The incidence of breast carcinoma after prophylactic mastectomy is probably less than 2% . Several studies such as those by Pennisi and Capozzi  and by Woods  have been conducted, where only a few patients, from more than 1,000 patients included in the study (prophylactic subcutaneous mastectomy), developed breast cancer after years of follow-up (incidence rate 0.6%). However, one of the major concerns about nipple sparing mastectomy is the persistent risk of breast cancer development when this is used for prophylaxis, with much controversy about the safety of these procedures from an oncological point of view [4, 5]. At present there are no randomized studies on the effects of long-term testosterone use on breast cancer risk. In a 20-year follow-up study of 110 female to male transsexuals in Serbia, there were none with breast carcinoma .
Our presenting case of breast cancer and lung metastases in a female to male transsexual exposed to exogenous androgens is very rare and has not previously been described. Direct effects of androgens on inducing breast cell proliferation and cancer via the AR are biologically impossible. In our patient, androgen-positive receptors were found in only 2% of breast tumor cells. In vitro studies have shown an inhibitory effect of androgens on breast cell proliferation and growth . Negative findings for estrogen and progesterone receptors open the question of whether there is any hormonal dependence, or genetically determined carcinogenesis, irrespective of testosterone therapy.
The role of elevated androgen levels and the AR expression in male breast cancer as well as in female breast cancer is still unclear [8, 9].
Based on a few early articles by Grattarola , the androgen excess theory states that urinary androgen excretion and intratumoral estrogen receptor status confirm the existence of hormone-dependent disease and predict the clinical outcome from ovariectomy in patients with metastatic breast cancer.
Positive AR immunostaining was found in approximately 70% of invasive female breast carcinomas and in a significant number of triple-negative tumors .
A recent study of case records for 1,849 patients with breast cancer revealed that positive AR immunostaining was inversely correlated with clinical stage, histological grade and mitotical score. Positive AR immunostaining was therefore associated with less aggressive tumors .
Standard therapy with antiestrogens and antiaromatase drugs is effective against increased estrogen production but quite ineffective against androgen excess. Additional therapy in these cases might be needed as well as determination of the origin (ovarian or adrenal) of the androgen excess in the particular patient. Ovariectomy (surgical, radiological or medical) would be indicated if the excess originates from the ovaries, while sulfatase inhibitors would be indicated in patients with adrenal source of androgen excess .
The Surveillance, Epidemiology and End Results cancer registry,which includes more than 2,000 male patients, has highlighted the fact that 93.7% of male breast cancers were ductal or unclassified, while 2.6% were papillary, 1.8% were mucinous and only 1.5% were lobular . Breast cancers in men are significantly more likely to express hormone receptors than cancers in the female breast [8, 13]. As much as 81% of male breast cancers express the progesterone receptor, and even 90% of them express the estrogen receptor. Knowing this, adjuvant hormonal therapy (including progestins, androgens, steroids, aminoglutethamide, estrogens, letrozole) has an important role in the treatment of these patients. However, literature data report AR expression in 34 to 95% of male breast cancer with no clear association with its prognosis . Mutations in the AR gene have been reported in male patients with breast cancer , but again no causal association could be demonstrated.
It would be even more difficult to hypothesize on the role of androgen excess and the AR expression in the evolution of breast cancer in female to male transsexual patients due to the small number of such cases reported in literature. However, for those clinicians who deal with these patients, it is important to bear in mind all of the complex relationships between AR expression in breast cancer and other steroid receptors and growth factors.
There are certain dilemmas that must be addressed. In spite of the fact that the excised glandular tissue was pathologically benign, were the diagnostic procedures performed before sex reassignment surgery in our case insufficiently precise or insufficiently reliable, so that breast cancer had not been revealed in time, or was androgen supplementation the trigger for activation of invasive ductal carcinoma of the breast and potential high-speed malignancy of breast cancer, resulting in metastases in both lungs within a very short time?
According to medical literature, in the last 50 years there have been only three papers with four cases of breast cancer in transsexual female to male patients [15–17]. The first case, a 33-year-old female to male transsexual who developed breast cancer 10 years after cosmetic bilateral subcutaneous mastectomy and nipple reimplantation, was described in an article in Breast. The following two patients mentioned in Clinical Breast were breast cancers diagnosed in two female to male transsexuals who had been treated with a supraphysiological doses of testosterone . In addition, Gooren reported a single case of breast cancer in a female to male transsexual receiving testosterone hormone replacement therapy .
One should point out that the regularly performed bilateral removal of breast tissue including the nipple–areola complex, axillary tail and pectoral fascia was probably insufficient, and that breast cancer occurred in the residual breast tissue of the transsexual patient. However, it is very hard to speculate whether the patient could have developed breast cancer after oophorectomy with androgen supplementation if a total mastectomy had been performed.
As well as demonstrating the complex and poorly understood hormonal influences involved in the etiology of breast cancer, our patient’s management raised some important clinical issues. In this study the potential causative role of androgen replacement in breast malignancy, and the benefits, risks and safety of such treatment in breast cancer survivors, were discussed. The protection afforded to high-risk women undergoing prophylactic mastectomy is reviewed and the optimal hormonal management of this case was considered.