Abstract

Multicentric Castleman's disease is an atypical lymphoproliferative disorder for which multiple chemotherapeutic regimens have been used without much success. Role of biological response modifiers like interferon used as a single agent is discussed in this case report.

The association between HIV infection and multicentric Castleman's disease (MCD) was recognized in 1984, very early in the HIV epidemic [1, 2]. The features common to HIV-related Castleman's disease have since been defined. They include the multicentric plasma cell variant, an association with Kaposi's sarcoma [3], and frequent pulmonary symptoms [4]. The optimal therapy for MCD has not been well defined. We describe here prolonged remission in an HIV-infected patient with MCD after treatment with IFN-α in combination with antiretroviral therapy.

A 51-year-old HIV-infected man presented with a 3-month history of progressive painful lymphadenopathy, fatigue, anorexia, and low-grade fever. He also complained of a nonproductive cough, dyspnea, and weight loss and developed progressive anemia that required transfusion. His medical history was significant for Kaposi's sarcoma treated with cryotherapy 2 years before presentation. His medications included stavudine, lamivudine, saquinavir, and trimethoprim-sulfamethoxazole.

Physical examination revealed hepatosplenomegaly and diffuse tender lymphadenopathy. His CD4+ cell count was 146 cells/mm3 (10%), and his viral load was 5800 copies/mm3 (branched DNA v2.0; Chiron, Emeryville, CA). CT of the chest and abdomen demonstrated hepatosplenomegaly and extensive intra-abdominal and intrathoracic adenopathy. Fine needle aspiration of a lymph node showed mixed lymphocytes and his-tio-cytes with some atypical lymphoid cells resembling follicular center cells. Acid-fast staining, Warthin-Starry staining, and culture of the lymph node specimen were negative. An increase in his viral load to 36,000 copies/mm3 and a decrease of his CD4+ cell count to 93 cells/mm3 prompted a switch of his antiretroviral therapy to zidovudine, lamivudine, and indinavir. His viral load dropped to 2500 copies/mm3, but there was no change in his symptomatology.

Subsequent lymph node biopsy showed florid germinal center hyperplasia with diminished mantle zones, dense interfollicular plasmacytosis, vascular proliferation, and follicular lysis (figures 1 and 2). Immunohistochemically, κ and λ light chains failed to demonstrate monoclonality of plasma cells in the interfollicular area, excluding the diagnosis of lymphoma. Human herpesvirus 8 (HHV-8) DNA sequences were recognized by PCR analysis of the lymph node specimen. In situ hybridization with use of the Epstein-Barr virus-encoded early RNA-1 (EBER-1) probe for detection of Epstein-Barr virus (EBV) was strongly positive in the interfollicular regions, thereby indicating EBV genomic sequences.

IFN-α treatment (5×106 U 3 times a week) was started. Within 4 weeks, his fevers and night sweats disappeared, his appetite improved, and the spleen and lymph nodes decreased in size and were less painful. CT performed 3 months later demonstrated significant reduction in the size of the spleen and lymph nodes. Intolerance of his antiretroviral regimen prompted a switch to zidovudine, lamivudine, and nelfinavir treatment, and subsequent failure of antiretroviral treatment (viral load, 10,086 copies/mm3; determined by branched DNA v3.0) resulted in a switch to stavudine, indinavir, and efavirenz therapy. Twenty-four months later, our patient was receiving IFN-α treatment and was in remission, with a CD4+ cell count of 123 cells/mm3 and a viral load of 1763 copies/mm3.

MCD, also known as angiofollicular lymphoid hyperplasia, is a neoplastic-like illness characterized by nonspecific constitutional symptoms, lymphadenopathy, and typical pathological findings [5]. Two oncogenic and lymphotropic herpesviruses (namely, HHV-8 and EBV) have been associated with HIV-related MCD [6, 7]. Fever, night sweats, respiratory symptoms, weight loss, hepatosplenomegaly, and lymphadenopathy are the most frequent findings. Anemia and an elevated C-reactive protein level are found in 70%–80% of cases [8]. High loads of HHV-8 in peripheral blood lymphocytes and high C-reactive protein levels correlate with the clinical symptoms of MCD [8].

In the absence of prospective randomized clinical trials, the optimal therapy for MCD is not well defined. In a recent series of patients with HIV-related MCD [8], vinblastine therapy resulted in remission in 24 of 28 patients, and etoposide treatment resulted in remission in 8 of 9 patients. Cidofovir therapy was effective in 1 of 4 patients. The median survival was 24 months.

The impact of highly active antiretroviral therapy (HAART) on MCD is not clear. Virological suppression with HAART does not necessarily stop the progression of MCD [9]. Furthermore, several cases of rapidly progressive and fatal disease after initiation of HAART have been described [10]. In our patient, there was no correlation between the fluctuation in viral load due to initiation and interruption of HAART and the symptoms of MCD.

The use of IFN-α in HIV-related MCD has been described in 3 patients who received this agent in combination with vinblastine and splenectomy [3]. The 2 patients who tolerated IFN-α had complete remission. The successful use of IFN-α alone to treat MCD has been described only in 3 HIV-uninfected patients [11–13]. Remission ranged from 11 months to at least 32 months. Possible mechanisms of action of IFN-α in MCD include an antiproliferative effect through direct binding of IFN-α on cell surface receptors, an antiviral effect via inhibition of viral replication, enhanced natural killer cell activity, and an increase in major histocompatibility complex class I expression on cells infected by HHV-8 [13]. IFN-α has also been reported to induce remission in B cell lymphoproliferative disorders after transplantation, possibly by restoring the cytokine balance and by inhibiting EBV-induced B cell growth [14, 15]. Successful treatment of HIV-related MCD with IFN-α alone has not been previously reported. Because of the simplicity of self-administration of IFN and a relatively favorable side effect profile, IFN-α may be considered as a sole agent in the treatment of HIV-related MCD.

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Figures and Tables

Figure 1

A lymph node biopsy specimen from a patient with HIV-related multicentric Castleman's disease; the stained preparation shows germinal center hyperplasia with a diminished mantle zone (hematoxy-lin-eosin stain; original magnification, ×250).

Figure 1

A lymph node biopsy specimen from a patient with HIV-related multicentric Castleman's disease; the stained preparation shows germinal center hyperplasia with a diminished mantle zone (hematoxy-lin-eosin stain; original magnification, ×250).

Figure 2

A lymph node biopsy specimen from a patient with HIV-related multicentric Castleman's disease; the stained preparation shows vascular proliferation and plasmacytosis (hematoxylin-eosin stain; original magnification, ×400).

Figure 2

A lymph node biopsy specimen from a patient with HIV-related multicentric Castleman's disease; the stained preparation shows vascular proliferation and plasmacytosis (hematoxylin-eosin stain; original magnification, ×400).

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