Breast enlargement in an HIV-infected man on combined antiretroviral therapy: what if it was carcinoma?

INTRODUCTION

The use of highly active antiretroviral therapy (HAART) has been linked with benign breast enlargement in HIV-infected men, including gynaecomastia (proliferation of ducts and periductal stroma) and lipomastia (adipose-tissue deposition). ^1–3 The main culprit antiretroviral drugs are efavirenz and didanosine. ^4–7 Breast enlargement, on the other hand, may be a consequence of malignant disease, including carcinoma, metastases from other sites to the breast, lymphoma and Kaposi sarcoma. ⁸ We describe here a case of an HIV-1-infected man presenting with a bilateral gynaecomastia revealing breast carcinoma.

CASE REPORT

A 51-year-old man, with a history of 23 years of HIV-1 infection, was started on protease inhibitor (PI)-based therapy in 1996 (nadir CD4 cell count: 200/mm³ in 1996), with an excellent immunological and virological response to stavudine (40 mg twice daily) plus lamivudine (150 mg twice daily) and indinavir (800 mg thrice daily). Protease inhibitor-based regimen was switched for non-nucleoside analogue reverse transcriptase inhibitor-based regimen in 2001 for more convenience, with didanosine (400 mg once daily) plus lamivudine (300 mg once daily) and efavirenz (600 mg once daily). At that time, plasma HIV-RNA was below 200 copies/mL and CD4 cell count was 461/mm³ (20%). Eighteen months after the initiation of lamivudine, didanosine and efavirenz, bilateral breast enlargement developed and was more pronounced on the left breast. The patient did not complain of any pain or galactorrhoea. Serum prolactin and testosterone were normal. He was not co-infected with hepatitis C virus. He was not receiving any concomitant medication known to induce breast enlargement (digitalis, spironolactone, phenothiazine derivates, tricyclic antidepressants, cimetidine, enalapril, amiodarone) and he did not report any consumption of marijuana, heroin, amphetamines or alcohol. Liver function tests and creatinine clearance were normal. No history of familial breast cancer was reported. Breast mammography showed no sign of malignancy. The patient was diagnosed to have gynaecomastia, a side-effect related to efavirenz and/or didanosine. In 2004, undetectability of HIV-RNA was sustained and CD4 cell count was 686/mm³ (26%). At that time, switching from efavirenz to nevirapine did not lead to any improvement in breast enlargement. A six-month course of percutaneous treatment with androstanolone was not successful. In 2006, didanosine was discontinued and replaced by abacavir 600 mg once daily, in association with lamivudine and nevirapine. Given the absence of improvement, a cosmetic surgery was performed in April 2008 and a glandular specimen of 50 g was resected from the left breast. Histological examination revealed intraductal carcinoma of 10 mm with minor necrosis. Given the in situ type of this carcinoma, no immunohistochemical markers were used to identify the presence of oestrogens and progesterone receptors. Surgery was subsequently completed by a large left breast excision and contralateral resection of gynaecomastia. The excision sample was large and included normal tissue. Follow-up breast ultrasonography will be performed every year for at least 20 years.

DISCUSSION

Breast enlargement in the HIV-infected population was first reported in 1987. ⁹ Evans et al. ¹⁰ described 13 HIV-infected men presenting with breast enlargement, all 13 had exposure to antiretroviral therapy. Nine out of 13 patients had gynaecomastia, only one had lipomastia, three had lymphoma (two non-Hodgkin's lymphoma and one had Hodgkin's disease) and no one had carcinoma. The median CD4 cell count at the time of presentation, available for 11/13 patients, was 210 cells/mm³. Allen et al. ¹¹ reported the cytological findings on 15 HIV-infected men presenting with breast masses, who underwent fine-needle aspiration. Gynaecomastia, although rare in young men, was the sole cause of breast masses.

Malignancy is a well-known complication of HIV infection, but mostly involves patients with incomplete CD4 reconstitution, ¹² which was not the case for our patient. Whether HIV-infected individuals are at an increased risk of primary breast carcinoma remains controversial. ^13,14 Furthermore, with HIV population ageing, an increase in malignancy prevalence could be expected even though a good response to HAART is observed. Therefore, clinical breast supervision and intensified supervision in case of breast enlargement (ultrasonography ± CA15.3) should be performed.

With regards to our patient, his bilateral breast enlargement was considered to be related to efavirenz and to a lesser extent to didanosine. ^4–7 Indeed, prolactin and testosterone levels were normal, and breast mammography did not show any evidence of malignancy. We therefore discontinued efavirenz. Unlike the improvement reported by Benveniste et al. ¹⁵ with percutaneous dihydrotestosterone, percutaneous treatment with androstanolone was not successful. We then discontinued didanosine, a drug that has also been implicated in the development of gynaecomastia. ⁷ The absence of clinical improvement in antiretroviral-related gynaecomastia after discontinuation of the culprit antiretroviral is not rare. ¹⁵ The persistence of breast enlargement despite the change of medicines became distressing for the patient and supported plastic surgery, which revealed the intraductal carcinoma. To the best of our knowledge, only two cases of breast carcinoma have been reported in HIV-infected men. ^16,17 Of note, some authors suggested that ritonavir might inhibit breast cancer growth. ¹⁸ Interestingly, our patient was not receiving a ritonavir-based regimen.

Concerns regarding breast enlargement in HIV-infected men frequently centre around cosmetic problems. Although malignancy is a rare condition, it should be considered as a potential cause of breast enlargement even if concealed under real gynaecomastia.