Breast Cancer in Men

Breast cancer is one of the leading causes of death in women. According to the American Cancer Society, an estimated 212,600 patients will be diagnosed with breast cancer in 2003. Of these, 1,300 will be men,[1] and of the 40,200 patients who will die from breast cancer, 400 will be men. From another perspective, less than 1 of every 100 cases of human breast cancer occurs in a man. This cancer accounts for approximately 0.2% of all malignancies in men. Because of the rarity of the disease and the low index of suspension, diagnosis is delayed in a significant fraction of patients. The object of this review is to increase the medical community's awareness of the disease in this setting, and thus favorably change its natural history by earlier diagnosis. Breast cancer is diagnosed 4 to 5 years later in men than in women, and the median age of diagnosis is 68 years. However, cases have been reported in males ranging in age from 5 to 93 years. The bimodal age distribution seen in women is absent in men, and incidence increases with age.[2] Risk Factors Several factors in men have been associated with an increased risk of this disease, and they are listed in Table 1. These risk factors are either associated with an excess of estrogen or a lack of androgens. Patients with a prior history of orchitis, undescended testis, or testicular injury are at increased risk of developing the disease, although the association between these conditions and the development of breast cancer in men remains uncertain. The strongest known risk factor for male breast cancer is Klinefelter's syndrome, a condition that results from inheritance of an additional X chromosome (47, XXY karotype).[2] Men with this condition have atro- phic testis, gynecomastia, high levels of gonadotropins (follicle-stimulating hormone, luteinizing hormone), and low levels of testosterone. The risk of breast cancer in these individuals is up to 50 times higher than it is in men with a normal genotype. Men with chronic liver disorders such as cirrhosis, chronic alcoholism, and schistosomiasis are also at increased risk of the disease. Because of the hepatic dysfunction, these individuals are unable to metabolize endogenous estrogen, with the result being a relative hyperestrogenic state. Chronic use of drugs such as digoxin(Drug information on digoxin) and thioridazine(Drug information on thioridazine),[3-5] as well as chronic marijuana use, ingestion of exogenous estrogen to treat prostate cancer (or by transsexuals), and con- ditions such as obesity, are also associated with an increased risk of breast cancer. In addition, men with BRCA2 mutations are at increased risk of developing the disease,[6] and a family history of breast cancer in female relatives has been shown to be an important predisposing factor. Clinical Presentations The most common presentation of male breast cancer is a painless, firm subareolar mass; the second most common presentation is a mass in the upper outer quadrant (Figure 1).[2,7] There is slight predilection for the left breast in multiple series. Bilateral breast cancer is distantly unusual in men (< 1%). Other presentations may include nipple retraction, ulceration of the nipple, skin fixation or fixation to the muscle, or enlarged axillary adenopathy. Nipple discharge is an unusual presentation of the disease, but patients may present with a bloody or serosanguineous discharge. In men presenting with a breast mass, a differential diagnosis includes gynecomastia, breast abscess, metastasis to the breast from other malignancies, and sarcomas not related to breast cancer. Radiologic criteria and evaluation can differentiate between gynecomastia and malignancy. Radiologic features may include a well-defined mass with spiculated margins and, occasionally, with microcalcifications. Gynecomastia appears as a round area of increased density in the areolar region and may be bilateral. Cancer in men with prior gynecomastia may be obscured on mammographic evaluation. (Moreover, due to the low incidence of breast cancer among men, screening mammography has no role in this population.) Tissue diagnosis is mandatory and can be established with the increasingly used fine-needle aspiration (FNA) procedure. If the index of suspicion is high and FNA does not yield the diagnosis, a core biopsy should be performed. It is important to have adequate histologic material with which to establish a diagnosis. Also at this time, assays should be performed to determine hormonereceptor and HER2/neu status of the tumor. Pathology The most common histopathologic type of male breast cancer is invasive ductal carcinoma. Approximately 90% of all breast cancer in men is invasive, and the remaining 10% is noninvasive. The fraction of males with noninvasive breast cancer was higher than that of women before the introduction of screening mammography, and that may be due to the small size of the male breast.[8,9] Almost all noninvasive carcinomas are ductal carcinoma in situ. Lobular carcinoma in situ occurs rarely because of the absence of terminal lob ules in the normal male breast. Most cases of ductal carcinoma in situ in men are of the papillary subtype and of low or intermediate histologic grade. The predominant histologic subtype of invasive carcinoma is infiltrating ductal carcinoma, representing more than 85% of cases, with papillary carcinoma representing approximately 5% of cases. Other histologic subtypes reported in men include medullary, tubular, mucinous, and squamous carcinomas. Inflammatory carcinoma and Paget's disease are seen with similar frequency in both men and women. In contrast to breast cancer in women, the majority of male breast cancers are hormone-receptor positive. A review of the literature indicates that 81% of the breast cancers in men are estrogen-receptor positive, and 74% are progesterone(Drug information on progesterone)-receptor positive. Receptor positivity does not increase with age, as observed in women. Limited data in men suggest that low rates of HER2/neu protein expression or overexpression, without gene amplification, are observed in men. Axillary lymph node status, size of the tumor, histologic grade, and receptor status have similar prognostic significance in men and women. Likewise, the prognosis of men with breast cancer is similar to that of women with a comparable stage of the disease.[10,11] The revised American Joint Committee on Cancer staging system for breast cancer was officially adopted in January 2003, and it does not differentiate between male and female patients; thus, the same staging system is used for men.[12] Local Treatment Most patients with localized disease require a total mastectomy to achieve adequate resection of the disease, as there is insufficient breast tissue with which to perform breastconservation surgery, ie, lumpectomy with radiation therapy (Figure 1). A majority of these lesions tend to be centrally located and may have skin involvement; lesser surgery is not a feasible option in this subset of breast cancer patients. Use of radical mastectomy vs modified radical mastectomy has been evaluated in men, and no difference in local control or survival was noted with either surgical approach. In several studies, postoperative radiation therapy was shown to reduce the risk of local recurrence. Its impact on survival, however, remains to be defined.[13] Systemic Adjuvant Therapy The use of adjuvant systemic endocrine therapy and chemotherapy has been evaluated in a small subset of male patients.[14-16] Because the majority of breast cancer cases in men are hormone-receptor positive, limited data suggest that tamoxifen(Drug information on tamoxifen) is effective in reducing the risk of re currence, but no randomized trials of this therapy have been conducted. In phase II studies, the efficacy of adjuvant tamoxifen therapy was compared to outcomes in historical controls, and results suggested that tamoxifen had a favorable impact on survival.[14] Adjuvant chemotherapy with either CMF (cyclophosphamide [Cytoxan, Neosar], methotrexate(Drug information on methotrexate), fluorouracil(Drug information on fluorouracil) [5-FU]) or FAC (5-FU, doxorubicin(Drug information on doxorubicin) [Adriamycin], cyclophosphamide(Drug information on cyclophosphamide)) has been reported in a small number of male patients.[15,16] The data from these small series suggest a reduction in the risk of recurrence. Recommendations for adjuvant therapy in men are adapted from the data on breast cancer in females. In patients with multiple positive nodes, the use of combined chemohormonal therapy should be considered. In female breast cancer, strong evidence suggests that combined chemohormonal therapy can further reduce the risk of recurrence. However, no such data have been reported for men. Treatment of Metastatic Disease Hormonal therapies can play an important role in palliation of the symptoms of metastatic disease (Figure 2). Orchiectomy has been shown to have an impact on disease progression. In earlier reports, adrenalectomy and hypophysectomy were associated with secondary responses. A small recent case report suggests that aromatase inhibitors may be of value as secondary therapy in patients with hormone-receptor-positive disease.[17] Hormonal agents-tamoxifen, progestins, and antiandrogens-have been evaluated in a small number of male patients. In men with hormonereceptor- positive breast cancer, these agents may palliate the disease.[2] Appropriate sequential use of these agents can enhance quality of life by controlling symptoms and may even have an impact on survival. Systemic cytotoxic agents should be offered to patients who have hormone- receptor-negative disease or have developed resistance to endocrine therapies. Various agents with established antitumor activity in female breast cancer patients can be used in men with similar guidelines.[ 18]