Male Gynecomastia and Risk for Malignant Tumours
Background
Men with gynecomastia may suffer
from absolute or relative estrogen excess and
their risk of different malignancies may be increased.
We tested whether men with gynecomastia
were at greater risk of developing cancer.
Methods
A cohort was formed of all the men having a
histopathological diagnosis of gynecomastia
at the Department of Pathology, University of
Lund, following an operation for either uni-
or bilateral breast enlargement between 1970–1979.
All possible causes of gynecomastia
were accepted, such as endogenous or exogenous
hormonal exposure as well as cases of unknown
etiology. Prior to diagnosis of gynecomastia
eight men had a diagnosis of prostate carcinoma,
two men a diagnosis of unilateral breast cancer
and one had Hodgkin's disease. These patients
were included in the analyses. The final cohort
of 446 men was matched to the Swedish Cancer
Registry, Death Registry and General Population
Registry.
Results
At the end of the follow up in December 1999,
the cohort constituted 8375.2 person years of
follow-up time. A total of 68 malignancies versus
66.07 expected were observed; SIR = 1.03 (95%
CI 0.80–1.30). A significantly increased
risk for testicular cancer; SIR = 5.82 (95%
CI 1.20–17.00) and squamous cell carcinoma
of the skin; SIR = 3.21 (95% CI 1.71–5.48)
were noted. The increased risk appeared after
2 years of follow-up. A non-significantly increased
risk for esophageal cancer was also seen while
no new cases of male breast cancer were observed.
However, in the prospective cohort, diagnostic
operations for gynecomastia may substantially
have reduced this risk
Conclusions
There is a significant increased risk of testicular
cancer and squamous cell carcinoma of the skin
in men who have been operated on for gynecomastia.
Background:
Gynecomastia is a benign condition
appearing both uni- and bilaterally. It is more
common during some time periods in life, such
as early puberty and late adulthood [1]. Beside
an endogenous hormonal imbalance in estrogen/androgen
ratio, drugs having estrogenic effects or diseases
associated with injuries to gonads or liver
affecting the estrogen/androgen ratio may predispose
to gynecomastia [2-4]. Also, many anti-psychotic
drugs may induce hyper-prolactinemia and thus
gynecomastia. It has been claimed
that gynecomastia is more common
among men who later develop testicular cancer
and breast cancer [5-12]. Sometimes the treatment
of malignancies may be the cause for gynecomastia,
such as oestrogen treatment in prostate carcinoma
and cytostatic treatment in various malignancies
[13-16].
The increased risk for malignant tumours with
gynecomastia has previously
been described in some case-control studies.
However, no earlier prospective study has been
published. In order to elucidate the possible
adverse or protective effect on malignancy risk
of gynecomastia we formed a
prospective cohort of men of whom a histopathological
diagnosis had been obtained through an operative
biopsy.
Methods
Four hundred forty five men who had been operated
for diagnostic purpose due to unilateral or
bilateral gynecomastia in 1970–79
and of whom the pathology specimens had been
sent for diagnosis to the Department of Pathology,
University Hospital, Lund, Sweden, were included
in the cohort. During this time period diagnostic
(open) biopsies were very common in men with
breast enlargement to exclude malignant processes.
Later the operative biopsy has been replaced
with fine needle biopsies. The Pathology Department
has an exclusive population based accrual of
specimen in the South-West of the South Swedish
Health Care Region. In this cohort 198 (44.5
%) men were older than 50 years and 73 (16.4
%) were younger than 20 years of age at time
of diagnostic operation for gynecomastia
(Table 1).
With the help of the unique personal identification
number the vital status and the cancer incidence
up to age 99 years of these referents were then
identified from the population based Census
Registry, the Cause of Death Registry and the
Swedish Cancer Registry (South Swedish Regional
and the National Swedish Tumour Registry). Any
individual could have had more than one tumour
registered. The vital status was determined
up to Jan 1st, 2000. The median follow up time
was 266 months, i.e. 22.2 years. No subject
was lost to follow up. During the follow up
time, 208 men had died and none emigrated. The
observed versus expected numbers of various
malignant tumours were then calculated using
reference data from the southern health care
region. Cause specific standardised incidence
ratios (SIRs) and 95 % confidence intervals
(CIs) were calculated. The observed number of
cancer cases was assumed to follow a Poisson-distribution.
Hence, both 95% confidence intervals for the
SIR's and the test hypothesis SIR = 1 (i.e.
the cancer incidence is the same in both populations)
were based on the Poisson distribution. The
term "significant" refers to a p value
of 0.05. All tests were two tailed.
Results
In table 2 the observed and expected numbers
of malignant tumours, the SIRs
and the 95 % CIs for all malignant tumours
and different tumour types
are shown. Men with gynecomastia
had an overall risk for malignant tumours
similar to that in the reference population;
i.e. 68 observed versus 66.07 expected cases,
SIR = 1.03 (95% CI 0.80–1.30). The risk
for testicular cancer in the gynecomastia patients
was significantly increased; 3 observed versus
0.52 expected, SIR = 5.82, (95% CI 1.20–17.00).
Also, there were13 observed cases of squamous
cell carcinoma of the skin versus 4.06 expected,
SIR = 3.21, (95%CI 1.71–5.48). Three men
developed esophageal cancer versus 0.78 expected,
giving a SIR of 3.82, (95% CI 0.79–11.17),
which does not reach the defined significance
level. The risk for prostate carcinoma was unaltered
and nobody developed breast cancer during the
follow-up. A decreased risk was observed for
rectal carcinoma 0 cases versus 3.57 expected,
SIR = 0.00 (95%CI 0.00–1.03).
In table, 3 the SIRs for all malignancies
and separately for testicular, esophageal and
squamous skin cancer are presented in relation
to the time interval since diagnosis of gynecomastia.
No increased risk for any malignancy
was seen within the first two years following
gynecomastia diagnosis. An increased risk was
seen for testicular cancer, esophageal cancer
and skin cancer after two years of follow up.
Whilst the risk of skin and esophageal cancer
increased with longer follow up, the risk for
testicular cancer remained the same.
In table 4 the SIRs for testicular, esophageal
and squamous skin cancer are shown associated
with the age at diagnosis and age during follow.
The risk for testicular cancer was significantly
increased only in men with gynecomastia diagnosed
before the age of 50 years and with follow up
to the age of 50 years; SIR = 6.71(95%CI 1.38–19.60).
The risk for esophageal cancer was significantly
increased in men with gynecomastia diagnosed
above 50 years of age, SIR = 4.75 (95%CI 1.00–13.90).
The risk for skin cancer was increased in men
with diagnosis of gynecomastia at any age but
with a follow up extending after 50 years of
age. Increased risk of squamous skin cancer
occurred both in unilateral and bilateral cases
while testicular cancer was predominantly seen
in unilateral cases (table 5).
Discussions
The present study, being the so far only published
prospective investigation in the literature
with a maximum follow up time of 30 years, demonstrates
a significantly increased risk for testicular
and squamous skin cancer in men with a prior
histopathological diagnosis of gynecomastia.
Also a non-significantly increased risk for
esophageal cancer was noted while no cases of
male breast cancer was seen. Overall the male
patients with gynecomastia did not show an incidence
of malignancy different to that in the general
population.
Gynecomastia develops in a setting of imbalance
between androgens and estrogens where there
is a relative estrogen excess [2-4]. Gynecomastia
is more common at pubertal ages and in oldermen
[1]. This was also evident in our material (table
1). It has previously been shown in case series
that testicular cancer may sometimes prior to
diagnosis induce gynecomastia due to pathologic
HCG secretion [5-7]. In this prospective series
two patients developed testicular seminomas
and one patient a testicular teratoma following
the diagnosis of gynecomastia years earlier.
Chemotherapy may injure gonadal and hormonal
functions and are associated with development
of gynecomastia [14-16]. Some drugs, mimicking
or having estrogenic or antiandrogenic effects,
may also be associated with development of gynecomastia
[2-4]. This explains the rather large group
of cases with gynecomastia with a prior diagnosis
of prostate carcinoma where estrogens have been
used as a treatment. Interestingly in our study
there was no sign of a protective effect for
prostate carcinoma due to the relative estrogen
excess.
A rare malignancy, male breast cancer, has
in epidemiological studies been associated with
prior history of gynecomastia [8-12]. In our
investigation no prospective cases of male breast
cancer was seen, while two men after they had
developed male breast cancer later developed
gynecomastia that was not drug induced in the
contralateral breast. Also one of the cases
had gynecomastia surrounding the breast tumour
at diagnosis. In 44 of the 445 cases bilateral
extirpation of the breast tissue was done and
in the remaining cases a unilateral excision
was done. This surgical removal of breast tissue
in men potentially prone to develop breast carcinomas
due to the gynecomastia, may have substantially
reduced the risk for carcinoma as prophylactic
operations or reduction mammoplastic surgery
previously has been shown to reduce the risk
of breast cancer in women [17,18]. Liver injury
may be associated with gynecomastia [2] and
in our series chronic alcoholism was present
in 7 cases of which two had known cirrhosis.
The increased risk of esophagus cancer may be
another indicator of alcoholism and secondary
liver injury in a subset of the patients [19].
All cases of esophageal cancer occurred in individuals
with a gynecomastia diagnosis after the age
of 50 years. We have no explaination for the
higher risk of squamous cell carcinoma of the
skin. No study has previously associated development
of squamous cell carcinoma with gynecomastia
and the finding needs to be confirmed in future
studies, although the risk relationship in our
study was strong. The reason for the relationship
is unclear as the development of skin tumours
in general has not been associated with hormonal
risk factors. That some skin tumours are due
to papilloma virus infections could lend support
to a theory of increased virus activity/effects
in individuals exposed to estrogens as is the
case in cervical carcinoma and its virus related
carcinogenesis due to papilloma virus [20].
Also synergistic action between chronic estrogen
exposure and the oncogenes of HPV16 that coordinates
squamous carcinogenesis in the female reproductive
tract of K14-HPV16 transgenic mice has been
found [21]. HPV16 is however confined to mucous
membranes and it is not known if other HPV types
in a similar matter would interact in the skin
with estrogen. A decreased risk of rectal carcinoma
was noted, and we have no biological explaination
for this finding although it has long been known
that females have a lower death rate and risk
of the tumour [22].
It is notable that among the 13 skin tumours
5 occurred in individuals with multiple squamous
cell carcinomas of the skin. Including tumours
occurring prior to gynecomastia 8 individuals
of 9 had multiple tumours of the skin. The age
at diagnosis of skin cancer was above 50 years
of age in all cases, and the risk increased
with longer follow up and was evident both for
cases with a gynecomastia diagnosis before as
well as after 50 years of age. From a clinical
point of view it is questionable whether screening
of tumours woul dbe worth while in patients
with gynecomastia. On the other hand, the two
tumours most clearly displaying an increased
risk, ie.testicular carcinoma and squamous skin
cancer rather easily can be screened by general
examination. If also male breast cancer is included
as a risk a possible clinical work up in a man
presenting with gynecomastia should evaluate
the following points; is there a endogenous
or exogenous hormonal cause?; has the patient
been taking drugs that may cause gynecomastia?;
is there a known accompanying disease causing
a liver or gonadal injury?; can tumour disease
in testis, skin and breast be excluded on clinical
grounds?. For men with a gynecomastia diagnosis
a after 50 years of age the risk of testicular
cancer is negligible whilst a gynecomastia diagnosis
before and after 50 years of age may both indicate
an increased the risk for skin cancer.
Conclusions
In conclusion the prospective investigation
confirms an increased risk for testicular cancerin
men with a prior history of gynecomastia. Also
skin cancer and esophageal cancer were morecommon
among men with gynecomastia. No prospective
case of male breast carcinoma was seen, although
two male breast cancer cases occurred prior
to gynecomastia diagnosis.
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