the ‘other half’ of breast cancer: a review of male breast cancer
TRANSCRIPT
Review
Keywords
Male breastcancer
Cause
Prognosis
Psychosocial
Treatment
Endocrinetherapy
Marcus W.L. Ying,FRCSEdDivision of Breast Surgery,University of Nottingham,Nottingham City Hospital,UK
Amit Agrawal, FRCSEdDivision of Breast Surgery,University of Nottingham,Nottingham City Hospital,UK
Kwok-Leung Cheung,MDDivision of Breast Surgery,University of Nottingham,Nottingham City Hospital,UK
E-mail:[email protected]
Online 17 November 2005
406 Vol. 2, No. 4, pp
The ‘other half’ of breastcancer: A review of malebreast cancerMarcus W.L. Ying, Amit Agrawal and Kwok-Leung Cheung
Abstract
Male breast cancer has always been shadowed by the attention received by its other half of the coin;
female breast cancer. It is widely known to be 1% of all breast cancer, constituting also about 1% of all
breast cancer literature. As a rare disease, it is fortunate that its female counterpart has provided it with
the wealth of knowledge to treat it effectively. Although very similar, male breast cancer has unique
characteristics requiring a different approach to female breast cancer. In this review, the cause, prognosis,
psychosocial effect and treatment options of male breast cancer are discussed, paying particular attention
to endocrine therapy. � 2005 WPMH GmbH. Published by Elsevier Ireland Ltd.
Introduction
Breast cancer in men has always existed along-
side female breast cancer (FBC). It is a rare
disease, and people do not realise that it is
possible for men to have breast cancer. As a
result, a lot of male breast cancer (MBC)
patients present late, and the disease is asso-
ciated with a poor outcome. Due to huge
advances in knowledge of FBC, the rare male
condition can now be treated just as effectively
as its female counterpart.
Epidemiology
Male breast cancer is widely quoted to be 1% of
all breast cancer, the figure lies between 0.6%
[1] and 6% [2], and varies greatly in different
geographical areas and ethnic groups. Men
have a smaller amount of breast tissue than
women but the same factors that influence
malignant changes in women operate inmuch
the same way in men. The incidence of MBC
increases with age, flattening out after age 80
years, with a mean age at diagnosis of 63.4
years compared with 58.2 years in women [3].
Data from the National Cancer Institute Sur-
veillance, Epidemiology and End Results
. 406–413, December 2005
(SEER) [4] showed that the incidence of MBC
has been increasing for the last 30 years, from
0.86 per 100,000 to 1.08 per 100,000 [1]. This
26% increase is modest, compared with the
52% increase in FBC.
Risk factors
There is a lot of interest in the literature
concerning the risk of MBC. In general, the
risk is similar to that of FBC, but not the same,
and themanifestations are different; some risk
factors like menstrual history and child birth
are absent in men. Traditionally, the risks are
stratified according to the causes. Most factors
are interrelated, and are thought to operate
through several common mechanisms;
genetic, hormonal and environmental. It is
therefore more useful to view them according
to current knowledge of their association with
MBC (Table 1).
Genetic and familial causes
Male breast cancer is known to have a strong
family history, especially among female mem-
bers. An estimated 15% of all MBC is familial
[5]. The BRCA2 gene, discovered in 1994 [6], has
been shown to be related to MBC. The life-time
� 2005 WPMH GmbH. Published by Elsevier Ireland Ltd.
Review
Table 1 Stratified risks of male breast cancer
High risk
� Klinefelter’s syndrome
� History of contralateral MBC
� BRCA2
� Treatment related (antiandrogens in prostatic
cancer, radiotherapy in Hodgkin’s disease)
Small to moderate risk
� High socio-economic status
� Occupational exposure to heat
� Occupational exposure to vehicle combustion
products, polycyclic hydrocarbons and industrial
solvents
� Comorbidity (cirrhosis)
� Hyperprolactinaemia
� Obesity
� Inactivity
Questionable risk
� Gynaecomastia
� Occupational exposure to extremely
low-frequency magnetic fields
� Alcohol
� Birth order (first born)
risk ofMBC in BRCA2 carriers is estimated to be
6.3% up to the age of 70 years [7]. Eleven
percent of all breast cancers in a large series
of BRCA2 families were MBC [8], compared
with 1% of all breast cancer. BRCA1 is asso-
ciated with most inherited breast and ovarian
cancer in women, the link is less strong toMBC
than that to BRCA2. Other genetic mutations
resulting in MBC include androgen receptor
(AR) gene mutation [9], CYP 17 polymorphism
[10], CHEK2 mutation (Li-Fraumeni syndrome)
[11], PTEN mutation (Cowden syndrome) [12],
and the Lynch syndrome (hereditary nonpoly-
posis colorectal cancer, HNPCC) [13]. A history
of MBC is associated with a 30-fold increased
risk on the contralateral side [14], which is
much higher than the increase of 2 to 4-fold
observed in women [15].
The other well-known association is Kline-
felter syndrome. Among a cohort of 3518
patients with Klinefelter syndrome 5 died of
breast cancer [16]. The standardised mortality
ratio was shown to be 57.8 and was attributed
to increased oestradiol in the circulation of up
to twice the normal level [17,18]. It is hard to
determine which factors operate in Klinefelter
syndrome; the chromosomal abnormality is
obvious and is likely to render the carrier
prone to cancer but the effect we see in MBC
may be brought about by hormonal changes.
Hormonal imbalance
Like FBC, MBC is highly sensitive to hormonal
changes. An increase in serum oestradiol
seems to increase the risk, as seen in reports
of exogenous oestrogen causing MBC in trans-
sexuals [19]. First-born men have been
observed to be at higher risk, which was pos-
tulated to be due to higher levels of intrauter-
ine oestrogen, but a large-scale study in 2000
of male twins concluded that the level of
intrauterine oestrogen has a negligible effect
on subsequent MBC risk [20]. Recently, a Dan-
ish study of 77 men with MBC concluded that
the risk of MBC is 1.71 times higher in first-
born men than in later-born men [21]. With
respect to decreased androgen levels, in the
past MBC has been associated more with a
history of testicular injuries, mumps orchitis
or working in high temperature environ-
ments [22]. The risk is likely to be amplified
in the presence of raised oestradiol (as seen in
Klinefelter syndrome). No large-scale studyhas
investigated androgen level alone in patients
with MBC.
The effect of increased prolactin level is
interesting. Patients with MBC have more his-
tories than normal of head injuries or skull
fractures and the use of prolactin-elevating
drugs [23]. A handful of cases in the literature
describe MBCwith pituitary prolactinoma [24–
28]; five out of six cases were bilateral, present-
ing as synchronous or metachronous tumours,
sometimes years after successful treatment for
prolactinoma. In two of the cases ductal carci-
noma in-situ (DCIS) were also observed [17,21].
Male breast cancer can be induced experimen-
tally in mice by pituitary grafting [29], and
indeed, prolactin receptors are shown in
MBC [30]. There seems to be a trend for male
breast tissue, subjected to long-term stimula-
tion from hyperprolactinaemia, progressing
from benign to premalignant and finally to
MBC. The risk of breast cancer in women with
prolactinoma is not known.
Occupation
There are some occupations where a cluster of
MBC cases have been reported. Based on small
numbers, work places with high temperatures
such as blast furnaces, steel works, and rolling
Vol. 2, No. 4, pp. 406–413, December 2005 407
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408 Vol. 2, No. 4,
mills have been found to cause a small increase
in risk [31]. Work involving exposure to extre-
mely low-frequency magnetic fields (ELFMF)
including that of electrical workers and power
plant workers was thought to increase risk [32].
A large-scale population-based study in Sweden
did not show any increase in risk for workers
exposed to ELFMF [33]. A meta-analysis con-
cluded the relative risk of MBC from ELFMF
to be small, about 1.37 [34]. The risk for work-
ers exposed to gasoline and vehicle combus-
tion products increases to 2.5, and to 5.4 when
the exposure is before the age of 40 years [35].
Other occupations suspected to increase risk
include those that exposure workers to poly-
cyclic aromatic hydrocarbons and various
industrial solvents.
Previous illness or treatment related
Prostate cancer is associated with MBC [36].
Both are hormonal-responsive tumours.
BRCA2 also increases the risk of prostatic can-
cer risk [37]. There are reports that long-term
use of anti-androgens and oestrogens in the
treatment of prostatic cancer has resulted in
MBC [38,27,39]. Cirrhosis is reported to be
related [40], the postulated cause being hyper-
oestrogenaemia associated with liver failure.
External irradiation, related to treatment for
Hodgkin’s disease, has been associated with a
few cases of MBC [41]. There is one report of
MBC following repeated fluoroscopy for pul-
monary tuberculosis [42]. Interestingly, where
the incidence of MBC is noted to be high in
some African countries, it correlated well with
cervical cancer in women, which is regarded to
behave like a sexually transmitted disease [43];
this may indirectly reflect a decrease in libido
in men associated with low androgen levels.
Much concern surrounds gynaecomastia and
subsequent MBC risk. An upset in oestrogen or
androgen balance is a causal factor in gynaeco-
mastia,much the same as inMBC. Sixty percent
of patients with MBC have a history of gynae-
comastia [44], although large-scale population-
based studies did not support gynaecomastia
alone as a risk factor [45].
Atypical ductal hyperplasia (ADH) is consid-
ered to be a risk factor in women, and has been
reported in male patients and in autopsy stu-
dies, 7% of unselected cases were found to have
ADH [46]. In gynaecomastia specimens, the
spectrum of pathologies ranging from ADH
pp. 406–413, December 2005
to DCIS and invasive carcinoma exist together
[47]. It is likely that ADH influences the male
breast in much the same way as it does to the
female.
Life style
Most reports support a trend that drinking
alcohol increases risk [48]. Even a dose-related
increase in risk has been shown [49]. One study
did not find an increased risk in alcoholics
[50]. All the reports in a large body of data on
the relation between smoking and MBC sug-
gest no increase in risk [2]. One based on a
small number of cases found a decrease in risk
[51]. The postulated mechanism is a decrease
in oestrogen level associated with smoking.
Regular exercise decreases the risk; inactivity
is associatedwith a small increase in risk of 1.3
[52]. Obesity increases the risk possibly
because of an increase in bioavailability of
oestrogen or a reflection of relative inactivity.
A dose-response type of increase in risk with
increasing BMI [52], and a 2.1 times increase in
risk with BMI >30 have been shown [45]. Diet-
ary factors are complex, with no clear associa-
tion with a particular type of food established
[53]. Most investigators have shown a higher
risk with higher social economic status
[31,33,52]. The increase in risk is well docu-
mented in FBC, but the explanation is unlikely
to be related to increased awareness or late
pregnancy in men!
Pathology
Like FBC, invasive ductal carcinoma is the com-
monest type of MBC, responsible for 76.5% [4],
often displaying more neuroendocrine differ-
entiation than FBC. The incidence of papillary
cancer is higher in MBC than FBC and because
of the lack of terminal lobules, invasive lobular
carcinoma is rare, constituting 1.5% (compared
with 11.8% in FBC) [4]. Most investigators have
reported high oestrogen receptor (ER) and pro-
gesterone receptor (PR) positivity [23]. Our
experience with 41 patients with MBC in Not-
tinghamwas that 93%wereERpositive and73%
PR positive, and most (73%) had grade III carci-
nomas [54]. These figures are higher than in
FBC. In contrast, MBC receptor positivity does
not appear to increase with age [55].
Ductal carcinoma in-situ is associated with
about 5% of MBC and is usually associated with
Review
invasive carcinoma. Pure DCIS is even more
uncommon. Most patients present with bloody
nipple discharge or a mass [56]. Histologically,
93% are of a papillary or cribriform type. Pure
DCIS are almost always low to intermediate
grade, high grade DCIS only exists along side
invasive cancer. Ductal carcinoma in-situ in
men is considered pre-malignant, and should
be treated by mastectomy [57].
Clinical presentation
Eighty five percent of MBCs present as a sub-
areolar mass [58]. Because of the unique anat-
omy of the male breast, the nipple more often
has ulceration (17%) or discharge (12%) than in
women [1]. These conditions in men should
always be investigated with biopsy [54,59].
The diagnostic workup for MBC is the same
as in FBC. Imaging like ultrasound and mam-
mography are both useful as part of a triple
assessment. There are rare benign pathologies
unique in the male breast lump [60] which
cytologists need to be aware of. Ultimately,
needle core biopsy is required. The diagnostic
accuracy of needle aspiration cytology is as
good as in women for diagnosing malignancy
[60]. Needle biopsy alone is adequate for clini-
cally obvious cancers.
Treatment
To conduct a randomised control trial on treat-
ment options would be virtually impossible
because of the rarity of the disease. Current
knowledge of treatment is based entirely on
experience with FBC and case series in differ-
ent institutes. The principle of treatment is the
same as in FBC; surgery and radiotherapy for
local regional control, hormonal therapy and
chemotherapy for systemic control.
Surgery
For early, operable tumours, the mainstay of
treatment is still surgery [26,61]. Wound infec-
tion is noted to be high (up to 53.8%) in isolated
series [62], possibly related to tumour ulcera-
tion or relatively poor blood supply in the skin
flaps. There is a mean delay of 6 months [62],
and about 57% of patients will present with
stage III disease [62,63]. Locally advanced dis-
ease occasionally requires extensive resection
and flap coverage [64]. Given the relatively
small number of patients presenting early,
there is little experience in breast conserving
surgery in the literature but whenever it is
feasible, there is no reason why it cannot be
done [65]. Radiotherapy should follow breast
conserving surgery for local control.
Following the success of sentinel lymph
node biopsy (SLNB) in women, there has been
a lot of interest in the literature recently for
using this procedure in MBC [66,67]. As in FBC,
there is no need for full axillary dissection if
the axilla is negative [68]. The technique is
similar to that in FBC with a very high success
rate. We are yet to see the long-term results of
these procedures. Proper staging of the axilla is
still required in node-positive cases, the num-
ber of lymph nodes involved have a direct
influence in prognosis; worst if four or more
nodes are involved [69].
Postoperative radiotherapy
In locally advanced disease, most patients with
MBC will require radiotherapy [70]. The indica-
tion and technique for radiotherapy is the same
as in FBC [71]. Some centres advise radiotherapy
for tumours >1 cm and for all lymph-node
positive patients, and it is recommended for
patients after breast-conserving surgery [65].
Adjuvant chemotherapy
There is not a great deal of experience with
chemotherapy with MBC in the literature.
Most centres will recommend doxorubicin-
based chemotherapy for stage II and III disease
with great success [72]. Because of the elderly
nature of the disease, most patients requiring
chemotherapy may not be fit enough to toler-
ate the treatment.
Endocrine therapy
In general, men are regarded as ‘postmenopau-
sal’ when endocrine therapy is considered.
Back in 1942, before the discovery of the ER,
the dramatic effect of orchidectomy on skele-
tal metastasis from MBC was already known
[73]. Since then, orchidectomy has been widely
accepted for treating metastatic MBC. Hormo-
nal therapy is ideal in MBC; the tumour is
highly positive for ER, much more than in
FBC, and many patients may not be fit for
Vol. 2, No. 4, pp. 406–413, December 2005 409
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410 Vol. 2, No. 4,
chemotherapy. Use of anti-oestrogen achieved
a similar response with orchidectomy [74]. It
was then shown that patients, who did not
have orchidectomy and failed after aminoglu-
tethimide treatment, responded to tamoxifen
[75]. Tamoxifen therapy for metastatic disease
was quite well established in the early 90s [76],
and there are reports of complete regression of
metastasis from MBC from the use of tamox-
ifen [42,77,78]. Its use in the adjuvant setting is
accepted by most people [79], largely because
patients with MBC find it more acceptable
than orchidectomy [80], but surprisingly, it
has more reported side effects in men than
in women, with a drop-out rate of about 20% in
less than a year [81]. The main complaints are
decrease in libido and weight gain as well as
serious complications like deep vein thrombo-
sis, reported to be 4.2%.
Recently, the newer generations of aroma-
tase inhibitors (AI) have been successful in FBC
[82]. In men, about 80% of the circulating
oestrogen is derived from peripheral aromati-
zation of androgens and only 20% comes from
the testes [83]. High circulating levels of oes-
trogen have been found in patients with MBC
who have developed tamoxifen resistance [84],
and the effectiveness of AI in this situation
would be a logical assumption. Early reports of
the use of AI in a metastatic setting are very
encouraging [1,85]. In Nottingham, we also
have clinical experience in the use of the pure
anti-oestrogen, fulvestrant, in treating meta-
static MBC. Currently, there is no data in the
literature regarding the use of AI in adjuvant
setting for MBC.
Prognosis
In general, risk factors for prognosis in MBC
are the same as in FBC, the lymph node invol-
vement being the most important prognostic
factor. The survival after 5 and 10 years is 90%
and 84% respectively in node-negative disease
versus 65% and 44% for node-positive disease
[86]. The prognosis is worst if four or more
nodes are involved (10-year survival drops to
14%). The impression is that patients with MBC
do worse than their female counterparts. In a
review of the literature the 5-year overall sur-
vival was quoted to be 36–66% and 10-year
overall survival to be 17–52% [1]. As a group,
MBC does have a slightly poorer survival than
pp. 406–413, December 2005
the 64% 5-year survival in FBC from the NSABP
data back in the 1970s [87]. This apparent
difference is likely to be related to the fact
that about a third to half of them died of other
causes [69,88]. This is the direct reflection of
the older age and comorbidity at presentation,
and shorter life expectancy in men. Disease-
specific survival is quoted to be about 10%
higher than overall survival in MBC [1,88,69].
In retrospective case-control studies with MBC
patients, matched by age, stage and known
prognostic factors to FBC, the overall survival
was the same [54,89].
Psychosocial aspect
Comparedwith that forwomen there is paucity
in the literature about the psychological con-
sequences of MBC. In one report six in-depth
interviews were conducted covering seven
major issues: delay in diagnosis, shock, stigma,
body image, causal factors, the provision of
information and emotional support [90]. The
investigators concluded that men developed
denial defence mechanisms which may be ben-
eficial in the short-term but delayed their seek-
ing professional help. They recommended that
a structured education programme should be
developed, aimed at primary health-care profes-
sionals and supported by themedia, for increas-
ing awareness along with availability of
preoperative and postoperative gender-specific
information to alleviate the potential psycho-
logical problems associated with the diagnosis.
They also recommended that there should be
appropriate support and counselling services
for partners of the patients. As nurses often act
as advocates for women with breast cancer, the
suggestion was that nurses are in an ideal posi-
tion to do the same for men with breast cancer
[91]. However, although men have acknowl-
edged support from breast care nurses they
would appreciate one-to-one discussions with
another male breast cancer patient [92].
Practice in Nottingham
In Nottingham, diagnosis of MBC is made by
needle core biopsy to obtain histological data,
provisional grade and oestrogen receptor (ER)
status. Patients with locally advanced disease
will be staged to rule out metastatic disease
Review
prior to surgery which, in most cases, will be
mastectomy. Staging the axilla with preopera-
tive ultrasonography and intraoperative node
sampling is routine for invasive carcinoma.
Axillary clearance will be performed for
node-positive disease diagnosed preoperatively
or if there is a heavily involved axilla following
sampling (metastases in �4 nodes). Postopera-
tive chest wall irradiation is carried out in
locally advanced disease and in those patients
with positive nodes, grade III tumour and
vascular invasion. Adjuvant systemic therapy,
if indicated, is usually in the form of endocrine
therapy such as tamoxifen.
Recurrence is managed using a multi-disci-
plinary team approach, depending on the type
of recurrence, presentation and fitness of the
patient. If systemic therapy is required, endo-
crine therapy (using agents such as AI, tamox-
ifen, fulvestrant, megestrol acetate) is the
predominant option due to the hormone-sen-
sitive nature of most MBC.
All MBC patients are followed up by clini-
cians in a dedicated breast clinic, supported by
a team of specialist breast care nurses.
[
[
Conclusion
Through the vast advances made in FBC
research, as a rare disease MBC can be mana-
ged with results similar to those for FBC. Most,
if not all, of the knowledge we have gained
from FBC, can be applied to MBC. Despite the
similarity, MBC on its own requires separate
attention, as the psychosocial effect of a
women’s disease occurring in men cannot be
underestimated. The improvement in outcome
will probably come with increased awareness
of the condition and acceptance of treatment.
Through our understanding of MBC, we are
also shedding light into the understanding of
FBC, and advances in either field in the future
are likely to benefit both sexes.
Conflict of interest
Kwok-Leung Cheung has received honorarium/
sponsorship from AstraZenca – the pharma-
ceutical company that produces fulvestrant.
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