown to increase with advance colorectal cancer disease state. However, the contribution of inflammatory cytokines to pre-malignant disease, such as the formation of adenomas, is unclear. Using the Milliplex® MAP Human Cytokine/ Chemokine Magnetic Bead Panel Immunoassay, serum cytokine and chemokine profiles were assayed among participants without an adenoma (n = 97) and those with an adenoma (n = 97) enrolled in the NCI-funded Insulin Resistance Atherosclerosis Colon Study. The concentrations of interleukin-10 (IL-10), IL-1β, IL-6, IL-17A, IL-2, IL-4, IL-7, IL-12(p70), interferon-γ (IFN-γ), macrophage chemoattractant protein-1 (MCP-1), regulated on activation, normal T cell expressed and secreted (RANTES), tumor necrosis factor-alpha (TNF-α), vascular endothelial growth factor (VEGF), granulocyte macrophage colony-stimulating factor (GM-CSF), and macrophage inflammatory protein-1β (MIP-1β) were determined. Multiple logistic regression analyses were used to evaluate the association between adenoma prevalence and cytokine levels. The presence of colorectal adenomas was not associated with significant increases in the systemic levels of proinflammatory (TNF-α, IL-6, IL-1β) or T-cell polarizing (IL-12, IL-2, IL-10, IL-4, IL-17, IFN-γ) cytokines. Furthermore, MCP-1 and RANTES levels were equivalent in the serum of study participants with and without adenomas. These findings suggest colorectal adenoma prevalence may not be associated with significant alterations in systemic inflammation.
    Full-text · Article · Dec 2015
    • "The risk factors in the development of advanced neoplasia from dysplastic lesions in the inflamed colon include primary sclerosing cholangitis (PSC), which promotes a change in the bile salt pool and an increased concentration of bile acids in the colon [12]. Lakatos et al. [6] revealed that PSC, together with long disease duration, dysplasia, and severe inflammation are important risk factors for CACRC in UC patients. Jess et al. [9] showed that young age at diagnosis of UC predisposes to CACRC. "
    [Show abstract] [Hide abstract] ABSTRACT: Colitis-associated colorectal cancer (CACRC) constitutes a severe complication of inflammatory bowel diseases (IBD) and occurs in more than one third of IBD patients. In this short review we focus on the mechanisms underlying CACRC pathogenesis, and discuss the approaches for prevention and therapy in CACRC.
    Full-text · Article · Nov 2014
    • "Moreover, experimental and association studies indicate the benefits of suppressing chronic inflammation in reducing the incidence of various types of cancers121314151617. Moreover, the risk of cancer is higher among colitis patients, and chronic bacterial infection by H. pylori is linked to gastric cancer181920212223. Nevertheless, the NF-κB mechanism, which contributes to the initiation and progression of cancer, is activated by anticancer drugs and radiation24252627. "
    [Show abstract] [Hide abstract] ABSTRACT: The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway is activated in cells exposed to various stimuli, including those originating on the cell surface or in the nucleus. Activated NF-κB signaling is thought to enhance cell survival in response to these stimuli, which include chemotherapy and radiation. In the present effort, we determined which anticancer drugs preferentially activate NF-κB in colon cancer cells. NF-κB reporter cells were established and treated with 5-fluorouracil (5-FU, DNA/RNA damaging), oxaliplatin (DNA damaging), camptothecin (CTP, topoisomerase inhibitor), phleomycin (radiomimetic), or erlotinib (EGFR inhibitor). The activation of NF-κB was assessed by immunofluorescence for p65 translocation, luciferase assays, and downstream targets of NF-κB activation (cIAP2, and Bcl-XL) were evaluated by immunoblotting, by ELISA (CXCL8 and IL-6 in culture supernatants), or by gene expression analysis. Colon cancer cells responded variably to different classes of therapeutic agents, and these agents initiated variable responses among different cell types. CPT activated NF-κB in SW480 colon cancer cells in a dose-dependent manner, but not in HCT116 cells that were either wild-type or deficient for p53. In SW480 colon cancer cells, NF-κB activation by CPT was accompanied by secretion of the cytokine CXCL8, but not by up-regulation of the anti-apoptotic genes, cIAP2 or Bcl-XL. On the contrary, treatment of HCT116 cells with CPT resulted in up-regulation of CXCR2, a receptor for CXCL8, without an increase in cytokine levels. In SW480 cells, NF-κB reporter activity, but not cytokine secretion, was inhibited by SM-7368, an NF-κB inhibitor. The results show that, in response to cancer therapeutic agents, NF-κB activation varies with the cellular make up and that drug-induced NF-κB activation may be functionally uncoupled from anti-apoptotic outcomes found for other stimuli. Some cancer cells in a heterogeneous tumor tissue may, under therapeutic pressure, release soluble factors that have paracrine activity on neighboring cells that express the cognate receptors.
    Full-text · Article · Aug 2014
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