384 Original article
Liver cirrhosis, other liver diseases, pancreatitis and
subsequent cancer: record linkage study
Michael J. Goldacrea, Clare J. Wottona, David Yeatesa, Valerie Seagroatta
and Jane Collierb
Objective To determine the risk of cancer in cohorts of
patients with alcoholic cirrhosis, other alcoholic liver
diseases, other and unspecified cirrhosis, primary biliary
cirrhosis, viral hepatitis, acute pancreatitis and chronic
pancreatitis compared with the risk in a control cohort.
Methods Analysis of statistical database of linked hospital
and mortality data in an area in southern England.
Results Compared with the control cohort, rate ratios
c 2008 Wolters Kluwer Health |
were elevated for cancer overall and were particularly high
for liver cancer in patients with alcoholic cirrhosis (rate
ratio for cancer overall 2.4, 95% confidence interval 2.0–3.0
and 27.8, 17.7–41.7 for liver cancer); with other and
unspecified cirrhosis (3.1, 2.7–3.6 and 35.1, 25.4–47.6); with
other alcoholic liver diseases (2.3, 2.0–2.7 and 17.7,
11.5–26.0); with primary biliary cirrhosis (1.4, 0.9–2.0 and
19.6, 8.4–39.1) and with viral hepatitis (1.5, 1.2–1.9 and
18.6, 9.8–32.2). Pancreatic cancer risk was significantly and
substantially elevated in all cohorts except that with
primary biliary cirrhosis. Lung cancer risk was significantly
high in all cohorts except those with primary biliary
cirrhosis and viral hepatitis. Oral cavity cancers were
elevated in alcoholic cirrhosis cohort (8.6; 3.1–18.9) and the
Introduction
High risks of liver cancer in people with alcoholic liver
disease, cirrhosis after hepatitis B and C infections and
primary biliary cirrhosis are well documented [1–4]. It is
less clear whether people with these hepatic conditions
have an altered risk for other types of cancer. For
example, a link between primary biliary cirrhosis and
breast cancer has been suggested [5,6], but more recent
studies have not confirmed this [1–3,7,8]. It is well
documented that chronic pancreatitis is associated with
an increased risk of pancreatic cancer [9–12], but little is
known about the risk (if any) of other cancers in people
with pancreatitis. We have used population-based data
from a health region in southern England to study the
occurrence of cancer in people with alcoholic cirrhosis,
other alcoholic liver diseases, other and unspecified
cirrhosis, primary biliary cirrhosis, viral hepatitis, acute
pancreatitis and chronic pancreatitis.
Methods
Population and data
We used data from the Oxford record linkage study
(ORLS). The ORLS includes brief statistical abstracts of
0954-691X
c 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
other alcoholic liver diseases cohort (10.1; 5.9–16.2), as
was colon cancer (2.8; 1.4–5.0 and 2.0; 1.2–3.3,
respectively). Non-Hodgkin’s lymphoma was significantly
elevated in the group of ‘other and unspecified cirrhosis’
(11.4; 7.2–17.3).
Conclusion All seven conditions carry an increased risk of
cancer, but each condition has a somewhat different profile
of cancer risk associated with it. Eur J Gastroenterol
Hepatol 20:384–392
Lippincott Williams & Wilkins.
European Journal of Gastroenterology & Hepatology 2008, 20:384–392
Keywords: acute pancreatitis, cancer, chronic pancreatitis, cirrhosis,
liver disease, record linkage
a
Unit of Health-Care Epidemiology, Department of Public Health, University of
Oxford and bJohn Radcliffe Hospital, Headington, Oxford, UK
Correspondence to Professor Michael J. Goldacre, BM, BCh, FFPHM, Unit of
Health-Care Epidemiology, Department of Public Health, University of Oxford,
Old Road Campus, Old Road, Headington, Oxford OX3 7LF, UK
Tel: + 44 01865 289377; fax: + 44 01865 289379;
e-mail: michael.goldacre@dphpc.ox.ac.uk
Received 4 May 2007 Accepted 8 November 2007
records of all hospital admissions, including hospital day
cases, in National Health Service (NHS) hospitals, and
all deaths regardless of where they occurred, in defined
populations within the former Oxford NHS Region from
January 1963 to March 1999 [13–17]. The hospital data
were collected routinely in the NHS as the Oxford
Regional Health Authority’s hospital discharge statistics.
The death data were derived from death certificates.
Data collection covered parts of one health district from
1963 (population 350 000), two districts from 1966
(population 850 000), six districts from 1975 (population
1.9 million) and all eight districts of the region from 1987
(population 2.5 million). With the agreement of the
Region’s Data Protection Steering Group, the data for
each individual were linked together routinely, as records
accrued, as part of the region’s health information system.
The data are now anonymized and archived. The current
programme of analysis of the data has been approved by
the English NHS Central Office for Research Ethics
Committees (reference number 04/Q2006/176).
The seven exposure cohorts were constructed by
identifying the statistical records of people who had

been admitted to NHS hospitals for each of these
conditions: alcoholic cirrhosis [571.2 in ICD9 (the
International Classification of Diseases, ninth revision)
and K703 in ICD10]; other alcoholic liver diseases (571.0,
571.1 and 571.3 in ICD9 and K70–K70.2, K70.4 and K70.9
in ICD10); other and unspecified cirrhosis (571.5, 571.8,
571.9 in ICD9 and K74.6 in ICD10); primary biliary
cirrhosis (571.6 in ICD9 and K74.3 in ICD10); viral
hepatitis (092 in ICD7, 070 in ICD8, 070 in ICD9 and
B15-B19 in ICD10); acute pancreatitis (587.0 in ICD7,
577.0 in ICD8, 577.0 in ICD9 and K85 in ICD10) and
chronic pancreatitis (587.1 in ICD7, 577.1 in ICD8, 577.1
in ICD9 and K86.1, K86.2 in ICD10). The analysis for
alcoholic cirrhosis, other alcoholic liver diseases, other
and unspecified cirrhosis and primary biliary cirrhosis was
confined to people admitted to hospital from 1979,
because earlier editions of the coding system did not
distinguish between these different groups of liver
diseases. The analysis for viral hepatitis, acute pancrea-
titis and chronic pancreatitis included patients admitted
from 1963. A reference cohort was constructed similarly
by selecting statistical records of admission for various
other medical and surgical conditions (see footnote,
Table 2). This is on the basis of our ‘reference’ group of
conditions that has been used in other studies on
associations between nonmalignant and malignant condi-
tions [13–17]. We followed the standard epidemiological
practice, when hospital controls are used, of selecting a
diverse range of conditions, rather than relying on a
narrow range (in case the latter are themselves atypical in
their risk of subsequent disease). As a check, we have
studied the risk of cancer in each of the control
conditions within the reference cohort, individually, to
ensure that the reference cohort does not include control
conditions that have atypically high or low cancer rates.
We searched the database for any subsequent NHS
hospital care for, or death from, each cancer in each of
these cohorts. We then repeated the analysis of each
patient group for the next cancer in the list. In this way,
each pair of associations – each exposure disease and each
individual cancer – was studied independently of every
other pair. We considered that rates of cancer in the
reference cohort would approximate to those in the
general population of the region while allowing for
migration in and out of it (data on migration of individuals
were not available). We excluded from the analysis all
people in the exposure and reference cohorts who had a
record of cancer before or at the time of admission for the
exposure or reference condition.
We analyzed the data with and without cancers that
occurred within a year after first admission for the
exposure and reference conditions. We did this to assess
whether associations that were close in time, and that
may have resulted from misdiagnosis of one disease for
the other, had any effect on the results.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Liver disease, pancreatitis and cancer Goldacre et al. 385
Statistical methods
We calculated rates of each cancer based on person-years
at risk. We took date of entry into each cohort as date of
first admission for the exposure condition or the
reference condition and we took the date of exit for
each individual disease as the date of subsequent
admission for the cancer (if it occurred), death, or 31
March 1999 whichever was the earliest.
In comparing the cohorts, we first calculated rates
of subsequent cancer, standardized by age at entry
(in 5-year age groups), sex, calendar year of first recorded
admission, interval from study entry and district of
residence, taking the combined exposure and reference
cohorts as the standard population. We applied the
stratum-specific rates from the standard population to
the exposure cohort and to the reference cohort to obtain
standardized rates for each cohort.
We then calculated the rate ratio of the standardized rate
of each cancer in the exposure cohort relative to the rate
in the reference cohort, and the 95% confidence interval
for the rate ratio using the methods of Breslow and Day
[18]. In the reference cohort, we included all the people
in the database with the comparison conditions in each
age group. We did this to maximize the numbers in each
stratum in the reference cohort and thereby to maximize
the statistical power of the study. Our purpose in
standardizing for age, year of admission and district of
residence was to ensure that the exposure cohorts and
the reference cohort were equivalent in these respects. In
the text, we give figures for rate ratios and their 95%
confidence intervals at one decimal place except that
where findings were of borderline significance we show
two decimal places.
Results
Table 1 shows the age distribution of the patients in the
exposure cohorts and the reference cohort at the time of
first recorded admission. It also shows the sex distribu-
tion, for example, two-thirds of the people with alcoholic
cirrhosis and of other alcoholic liver diseases were men
compared with only 20% of the people with biliary
cirrhosis.
Alcoholic cirrhosis (Tables 2 and 3)
A significant two-fold elevation of the risk of cancer,
overall, was observed in people admitted to hospital with
alcoholic cirrhosis (rate ratio 2.4, 95% confidence interval
2.0–3.0). After exclusion of cases of cancer that occurred
within a year of the first recorded admission for alcoholic
cirrhosis, the rate ratio dropped very slightly to 2.3
(1.8–2.9). Significantly high rate ratios were observed for
cancers of the oral cavity (rate ratio 8.6), colon (2.8), liver
(27.8), pancreas (9.5) and lung (2.3), see Table 2 for
confidence intervals. Exclusion of the first year cases had
 386 European Journal of Gastroenterology & Hepatology 2008, Vol 20 No 5

little effect on the rate ratios of the individual cancers. oropharynx and hypopharynx, but cancer of the tongue
The increased risk of oral cavity cancers was mainly and other parts of mouth were nonsignificantly elevated
attributable to significant excesses of cancers of the too (Table 3).

Table 1 Number of people admitted to hospital with each condition in each age group, and number in the reference cohort
Exposure cohort (and ICD code)a < 30 (% men) 30–44 (% men) 45–59 (% men) 60–74 (% men) 75 + (% men) Total (% men)
b
Reference cohort 317861 (57) 96500 (57) 83357 (59) 68425 (56) 33165 (38) 599308 (56)
Alcoholic cirrhosis (571.2) 12 (42) 262 (63) 556 (63) 389 (63) 100 (66) 1319 (63)
Other and unspecified cirrhosis (571.5, 571.8, 571.9) 122 (69) 217 (68) 436 (59) 678 (55) 311 (42) 1764 (56)
Alcoholic liver disease (571.0, 571.1, 571.3) 80 (66) 719 (67) 1112 (63) 710 (63) 143 (58) 2764 (64)
Primary biliary cirrhosis (571.6) 6 (67) 38 (24) 137 (15) 179 (22) 64 (19) 424 (20)
Acute pancreatitis (577.0) 652 (49) 1141 (58) 1391 (57) 1684 (49) 1208 (33) 6076 (49)
Chronic pancreatitis (577.1) 126 (49) 337 (69) 457 (56) 370 (53) 206 (36) 1496 (55)
Viral hepatitis (070) 942 (58) 633 (68) 370 (66) 178 (62) 71 (42) 2194 (62)

ICD, International Classification of Diseases.

a
ICD 9 codes for each cancer (equivalent codes were used for cases coded in ICD Revisions 7, 8 and 10).
b
All comparisons between each exposure cohort and the reference cohort in the tables that follow were standardized for age, sex and year of admission – see Methods
for details.

Table 2 Occurrence of cancer in people admitted for alcoholic cirrhosis or other and unspecified cirrhosis
Alcoholic cirrhosis Other unspecified cirrhosis

Adjusted rate Adjusted rate

ratio (95% ratio (95%
a
Cancer (ICD code) and number Observed Expected confidence Observed Expected confidence
of cases in reference cohort number number intervals)b P value number number intervals)b P value

All cancers (140–208), 99 40.9 2.43 (1.97–2.96) < 0.001 188 60.4 3.13 (2.70–3.61) < 0.001
n = 25014
Oral cavity, pharynx, lip 6 0.7 8.62 (3.14–18.9) < 0.001 3 1.3 2.40 (0.49–7.06) 0.954
(140–141,143–146,
148–149), n = 395
Oesophagus (150), n = 826 2 1.5 1.29 (0.16–4.86) 0.969 5 2.1 2.40 (0.78–5.61) 0.096
Stomach (151), n = 1353 1 2.3 0.44 (0.01–2.43) 0.600 7 3.8 1.83 (0.73–3.78) 0.172
Colon (153), n = 2583 11 3.9 2.81 (1.40–5.04) < 0.001 12 6.5 1.84 (0.95–3.23) 0.051
Rectum (154), n = 1530 4 2.3 1.75 (0.48–4.50) 0.420 7 3.9 1.82 (0.73–3.76) 0.178
Liver (155), all, n = 315 25 1.0 27.8 (17.7–41.7) < 0.001 49 1.6 35.1 (25.4–47.6) < 0.001
Men, n = 190 22 0.8 32.3 (19.8–50.4) < 0.001 40 0.9 56.9 (39.3–80.5) < 0.001
Women, n = 125 3 0.2 14.4 (2.93–43.1) < 0.001 9 0.8 12.7 (5.67–24.9) < 0.001
Pancreas (157), n = 846 10 1.1 9.47 (4.52–17.5) < 0.001 12 2.5 4.86 (2.50–8.53) < 0.001
Lung (162), n = 4303 17 7.3 2.32 (1.35–3.72) 0.001 27 10.8 2.50 (1.65–3.65) < 0.001
Breast (women only) (174), 7 4.3 1.64 (0.66–3.38) 0.281 8 7.1 1.13 (0.49–2.23) 0.875
n = 2608
Ovary (183.0), n = 505 1 0.8 1.22 (0.03–6.82) 0.723 5 1.5 3.27 (1.06–7.68) 0.017
Prostate (185), n = 2310 2 3.5 0.57 (0.07–2.07) 0.598 7 5.5 1.27 (0.51–2.62) 0.674
Bladder (188), n = 1730 3 2.8 1.07 (0.22–3.14) 0.858 4 3.7 1.07 (0.29–2.75) 0.903
Other skin cancers (173), 5 3.5 1.42 (0.46–3.31) 0.607 8 6.0 1.34 (0.58–2.64) 0.534
n = 1942
Lymphoma (200–202), 2 1.6 1.21 (0.15–4.40) 0.975 25 2.2 11.8 (7.58–17.5) < 0.001
n = 1008
Non-Hodgkin’s lymphoma 1 1.6 0.62 (0.02–3.47) 0.930 23 2.1 11.4 (7.21–17.3) < 0.001
(200,202), n = 875
Hodgkin’s disease (201), 1 0.2 5.13 (0.13–28.9) 0.491 4 0.2 17.0 (4.60–44.3) < 0.001
n = 202
Leukaemia (204–208), n = 837 1 1.4 0.73 (0.02–4.07) 0.913 9 2.0 4.57 (2.08–8.73) < 0.001
Myeloid leukaemia (205), 1 0.7 1.48 (0.04–8.29) 0.694 7 0.9 7.69 (3.07–16.0) < 0.001
n = 409

ICD, International Classification of Diseases.

Number of people in the reference cohort with each cancer, observed and expected number of people with cancer in the alcoholic cirrhosis or other and unspecified
cirrhosis cohort, ratio of rate in the alcoholic cirrhosis or other and unspecified cirrhosis cohort to that in the reference cohort, and 95% confidence intervals for the rate
ratio [Conditions used in reference cohort, with Office of Population, Censuses and Surveys (OPCS) code edition 3 for operations and ICD9 code for diagnosis
(with equivalent codes used for other coding editions): knee arthroplasty (812), hip arthroplasty (810, 811), squint (378), otitis externa, otitis media (380–382), upper
respiratory tract infections (460–466), deflected septum, nasal polyp (470–471), impacted tooth and other disorders of teeth (520–521), inguinal hernia (550),
ingrowing toenail and other diseases of nail (703), sebaceous cyst (706.2), internal derangement of knee (717), bunion (727.1), selected fractures (810–816, 823–826),
dislocations, sprains and strains (830–839, 840–848), superficial injury and contusion (910–919, 920–924)].
We only show cancers with four or more observed cases in people with either alcoholic liver disease or other unspecified cirrhosis. Cancers that were studied in addition
to those shown in the tables were: salivary gland, nasopharynx, larynx, uterus, cervix, testis, kidney, malignant melanoma, malignant brain, benign brain, other nervous
system, thyroid and bone cancers. Results available on request from the authors.
a
ICD 9 codes for each cancer (equivalent codes were used for cases coded in ICD Revisions 7, 8 and 10).
b
Adjusted for sex, age in 5-year bands, time-period in single calendar years and district of residence.

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 Liver disease, pancreatitis and cancer Goldacre et al. 387

We analyzed the data separately for men and women for
each cancer. For liver cancer, the rate ratios were 32 for
men and 14 for women (Table 2). The ratio for women,
however, was based on only three cases and the difference
between men and women was not statistically significant.
confidence intervals. Exclusion of the first year cases had
little effect on the rate ratios of the individual cancers.
The increased risk of oral cavity cancers was attributable
to significant increases in cancers of the tongue, other
parts of mouth, oropharynx and hypopharynx (Table 3).

Other and unspecified cirrhosis (Table 2) Primary biliary cirrhosis (Table 4)

These were mainly admissions with a diagnosis of liver
cirrhosis without qualification of type. A three-fold
increased risk of cancer overall (3.1; 2.7–3.6) was
observed. Excluding the first year cases, the rate ratio
dropped to 1.9 (1.6–2.4). Significant elevations of risk
were seen for cancers of the liver (35.1), pancreas (4.9),
lung (2.5), ovary (3.3) and for lymphoma (11.8) and
myeloid leukaemia (7.7), see Table 2 for confidence
intervals. The only cancers that remained significant
when the first year cases were removed were liver cancer
(15.0; 8.9–23.7, based on 18 observed cases and one
expected) and non-Hodgkin’s lymphoma (14.5; 2.5–11.3,
based on eight observed cases and one expected).
Liver cancer was significantly elevated in both men and
women [rate ratio 57 (39–81) and 13 (6–25), respec-
tively]. As the nonoverlapping confidence intervals show,
the increased risk of liver cancer was significantly greater
in men than women.
Other alcoholic liver diseases (Tables 3 and 4)
A significant two-fold elevation was observed in the risk
of cancer in people admitted to hospital with alcoholic
liver diseases other than cirrhosis (2.3; 2.0–2.7). After
exclusion of cases of cancer that occurred within a year of
the first recorded admission for other alcoholic liver
diseases, the rate ratio dropped slightly to 2.1 (1.7–2.4).
Significantly high rate ratios were observed for cancers of
the oral cavity (rate ratio 10.1), larynx (5.0), oesophagus
(4.1), colon (2.0), rectum (2.5), liver (17.7), pancreas
(4.4), lung (2.7) and uterus (3.9), see Table 4 for
A nonsignificant elevation of risk of cancer was observed
in people admitted to hospital with primary biliary
cirrhosis (1.40; 0.94–2.02). The risk of liver cancer was
substantially increased (19.6; 8.4–39.1). The increased
risk for liver cancer was seen in both men (53.6; 14.4–
141) and women (11.4; 3.0–30.2). No other cancer was
associated with hospital admission for primary biliary
cirrhosis and, specifically, there was no hint of an
elevation of risk of breast cancer (Table 4). Excluding
the first year cases had little effect on the rate ratios.
Viral hepatitis
The rate ratio for cancer overall was 1.5 (1.2–1.9). The
rate ratio for liver cancer was 18.6 (9.8–32.2) based on 13
observed cases and 0.7 expected cases. Eleven of the
cases occurred within the first year after admission for
viral hepatitis and, excluding these cases, the rate ratio
was 2.5 (0.1–13.9, based on one observed case and an
expected value of 0.4). The rate ratio for cancer of the
pancreas was 5.8 (2.9–10.4) based on 11 cases and an
expected value of 1.9. The rate ratio remained significant
when the first year results were excluded (5.7; 1.6–14.6).
Acute and chronic pancreatitis (Table 5)
The rate ratios for cancer overall were 1.3 (1.1–1.4) in
people who had acute pancreatitis and 2.5 (2.1–2.8) in
people who had chronic pancreatitis. As the nonoverlap-
ping confidence limits show, the higher cancer rate in
chronic than acute pancreatitis was statistically signifi-
cant. The rate ratios for liver cancer were 2.3 (1.3–4.0)
associated with acute pancreatitis and 5.6 (2.1–12.4)

Table 3 Occurrence of individual oral cancers in people who had alcoholic cirrhosis or other alcoholic liver diseases
Alcoholic cirrhosis Other alcoholic liver diseases

Observed Expected Adjusted rate 95% confidence Observed Expected Adjusted rate 95% confidence
Cancer (ICD code)a number number ratiob interval number number ratiob interval

Lip (140) 0 0.1 0 0–37.2 0 0.1 0 0–32.0

Tongue (141) 1 0.2 4.79 0.12–27.2 6 0.8 8.14 2.93–18.3
Gingiva (143) 0 0.1 0 0–52.2 1 0.2 5.87 0.14–35.6
Floor of mouth (144) 1 0.2 6.42 0.16–37.9 1 0.2 5.27 0.13–31.2
Other parts of mouth (145) 1 0.1 13.1 0.33–75.6 5 0.2 29.6 9.29–72.7
Oropharynx (146) 2 0.1 15.9 1.89–59.4 5 0.5 11.0 5.77–16.2
Hypopharynx (148) 2 0.1 24.0 2.84–90.5 4 0.4 11.9 3.14–32.1
Other, unspecified (149) 0 0.1 0 0–38.5 1 0.3 3.98 0.10–23.1

Number of people in the reference cohort with each cancer, observed and expected number of people with cancer in the alcoholic cirrhosis or other and unspecified
cirrhosis cohort, ratio of rate in the alcoholic cirrhosis or other and unspecified cirrhosis cohort to that in the reference cohort, and 95% confidence intervals for the
rate ratio [Conditions used in reference cohort, with Office of Population, Censuses and Surveys (OPCS) code edition 3 for operations and ICD9 code for diagnosis
(with equivalent codes used for other coding editions): knee arthroplasty (812), hip arthroplasty (810, 811), squint (378), otitis externa, otitis media (380–382), upper
respiratory tract infections (460–466), deflected septum, nasal polyp (470–471), impacted tooth and other disorders of teeth (520–521), inguinal hernia (550),
ingrowing toenail and other diseases of nail (703), sebaceous cyst (706.2), internal derangement of knee (717), bunion (727.1), selected fractures (810–816, 823–826),
dislocations, sprains and strains (830–839, 840–848), superficial injury and contusion (910–919, 920–924)].
For footnotes see Table 2.

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 388 European Journal of Gastroenterology & Hepatology 2008, Vol 20 No 5

Table 4 Occurrence of cancer in people admitted for other alcoholic liver diseases or primary biliary cirrhosis

Other alcoholic liver diseases Primary biliary cirrhosis

Adjusted rate ratio Adjusted rate ratio

Observed Expected (95% confidence Observed Expected (95% confidence
a
Cancer (ICD code) number number interval)b P value number number interval)b P value

All cancers (140–208), 193 83.8 2.31 (2.00–2.67) < 0.001 29 20.7 1.40 (0.94–2.02) 0.084
n = 24993
Oral cavity, pharynx, lip 18 1.9 10.1 (5.94–16.2) < 0.001 0 0.5 0 (0–7.59) 0.986
(140–141,143–146,
148–149), n = 391
Larynx (161), n = 274 7 1.4 5.01 (1.99–10.5) < 0.001 0 0.3 0 (0–11.9) 0.734
Oesophagus (150), n = 826 13 3.3 4.05 (2.15–6.96) < 0.001 1 0.6 1.76 (0.04–9.84) 0.928
Stomach (151), n = 1353 7 3.5 2.01 (0.81–4.16) 0.106 2 0.97 2.05 (0.25–7.43) 0.594
Colon (153), n = 2578 17 8.4 2.04 (1.19–3.27) 0.005 2 2.1 0.96 (0.12–3.49) 0.767
Rectum (154), n = 1527 13 5.3 2.47 (1.31–4.24) 0.002 1 1.2 0.86 (0.02–4.80) 0.754
Liver (155), all, n = 314 28 1.7 17.7 (11.5–26.0) < 0.001 8 0.4 19.6 (8.39–39.1) < 0.001
Men, n = 189 22 1.3 18.7 (11.4–29.1) < 0.001 4 0.1 53.6 (14.4–141) < 0.001
Women, n = 125 6 0.4 15.3 (5.50–34.1) < 0.001 4 0.4 11.4 (3.03–30.2) < 0.001
Pancreas (157), n = 845 12 2.7 4.43 (2.28–7.77) < 0.001 3 0.7 4.48 (0.92–13.1) 0.026
Lung (162), n = 4302 37 13.9 2.68 (1.88–3.70) < 0.001 3 3.2 0.93 (0.19–2.72) 0.876
Breast (women only) (174), 16 9.2 1.75 (1.00–2.84) 0.037 5 4.3 1.17 (0.38–2.75) 0.687
n = 2605
Uterus (182), n = 385 4 1.0 3.86 (1.05–9.97) 0.016 0 0.6 0 (0–6.21) 0.901
Prostate (185), n = 2310 5 6.8 0.73 (0.24–1.71) 0.609 0 1.2 0 (0–3.20) 0.544
Kidney (189.0,189.1), n = 531 5 1.7 2.90 (0.94–6.80) 0.036 1 0.3 3.94 (0.10–22.0) 0.626
Bladder (188), n = 1731 7 6.2 1.13 (0.45–2.34) 0.899 2 1.3 1.56 (0.19–5.64) 0.849
Other skin cancers (173), 7 7.4 0.94 (0.38–1.95) 0.976 0 1.6 0 (0–2.32) 0.386
n = 1941

Number of people in the reference cohort with each cancer, observed and expected number of people with cancer in the other alcoholic liver disease or primary biliary
cirrhosis cohort, ratio of rate in the other alcoholic liver disease or primary biliary cirrhosis cohort to that in the reference cohort, and 95% confidence intervals for the
rate ratio [Conditions used in reference cohort, with Office of Population, Censuses and Surveys (OPCS) code edition 3 for operations and ICD9 code for diagnosis
(with equivalent codes used for other coding editions): knee arthroplasty (812), hip arthroplasty (810, 811), squint (378), otitis externa, otitis media (380–382), upper
respiratory tract infections (460–466), deflected septum, nasal polyp (470–471), impacted tooth and other disorders of teeth (520–521), inguinal hernia (550),
ingrowing toenail and other diseases of nail (703), sebaceous cyst (706.2), internal derangement of knee (717), bunion (727.1), selected fractures (810–816, 823–826),
dislocations, sprains and strains (830–839, 840–848), superficial injury and contusion (910–919, 920–924)].
We only show cancers with 4 or more observed cases in people with either other alcoholic liver disease or primary biliary cirrhosis. Cancers that were studied in addition
to those shown were: salivary gland, nasopharynx, ovary, cervix, testis, malignant melanoma, malignant brain, benign brain, other nervous system, thyroid and bone
cancers, and lymphoma and leukaemia. Results are available on request from the authors.
For further footnotes see Table 2.

associated with chronic pancreatitis. The risk, however,
was not significant after omitting liver cancer cases
diagnosed within a year of admission for pancreatitis;
omitting them the rate ratio was 0.6 (0.1–1.7) in people
with acute pancreatitis and 1.6 (0.2–6.0) in people with
chronic pancreatitis. The rate ratios for pancreatic cancer
were 5.7 (4.5–7.1) associated with acute pancreatitis and
27.0 (21.4–33.8) associated with chronic pancreatitis.
They dropped, but remained significantly high after
omitting the first year cases: they were 3.0 (2.2–4.0) in
acute pancreatitis and 10.7 (7.3–15.3) in chronic pan-
creatitis. Thus, as the confidence intervals confirm, the
risk of pancreatic cancer was significantly and substan-
tially higher in patients with chronic than acute
pancreatitis. Lung cancer was significantly high in people
with acute pancreatitis (1.3; 1.0–1.6) and in chronic
pancreatitis (2.3; 1.5–3.3).
Discussion
Methodological issues: dataset, population and
multiple comparisons
A strength of using the Oxford linked dataset is that we
were able to study a wide range of cancers with large
numbers of the common cancers in people with the seven
hepatic and pancreatic conditions in a geographically
defined population. Moreover, because the diseases were
studied in the same general population, the differences
and similarities in their cancer profiles can be compared.
We have also used the same populations, reference
cohorts and methods to study cancers after a range of
other conditions [14–17]. In these studies, the rate ratios
for cancer overall were all very close to one with tight
confidence intervals and we found no elevation of risk of
the great majority of individual cancers studied. By
contrast, in this paper we show elevated risks of cancer in
relation to earlier liver diseases and pancreatitis with very
distinctive patterns – especially the very high risks of
liver and pancreatic cancer. This strengthens our
confidence that the findings are real and not an artefact
of the method or data quality.
The data also have some limitations. The cohorts are
based on prevalent cases – the first recorded hospital
admission or episode of day case care for each person with
each condition – rather than being cohorts with follow-up
from the date of first diagnosis. Data are not recorded on
patients who move out of the area covered by data
collection or who are treated in hospitals outside the area.

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 Liver disease, pancreatitis and cancer Goldacre et al. 389

Table 5 Occurrence of cancer in people admitted for acute pancreatitis or chronic pancreatitis
Acute pancreatitis Chronic pancreatitis

Adjusted rate Adjusted rate

ratio (95% ratio (95%
Observed Expected confidence Observed Expected confidence
Cancer (ICD code)a number number interval)b P value number number interval)b P value

All cancers (140–208), 509 409 1.25 (1.14–1.36) < 0.001 178 72.9 2.45 (2.11–2.84) < 0.001
n = 24926
Oral cavity, pharynx, lip 12 6.4 1.91 (0.98–3.37) 0.041 5 1.4 3.51 (1.13–8.26) 0.010
(140–141,143–146,
148–149), n = 393
Larynx (161), n = 274 6 4.0 1.50 (0.55–3.30) 0.462 3 0.81 3.73 (0.76–11.0) 0.060
Oesophagus (150), n = 821 16 14.7 1.09 (0.62–1.78) 0.836 1 3.0 0.33 (0.01–1.87) 0.390
Stomach (151), n = 1341 38 23.1 1.66 (1.17–2.30) 0.002 6 3.9 1.54 (0.56–3.36) 0.420
Colon (153), n = 2573 42 46.9 0.89 (0.64–1.21) 0.521 13 8.2 1.58 (0.84–2.71) 0.136
Rectum (154), n = 1525 23 27.9 0.82 (0.52–1.24) 0.401 4 5.8 0.69 (0.19–1.76) 0.581
Liver (155), all, n = 319 14 6.1 2.34c(1.26–3.98) 0.003 6 1.1 5.64c(2.06–12.4) < 0.001
Men, n = 194 8 2.8 2.90 (0.67–4.15) 0.005 4 0.6 6.40 (1.73–16.6) < 0.001
Women, n = 125 6 3.3 1.85 (0.67–4.15) 0.221 2 0.4 4.57 (0.55–16.8) 0.112
Pancreas (157), n = 826 91 17.4 5.70c(4.54–7.08) < 0.001 86 3.5 27.0c(21.4–33.8) < 0.001
Lung (162), n = 4289 86 68.4 1.26 (1.01–1.56) 0.037 27 12.0 2.26 (1.49–3.29) < 0.001
Breast (174), women only, 33 43.3 0.76 (0.52–1.07) 0.132 6 7.6 0.78 (0.29–1.71) 0.680
n = 2605
Uterus (182), n = 384 5 6.8 0.73 (0.24–1.71) 0.606 1 1.1 0.88 (0.02–4.94) 0.730
Ovary (183.0), n = 505 6 8.0 0.75 (0.27–1.64) 0.600 4 1.5 2.71 (0.74–6.98) 0.097
Prostate (185), n = 2303 40 39.4 1.01 (0.72–1.39) 0.992 4 6.6 0.61 (0.17–1.55) 0.415
Kidney (189.0,189.1), n = 530 12 8.3 1.46 (0.75–2.57) 0.261 3 1.5 2.00 (0.41–5.86) 0.418
Bladder (188), n = 1726 22 27.5 0.80 (0.50–1.21) 0.333 4 4.7 0.85 (0.23–2.17) 0.920
Malignant melanoma (172), 5 5.7 0.87 (0.28–2.05) 0.928 1 0.97 1.03 (0.03–5.76) 0.631
n = 420
Other skin cancers (173), 33 33.6 0.98 (0.67–1.38) 0.982 9 6.4 1.41(0.64–2.67) 0.409
n = 1933
Malignant brain (191), n = 511 8 6.8 1.18 (0.51–2.34) 0.791 1 1.3 0.76 (0.02–4.24) 0.874
Non-Hodgkin’s lymphoma 16 13.6 1.18 (0.67–1.92) 0.608 6 2.9 2.09 (0.76–4.56) 0.123
(200,202), n = 871
Multiple myeloma (203), n = 485 7 8.8 0.79 (0.32–1.65) 0.661 2 1.7 1.15 (0.14–4.17) 0.854
Leukaemia (204–208), n = 833 14 13.6 1.03 (0.56–1.74) 0.990 1 2.0 0.50 (0.01–2.80) 0.725
Lymphoid leukaemia (204), 6 6.3 0.96 (0.35–2.10) 0.922 0 1.2 0 (0–3.16) 0.536
n = 416
Myeloid leukaemia (205), 10 6.8 1.48 (0.71–2.76) 0.296 1 0.97 1.03 (0.03–5.79) 0.634
n = 407

Number of people in the reference cohort with each cancer, observed and expected number of people with cancer in the acute pancreatitis or chronic pancreatitis cohort,
ratio of rate in the acute pancreatitis or chronic pancreatitis cohort to that in the reference cohort, and 95% confidence intervals for the rate ratio [Conditions used in
reference cohort, with Office of Population, Censuses and Surveys (OPCS) code edition 3 for operations and ICD9 code for diagnosis (with equivalent codes used
for other coding editions): knee arthroplasty (812), hip arthroplasty (810, 811), squint (378), otitis externa, otitis media (380–382), upper respiratory tract infections
(460–466), deflected septum, nasal polyp (470–471), impacted tooth and other disorders of teeth (520–521), inguinal hernia (550), ingrowing toenail and other
diseases of nail (703), sebaceous cyst (706.2), internal derangement of knee (717), bunion (727.1), selected fractures (810–816, 823–826), dislocations, sprains and
strains (830–839, 840–848), superficial injury and contusion (910–919, 920–924)].
We only show cancers with four or more cases in people with pancreatitis. Cancers that were studied in addition to those shown were: salivary gland, nasopharynx,
cervix, testis, benign brain, other nervous system, thyroid and bone cancers and Hodgkin’s lymphoma.
c
Omitting cancers in the first year, the rate ratio for liver cancer fell to 0.6 (0.1–1.7) in people with acute pancreatitis and 1.6 (0.2–6.0) in people with chronic pancreatitis;
omitting the first year cases, the rate ratio for pancreatic cancer fell to 3.0 (2.2–4.0) in acute pancreatitis and 10.7 (7.3–15.3) in chronic pancreatitis.
For further footnotes see Table 2.

The fact that the dataset is limited to people who were
admitted to hospital or who received day case specialist
care is also a limitation. These factors are part of our
reasoning for including a comparison cohort from the
same database and for tight ‘matching’ through stratified
analysis for district of treatment and for year of first
recorded diagnosis as well as for age and sex. A further
limitation of our data is that we have no data on lifestyle
factors, such as alcohol consumption or smoking. Some of
the cancers in people with alcoholic cirrhosis or other
alcoholic liver diseases that show higher rates than those
in the comparison cohort are no doubt direct or indirect
consequences of heavy alcohol consumption – cancers of
the oral cavity, oesophagus, liver, pancreas and perhaps
colon and rectum. Rate ratios for liver cancer were very
high not only in association with alcoholic cirrhosis (27.8)
and other alcoholic liver diseases (17.7), but also with
unspecified cirrhosis (35.1), primary biliary cirrhosis
(19.6) and viral hepatitis (18.6). This suggests that
chronic liver pathology itself, as well as alcohol-induced
damage, contribute very substantially to the development
of liver cancer. Rate ratios for pancreatic cancer showed
very similar levels of elevation in those with alcoholic
cirrhosis (9.5), other alcoholic liver diseases (4.4), primary
biliary cirrhosis (4.5), unspecified cirrhosis (4.9) and viral
hepatitis (8.8). This suggests that the risk of pancreatic
cancer is increased by pathology associated with the liver
in addition to that caused by alcohol. In the alcoholic

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 390 European Journal of Gastroenterology & Hepatology 2008, Vol 20 No 5
cirrhosis and other alcoholic liver diseases cohorts, the
elevated rate of lung cancer is probably attributable to
high rates of smoking in heavy consumers of alcohol.
We studied a large number of associations between
diseases and the effect of making multiple comparisons
needs to be considered. For every (approximately) 100
comparisons, about five significant results would be
expected by chance alone. For this reason, we have given
exact P values as well as confidence intervals, so that the
reader can readily see the degree of significance of each
combination of earlier disease and subsequent cancer. It
is possible that some of the associations that are
significant at a level of P < 0.05 or even P < 0.01 may
result from making multiple comparisons and the play of
chance. This may particularly be so where there is no
earlier hypothesis to support the finding, for example, our
finding of an association between other and unspecified
cirrhosis and cancer of the uterus. On the other hand, in a
study with the number of comparisons that we have
made, findings where the significance level is less than
0.001 are very unlikely to be attributable to chance alone.
Our study is similar to that reported by Sørensen et al. [1]
who used national record linkage in Denmark to study
cancer in people with cirrhosis. They published most of
their findings for cancers excluding those in the first year
after admission for cirrhosis. We analyzed our data with
and without the cancers that occurred within the first
year after admission for each exposure disease. We did so
because we think that exclusion of first year cases, though
it may help with interpretation of associations that could
be attributable to misdiagnosis or referral bias, can risk
the loss of useful evidence about the true scale of disease.
Accordingly, we favour studying disease associations both
with and without the cases of ‘exposure’ and ‘outcome’
disease that occur close together in time. We found a
significant elevation of the rate ratio for liver cancer in
people with acute or chronic pancreatitis when the first
year cases were included, but no elevation of risk after
their exclusion. One possible explanation is that in some
people pancreatitis and liver cancer may coexist close to
the time of diagnosis of pancreatitis, but there are other
possible explanations for the findings.
Alcoholic cirrhosis
In the Danish record linkage study [1], the authors
reported that alcoholic cirrhosis was associated with a
two-fold increased risk of cancer overall, with specific
significant excesses of cancers of the liver, lung, kidney,
pancreas, buccal cavity and pharynx, oesophagus, larynx,
breast, stomach and colon [1]. We, too, found a two-fold
elevation of risk overall; and we also found significant
elevations for liver, lung, pancreas, oral cavity/pharynx and
colon cancer. Numbers in our study were too small
to comment on the other associations noted in the
Danish study.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Other and unspecified cirrhosis
It is possible that some of the patients in this category had
alcohol-associated cirrhosis that was either not recognized
as such or, perhaps to avoid perceptions of stigma, not
labelled as such. It is also likely that some patients in this
category would have had viral hepatitis C (the test for this
condition was only available from 1991) or cirrhosis owing
to fatty liver disease (nonalcoholic steatohepatitis). The
profile of cancer in this group does not entirely reflect that
in the alcoholic cirrhosis cohort. The risk of liver cancer is
appreciably higher in the unspecified cirrhosis cohort (rate
ratio 35.1; 25.4–47.6) than in the alcoholic cirrhosis cohort
(27.8; 17.7–41.7). The risk of liver cancer in hepatitis C
cirrhosis is said to be 1–5%, so this may account for some of
the liver cancer elevation. Associations with other alcohol-
related cancers are less striking in the unspecified cirrhosis
cohort than the alcoholic cirrhosis cohort; and there are
substantial and significant elevations of risk of non-
Hodgkin’s lymphoma and myeloid leukaemia in the
unspecified cirrhosis cohort (11.4; 7.2–17.3 and 7.7; 3.1–
16.0, respectively), but not in the alcoholic cirrhosis cohort
(0.6; 0.02–3.5 and 1.5; 0.04–8.3, respectively). An associa-
tion between cirrhosis, particularly hepatitis C cirrhosis,
and lymphoma in the liver is recognized in the literature,
although generally in single case reports [19].
The Danish record linkage study also found a two-fold
increased risk of cancer overall in the group of other and
unspecified cirrhosis (when first year cases were ex-
cluded) [1]. They reported elevations in risk of cancers
of the liver, lung, bladder, pancreas, buccal cavity and
pharynx, oesophagus and stomach [1]. After removing the
first year cases from the analyses, we found an increased
risk of liver cancer, but not of the other cancers that were
found to be elevated in the Danish study.
Other alcoholic liver diseases
The profile of cancers in this cohort was similar to that of
the alcoholic cirrhosis cohort. In addition, cancers of the
larynx and oesophagus were significantly elevated in the
other alcoholic liver diseases cohort. The elevated risks
are probably related to alcohol consumption, as laryngeal
and oesophageal cancers are known to be associated with
high alcohol consumption, but some confounding with a
causal relationship between smoking and the cancers is
also possible. Colon cancer was significantly elevated in
this cohort, as it was in the alcoholic cirrhosis cohort. It
was not elevated in the other liver condition cohorts
suggesting that, as others have found, colon cancer is also
related to alcohol consumption. It is possible that some
patients in the other alcoholic liver diseases cohort did, in
fact, have cirrhosis as the discharge diagnosis and that
coding for these conditions is not always precise.
Primary biliary cirrhosis
The Danish record linkage study reported an increased
risk of liver cancer very similar to ours (standardized

incidence ratio 18.5 in the Danish study; rate ratio 19.6 in
ours) [1]. Relative risks for men and women were high
(53.6 in men and 11.4 in women). Women with primary
biliary cirrhosis unlike men are not routinely screened for
liver cancer. Although our results are based on only four
observed cases of liver cancer in women, the high risk
suggests that perhaps this policy should be reviewed.
Several other studies have shown a substantially in-
creased risk of liver cancer in people with primary biliary
cirrhosis [2,3]. The Danish study, like ours, found no
increased risk in any other type of cancer although
numbers in our study were fairly small. Although some
published studies have reported an elevated risk of breast
cancer in people with primary biliary cirrhosis [5,6], our
study, like the Danish record linkage study and some
others, found no such association [1–3,7,8].
Viral hepatitis
Viral hepatitis showed an association with liver cancer
that was of similar strength as that found with the other
liver diseases. We have no information on virology or
serology and, therefore, cannot distinguish between
different types of viral hepatitis. In the Oxford area,
however, chronic hepatitis C infection is more prevalent
than hepatitis B infection, which can cause hepatoma in
the absence of cirrhosis. It is also possible that some of
the patients coded as having viral hepatitis may have also
had fibrotic liver disease.
Pancreatitis
Several studies have found an association between
chronic pancreatitis and cancer of the pancreas [9–12].
In three of these studies [9–11], as in ours, the risk
declines over time, which suggests that the association
may not all be causal, but that some of it may be as a
result of misdiagnosis of early symptomatic pancreatic
cancer as pancreatitis. Alcohol, however, is a risk factor for
pancreatitis, particularly for chronic pancreatitis, and
alcohol is associated with an elevated risk of pancreatic
cancer. Some of the association between pancreatitis and
pancreatic cancer may be attributable to a shared link
with chronic high alcohol consumption. In addition,
smoking is known to be a risk factor for pancreatic cancer
[20,21] and smoking is likely to be common among
patients with high levels of alcohol consumption. The
cancers we found to be significantly higher in people with
pancreatitis, compared with those without, are all
considered to be related to either alcohol consumption
or cigarette smoking. The risk of cancer overall, and in
particular of cancer of the liver and pancreas, was
considerably higher in people with chronic pancreatitis
than in those with acute pancreatitis. The differences in
cancer profiles between acute and chronic pancreatitis no
doubt reflect differences between them in their aetiolo-
gical factors. Chronic pancreatitis is more closely
associated than acute pancreatitis with chronic excessive
alcohol consumption, although some alcohol-related
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Liver disease, pancreatitis and cancer Goldacre et al. 391
chronic pancreatitis may begin as a process of repeated
acute episodes of pancreatic damage [22].
In summary, the profile of cancer occurrence in the
hepatic and pancreatic conditions varied according to the
specific condition. Similarities were, however, present
with regards to liver cancer risk, which was elevated to
some degree after admissions for all of the hepatic
conditions studied. Cancer of the pancreas was signifi-
cantly elevated in all cohorts, except that of primary
biliary cirrhosis. Lung cancer was elevated in most cohorts
and oral cavity cancers were high in people with alcohol-
related liver conditions. Colon cancer was significantly
associated with alcohol cirrhosis and other alcoholic liver
diseases, but not with the other conditions. Breast cancer
was not found to be associated with primary biliary
cirrhosis.
Acknowledgements
The Unit of Health-Care Epidemiology and its work on
the ORLS is funded by the English Department of
Health’s National Coordinating Centre for Research
Capacity Development.
Conflict of interest: none declared.
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