Fine Needle Aspiration of Breast Masses in HIV-Infected Patients

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1 Fine Needle Aspiration of Breast Masses in HIV-Infected Patients Results From a Large Series Pam Michelow, MD 1 ; Bruce J Dezube, MD 2 ; and Liron Pantanowitz, MD 3 BACKGROUND: There are limited studies investigating the cytopathology of HIV-related breast disease. The aim of the current study was to evaluate a large series of fine needle aspirations (FNA) performed on breast lesions in HIV-positive patients. METHODS: A retrospective review at the National Health Laboratory Service (NHLS) in Johannesburg, South Africa, was performed on confirmed HIV-positive patients who underwent breast FNA. Cases were evaluated for patient age and sex, presence of a clinical breast lesion, antiretroviral therapy use, specimen adequacy, and cytologic diagnosis. RESULTS: A total of 152 breast FNA procedures were recorded in patients of average age 36 years (range, years). Cytologic findings in 100 females patients included 28 inadequate aspirates, 29 cases with a benign diagnosis, 25 abscesses, 3 with reactive intramammary lymphadenopathy, 3 with fat necrosis, 1 galactocele, 1 papillary lesion, 8 breast carcinomas, and 2 non-hodgkin lymphomas. Fifty-two males underwent breast FNA, of which 6 were inadequate, and 43 (82.7%) showed gynecomastia. In 17 (40%) males with gynecomastia, a history of antiretroviral therapy was recorded. Two males were diagnosed with breast abscess and 1 with Kaposi sarcoma. Microbiology culture revealed 7 Mycobacterium tuberculosis infections in this patient population. CONCLU- SIONS: FNA is a procedure to evaluate breast lesions and is capable of rendering results useful for a broad range of diagnoses likely to be encountered in an human immunodeficiency virus (HIV)-positive population. Unlike HIV-infected females who may present with a wide range of benign and neoplastic breast entities, HIV-positive males may have breast lesions that will most likely be attributed to gynecomastia associated with antiretroviral therapy. Cancer (Cancer Cytopathol) 2010;118: VC 2010 American Cancer Society. KEY WORDS: antiretroviral, human immunodeficiency virus (HIV), breast, fine needle aspiration (FNA), gynecomastia, abscess, mycobacterial infection. It is not unusual for human immunodeficiency virus (HIV)-positive individuals to present to their healthcare provider with a mass lesion. In the setting of underlying HIV infection, these lesions may be related to reactive conditions such as lymphadenopathy, opportunistic coinfections, and neoplasia. Fine needle Corresponding author: Pam Michelow, MD, Cytology Unit, National Health Laboratory Service, PO Box 1038, Johannesburg, South Africa 2000; Fax: (011) ; pamela.michelow@nhls.ac.za 1 Cytology Unit, Department of Anatomical Pathology, Faculty of Health Sciences, University of the Witwatersrand and National Health Laboratory Service, Johannesburg, South Africa; 2 Department of Medicine, Beth Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; 3 Department of Pathology, Tufts University School of Medicine, Springfield, Massachusetts The authors thank Alex Fourie for compiling and maintaining the database. In addition, we thank the University of the Witwatersrand and National Health Laboratory Service anatomical pathology and microbiology departments for the histologic and microbiologic diagnoses, respectively, and Eric Liebenberg for his photographic assistance. Received: March 3, 2010; Revised: April 11, 2010; Accepted: April 16, 2010 Published online June 22, 2010 in Wiley InterScience ( DOI: /cncy.20083, Cancer Cytopathology August 25, 2010

2 FNA of Breasts in HIV Patients/Michelow et al aspiration (FNA) is often used as one of the primary investigations in the workup of these mass lesions, as it is minimally invasive, cost-effective, accurate, and rapid, allowing prompt and appropriate management. 1 This is particularly useful in resource-poor settings like South Africa. In HIV-infected patients, commonly aspirated sites include superficial lymph nodes and the major salivary glands. 2 However, deep visceral lesions are equally amenable to FNA provided that that resources, such as radiologic-image guidance, are available. Breast masses arising in HIV-positive patients can be due to conditions like gynecomastia, pseudoangiomatous stromal hyperplasia, intramammary lymphadenopathy, opportunistic infections, and/or malignant conditions such as mammary carcinoma, lymphoma, Kaposi sarcoma, and metastases. 3-7 There are a limited number studies that have investigated the cytopathology of HIV-related breast masses. Therefore, the aim of the current study was to evaluate findings from a large series of FNAs performed on breast lesions in HIV-positive patients. MATERIALS AND METHODS The study cases originate from the University of the Witwatersrand and National Health Laboratory Service (NHLS) Cytology Unit, Department of Anatomical Pathology, Johannesburg, South Africa. Drs. Pantanowitz and Dezube are HIV research advisers and long-standing collaborators with this cytology unit. The NHLS is the South African public-sector laboratory. The cytology unit of the NHLS in Johannesburg receives specimens from approximately 20 hospitals, over 400 primary health care clinics, and several nongovernmental organizations (NGOs). In 7 of these hospitals, the cytology unit runs FNA clinics, whereby FNAs are performed by cytology personnel. In the remaining hospitals and clinics, FNAs are performed by the patient physician. In 2007, approximately 120,000 specimens including 12,000 FNA specimens were reported by this cytology unit. The current retrospective and descriptive study at the NHLS Cytology Unit in Johannesburg reviewed an accrued database of 3501 confirmed HIV-positive patients, in which each of these patients underwent an FNA procedure of various body sites during a 5-year period (years ). FNA cases of only the breast were further evaluated capturing data pertaining to patient age and sex, breast lesion (laterality, clinical signs), antiretroviral therapy use, specimen adequacy, and cytologic diagnosis. Details related to HIV status (HIV duration, CD4 cell count, HIV viral load) and antiretroviral therapy regimen were unavailable. Available follow-up of microbiology studies and corresponding or subsequent histopathologic findings were documented. Ethics approval to conduct the study was obtained from the University of the Witwatersrand, Johannesburg, Human Research Ethics Committee. RESULTS A total of 152 breast FNA procedures (4% of all FNAs) were recorded in patients of average age 36 years (range, years) with a female:male ratio of 2:1. Aspirated breast lesions were predominantly unilateral palpable masses ranging from 1 cm to 7 cm in size. Of 152 aspirates, 114 were performed by staff from this cytology unit, 12 (10.5%) of which proved inadequate, whereas 38 were performed by clinicians, of which 16 (42.1%) were suboptimal for cytologic evaluation. One hundred (66%) HIV-positive females underwent breast FNA. FNA was inadequate in 28 (28%) females because of insufficient cellularity to render an interpretation. Where diagnosis was possible, females patients exhibited a wider variety of breast diagnoses compared with males. Twenty-nine (29%) females were diagnosed with benign breast diseases that included cysts, fibroadenoma, and fibrocystic change. Twenty-five (25%) females had a cytologic diagnosis of abscess, of which 6 proved positive for Mycobacterium tuberculosis (Figs. 1 and 2). One abscess proved positive for Propionibacteria on culture. The age range of females manifesting with a breast abscess was 12 to 40 years. Although the majority of these patients with a breast abscess presented with mass lesions varying in size from 2 cm to 5 cm, 2 patients exhibited more diffuse enlargement of their breasts, and 1 had a draining sinus. Breast carcinoma was diagnosed in 8 (8%) females of an average age of 43 years (range, years), and all were reported to be ductal carcinoma. There were 3 (3%) cases of reactive intramammary lymphadenopathy (Fig. 3), 3 (3%) females with cytologic findings in keeping with fat necrosis, and 1 FNA compatible with a galactocele in a 25-year-old lactating female. One (1%) case was diagnosed as a papillary lesion. Two Cancer Cytopathology August 25,

3 FIGURE 1. A Mycobacterium tuberculosis infection with groups of epithelioid histiocytes and scattered lymphoid cells is shown in a necrotic background (Papanicolaou stain; Original magnification, 200). (2%) females, of 12 and 23 years of age who presented clinically with a breast abscess, were diagnosed with non- Hodgkin lymphoma. One was further subtyped as a Burkitt lymphoma (Fig. 4). Fifty-two (34%) HIV-infected males underwent breast FNA. Six (11.5%) breast FNAs in males proved inadequate. Gynecomastia was reported in 43 (83%) of these males. Men with gynecomastia were of average age 42 FIGURE 3. Reactive intramammary lymphadenopathy shows mature and immature polymorphous lymphocytes admixed with few tingible body macrophages (Papanicolaou stain; Original magnification, 400). years (range, years). These males presented primarily with a unilateral breast mass and infrequently (1%) with bilateral breast enlargement. In 17 (40%) gynecomastia cases, a history of antiretroviral therapy was recorded. The size of the breast mass measured 2 cm to 3.5 cm (Fig. 5). Two (4%) males were diagnosed with a breast abscess, 1 in which Mycobacterium tuberculosis was cultured and the other Streptococcus pyogenes. One (2%) male aged 43 years was diagnosed with Kaposi sarcoma that was confirmed on histologic examination. There were no cases of breast carcinoma or lymphoma diagnosed in males (Table 1). FIGURE 2. A Mycobacterium tuberculosis infection is depicted with numerous acute inflammatory cells in a necrotic background. (Papanicolaou stain; Original magnification, 200). FIGURE 4. Illustrated is a Burkitt lymphoma comprising single malignant lymphoid cells with round nuclei, granular chromatin, and several nucleoli per nucleus. (Papanicolaou stain; Original magnification, 600). 220 Cancer Cytopathology August 25, 2010

4 FNA of Breasts in HIV Patients/Michelow et al FIGURE 5. Gynecomastia is depicted. Groups of cohesive ductal cells are shown in a background of stromal cells. (Papanicolaou stain; Original magnification, 200). DISCUSSION South Africa has one of the highest rates of HIV infection worldwide, involving a largely heterosexual population. The national HIV-seroprevalence in pregnant females aged years in 2008 was 29.3%. It is estimated that, at present, approximately 5.5 million South Africans are HIV-positive, which is one-sixth of the global HIV-positive population. 8,9 Given that several conditions may involve the breast in patients with HIV infection, it was not unexpected for us to encounter 152 breast FNA procedures over a 5-year study period in our HIV-positive Table 1. Summary of Cytologic Diagnoses of Breast FNA in HIV-Positive Patients FNA Diagnosis Females (%) Males (%) Inadequate 28 (28) 6 (11.5) Benign breast pattern a 29 (29) Gynecomastia 43 (82.7) Abscess 25 (25) 2 (3.8) Reactive lymphadneopathy 3 (3) Fat necrosis 3 (3) Galactocoele 1 (1) Papillary lesion 1 (1) Breast carcinoma 8 (8) Non-Hodgkin lymphoma 2 (2) Kaposi sarcoma 1 (1.9) Total 100 (100%) 52 (100%) a Benign breast pattern was used in females only and included benign cysts, fibroadenoma, and fibrocystic disease. South African population. This is, to the best of our knowledge, the largest such reported series to date. Our data are limited by the retrospective nature of the study, in some cases by limited clinical follow-up, and lack of a control group. It was impracticable at the time of this study to obtain a control group of patients (especially males with gynecomastia) who were tested and proven to be HIV negative, as the HIV prevalence in South Africa is so high and because the HIV status of the majority of individuals who have FNAs performed in our setting is, unfortunately, unknown. HIV-positive patients within the South African public healthcare system are usually treated predominantly in primary healthcare clinics. The limited communication between these primary clinics and the secondary or tertiary hospitals where FNA procedures are likely to be performed makes follow-up of patients in our setting very difficult. HIV can directly (via immunodeficiency) and indirectly (via coinfection or drug-induced alteration) affect breast glandular tissue, resulting in gynecomastia, adipose tissue deposition in the breast (lipomastia), pseudoangiomatous stromal hyperplasia, and reactive lymphoid-tissue hyperplasia causing intramammary lymphadenopathy. On the basis of these data, unlike HIV-infected females who may present with a wide range of benign and neoplastic breast entities, HIV-positive males may present with breast lesions that are mainly due to gynecomastia associated with antiretroviral therapy. In the era of antiretroviral therapy, breast enlargement is emerging as a problem in the treatment of male HIV-infected patients. In this series, most (83%) of the males who underwent breast FNA were diagnosed with gynecomastia, 40% of whom had a recorded available history of antiretroviral therapy. South Africa began its antiretroviral therapy-rollout program in early 2004, but this medication had been available to a small percentage of HIV-positive patients several years earlier through NGOs and clinical trials. True gynecomastia (not mere clinical breast enlargement) is enlargement of the male breast due to an increase of ductal epithelial and stromal components. HIV may cause gynecomastia both directly, possibly through hypogonadism, hormonal imbalances like excess prolactin production, and other HIV-associated diseases like cirrhosis. Gynecomastia may also indirectly be due to medications such as antiretrovirals, especially protease inhibitors, non-nucleoside reverse transcriptase inhibitors, and antifungals such as ketoconazole. In this Cancer Cytopathology August 25,

5 HIV population, there may be additional causes of gynecomastia such as marijuana use. 7,10-13 FNA in the current series was helpful in diagnosing gynecomastia and confirming observations by others of the association between HIV and gynecomastia. 10 On FNA, gynecomastia may yield variable cellularity and cohesive fragments of ductal epithelial cells, stromal tissue fragments, and associated isolated myoepithelial cells. Significant cellular atypia is sometimes associated with gynecomastia and should not be mistaken for carcinoma. 13 Antiretroviral therapy may also result in lipomastia (increased breast adipose tissue deposition), a component of the lipodystrophy syndrome. Gynecomastia tends to present as a unilateral focal mass, whereas lipomastia is usually bilateral and more generalized, extending beyond retroareolar breast tissue. 12,14,15 On FNA, lipomastia will likely yield only adipose tissue and/or few adipocytes. The cytomorphology of lipomastia has not been described. It is possible that in our series, some of the breast FNAs that contained only fat and were reported as inadequate may, in fact, have been lipomastia. The current study has highlighted the need for better clinical-cytologic correlation in our setting to improve FNAinadequacy rates and the need to educate clinicians on how to properly perform aspirates in hospitals and clinics where an FNA service is not provided by the laboratory. The type of infections likely to be encountered in the breast of HIV-positive individuals will depend, to some extent, on the country in which they live and their degree of immunosuppression. HIV-related breast infections may be due to a pyogenic abscess, mammary tuberculosis, or even unusual microorganisms. In this study, 27 (18%) patients presented with breast abscesses. In 8 (30%) of these cases, microbiology studies confirmed M. tuberculosis infection. Despite the huge burden of mycobacterial infection seen in HIV-infected patients in South Africa, mycobacterial infection of the breast is very uncommon. Nevertheless, mycobacterial breast infection may, on occasion, be the presenting symptom in HIVpositive patients. M. tuberculosis is the most common Mycobacterium to infect the breast. Mammary tuberculosis may present as a breast lump, abscess, discharging sinus, and/or nonhealing ulcer. Clinically, the differential diagnosis may be carcinoma. 7,16,17 Although tubercular mastitis is more common in females than males, as reflected in our series, a recent literature review included 24 cases of male tubercular mastitis (HIV status not taken into account). 18 These authors pointed out that ZN, the most frequently used diagnostic modality to diagnose mammary tuberculosis, permitted observation of only acid-fast bacilli in 33% of cases. Three cytologic patterns of mycobacterial infection were observed in our study. One of the presentations was of a granulomatous lesions consisting of epithelioid histiocytes, multinucleated giant cells, and various numbers of lymphocytes in a background showing small to medium amounts of necrosis. Other patterns of mycobacterial infection included large amounts of necrosis with scattered lymphoid cells only and abscess with large numbers of neutrophils and scattered lymphoid cells in a necrotic background. Ductal epithelial cells in these FNA specimens were seen in some cases. No cases of Mycobacterium avium complex (MAC) were noted in our study. When identified, MAC infection of the breast is more likely to occur in patients with less severe HIV disease and higher CD4 counts. 19 Moreover, there have been some case studies of MAC developing after breast augmentation or instrumentation in HIV-positive females. In the general (HIV-negative) population, the most common microorganism isolated from nonmycobacterial breast abscesses is Staphylococcus aureus, including methicillin-resistant forms. Propionibacteria and S. pyogenes were isolated in 2 of our abscess cases. There is very little literature concerning microorganisms involved in the pathogenesis of breast abscess in HIVinfected patients, except for case studies of unusual infections including Cryptococcus neoformans and Pseudomonas aeruginosa Several noninfectious conditions in HIV-infected persons may cause breast enlargement or a palpable mass. Discrete mass lesions may be caused by lesions unrelated to HIV, for example, fibroadenoma or reactive lymphadenopathy secondary to HIV infection. Intramammary lymph nodes can occur in any quadrant of the breast. Intramammary lymphadenopathy in an HIV-positive patient may be due to local or systemic conditions including generalized lymphadenopathy associated with HIV infection, Castleman disease, lymphoma, Kaposi sarcoma, or metastases. The cytologic findings of intramammary lymphadenopathy are identical to those seen in reactive lymphadenopathy from nonmammary sites, which include a polymorphous lymphoid population associated with tingible body macrophages. 23 Based upon FNA, 3 females were diagnosed with reactive intramammary 222 Cancer Cytopathology August 25, 2010

6 FNA of Breasts in HIV Patients/Michelow et al lymphadenpathy in the current study. In our series, 29% of the females presented with benign diagnoses (cysts, fibroadenomas, and fibrocystic disease) presumably unrelated to their HIV infection. Benign proliferative breast conditions like fibroadenoma arise mainly in females younger than 35 years. 13 Given that the average age of the HIV-positive females in our study was 36 years, it is not surprising that we encountered several cases with benign breast lesions. There is no literature to suggest that the incidence of these benign conditions is changed in HIVpositive females. There is also a paucity of literature on the effect of antiretroviral therapy on the female breast. HIV-positive patients are at increased risk for acquired immune deficiency syndrome (AIDS)-defining cancers, like non-hodgkin lymphoma and Kaposi sarcoma. Next to Kaposi sarcoma, non-hodgkin lymphoma is the second most common AIDS-associated malignancy. Despite this, involvement of the breast by lymphoma is rare. 6,7,24-26 To date, there have been limited reports of breast lymphoma in HIV-infected individuals. 5,7 Such HIV-associated breast lymphoma cases tend to be highgrade, such as Burkitt lymphoma and plasmablastic lymphoma, with an aggressive clinical course. In this study, there were 2 non-hodgkin lymphoma cases of the breast diagnosed by FNA in females aged 12 and 23 years. Highgrade lymphomas like plasmablastic lymphoma that lack typical lymphoid markers, like LCA and/or B-cell markers like CD20, will need to be distinguished from poorly differentiated breast carcinomas. Kaposi sarcoma of the breast is exceedingly rare, but it has been reported in HIVpositive patients. 27 There was 1 male in this series with Kaposi sarcoma of the breast. On cytology, occasional groups of oval to spindled cells were present in a bloodstained background. The differential diagnosis for spindled cells on FNA in an HIV-positive patient includes histiocytes from granulomatous inflammation, mycobacterial spindle cell pseudotumor, Epstein Barr Virus (EBV)-associated smooth muscle tumors, and spindle cell lesions independent of HIV infection (like fibromatosis). In difficult cases, detection of human herpes virus-8 (HHV8) coinfection, found by using the LNA-1 immunocytochemical stain, may be necessary to confirm a diagnosis of Kaposi sarcoma. There is also an increased risk of developing non- AIDS defining malignancy in the HIV-infected population such as lung carcinoma, liver cancer, and Hodgkin lymphoma. In this series, 8% of females and 0% of males were diagnosed with breast carcinoma. Although several cases of breast carcinoma have been reported in females with HIV infection, the overall incidence of breast cancer does not appear to be increased in HIV-positive females Nevertheless, with the advent of antiretroviral therapy, HIV-positive females are living longer, and older patients are more likely to develop breast cancer. It is controversial whether HIV-infected patients with breast carcinoma present with a more advanced cancer stage. Clinical details regarding cancer stage, treatment, and outcome were not determined in the current study. Late-stage presentation of breast carcinoma and poorer prognosis may certainly be related to delay in seeking medical attention, an important consideration in low-resource communities where the availability of medical care is limited. Although breast FNA is falling out of favor in the United States, in countries like South Africa, FNA still provides a suitable, accurate, and cost-effective means to diagnose breast carcinoma. In summary, the current study presented the cytologic findings of the largest series of FNAs performed on breast lesions in HIV-positive patients. These data indicate that FNA in South Africa is a useful procedure to evaluate breast lesions in both males and females, capable of rendering a broad range of diagnoses likely to be encountered in a HIV-positive population. Unlike HIVinfected females who may present with a wide range of breast entities ranging from benign conditions to neoplasia, in HIV-positive males, breast lesions are most likely to be attributed to gynecomastia associated with antiretroviral therapy. CONFLICT OF INTEREST DISCLOSURES This study was funded, in part, from the AIDS Malignancy Treatment and Research Center of Beth Israel Deaconess Medical Center, Boston, Massachusetts. The authors have no connection to any companies or products mentioned in this article. REFERENCES 1. Ellison E, Lapuerta P, Martin S. Fine needle aspiration (FNA) in HIVþ patients: results from a series of 655 aspirates. Cytopathology. 1998;9: Kocjan G, Miller R. The cytology of HIV-induced immunosuppression. Changing patterns of disease in the era of highly active antiretroviral therapy. Cytopathology. 2001;12: Cancer Cytopathology August 25,

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