Methods

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Clinical Data

Nine HIV-infected patients with chronic lymphoepithelial cysts were followed prospectively between January 1993 to October 1997, with the approval of the human studies committee. All patients had evidence of HIV-1 antibody by enzyme immunoassay and Western blot. CD4 and CD8 lymphocyte counts were measured by flow cytometry, and plasma viral loads were measured by branched-chain DNA assay (Chiron, Emeryville, California). Computed tomography or magnetic resonance imaging was done in eight patients who also had fluid aspirated from at least one parotid cyst.

Antiretroviral therapy for HIV infection was administered to all nine patients; five patients also received one or two courses of rapidly tapered prednisone therapy (60 mg daily for 2 days, 40 mg daily for 2 days, 20 mg daily for 2 days, and 10 mg daily for 1 day). Before and after treatment, we clinically estimated cyst size by measuring maximum length and width; the estimated depth of the lesions varied between 5 and 10 cm. Patients with a reduction in gland size of more than 95% and no visible parotid enlargement were considered to have completely responded to medical therapy.

Pathologic Evaluation and Immunohistochemical Studies

Surgical sections from patient 9 were exposed to lymphocyte cell antigens (CD45), B-cell antigens (CD20, CD79a), T-cell antigens (CD3, CD45Ro), CD68, p24 antigen of HIV (Dako Corp., Carpenteria, California), cytokeratins (AE1/3) and S-100 protein, and cytokeratins (Cam 5.2) and CD1. These antigens were detected by using the strepavidin-horseradish peroxidase detection kit.

Results

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Clinical Data

Demographic data, risk behaviors for HIV infection, and CD4 lymphocyte counts are summarized in the Table 1 and Table 2. The patients presented with parotid enlargement that had been present for a mean of 5.4 years (Figure 1, left); four patients also had mild symptoms of dry mouth or dry eyes. In eight patients, computed tomography or magnetic resonance imaging showed bilateral, giant, multiloculated cysts in the intraparotid and periparotid area, with evidence of cervical adenopathy and dense nodular infiltration in and around the parotid gland.

View larger version (115K): [in this window] [in a new window]   Figure 1. Lymphoepithelial parotid cyst disease in an HIV-infected patient (patient 2) before (left) and after (right) combination antiretroviral therapy.

Parotid enlargement was the initial sign of HIV infection in at least seven patients, and all patients reported several previous examinations by health care providers who did not provide a diagnosis, suggest HIV testing, or initiate specific treatment. Related psychosocial reactions, such as anxiety, depression, and reclusiveness, were reported by all patients; six patients who completely responded to medical treatment reported improvement in these problems after therapy.

Medical Treatment

Although response to medical treatment often varied by the affected side and by patient, all nine patients responded (Table 1 and Table 2). The cysts completely resolved with combination antiretroviral therapy in six patients (Figure 1, right). Of these patients, five received an HIV protease inhibitor and had sustained responses that lasted for a mean of at least 15 months and were associated with increases in CD4 counts and undetectable plasma HIV branched-chain DNA levels. The sixth patient was lost to follow-up 5 months later. Four of the six patients also received one or two short courses of prednisone therapy that produced a rapid and dramatic reduction in parotid gland size without side effects. Eight patients also had cyst aspiration, which was well tolerated but usually provided only temporary and limited improvement. Partial responses followed by relapses were noted in the three patients who were poorly compliant with antiretroviral therapy.

Pathologic Evaluation and Immunohistochemical Studies

Six months after antiretroviral therapy was stopped, a cystic parotid mass that measured 7 x 4 x 3 cm and contained three separate cysts (which ranged from 1.8 to 2.5 cm in diameter) was removed from patient 9. The cysts were distinct from the normal parotid tissue and were lined by both keratinizing and nonkeratinizing squamous epithelium, which was variably infiltrated by small lymphocytes. Adjacent dense lymphoid tissue showed various degrees of follicular hyperplasia, occasional secondary follicle lysis, and multinucleated giant cells. The interfollicular areas were notable for marked proliferation of plasma cells and prominent postcapillary venules.

Immunoperoxidase studies of the cyst lining yielded positive results for cytokeratin, which confirmed the cyst's epithelial origin. The lymphoid component was positive for CD45, and B cells (CD20, CD79a) were localized in secondary follicles and T cells (CD3, CD45Ro) that stained the paracortical and intrafollicular areas. Lymphocytes that infiltrated the cyst epithelial lining stained predominantly as B cells. Antisera to the HIV p24 antigen localized the virus to germinal centers of secondary follicles and had an interstitial or dendritic pattern. Large multinucleated cells that were present in germinal centers and paracortical areas also stained strongly positive for HIV p24 antigen and expressed CD68 antigen (Kp1); this is consistent with a cell of histiocytic or macrophage lineage. Langerhans cells were occasionally present in paracortical areas.

Discussion

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Our data suggest that lymphoepithelial cysts are not widely recognized as a manifestation of HIV disease. This lack of recognition results in delayed diagnosis and treatment [4, 12]. Patients with benign lymphoepithelial cysts are usually asymptomatic and have CD4 lymphocyte counts that range from 300 to 600 cells/mm³ [4, 9, 11-13]. The cysts are usually chronic, large, multiloculated, and bilateral [4, 12, 13]. Parotid cysts may be diagnosed clinically and confirmed by computed tomography or magnetic resonance imaging [1, 13]. Although lymphoepithelial cysts are highly suggestive of HIV infection, they may be seen with the Sjogren syndrome, the diffuse infiltrative CD8 lymphocytosis syndrome, or tumors or opportunistic infections of the parotid gland [1-3]. In the absence of HIV infection or for patients who have unusual clinical findings or inadequate response to medical therapy, fine-needle aspiration biopsy and surgical resection should be considered.

Previous studies of lymphoepithelial cysts often lacked proper documentation of HIV infection, focused on surgical treatment, and provided limited data on the efficacy of antiretroviral therapy [4-14]. Shaha and coworkers [11] reported a complete response in one of two patients treated with zidovudine, and Schiodt and coworkers [13] reported regression of parotid cysts in four patients treated with zidovudine and steroids. Terry and coworkers [4] reported a complete response in one of six patients treated with zidovudine and a partial response in two patients treated with zidovudine and radiation. Low-dose radiation therapy may provide temporary cosmetic palliation of benign lymphoepithelial cysts [17].

Treatment of HIV disease has improved dramatically with the recent increase in our understanding of HIV dynamics and pathogenesis and progress in the use of viral load assays and combination antiretroviral therapy [15, 16, 18]. In our series, complete, sustained resolution of parotid cyst disease was associated with continued compliance with combination antiretroviral therapy, undetectable HIV branched-chain DNA levels, and increases in CD4 lymphocyte counts. Therefore, for HIV-infected patients with lymphoepithelial cysts, we advocate the currently recommended treatment of combination antiretroviral therapy that includes a protease inhibitor [15, 16]. Although corticosteroid therapy (probably because of its anti-inflammatory and lympholytic effects) resulted in rapid, dramatic decreases in the size of parotid cysts, it may be unnecessary for patients receiving highly active antiretroviral combination therapy [13]. Cyst aspiration was helpful in patients with large cysts that did not regress with antiretroviral therapy but, when used alone, it yielded only temporary improvement.

Bernier and Bhaskar [5] hypothesized that lymphoepithelial cysts in patients without HIV infection arise from epithelial ductular inclusions in lymph nodes. The increased incidence of lymphoepithelial cysts and the different clinical presentation associated with HIV infection probably reflect the high concentrations and rapid turnover of HIV in hyperplastic lymphoid tissue in and adjacent to the parotid parenchyma [1, 5, 18]. Our immunohistologic studies showed high concentrations of HIV p24 antigen in lymphoid tissue; this confirmed the earlier reports of HIV-infected lymph tissues and the immunohistochemical analysis of a patient with benign lymphoepithelial cysts [19, 20]. We hypothesize that HIV-induced cytokines and lymphoid hyperplasia stimulate the adjacent ductal epithelium to produce secretions, which then form cysts that lack communicating ducts. Thus, combination therapy with antiretroviral agents effectively reduces viral replication, lymphoid hyperplasia, and cyst formation; similarly, poor compliance with antiretroviral therapy or infective therapy permits viral replication that limits response and causes relapse.

Patients who present with chronic parotid cysts should be encouraged to undergo HIV testing because these cysts were the presenting manifestation of HIV disease in at least seven of nine patients in our series. Our data showed that the six patients who complied with combination antiretroviral treatment had complete, sustained resolution of parotid cyst disease. Resolution of disease was associated with anecdotal reports of improved self-esteem. Although our data need to be confirmed by other studies, the efficacy of current combination antiretroviral therapy coupled with the potential risks associated with surgical resection suggest that parotid cysts in HIV-infected patients should be managed medically and that surgery should be reserved for patients who refuse, are poorly compliant with, or do not respond to medical therapy.

Presented in part at the Fourth Conference on Retroviruses and Opportunistic Infections, Infectious Diseases Society of America, National Institutes of Health, and the Centers for Disease Control and Prevention, Washington, D.C., 26 January 1997 (abstract 717); and the 35th Annual Meeting of the Infectious Diseases Society of America, San Francisco, California, 15 September 1997 (abstract 420).

Dr. Duncan: Infectious Disease Section, Lahey Hitchcock Clinic, 41 Mall Road, Burlington, MA 01805.

Dr. Stram: Department of Otolaryngology, Boston University School of Medicine, Boston Medical Center, 1 Boston Medical Center Place, Boston, MA 02118.

Dr. O'Hara: Department of Pathology, Boston Medical Center, 1 Boston Medical Center Place, Boston, MA 02118.

Dr. Jhamb: Department of General Internal Medicine, Boston Medical Center, 1 Boston Medical Center Place, Boston, MA 02118.

Dr. Hirschhorn: Dimock Community Health Center, 55 Dimock Street, Roxbury, MA 02119.