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Incidence of Cancer Among Persons With Schizophrenia and Their Relatives
Dirk Lichtermann, MD;
Jesper Ekelund, MD;
Eero Pukkala, PhD;
Antti Tanskanen, MSc;
Jouko Lönnqvist, MD, PhD
Arch Gen Psychiatry. 2001;58:573-578.
ABSTRACT
| |
Background It has repeatedly been reported that the risk for cancer in patients
with schizophrenia is different from that of the general population, specifically
a lower risk for lung cancer despite increased smoking. Confirmation of these
associations could lead to hypotheses on shared risk or protective factors,
either genetic or environmental.
Methods From Finland's National Hospital Discharge and Disability Pension registers,
Helsinki, we identified a cohort of 26 996 individuals born between 1940
and 1969 and treated for schizophrenia between 1969 and 1991. They were followed
up for cancer from 1971 to 1996 by record linkage with the Finnish Cancer
Registry, yielding 446 653 person-years at risk, and standardized incidence
ratios (SIRs) were calculated. Likewise, 39 131 parents and 52 976
siblings of the patients with schizophrenia were followed up to explore familial
genetic hypotheses on deviations in cancer risk.
Results In patients with schizophrenia, an increased overall cancer risk was
found (724 cases observed vs 619 expected; SIR, 1.17; 95% confidence interval
[CI], 1.09-1.25). Half of the excess cases were attributable to lung cancer
(SIR, 2.17; 95% CI, 1.78-2.60), and the strongest relative increase in risk
was in pharyngeal cancer (SIR, 2.60; 95% CI, 1.25-4.77). Cancer incidence
in siblings (SIR, 0.89; 95% CI, 0.83-0.94) and parents (SIR, 0.91; 95% CI,
0.89-0.93) was consistently lower than that in the general population.
Conclusion Although specific lifestyle factors, particularly tobacco smoking and
alcohol consumption, probably account for the increased cancer risk in patients
with schizophrenia, the decreased risk in relatives would be compatible with
a postulated genetic risk factor for schizophrenia offering selective advantage
to unaffected relatives.
INTRODUCTION
NUMEROUS reports have suggested that the rates of physical illness differ
between patients with schizophrenia and the general population. Although most
evidence must be regarded as anecdotal,1 some
observations deserve further study, among them a decreased incidence of lung
cancer,2, 3 which is counterintuitive
given the increased rate and intensity of smoking among individuals with schizophrenia.4 In genetic terms, the hypothesis is attractive that
a schizophrenia vulnerability gene would simultaneously decrease the risk
of lung cancer, despite heavy exposure to the strongest known environmental
risk factor: tobacco smoke.
Proportionate mortality studies of schizophrenia and cancer risk are
biased in favor of lower cancer risk estimates because of the high rate of
suicide associated with schizophrenia. On the other hand, patients with schizophrenia
in permanent institutional care might have easier access to diagnostic screening
measures or more regular postmortem examination than in the control population,
thereby leading to an overestimate of cancer incidence. A well-designed, population-based,
3-center cohort study5 found a decreased risk
of lung cancer in patients with schizophrenia. A lower-than-expected incidence
of cancers of the prostate, cervix, and corpus uteri and an increased incidence
of female breast cancer was observed, but not consistently among the study
centers.5 We sought confirmation of these associations
by record linkage in a yet larger and more homogeneous sample covering the
entire population of Finland. Furthermore, we tried to identify and separate
genetic effects from environmental ones by monitoring the nonpsychotic siblings
and parents of patients with schizophrenia for cancer incidence. Although
risk-enhancing behaviors associated with schizophrenia (eg, increased smoking)
could still override a putative genetically based protection against cancer
accompanying genetically transmitted schizophrenia vulnerability in patients,
any associated selective advantage with respect to cancer risk should appear
more clearly among their nonpsychotic relatives as a general decrease of cancer
incidence compared with the general population.
SUBJECTS AND METHODS
SUBJECTS
From the National Hospital Discharge Register and the National Disability
Pension Register, Helsinki, Finland, we identified all individuals born between
1940 and 1969 who were hospitalized or received a disability pension for schizophrenia
between 1969 and 1991, as described elsewhere.6
Full operation of both registers started in 1968, and they cover Finland's
total population of slightly more than 5 million. Register diagnoses were
based on ICD-87 until
1987, after which ICD-98
codes were used (based on DSM-III-R9
criteria for psychiatric diagnoses) until 1996. All diagnoses coded as 295
in ICD-8 or ICD-9 were accepted
as cases to be followed up for cancer; this includes schizophrenia, schizophreniform
disorder, and schizoaffective disorder, syndromes repeatedly shown to cosegregate
in families on a common genetic basis (schizophrenia spectrum). Schizophrenia
register diagnoses in Finland have been tested several times for reliability
and specificity and were found to be directly applicable in epidemiological
studies.6
By record linkage with the Central Population Register, Helsinki, via
the unique personal identifiers assigned to all Finnish subjects on January
1, 1967 (or at birth, subsequently), we identified the parents and all siblings
of the patients with schizophrenia. Cross-checks were made with the Central
Population Register to obtain dates of emigration or death until December
31, 1996. Through the Finnish Cancer Registry, all patients with schizophrenia
and their siblings and parents were followed up for cancer incidence up to
December 31, 1996. The use of personal identifiers throughout the health care
system leads to great precision of the record linkage procedure.10
The Finnish population registration system is in principle complete, but some
of the relatives who died in the 1970s may not have been linked to the index
patient, and therefore the standardized incidence ratio (SIR) estimates in
the first years of our follow-up tend to be slightly too low. This error,
however, only marginally affects the overall SIRs among relatives. Permission
for examining and linking the above registers was granted by the Ministry
of Social Affairs and Health, Helsinki, Finland, and the institutional review
board of the National Public Health Institute, Helsinki.
The 26 996 subjects with schizophrenia were from 23 083 families
and were therefore expected to have 46 166 parents. Primarily because
of unknown paternity or maternity or both and, less commonly, because of parental
divorce or death before 1960 (when the register was computerized), the data
on 3795 fathers (16.4% of families) and 889 mothers (3.9%) could not be retrieved
from the population register. Another 1071 fathers (4.6%) and 1280 mothers
(5.5%) had died by 1971 (when the follow-up for cancer started) and were thus
excluded. Instances of unidentified siblings should be much rarer because
they would have had to die before the age of about 20 years to not appear
in the register. However, as the same restrictions of ascertainment apply
to the control population, resulting biases should be small.
DIAGNOSIS AND REGISTRATION OF CANCER
All medical care in Finland is provided by a national health care system
to which everybody has almost cost-free access. This results in extraordinarily
complete, unbiased ascertainment of schizophrenia and cancer cases by the
respective registers. Starting in 1961, the Finnish Cancer Registry has continuously
received obligatory reports on all newly diagnosed cases of cancer from hospitals,
practicing physicians, and hematologic and pathologic laboratories all over
Finland, with about 90% of diagnoses based on histologic confirmation.11 Death certificates mentioning cancer are automatically
forwarded from Statistics Finland, Helsinki, to the Cancer Registry for review;
fewer than 2% of all cancer cases came to the registry in this way alone.
Ascertainment of cancer cases has been shown to be virtually complete.12
In Finland, medical or forensic autopsies are performed on average in
32% of all deaths and in 64% of deaths before the age of 65 years.13 Forensic autopsy is obligatory in all cases of violent
death, including suicide. Because about 40% of the excess mortality in schizophrenia
is accounted for by unnatural causes,14 the
autopsy rate may be higher in patients with schizophrenia than that in the
control population, resulting in a higher postmortem detection rate of clinically
undiagnosed cancer in the former. However, this bias can be expected to be
small because chance detection on autopsy of clinically unsuspected cancer
should be rare, while the base rate of autopsies in the general population
is exceptionally high in Finland, especially in cases of death under 65 years
of age.
STATISTICAL ANALYSES
Individual follow-up of patients, siblings, and parents for cancer started
on January 1, 1971. For patients with a first diagnosis of schizophrenia (or
spectrum disorders) in the Hospital Discharge Register or Disability Pension
Register after this date, follow-up began from the date of first diagnosis.
For all 3 groups, individual follow-up ceased on December 31, 1996, or on
the date of emigration or date of death, whichever occurred earlier. Person-years
were calculated by duration of follow-up (<2, 2-11, or >11 completed years
of follow-up) and by 5-year age strata. Expected numbers of cancer cases (total
and specific cancers as classified by primary site) in each stratum were obtained
by multiplying the number of person-years at risk times the corresponding
mean incidence rate of cancer in the general population of Finland during
the same observation period. Standardized incidence ratios were calculated
by dividing the number of observed cancer cases in each group by the expected
number of cases. Calculation of 95% confidence intervals (CIs) of SIRs was
based on the assumption that the numbers of observed cases followed a Poisson
distribution.
RESULTS
Altogether, 26 996 patients with schizophrenia, 52 976 of
their nonschizophrenic siblings, and 39 131 of their parents were eligible
for follow-up (see Table 1 for
sex distribution). This corresponded to 446 653, 1 438 143,
and 905 947 accumulated person-years at risk of cancer (or a mean 16.5,
27.1, and 23.2 years at risk), respectively. Of all the cases reported to
the Finnish Cancer Registry, 1533 were benign lesions (mainly basal cell carcinomas
of the skin) and thus excluded.
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Table 1. Number of Patients With Schizophrenia and Their Nonpsychotic
Siblings and Parents Followed Up for Cancer Risk
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CANCER INCIDENCE IN PATIENTS WITH SCHIZOPHRENIA
Among patients with schizophrenia, 724 cancers were diagnosed during
follow-up, although 619 would have been expected from the incidence in the
general population. The overall risk of cancer was significantly increased
(SIR, 1.17; 95% CI, 1.09-1.25), more so in men than in women (Table 2). The largest increases were found for primary cancer of
the lung (SIR, 2.17; 95% CI, 1.78-2.60) and pharynx (SIR, 2.60; 95% CI, 1.25-4.77).
Significant increases were also seen for cancer of the gallbladder (SIR, 2.07;
95% CI, 1.03-3.70), the SIR being higher in men (SIR, 3.01; 95% CI, 0.98-7.01)
than in women (SIR, 1.64; 95% CI, 0.60-3.57), and for cancer of the corpus
uteri (SIR, 1.75; 95% CI, 1.19-2.48). Incidence of rectal cancer was decreased
(SIR, 0.35; 95% CI, 0.13-0.75).
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Table 2. Number of Cancers Observed and Expected in Probands, Siblings,
and Parents, by Cancer Site*
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CANCER INCIDENCE IN RELATIVES WITHOUT SCHIZOPHRENIA
Among nonschizophrenic siblings and parents of patients with schizophrenia,
fewer cases of cancer emerged than were expected (siblings: 886 observed vs
999 expected; SIR, 0.89; 95% CI, 0.83-0.94; parents: 6165 vs 6755; SIR, 0.91;
95% CI, 0.89-0.93), similarly in both sexes (Table 2). Decreased incidence of lung cancer (SIR, 0.82; 95% CI,
0.68-0.97) and breast cancer (SIR, 0.77; 95% CI, 0.71-0.83) was seen in patients'
mothers but not in other relatives. Cancer of the corpus uteri occurred less
frequently than was expected in mothers (SIR, 0.81; 95% CI, 0.69-0.92) and
in sisters (SIR, 0.38; 95% CI, 0.14-0.83). Prostate cancer in patients' fathers
also occurred at a lower rate, although the 95% CI included unity (SIR, 0.97;
95% CI, 0.89-1.04). Incidence of colon cancer in parents was lower than was
expected (291 observed vs 347 expected; SIR, 0.84; 95% CI, 0.75-0.93).
COMMENT
In contrast to previous reports5, 15
of decreased or equal risk of cancer in patients with schizophrenia compared
with controls, we found a moderately increased overall risk of cancer in these
patients. To our knowledge, only these 2 published studies, a multicenter
collaborative effort of the World Health Organization5
and a more recent study in Denmark,15 are directly
comparable to ours in using population-based case registers of schizophrenia
and of incident cancers to arrive at SIRs. Although 2 of the 3 study locations
in the World Health Organization's collaborative study, Honolulu, Hawaii,
and Nagasaki, Japan, also found cancer risks to be slightly increased in patients
of Japanese descent with schizophrenia, a decreased overall cancer risk in
both sexes emerged from the largest of the 3 study samples, the Danish (men:
SIR, 0.67; 95% CI, 0.60-0.74; women: SIR, 0.92; 95% CI, 0.84-1.01).5 The more recent record linkage study15
from Denmark yielded the same result (SIR, 0.79; 95% CI, 0.66-0.94).
Lung cancer comprised the greatest discrepancy in total cancer rates
between the present Finnish and the 2 Danish studies.5, 15
Incidence in patients with schizophrenia was strongly reduced in the first
sample from Denmark (men: SIR, 0.38; 95% CI, 0.26-0.53; women: SIR, 0.33;
95% CI, 0.13-0.68),5 but was 2-fold increased
in Finland. Although formal data are lacking, it has been suggested that the
decreased risk in Denmark might have resulted from tough restrictions on smoking
on psychiatric wards.16 Indeed, the second
study15 from Denmark on a more recent cohort
not subjected to smoking control measures (72% of whom were smokers) showed
a markedly higher relative lung cancer risk than the first study did (SIR,
0.78; 95% CI, 0.41-1.33). No restrictions on smoking in psychiatric care settings
are imposed in Finland. This is therefore the first study, to our knowledge,
to show in a population-based sample that schizophrenia is not paradoxically
associated with decreased lung cancer risk, but rather with significantly
increased risk, which corresponds well to what is expected from consistently
and strongly increased prevalence and intensity of smoking in patients with
schizophrenia.4, 17, 18
In Finland, 61% of individuals with schizophrenia are regular smokers (70%
of men and 50% of women; 36% smoke >20 and 25% smoke  20 cigarettes a day),
while 3% smoke occasionally and 36% do not smoke at all.19
Among 88 Finnish outpatients with chronic schizophrenia, 49 (56%) were smokers.20 In the Finnish general population, 23% are regular
smokers (27% of men and 19% of women), while 8% smoke occasionally.21 Other conceivable reasons for a substantially reduced
lung cancer risk in the older Danish cohort include a likely protective effect
by longer exposure to phenothiazines, or systematic differences between the
Danish and the Finnish populations with respect to genetic variants influencing
cancer risk.
In conjunction with alcohol abuse and poor dental hygiene, smoking also
increases the risk of cancers of the mouth and pharynx. Data on the prevalence
of alcohol problems in Finnish patients with schizophrenia derive from an
unselected cohort of all 12 058 live-births during 1966 in the northern
half of Finland. Among the 76 cases of schizophrenia identified in this birth
cohort up to 1996, 25% tended to be heavy drinkers or have other alcohol use
problems in daily life,22 and 18% fulfilled DSM-III-R9 criteria for
alcohol abuse or dependence.23 In accordance
with expectations from increased exposure to tobacco and alcohol, the incidence
of cancers of the oral cavity and pharynx was indeed doubled in our cohort.
The World Health Organization's 3-center study5
found a significantly lower incidence of cancers of the prostate (relative
risk, 0.38) and the cervix uteri (relative risk, 0.53) in the Danish schizophrenia
subsample, and an increased incidence of female breast cancer in the Japanese
subsample (relative risk, 3.23). Of these, only the deviation in prostate
cancer risk could be confirmed in our Finnish sample (SIR, 0.49; 95% CI, 0.20-1.00).
We observed cancers of the corpus uteri more often than was expected (SIR,
1.75; 95% CI, 1.19-2.48), consistent with a higher prevalence of risk factors
to endometrial cancer24, 25, 26
among women with schizophrenia, namely, fewer childbirths (low parity), higher
body weight, and lower physical activity than are found in reference populations.27, 28, 29
It is reassuring to female patients with schizophrenia that the risk
increase for breast cancer recently suggested by a case-control study,30 albeit controversial for methodological reasons,31, 32, 33, 34 was
not upheld in our population-based register linkage study. Neither neuroleptic
treatment, previously thought to increase breast cancer risk by prolactin
secretion, nor low parity or obesity seems to expose patients with schizophrenia
to a markedly higher risk than that in the general population (but possibly
to a higher relative risk than their mothers have; as suggested forthwith).
Cancer of the gallbladder was twice as common in patients with schizophrenia
as it was in the general population. In epidemiological studies, gallstones
have been suggested to be the main factor, increasing risk 4- to 5-fold; other
risk factors include high parity, obesity, and a high-energy, high-fat diet.35 Although high parity does not apply to women with
schizophrenia, who tend to be less fertile than age-matched controls,27 diet and high body weight (also medication-induced)36, 37 might explain this finding. To our
knowledge, there are no studies on the incidence of gallstones and only a
few28, 29 on body weight and dietary
habits in schizophrenia, but one29 did indeed
show a higher dietary intake of fat in patients with schizophrenia. In Finland,
the mean body mass index in women with schizophrenia has also been found to
be higher than that in subjects from the general population (28.4 vs 24.6),
although the difference was smaller in men (26.8 vs 25.6).19
In our study, the rectum was the only cancer site for which incidence was
strongly and significantly decreased in patients with schizophrenia (SIR,
0.35; 95% CI, 0.13-0.75). No risk difference from the general population was
found for colon cancer, which is considered to have a similar (mainly dietary)
origin.38, 39, 40, 41
Although it appears from the aforementioned that the elevated incidence
of cancer in patients with schizophrenia is largely due to increased risk
behaviors in this group (especially tobacco smoking and alcohol abuse), this
does not preclude the possibility that some genetic risk factor for schizophrenia
vulnerability also confers lower liability to cancer, which is, however, overridden
in manifest schizophrenia by the augmented risk behaviors mentioned. Although
data were lacking to adjust individual cancer risk for duration and intensity
of smoking (and for other environmental exposures) to determine whether the
increase in incidence was smaller than, equal to, or larger than what would
be expected owing to schizophrenia-associated risk behaviors, we had the unique
opportunity to test this hypothesis because patients' siblings and parents
who were unaffected by schizophrenia could be identified from the population
register and followed up for cancer incidence in the same way as patients
were. In both groups of relatives, we found a significantly decreased overall
incidence of cancer in both sexes. We know of no other record linkage study
on cancer in the relatives of patients with schizophrenia, but if replicable
in independent cohorts, this finding would appear consistent with a hypothetical
schizophrenia vulnerability gene that also leads to better cancer resistance
in relatives. Its identity is speculative, but genes involved in the immune
system might be candidates.42, 43, 44, 45, 46
Alternatively, relatives' lifestyles may have contributed to their decreased
cancer risk, and it is a limitation of our study design that we were unable
to consider possible differences in risk behavior between the general population
and first-degree relatives of patients with schizophrenia. It could be that
being in close contact with a heavily smoking or drinking patient might deter
relatives from substance abuse and thus protect them from associated cancers,
but this seems unlikely given the limited effect of shared environment on
the risk of alcohol or nicotine dependence, as has been documented by twin
studies (<3.5% of variance explained),47
and given the generally low age at onset of addiction47
that would still allow for uninhibited decades of drug exposure at least in
parents. However, any attempt to separate genetic factors from environmental
exposure by "lifestyle" is somewhat artificial as it has been shown that genetic
factors, the "nature of nurture," determine environmental exposure to a large
degree. Smoking as the crucial risk behavior underlying lung cancer is probably
intimately related to the neurobiology of schizophrenia.4, 17, 18, 48, 49
From a clinical standpoint, our finding of a substantially increased risk
of lung cancer and some other smoking related cancers in patients with schizophrenia
should lead to intensified efforts in developing addiction treatment programs
specifically suited to the needs of this vulnerable population.18
AUTHOR INFORMATION
Accepted for publication September 25, 2000.
This study was supported by Finska Läkaresällskapet, Helsinki,
Finland; the Ministry of Social Affairs and Health, Helsinki; grant 111/38
of the BONFOR (Bonner Medizinische Fakultät, Forschungskommission) Research
Commission of the Medical Faculty, University of Bonn, Bonn, Germany; and
jointly funded by DAAD (Deutscher Akademischer Austauschdienst, German Academic
Exchange Service), Bonn, and the Academy of Finland, Helsinki.
From the Departments of Human Molecular Genetics (Drs Lichtermann and
Ekelund) and Mental Health and Alcohol Research (Drs Lichtermann, Ekelund,
and Lönnqvist and Mr Tanskanen), National Public Health Institute, Helsinki,
Finland; and the Finnish Cancer Registry, Institute for Statistical and Epidemiological
Cancer Research, Helsinki (Dr Pukkala). Dr Lichtermann is now with the Department
of Psychiatry, University of Bonn, Bonn, Germany. Drs Lichtermann and Ekelund
contributed equally to the article.
Corresponding author and reprints: Dirk Lichtermann, MD, Department
of Psychiatry, University of Bonn, Sigmund-Freud-Str 25, D-53105 Bonn, Germany
(e-mail: lichtermann{at}uni-bonn.de).
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