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:kl.cheung@nottingham.ac.uk

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

Review

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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