cancer of the male breast

Review

Cancer of the male breast

Joseph C. English III, MD, Crystan Middleton, MD, James W. Patterson, MD, andCraig L. Slingluff, MD

From the Department of Dermatology, University of Virginia Health

System, Charlottesville, Virginia

Correspondence

Joseph C. English III, MD, Department of Dermatology, University of

Virginia Health System, Box 800718, Lee St., Charlottesville,

VA 22908-0718. E-mail: [email protected]

Drug names

tamoxifen: Nolvadex

cyclophosphamide: Cytoxan

doxorubicin: Adriamycin

Introduction

In 1999, United States cancer statistics estimated 176,000

cases of newly diagnosed breast cancer, of which 1300

were expected in men, giving a 0.7% incidence.1 Male

breast cancer (MBC) was estimated to constitute only

0.2% of malignancies in men (1300 out of 623,000 cancer

cases) and to be responsible for 0.1% of all cancer deaths

in men (400 out of 291,000 cancer deaths) in 1999.1

Despite its low incidence, it is important for the

dermatologist to be aware of this malignancy. By

performing complete skin examinations, the dermatologist

may be the ®rst to detect changes in the nipple, areola, and

breast suggestive of a primary breast cancer. Any changes

in the nipple, areola, and breast anatomy in the male

patient should alert the dermatologist to further investigate

with tissue biopsy and to initiate appropriate referral to

oncology specialists (surgical and medical).

Epidemiology/etiology

In the United States, less than 1% of all cases of breast

cancer occur in men. MBC constitutes less than 1% of

malignancies in men and is responsible for 0.1% of male

cancer deaths.1,2 Due to the rarity of the disease, as

illustrated by the above statistics, many of the current

treatment modalities are based upon experience with

female breast cancer.3 The prevalence of MBC increases

with age, with a mean age of 60±65 years at presenta-

tion.2,4 Afro-Americans have a greater incidence of MBC

than do Caucasians.5 Geographic variance occurs in the

incidence of MBC, as noted by the higher rates of disease in

Africa, North America, and Great Britain.5,6 The incidence

of MBC parallels the incidence of prostate cancer with

age.5

The etiology of MBC remains controversial, and may

be multifactorial. Hormonal alterations, namely an

imbalance in the estrogen to testosterone ratio, have

been implicated as important factors.2,5 Reduced testi-

cular function, as may occur in mumps orchitis,

undescended testes, testicular injury, inguinal hernior-

rhaphy, and Klinefelter syndrome (KS), has been

identi®ed as a risk factor.3

KS is the strongest risk factor for the development of

MBC.5 Occurring in 1 out of 500 patients, KS is de®ned as

the presence of an additional X chromosome (47 XXY)

which produces a tall male, small testes with hypogonad-

ism, androgen de®ciency, impaired spermatogenesis with

resultant infertility, sparse body hair, and gynecomastia.7

In retrospective studies of MBC, KS has been shown to

coexist in 4±7.5% of cases.8,9 KS patients have a 50-fold

increased risk for the development of breast cancer.8

Excess estrogen exposure may be identi®ed as a risk

factor for the development of breast cancer. Primary breast

cancers have been reported in men with prostate cancer

who had been treated with estrogen therapy, in men

occupationally exposed to exogenous estrogen, and in men

with liver dysfunction.3,6,10 Additional associations with

MBC include: Jewish ancestry, radiation exposure, hyper-

prolactinemia, previous breast pathology (i.e. gynecomas-

tia), obesity, alcohol consumption, and a familial history of

breast cancer.3,11,12 Sandler et al.13 reported obesity in

60% of 28 patients with MBC. No association has been

found with tobacco use to date.5

ã 2000 Blackwell Science Ltd International Journal of Dermatology 2000, 39, 881±886

881

Genetic susceptibility, as in female breast cancer, has

been demonstrated in MBC. Familial susceptibility to MBC

has been linked to the BRCA2 locus on chromosome

13q.14 BRCA1 on chromosome 17q, which is linked to

female breast cancer, has shown no linkage to MBC.15 Of

interest, Haraldsson et al.16 found that seven of 34 MBC

patients had the BRCA2 gene mutation with no familial

history of breast cancer. Carmalt et al.17 stated that there is

a two-fold increased risk of breast cancer in ®rst-degree

female relatives of MBC patients and a six-fold increased

risk in ®rst-degree male relatives. Storm and Olsen18

demonstrated that daughters of MBC patients are at

increased risk, and BRCA gene mutation screening may

be indicated in this population. In summary, a family

history of either male or female breast cancer is a risk

factor for MBC.19 Familial breast cancer cases show the

same features as sporadic breast cancer in terms of clinical

behavior and survival.14

Clinical presentation/evaluation

The presenting clinical ®nding in the majority of patients

with MBC is a unilateral painless mass, which is centrally

located.2,3,17 Bilateral MBC is rare, and was noted in only

0.9% of 229 cases studied by Goss et al.20 The average size

of the tumor at diagnosis ranges from 0.5 to 12.0 cm.2,3

There is also generally a delay before the condition is

brought to the attention of the physician.10 O'Hanlon

et al.11 studied 67 cases of unilateral breast masses. Sixteen

per cent were diagnosed as carcinoma of the breast. The

median time to presentation for these patients was

33 months. This may be the reason why MBC presents at

a more advanced stage, with nodal involvement, when

compared with female breast cancer.21

Additional cutaneous manifestations include: nipple/

areolar retraction (dimpling), inversion or ®xation, ®rm

papulonodular plaques with anatomic disruption (Figs 1

and 2), ulceration, edema, dermatitis, erythema, or

discharge.3,4,6,22 MBC is more often associated with a

bloody nipple discharge than is the case in female breast

cancer.23 Paget's disease of the breast is a rare subset of

MBC. This cutaneous change of the nipple and areola

indicates an underlying malignancy of the breast. Clinical

®ndings include a nipple/areolar dermatitis mimicking

eczema with progression to ulceration, bleeding, crusting,

and nipple discharge.24 This is a histopathologic diagnosis

with intraepidermal changes that must be differentiated

from Bowen's disease and malignant melanoma. It is most

commonly associated with invasive ductal carcinoma.24

Two of 12 patients reviewed by Raton et al.22 initially

sought dermatologic consultation; this emphasizes the need

for the dermatologist to be familiar with Paget's disease as

a possible accompaniment of MBC. MBC may also present

with axillary adenopathy as the only sign;25 however, the

Figure 1 Dimpling phenomenon in the breast of a man with

primary invasive ductal carcinoma. Patient with a history of

bilateral breast reduction mammoplasties for gynecomastia

20 years previously

Figure 2 Nipple and areolar anatomic destruction from a

invasive ductal carcinoma

Review Cancer of the male breast English et al.

International Journal of Dermatology 2000, 39, 881±886 ã 2000 Blackwell Science Ltd

882

accuracy of the clinical evaluation of the axilla in MBC is

notoriously poor.3

The clinical differential diagnosis of MBC includes

in¯ammatory breast disease (subareolar abscess, duct

ectasia), gynecomastia, nonbreast-related chest wall malig-

nancies such as sarcomas, metastases to the breast, and

benign neoplasms (®broadenomas, leiomyomas).3,6 The

most common cause of a benign mass is gynecomastia,

which has a third peak incidence in the ®fth to eighth

decades (same age range as for MBC).6,11,26 Gynecomastia

is usually bilateral; however, it may present as a unilateral

central enlargement of the breast with poorly de®ned

borders, mobility, and tenderness to palpation in the early

stages of development.10,26 In contrast, synchronous

bilateral breast carcinomas in men are uncommon,

occurring in less than 1.0% of MBC cases.20 Therefore in

any middle-aged male presenting with a unilateral breast

mass, carcinoma of the breast must be excluded.11

Physical examination is perhaps the most important

initial diagnostic tool in MBC. Nevertheless, histopatho-

logic con®rmation is needed for the de®nitive evaluation of

any breast lesion in a male or female patient. Fine needle

aspiration (FNA) biopsy is useful for con®rming malig-

nancy.6 A case±control study, involving three multidisci-

plinary breast clinics, demonstrated that the combination

of physical examination and FNA was diagnostically

accurate and that mammography (MMGX) added no

additional diagnostic information.27 Due to the relative

ease of diagnosing MBC on physical examination, as well

as the scarcity of this malignancy, routine MMGX screen-

ing for men is not indicated.20,21 Contralateral MMGX

screening in MBC is unlikely to become important due to

the low incidence of bilateral disease.20 Mammography has

been found to be more useful in the evaluation of

gynecomastia rather than as a screening or diagnostic tool

for MBC. Mammography is not foolproof in distinguishing

gynecomastia from carcinoma, however, because the

diffuse increase in radiographic density that accompanies

extreme gynecomastia may mask underlying carcinoma.12

FNA may also confuse the proliferative phase of gyneco-

mastia with malignancy. If any doubt remains, a more

de®nitive breast biopsy is the next step.11 The dermatol-

ogist can use the punch biopsy technique easily in the clinic

to con®rm a diagnosis of MBC that presents with

cutaneous manifestations. Further diagnostic work-up

should include clinical evaluation of the axilla for

adenopathy, biochemical evaluation of renal and liver

function, and a chest radiograph. In more advanced cases,

computed tomography of the chest, abdomen, head, and

bone may be included.3,6

Histopathology

Breast cancers in men and women do not differ in their

histologic types.28 All histologic variants of breast cancer

have been identi®ed in men.3 The most common cancer is

invasive ductal carcinoma, which constitutes approxi-

mately 80% of malignant tumors in MBC.2,3,6,10,28

The histopathologic diagnosis of breast carcinoma with

cutaneous involvement can be dif®cult, because this tumor

resembles adenocarcinomas from other primary sites,

including sweat gland, salivary gland, lung, and gastro-

intestinal tract (Fig. 3). This issue is of particular relevance

to breast cancer arising in men, because the latter

occurrence is rare, and therefore the likelihood that a

given tumor has arisen from another location becomes

substantial. Fortunately, immunohistochemical marker

Figure 3 Histopathologic evaluation revealing an acinar

structure consistent with invasive ductal carcinoma (3 40).

Immunohistochemical studies demonstrated the tumor to be

cytokeratin, BRST2, and estrogen receptor positive.

HER-2/neu and progesterone receptors were negative

Figure 4 Postoperative scar with ecchymoses on right chest

wall after mastectomy for primary male breast cancer

English et al. Cancer of the male breast Review


883

studies now permit a greater degree of diagnostic precision.

Positive staining for gross cystic disease ¯uid protein-15

(GCDFP-15) is characteristic for breast cancer29 and

unusual in eccrine sweat gland tumors.30 The presence of

GCDFP-15 can also be demonstrated by using the

monoclonal antibody against the protein, BRST2. Positive

staining for estrogen or progesterone receptor proteins,

when present, also supports a diagnosis of breast cancer,

but is not entirely speci®c; for example, eccrine sweat gland

carcinomas can be positive for both.30 Carcinoembryonic

antigen (CEA) is typically negative or weakly positive in

breast carcinoma.30 According to one study, cathepsin D is

expressed in skin metastases of breast carcinoma, but not

in gastric or most pulmonary carcinomas.31 In dif®cult

cases, cytokeratin (CK) staining can be useful in distin-

guishing among subsets of adenocarcinomas. For example,

the CK7+/CK20± phenotype can occur in carcinomas of

the breast as well as lung, ovary, and endometrium, while

CK7±/CK20+ is seen in colorectal carcinoma, CK7+/

CK20+ in pancreatic adenocarcinoma, and CK7±/CK20±

in hepatocellular, prostate, and renal cell carcinoma.32

Molecular markers for estrogen receptor positivity occur

in up to 86% of MBC cases.33,34 Estrogen receptors are

more commonly positive in MBC than in female breast

cancer.3 Estrogen/progesterone receptor positivity is con-

sidered to provide a proliferative advantage to tumor cells

in MBC.35 Androgen receptor negativity is associated with

MBC in younger patients.35 The status of hormonal

receptors in tumors is pertinent in developing a course of

therapy, but has not yet been proven to predict disease

outcome.10,33 Wick et al.36 noted that there was no

signi®cant difference in 5-year survival or expression of

breast cancer-associated gene products in a comparison of

10 male with 75 female stage IIb breast cancers.

The diagnostic utility of cellular kinetics and oncogene

expression in MBC remains inadequate.3 DNA ploidy,

epidermal growth factor or HER-2/neu oncogene expres-

sion, presence of p53 tumor suppressor gene, and

lysosomal protease cathepsin D have not been predictive

of disease-free survival.3 The small number of cases make it

dif®cult to draw conclusions about the prognostic value of

immunohistochemical markers.37

Staging/prognosis

The staging of MBC is the same as that in women using the

TNM system6,28 (see the AJCC Cancer Staging Manual,

5th edn. Philadelphia: Lippincott-Raven, 1997 for details).

The most important prognostic indicators of breast cancer

are tumor size and axillary node status.2,23 MBC most

commonly develops in the central retro-areolar/nipple area,

which has the greatest lymphatic drainage in the breast.

Therefore, it is postulated that MBC has a propensity for

nodal metastasis.21 In a review of 170 MBC cases,

Salvadori et al.38 found that, with tumors > 2 cm in

diameter, the risk of dying from the disease was 2.1 times

higher than if the tumor was < 2 cm; in addition, nodal

involvement was associated with a 3.3 times higher risk for

dying than was the case in node-negative patients. In a

report of 335 MBC cases, Guinee et al.39 showed that

patients with four or more histologically positive nodes had

a 6.75 times increased risk of dying. A review of MBC by

Hecht and Winchester28 revealed 5-year survival rates for

stage I, II, III, and IV of 82±100%, 44±77%, 16±45%, and

4±8%, respectively. Overall, 5-year survival of MBC is

approximately 50%.17,33 It is now known that, with the

consideration of prognostic factors such as tumor size,

grade, and axillary nodal involvement, the overall survival

rate for men and women is nearly identical.40 Donegan

et al.33 noted that adjuvant therapy (chemotherapy/hormo-

nal therapy) improved prognosis in MBC with axillary

metastasis and hormonal receptor-positive tumors. This

treatment increases 5-year survival rates but, due to the

older patient population with coexisting medical condi-

tions, the survival curves converge at 10 years.

Therapy

The mainstay of therapy for MBC is surgical excision.10

This typically includes mastectomy (Fig. 4). Although

breast conservation therapy (lumpectomy and radiation)

could be considered in patients with MBC, it typically is

not practiced because of the small size of the male breast

relative to the tumor. Axillary nodal dissection is also

indicated as clinical assessment of the axilla is not reliable

for the determination of prognosis and adjuvant ther-

apy.2,17 This may eventually be replaced, in some patients,

by sentinel node biopsy and selective lymphadenectomy,

which are currently under investigation for female breast

cancer.41,42 The value of postoperative radiotherapy is

uncertain due to the small sample sizes. In some series, it

has shown bene®t in reducing locoregional recurrence

without subsequent survival bene®t.43

The success of adjuvant chemotherapy in female

breast cancer has led to the endorsement of such agents

to treat localized MBC;20 however, the data supporting

this treatment as equally optimal in men are insuf®cient

due to the small sample sizes and nonrandomized nature

of the studies advocating the use of these agents.2±4,20

The presence of nodal involvement is an indicator for

adjuvant therapy.9 The ®rst-line adjuvant treatment is

tamoxifen, both because of the high number of estrogen

receptor-positive cancers and the older age at time of

diagnosis, which often contraindicates the use of

traditional chemotherapy.20,44 Tamoxifen is a selective

estrogen receptor modulator whose antitumor effects are



884

due to its antiestrogen activity.45 Tamoxifen inhibits

estrogen-related genes, growth factors, and angiogenic

factors secreted by breast cancers, with a net result of

blocking the G1 growth phase and a subsequent

decrease in cellular proliferation.45 In MBC, a high

incidence of tamoxifen side-effects have been reported.46

Moredo Anelli et al.46 reviewed 24 MBC patients on

tamoxifen who reported side-effects of decreased libido,

weight gain, hot ¯ushes, mood alterations, depression,

insomnia, and deep vein thrombosis. In this study, ®ve

patients (20%) did not complete a 1-year treatment

course due to side-effects. Additional side-effects include

ocular toxicity, thrombocytopenia, or leukopenia.45

Ribeiro and Swindell47 analyzed 39 MBC patients with

nodal involvement who were started on tamoxifen after

mastectomy with or without radiotherapy for 1±2

years' duration. The actuarial survival of tamoxifen

patients was 61% compared to 44% for historical

controls. Disease-free survival at 5 years was 56%.

For estrogen receptor-negative cancers or tamoxifen

failures in estrogen receptor-positive tumors, adjuvant

systemic combination chemotherapy is suggested. The use

of cyclophosphamide, methotrexate, and 5-¯uorouracil

after surgery in patients who were node positive has been

associated with an 80% 5-year survival rate.48 Another

small study of patients with stage I and stage II disease,

who were treated with 5-¯uorouracil, doxorubicin, and

cyclophosphamide, showed a 63% disease-free survival

rate at 52 months of follow-up.49 As noted in most studies

of MBC, however, the rarity of this malignancy limits the

feasibility of clinical trials.20 In conclusion, after a review

of the literature, the optimal treatment consists of modi®ed

radical mastectomy, irradiation for cases susceptible to

local recurrences (lymph node positivity, large tumors,

muscle involvement), ®rst-line adjuvant therapy with

tamoxifen, and the use of adjuvant chemotherapy as

necessary to improve survival.9,44

About one-third of patients will develop distant

metastases (beyond lymph nodes) at some time during

the course of their disease.6 The most common sites of

distant metastases in men, as well as in women, include

bone, lung, liver, and brain.2,9 The median survival

from the time of presentation with metastatic disease

was 26.5 months in a study of 41 MBC cases.13 The

®rst-line palliative therapy currently recommended is

tamoxifen for estrogen receptor-positive tumors. In

hormone receptor-negative or estrogen receptor-positive

metastatic MBC not responsive to tamoxifen, combina-

tion chemotherapy with doxorubicin-containing regimens

has produced some promising results.50 Isolated metas-

tases (bone lesions, lung nodules without malignant

effusions) may be treated with localized radiotherapy or

occasionally with surgery.9,17

Conclusions

Examination of the male breast by the dermatologist

during routine of®ce visits can be signi®cant in establishing

the diagnosis of MBC. This is particularly the case as the

physical characteristics of MBC are often missed by the

patient. As with malignant melanoma, early detection can

improve patient survival. Similarities between MBC and

female breast cancer provide insight into the management

of this rare disease.

Acknowledgments

Mark R. Wick, MD, Professor of Pathology and Dermatol-

ogy, University of Virginia Health System, reviewed the

manuscript.

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cancer of the male breast

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