The Role of Psychological Factors in Cancer Incidence and Prognosis
The Role of Psychological Factors in Cancer Incidence and Prognosis
This article reviews the literature regarding the possible effects
of various psychological factors on cancer incidence and prognosis.
For a clear understanding of the findings in the literature, a
number of terms need to be defined. The term "psychological
factors" refers to personality or behavior traits or reactions.
In studies of psychological factors and cancer, these are the
independent variables, with one restriction: If a psychological
factor is associated with a physical carcinogen, it will not be
considered an acceptable independent variable, although it may
be regarded as a possible confounder. For example, it is claimed
that certain traits predispose a person to smoking. Those traits
will not be of interest insofar as they affect smoking and its
carcinogenic consequences, but only insofar as they may affect
cancer independently of smoking.
The dependent variables are cancer incidence, mortality, and prognosis
(disease-free interval and survival time). Possible confounders,
cofactors, or primary etiologic agents that may act in conjunction
with psychological factors include familiar factors such as radiation,
genetic attributes, viruses, smoking, and exposure to chemicals,
as well as some less familiar factors.
Incidence of cancer is determined in two ways, either by clinical
diagnosis or at autopsy. In both cases, the malignancy has had
to grow to the point of detection. That is, if it is a blood or
lymphatic cancer, enough cells have been transformed to be detected,
and if a solid tumor, it has grown large enough to be detected
by x-ray, palpation, sonogram, visualization, or some other method.
The first actual mutation of a cell to malignancy, however, has
taken place long before-in rare cases months before, and in most
cases years before [1,2]. For example, the median time to detection
of leukemia incidence after the atomic bomb was dropped on Hiroshima
was between 6 and 7 years . The estimated median growth time
to detection for breast cancer is 7 to 11 years, depending on
the researchers [1,4]. According to Steel , in a mix of several
cancers, with lung heavily represented, the median was about 5.5
years. Thus, all incidence statistics are a combination of the
first mutation of a cell to cancer and the progression of that
cancer to detectable size.
Another issue is type of study. The two classic types of epidemiologic
studies are case-control, sometimes called retrospective, and
cohort, sometimes called prospective. In case-control studies,
a group of cancer patients, cancer survivors, or patients with
recurrence is selected, together with a control group, and the
researcher measures some putatively discriminating attribute in
both groups to see whether they differ in respect to that attribute.
In cohort studies, an attribute is measured in all members of
the cohort before the outcome of disease, death, or recurrence,
and the researcher waits to see who gets cancer or not, survives
or not, or suffers a recurrence or not. The pair of groups being
tested is examined for differences in outcome that may have emerged,
given the existence of differences in the attributes originally
measured. For example, if the pair of groups in the population
is defined as "those who are stressed" and "those
not stressed," the risk factor is the condition of being
stressed, and the control condition is not being stressed. The
proportion who get cancer during the given follow-up period in
the group with the risk factor is compared with the proportion
who get cancer during this period in the group without
the risk factor.
This distinction between types of study is important, because
the case-control type, when used only on a sample and not the
population, is subject to a number of possible biases. Such potential
biases make it difficult to decide which case-control studies
to accept, doubt, or reject. Cohort studies, which are also subject
to some biases, but not nearly so many or so damaging as those
characterizing many case-control studies, are more trustworthy
and involve less risk of a false conclusion.
A variety of psychosocial factors have been used as independent
variables in the past. These include not only directly measured
variables but also those inferred from results on an instrument
that provides an indirect measure (eg, the Rorschach test). In
most case-control studies, the authors imply that because they
found a relationship, the factor existed before the tumor was
discovered, and they seldom remark on whether it existed before
malignant transformation. The analyst is left hanging in the air
because the researchers had not learned enough about the disease
to know the meaning or implication of their finding.
The Table lists a number of psychosocial factors (with the most
important items discussed below). Each of them has been examined
at least once as a risk factor in some study in the literature
(see Fox  for a bibliography). Very few mention the possibility
that the factor, eg, depression or suppression of emotions, may
have arisen from the biologic effects of the cancer itself or
from the patient's knowledge that he or she had the disease. Personally,
I do not think that such a possibility was ignored; I think the
possibility never even occurred to the researchers in the first
place because of their narrow disciplinary focus. Most of those
researchers were psychologists or psychiatrists, although a few
were somatic physicians, eg, Kissen and Thomas .
More recently, both psychologists and psychiatrists have become
more aware of the need to examine the effects of cancer on the
psyche, as well as the potential interference by a number of possible
confounders, both demographic and biologic, with proper research
methods. Nonetheless, such confounders still receive limited attention.
Stress will be defined here as the psychic and physiologic disequilibrium
caused by some event, which will be called a stressor.
Stress in Animals
The earliest work on the effect of psychological factors on cancer
dealt mainly with humans. But soon afterwards, a number of studies
appeared in which the relationship of stress and cancer in animals
was explored. Important early work on this topic was done by Riley
, who carried out extensive studies on the topic, and Seifter
et al . They and others who followed found clear evidence that
stress in rodents led to faster growth of transplanted tumors
or those caused by injection of oncogenic viruses, and shorter
survival times than in nonstressed control animals. This was also
true for development and growth of spontaneous tumors. It is of
note that Riley's early work on spontaneous tumors was done in
animals with virus-infected milk, like the mammary tumors caused
by the Bittner virus.
On the other hand, some researchers, eg, Newberry and Sengbusch
, found stress to inhibit tumor development and growth
in animals under some conditions. In a thorough review of these
and other findings, Justice  presented an extensive list of
variables that stimulate and inhibit tumor development. The most
important inference he drew, now well confirmed, was that viral
tumors in animals are adversely affected by stress, while those
induced by chemical carcinogens are favorably influenced by stress.
In view of the role attributed to the immune system in protecting
against cancer growth and possibly initiation, one might be tempted
to transfer these animal findings to humans. Yet several facts
1. Humans, guinea pigs, and certain other animals are considerably
less sensitive to corticosteroid proliferation than the major
rodent species used in the laboratory,  and, indeed, even
among these rodent species, various strains differ in their sensitivity
to glucocorticoids. Thus, the major finding of Riley , Seifter
, and others that stress-induced high glucocorticoid levels
in rodents led to increased tumor growth might not be duplicated
in humans, even if human cortisol levels did rise with stress.
2. Humans are outbred, with a variety of responses to many physiologic
stimuli; mice and rats used in laboratories historically have
been inbred to produce cancer-prone strains. While there are now
more varied strains, overall that history cannot be ignored.
3. Tumor transplants or heavy doses of carcinogens introduce strong
antigens, that is, stimuli to immune recognition and response,
with consequent greater protection against the tumor. Spontaneous
human tumors take a long time to develop and probably involve
relatively weak or even absent antigen proliferation, and hence
limited or even absent immune recognition of and response to antigens.
4. When animals are immunosuppressed, they develop tumors in excess
of normal at many sites, each strain being susceptible to tumors
at the site peculiar to that strain, eg, liver, lung, testes.
When humans are immunosuppressed, they also develop tumors in
excess of normal, but most frequently lymphoreticular tumors;
that is, the focus of the immunosuppressive stimulus is the immune
system itself. The incidence of reticulum cell sarcoma in immunosuppressed
individuals, for example, is 150 times that of the population,
whereas the incidence of other tumors (except other lymphomas,
which is also very high) is about twice that of the population.
5. Justice reported  that stress inhibited growth in chemically
induced animal tumors. While many stress experiments in animals
involve viral tumors, with associated stimulation of tumor growth,
in humans, the proportion of viral tumors is small, on the order
of 3% to 4% of all tumors.
Thus, if one extrapolated directly and incautiously to humans
from animal findings, one would conclude that overall, stress
is a depressant of tumor development and growth, as found by Newberry
 and others in animals, rather than a stimulant to tumor growth,
as many researchers suggest. For a number of reasons, such a conclusion
should not be drawn. Although the animal findings are important,
they should form the bases for hypotheses, not conclusions, about
the effects of stress on human cancers.
This discussion will focus on cohort studies, as there are several
reasons for giving little emphasis to case-control studies. First,
cancer can and does produce physical, psychological, and attitudinal
changes, mostly negative, that can bias conclusions . Second,
these changes in patients are known to increase reports of stressful
events when compared with controls .
Third, and perhaps most important, one can never be sure that
the patient group sample is unbiased, and that the control group
is matched to the patient group in regard to variables that might
lead to erroneous conclusions. A very limited list of such variables
would include the tumor's site, stage, histologic grade, depth
of invasion, and size; the degree of lymphocytic invasion at the
tumor site; the degree of microvascularization; the patient's
age, sex, socioeconomic level, race, smoking status, prior tumor
history, alcohol habits, body mass index, status of certain genes
(eg, p53), compliance with treatment regimen, and, for breast
cancer, age at menarche, age at menopause, oral contraceptive
use, estrogen-receptor level, and menstrual stage at operation.
In a large cohort study, one hopes that the sheer size of the
sample will cause most of these variables to even out among the
groups with and without the risk factor.
Case-Control Studies--Several early workers, using the
case-control model, reported a greater number of stressful events
occurring earlier in life in patients with cancer than in the
noncancer groups, eg, Greene , and LeShan and Worthington
. But most later case-control studies showed no excess of
traumatic events among patients, eg, Schonfield  and Greer
 (a short review of his studies).
Among the more recent case-control studies, we find similar contradictory
results. Ramirez et al  compared frequency of traumatic events
between diagnosis of breast cancer and first recurrence among
50 patients with recurrence with the frequency of such events
during a similar period in 50 patients without recurrence. They
found an excess of reported stressful events among those patients
In contrast, Priestman et al , who studied 300 women, 100
with malignancy, 100 with benign tumors, and 100 controls, found
that the severity and nature of the stressors did not differ among
the groups. In fact, the controls experienced more stressful events
than did the benign group, and the benign group experienced more
than those with cancer.
Early Cohort Studies--The earlier cohort studies found
no more cancers among stressed than unstressed members of the
cohort. For example, Keehn et al  found no greater cancer
mortality among 9,813 soldiers of World War II discharged for
psychoneurosis than among 9,942 controls over the period January,
1946, to December, 1969.
Keehn  studied cancer mortality among prisoners of war in
World War II from 1946 through 1975, and the Korean conflict from
1954 through 1978. No excess cancer mortality was found for either
Pacific or European World War II veterans (n = 6,023), or for
Korean veterans (n = 3,959) over their respective controls (n
= 5,223 and n = 3,953).
Joffres et al  looked at 4,581 Japanese men in Hawaii and
found no more stressful events among cancer patients than among
controls. While this is a case-control analysis, it should be
noted that if such an analysis is done on all the cases and all
the controls in a population, the results are no more biased than
those in a cohort study, in which all the later cases and later
controls are similarly identified. Stronger bias is found in smaller
sample case-control studies in which both the controls and cases
are selected. In the Joffres study, neither group was selected
beforehand, and it could therefore be judged to be as trustworthy
as a parallel cohort study.
Recent Cohort Studies--There have been relatively few recent
cohort studies. An example is a study by Barraclough et al ,
who found no relationship between stressful events and breast
cancer survival. In a widely cited series of studies, Grossarth-Maticek
et al  did find a relationship between stressful events and
later cancer, but this work has been criticized most severely
 and will not be further dealt with here.
Readers should be aware of a demonstrated bias that may affect
these studies . It appears that, on the whole, cancer patients
tend to recall more stressful events than noncancer controls,
even though some studies report otherwise . A few defining
studies have shown that cancer patients' reports of stressful
events do not reflect actual events experienced. In a thorough
review of memory as it is influenced by affect (that is, emotion,
mood, or feeling), Blaney  concluded that people with negative
affect report more negative events than people with average or
positive affect. Studies reflecting his conclusions are those
of Brett et al  and Cohen et al . Almost all patients
who have cancer and know it have negative affect to varying degrees.
Even if not all but a substantial number had negative affect,
their excessive recall of negative events would be enough to bias
the average recall level of the whole cancer group.
These three sets of findings lead us to the following conclusions
1. Case-control studies yield mixed results but are subject to
2. Most cohort studies show no excess stressful events associated
with cancer incidence, mortality, or survival.
3. People with negative affect report having experienced more
stressful events than those with average or positive affect, when
the true frequencies are alike.
The last fact explains many, if not all, of the case-control findings.
It is also the basis for predicting that in the absence of such
bias, there will be no excess of stressful events among the cancer
group. The prediction is confirmed by the findings of the cohort
studies, in which that particular bias cannot exist. Thus, it
is almost certain that stressful events do not occur more often
among those who later get cancer, die of it, or survive a shorter
time than among controls.
Bereavement is an important category of stress that has been studied
for its possible effects on later cancer incidence and mortality.
Holmes and Rahe  ranked loss of spouse as the most stressful
among 43 possible stressful events. Yet, several writers have
observed that bereavement is not always accompanied by sadness,
distress, or regret. For example, the death of a spouse with a
fatal and painful disease can produce relief rather than sadness
or distress. Although the number of such cases is quite probably
relatively small, I know of no studies on this matter.
An overall measure of the effects of bereavement combines data
from those who are distressed by the death and those who are relieved.
The result is conservative, since the possible effect of distress
in producing cancer will be diminished overall by the lack of
reported stress among those experiencing relief. The result will
be even more conservative if the bereaved who are relieved at
a close person's death do, in fact, have reduced susceptibility
to later cancer.
Some of the earlier case-control studies reported increased cancer
incidence among widowed persons. These have been intensively analyzed,
as have prospective studies up to 1986, and their problems and
difficulties have been carefully delineated .
In the cohort studies, as before, the bias that may exist in case-control
studies has been removed. None of the large cohort studies carried
out over an extended period have shown excess cancer deaths in
bereaved spouses, compared with still-married spouses. In the
exceptions, the excess lasted 6 months, a year, or, in one study,
as long as 2 years. Since the development time to diagnosis of
most cancers is on the order of years--3, 10, 15--those findings
could not have referred to cancer initiation. One such large cohort
study, a 1987 Finnish study of 95,647 persons widowed in 1972
, showed no excess deaths during the subsequent 4 years among
7,600 cancer cases. One can ignore the excess mortality seen among
widows in the first week following death and in the first month
among widowers as not being attributable to cancer.
Another study, conducted in Washington County, Maryland, of 4,032
white persons widowed between 1963 and 1974 and followed for approximately
12 years  showed no excess of cancer deaths. A third large
cohort study looking at this question  reported a similar
lack of excess cancer deaths over 10 years among persons widowed
in 1971. Here, the sample was 1% of the whole population of England
and Wales, observed from 1971 to 1981. The authors write, "No
peak of postbereavement mortality from malignant disease is clearly
established in either sex ". In a fourth such study of
1,782 breast cancer patients--all those diagnosed in Denmark from
March 1, 1983, to February 29, 1984--and 1,738 controls, Ewertz
 found no difference in the death rates of married and widowed
In summary, while some studies have reported a short-term excess
of cancer following bereavement, large cohort studies have not,
in general, found excess cancer incidence or death over the long
term. This conclusion is consistent with the previous one that
stress other than bereavement cannot be said to increase later
cancer incidence or death.
A few studies have looked at cancer survival among widows, eg,
Neale , and one or two have included widowers' survival. Also,
one or two studies have looked at disease-free interval. However,
the results have been mixed, some finding reduced survival among
the widowed and some not. In either case, those results cannot
be applied to the current issue-bereavement as a psychological
factor-since none of the studies on survival even mention the
time of bereavement in respect to the cancer diagnosis. Only one
thing can be certain in these studies: the marital status of the
patient at the time of cancer diagnosis. Thus, the cancer could
have been detected 1 day after bereavement or 20 years after bereavement.
This fact allows no conclusions to be drawn from the marital status
studies with regard to bereavement as a psychological factor.