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The first reported case and management of multicentric Castleman's disease associated with Kaposi's sarcoma in an HIV-2-infected patient

Sophie, Bouvressea; Anne-Geneviève, Marcelinb; Nathalie, Francka; Stéphanie, Regniera; Florence, Damondc; Micheline, Tulliezd; Nicolas, Dupina

doi: 10.1097/QAD.0b013e3281df33fc

aAssistance Publique Hôpitaux de Paris, Department of Dermatology, Tarnier–Cochin Hospital, Paris, France

bAssistance Publique Hôpitaux de Paris, Department of Virology, Pitie-Salpetriere Hospital, Université Pierre et Marie Curie, Paris, France

cAssistance Publique Hôpitaux de Paris, Department of Virology, Bichat Hospital, Paris, France

dAssistance Publique Hôpitaux de Paris, Department of Pathology, Cochin Hospital, Paris Cedex, France.

The multicentric variant of plasma-cell Castleman's disease (MCD) often coexists with Kaposi's sarcoma (KS) in HIV-1-infected patients, and this association could be explained by the possible involvement of human herpes virus 8 (HHV-8) in their pathogenesis. MCD has never been described in an HIV-2-infected patient. We report the first case of MCD associated with HIV type 2 infection and its successful management with rituximab.

A 46-year-old man was referred for asthenia and anorexia with important loss of weight. This homosexual patient originating from Cape Verde had no past medical history. A few days before his admission, seropositivity for HIV-2 was discovered. Physical examination revealed enlargement of all lymph nodes, mild hepatomegaly and palpable spleen. The initial laboratory evaluation included the following: moderate normocytic aregenerative anaemia and positive direct Coombs tests without haemolysis, hypergammaglobulinemia, elevated C-reactive protein (45 mg/l), and a high ferritin level with low serum iron level. HIV-2 was confirmed, with a high viral load (93 100 copies/ml) and low CD4 lymphocyte count (133 cells/μl). The HHV-8 viral load was detectable (3231 copies/150 000 cells).

Histological examination of the biopsy specimen from axillary lymph nodes confirmed the diagnosis of Castleman's disease, and staining for HHV-8 (Fig. 1) underlined HHV-8-positive cells in the mantle zone, large HHV-8-positive cells dispersed in interfollicular areas and foci of KS with HHV-8 and latent nuclear antigen type 1 stain being present in fusiform-shaped cells. The patient was treated with two cycles of vinblastine, with a dramatic improvement, but symptoms relapsed within 2 weeks. At this time, bone marrow analysis showed evidence of toxic aplasia and a large amount of cytomegalovirus (290 000 copies/ml) in spite of cytomegalovirus viraemia negativity. HAART combining tenofovir, emtricitabine, lopinavir and ritonavir was initiated one week after the beginning of vinblastine; it was interrupted a few weeks later because of an episode of massive bloody diarrhoea with important loss of weight. Histological analysis of a colic biopsy sample showed non-specific ulcerated colitis with marked nuclear dystrophy, evocating a viral disease, but imunohistochemical methods failed to isolate any pathogen (including cytomegalovirus or HHV-8). Considering the possibly viral diarrhoea and the prolonged aplasia with high cytomegalovirus load in bone marrow, the patient underwent intravenous ganciclovir for 2 weeks. We observed a neutrophil count normalization and remarkable improvement of diarrhoea, and HAART was then started again.

Fig. 1

Fig. 1

Vinblastine was discontinued because of persisting fever, high HHV-8 viral load, and increased C-reactive protein. He was treated with four weekly infusions of rituximab at a standard dose of 375 mg/m2 without adverse reactions. Systemic symptoms quickly improved, and hepatosplenomegaly and lymphadenopathy disappeared. Moreover, the biological parameters normalized with negation of HHV-8 viraemia. At the 4-month follow-up, the patient remained symptom free, with normal biological analysis and non-detectable HHV-8 and HIV-2 viral loads.

The development of HHV-8-related diseases such as KS and MCD is explained partly by the immunodeficiency induced by HIV infection. Also, the association of concurrent or preceding MCD with KS is well documented, especially in HIV-positive patients [1,2]. To our knowledge, however, no MCD associated with HIV type 2 infection has ever been reported. When Ariyoshi et al. [3] demonstrated that KS was less frequent in HIV-2 than in HIV-1 infection, Gallo [4] suggested that an RGD domain in HIV-1 Tat would be involved in the development of the microvascular lesions of KS. As HIV-2 Tat protein does not contain this RGD domain, it is predictable that KS is less diagnosed in HIV-2-infected patients. Although single-agent chemotherapy with vinblastine may be effective, clinical remission is typically short lived. In HIV-positive patients, the initiation of HAART has little effect on the course of MCD, and could even precipitate its onset [5,6]. Considering that symptoms of MCD could be mediated by either HHV-8 gene product or the immune response to viral replication, then the use of antiviral agents would seem appropriate. Whereas one study reported the efficacy of ganciclovir [7], others failed to demonstrate any action of cidofovir, which seem to be the most active drugs on HHV-8 replication in vitro [8].

The lymph nodes of patients with HHV-8-related MCD specifically harbour the virus in B cells located in the mantle zone, which stain positively for the CD20 surface antigen. Therefore, rituximab has been proposed and increasingly used to target and purge HHV-8-infected neoplastic B cells, with various clinical results [9,10]. In this observation, although ganciclovir may have a responsibility in clinical outcome, rituximab was the only drug associated with a persistent decrease in HHV-8 viral load and C-reactive protein, as well as the relief of clinical symptoms with a follow-up of more than 4 months.

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