Bilateral synchronous carcinoma of the male breast in a patient receiving estrogen therapy for carcinoma of the prostate: cause or coincidence?

Abstract: An unusual case of bilateral, synchronous breast cancer in a male patient who had a history of long-term estrogen therapy for prostate cancer is presented. The possible role of estrogen in the development of male breast cancer is revisited.

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In contrast to carcinoma of the female breast, male breast cancer is a tumor that rarely occurs in all parts of the world, with the incidence in most populations less than 1 case per 100,000 men. (1) Although the etiology of female breast cancer is being aggressively investigated, that of male breast cancer is generally less well studied (although admittedly more so in recent rather than previous years). Several factors have been implicated in the genesis of male breast cancer; among the most compelling is the role of estrogen, but many questions remain unanswered. In further support of this role, we report a case of bilateral, synchronous carcinoma of the breast in a male patient who was being treated with estrogen for carcinoma of the prostate.

Case Report

A 75-year-old man presented to a hospital because of a mass in the right breast, which he had detected at least 1 year previously but which had been increasing in size recently. His medical history was significant for carcinoma of the prostate gland, which had been diagnosed by needle biopsy 6 years earlier, and for which he was receiving estrogen in the form of stilbestrol, 2 mg/d. The patient admitted noticing bilateral breast enlargement approximately 2 years after starting the hormone therapy, but had become aware of a discrete mass in the right breast only in the year before presentation. He decided to seek medical attention because the mass was becoming progressively larger.

An examination revealed an otherwise healthy elderly male in whom abnormal findings were confined to both breasts. A 6-cm, firm mass fixed to underlying muscle was palpated in the upper, outer quadrant of the right breast. There was also a 3-cm, mobile mass palpable in the left breast. The masses were associated with bilateral palpable axillary lymphadenopathy. There was no clinical evidence of generalized metastatic disease.

A biopsy confirmed the malignancy, and the patient underwent bilateral, modified radical mastectomy and bilateral orchiectomy. The surgical specimen consisted of both breasts, each with attached axillary tail, and both testes. Two tumor nodules were observed on the skin of the right breast. Contiguous with the skin nodules within the right breast was a well-defined, cream-colored tumor, measuring 8 cm in maximum diameter. Within the left breast, an ill-defined, cream-colored tumor, measuring 3 cm in maximum dimension, could also be discerned. Ten lymph nodes were identified within the right axillary dissection specimen, and nine lymph nodes were identified within the left.

The tumors were histologically similar, with extensive infiltration of the breast tissue by moderately pleomorphic malignant epithelial cells, the features of which were consistent with an infiltrating duct carcinoma of the breast. Neither of the tumors extended to the deep margins of resection. Immunohistochemical tests of the tumors from both breasts using antibodies to prostate-specific antigen (PSA) were negative. However, estrogen-receptor (ER) status was also negative. Nine of the 10 lymph nodes present in the axillary tail on the right and 6 of the 9 present on the left contained metastatic tumor. Histologic evaluation of the testes revealed severe atrophy, with complete hyalinization of all tubules. The interstitium was markedly hypocellular, and Leydig cells were not identified.

The patient's postoperative course was uneventful, and he was discharged from the hospital 1 week later. Follow-up was limited to four monthly visits, after which he failed to return to the clinic. He died at home a year later, allegedly following a cerebrovascular accident. At the time of his last clinic visit, there was no evidence of metastatic disease.

Discussion

Carcinoma of the breast is uncommon in men. It is estimated to constitute only 1% of all cases of breast cancer and less than 1.5% of all malignant tumors in men. (1) Recent data from Jamaica cite an annual incidence of male breast cancer of 0.3 per 100,000 men, (2) a figure in keeping with the incidence in most other countries. (3)

The etiology of breast cancer is as obscure in male as in female patients, but, increasingly, factors that are thought to put men at increased risk are being postulated. Because of the rarity of these tumors, however, epidemiologic data are generally scant, and some of these suggested associations are controversial. Among the more recent putative risk factors are sociodemographic characteristics, such as social class and number of offspring, and anthropometric characteristics. (4) A family history of breast cancer, including occurrence in female relatives, has increasingly been recognized as a possible risk factor. (4,5)

Given the almost 100-fold difference in the incidence of breast cancer in men and women, and because of the known effect of estrogen on breast tissue development (including development in the male breast), estrogen level seems a logical risk factor to evaluate. The variety of evidence implicating estrogen in the causation of male breast cancer is overwhelming, and high estrogen levels have been considered by many to be a significant risk factor in male breast cancer, (3,6) although the issue is still very unsettled. Many of the data suggest that a relative or absolute increase in endogenous estrogen increases the risk, while others demonstrate increased risk with an absolute increase in exogenous estrogen.

There is evidence implicating endogenous estrogen in breast cancer. The risk of breast cancer is estimated to be 20 times higher in patients with Klinefelter syndrome than in male patients without this condition. (7) In Klinefelter syndrome, atrophic testes are associated with decreased testosterone level and relative hyperestrogenism. A similar mechanism is thought to account for the increased frequency of breast cancer reported in men with antecedent mumps orchitis. (8) There are suggestions that obesity increases the risk of breast cancer, (9) the presumed mechanism being the increased conversion of androgens to estrogens through peripheral aromatization. Increased frequency of male breast cancer has been reported in Egypt in association with liver damage caused by schistosomiasis, with resultant hyperestrogenism. (10) Finally, an increased incidence of male breast cancer has been reported in conditions associated with an increase in prolactin level caused by head trauma, (11) drugs, (11) or tumors. (12,13) The proposed mechanism, once more, is via a decrease in testosterone level and relative increase in estrogen level, by virtue of feedback of the elevated prolactin levels on the pituitary gland. By a similar mechanism, chronic alcoholism has also been cited as a possible risk factor for male breast cancer, (11) although this association has been denied in a recent case-control study. (14)

Meanwhile, the evidence implicating exogenous estrogen in breast cancer has also been mounting. There have been several reports of breast cancer developing in men receiving estrogen therapy for prostate carcinoma. (15-19) Breast cancer has also been described in transsexuals after castration and prolonged treatment with estrogen. (20,21) The evidence of a possible role of estrogen appears too convincing to ignore, yet the number of cases of breast cancer following estrogen therapy is relatively small, considering the number of patients who receive such treatment, particularly for prostate cancer. It is clear that, while strongly implicated, the exact role of estrogen needs further refinement and no doubt is related to the relative levels of androgens and estrogens rather than either level alone. It is noteworthy that the degree of testicular atrophy seen in this case was especially marked and greater than expected, even for a patient of his age.

As it does in women, bilateral breast cancer does occur in men, but the prevalence of bilaterality in men is said to be less than that in women, (1) with a cited incidence of only 1.4% of all cases in a collected series. (22) Moreover, bilateral synchronous involvement is estimated to be approximately one-third that of metachronous involvement, making this occurrence even more unusual. Whenever cancer is detected in the contralateral breast, the question of whether it is another primary tumor or a metastatic lesion will always arise. The latter question is even more pertinent in the presence of another known malignancy, particularly prostate cancer, which is known to have a propensity for widespread dissemination. The negative results of staining the breast cancer for PSA in this case, however, effectively ruled out prostate cancer metastatic to the breast. The bilateral nature of this case certainly makes the evidence of a causative association with the therapy even more compelling. Cases of bilateral disease in men have been reported in the literature, but they are not at all common. Some of these bilateral tumors have been associated with prolactin-producing tumors, (12,13) and there has been at least one previous case report of bilateral synchronous male breast cancer after estrogen therapy for prostate cancer. (15)

A higher proportion of breast cancers are ER-positive in male than in female patients. (23) This tumor, therefore, is in the minority of tumors that are ER-negative. Fortunately, this was not a factor in making treatment decisions in this case, which is the main significance of knowledge of the ER status in breast cancers in either sex.

Conclusion

Although a link is strongly suspected, convincing evidence about the role of estrogen therapy in the etiology of male breast cancer is still weak. This unusual case of bilateral, synchronous breast cancer in a man may provide further support for the causative role of estrogen, although we cannot exclude the possibility that it is a chance finding.

Accepted May 30, 2002.

Copyright [c] 2004 by The Southern Medical Association

0038-4348/04/9703-0308

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RELATED ARTICLE: Key Points

* Male breast cancer is a rare tumor worldwide, accounting for approximately 1% of all cases of breast cancer; the estimated incidence is less than 1 of 100,000 men.

* The prevalence of bilateral breast cancer in men is 1.4% of all cases in men, with synchronous involvement accounting for only one third of those.

* Among the factors implicated in the genesis of male breast cancer, estrogen is the most compelling.

* A list of conditions/diseases resulting in a relative or absolute increase in levels of endogenous or exogenous estrogen in male breast cancer patients has been compiled.

* This case of bilateral, synchronous breast cancer in a man after long-term estrogen therapy lends further support to the possible role of estrogen in the genesis of this disease.

Kathleen Coard, DM(PATH), and Trevor McCartney, DM(SURG), FRCS(EDIN)

From the Department of Pathology and the Section of Surgery, Department of Surgery, Radiology, Anesthesia, and Intensive Care, Faculty of Medical Sciences, University of the West Indies, Kingston, Jamaica.

Reprint requests to Kathleen Coard, DM, Department of Pathology, University of the West Indies, Kingston 7, Jamaica. Email: [e-mail]