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Multicentric Castleman's Disease (MCD) Christian Hoffmann

Although rare, multicentric Castleman's disease is a highly problematic illness for the affected patients - not only due to the (in HIV infection) poor prognosis, but also because many clinicians and pathologists are not very familiar with this entity. The usually severely ill patients are often subjected to diverse diagnostic and therapeutic procedures. In comparison to the benign, localized hyperplasia of lymphatic tissue, first described by Castleman in 1956, HHV-8-associated multicentric Castleman's disease, as it occurs in HIV infection, is a malignant lymphoproliferative disease (Oksenhendler 1996). Although multicentric Castleman's disease in HIV is not classified as a lymphoma or AIDS-defining illness, prognosis is poor. In a prospective study, the median survival was 14 months (Oksenhendler 1996).

The pathogenesis of the disease is not well understood. There is a close association to HHV-8, and as a result about half of the patients also have Kaposi's sarcoma. Cytokine dysregulation seems to play an important role - in particular IL-6 and IL-10 are elevated with close association to the HHV-8 viral load (Oksenhendler 2000). The extent of immunodeficiency varies significantly. We have seen an MCD patient with a normal immune status and low viral load. Progression to malignant lymphoma (often HHV-8-associated entities such as PEL) is frequent. In by far the largest prospective study to date with 60 MCD cases, 14 patients developed malignant lymphoma after a median observation period of 20 months (Oksenhendler 2002).

The main signs are the often significant lymph node enlargements, which are almost always combined with considerable B symptoms including fever, night sweats and weight loss. Patients complain of weakness and malaise. There is always massive splenomegaly. Hepatomegaly (70 %), respiratory symptoms (65 %) and edema with hypoalbuminemia (55 %) are also seen in the majority of cases. The extent of symptoms is very variable and may fluctuate considerably. Some patients have Castleman "episodes". Lymph nodes, which may be anything from very soft (as with tuberculosis) to rock hard (as with lymphoma) on palpation, can normalize or relapse within weeks without any intervention.

Ultrasound reveals hepatosplenomegaly. Laboratory tests show constantly elevated CRP, hypergammaglobulinemia and hypoalbuminemia. There is often significant anemia (may be hemolytic, often reflecting pancytopenia).

The diagnosis is made histologically after lymph node extirpation - providing that the pathologist knows what HIV-associated multicentric Castleman's disease looks like. Clinicians should explicitly indicate their suspicion. It is possible that a significant proportion of cases are never correctly diagnosed. In the case of the symptoms described above, the pathological diagnosis of HIV-associated lymphadenopathy should not be accepted too easily. HIV alone rarely causes such severe illness! The germinal centers of affected lymph nodes have an onion-skin appearance with vascular proliferation. Hyaline-vascular and plasma cell types of Castleman's disease can be distinguished.

At present, there is no clear recommendation for a specific treatment for MCD. HAART should always be given, although it doesn't always help (Dupin 1997, Lanzafame 2000, Aaron 2002, de Jong 2003, Sprinz 2004). Some cases have even been described to occur after starting HAART, leading to the suspicion that the inflammatory component of MCD may be increased by immune reconstitution (Zietz 1999). Apart from HAART, there are numerous, very diverse forms of therapy, which unfortunately means that so far none of them is particularly convincing. The problem lies also within the countless case reports, where a probable positive "publication bias" has to be taken into account. On the other hand, something has to be done quickly in HIV patients with MCD: the course of disease can be extremely fulminant. In our experience, CRP is a useful parameter aside from symptoms and signs, for measuring the course of disease and observing the effectiveness of MCD treatment.

Immunomodulation - because of the association with HHV-8, several antiviral substances have been tried, including ganciclovir, which was successful on at least one patient (Caspar 2003). However, in other cases, antiviral therapy with foscarnet or cidofovir had no benefit (Coty 2003, Senanayake 2003, Berezne 2004). For interferon, there are positive as well as negative examples (Coty 2003, Nord 2003). In HIV-negative patients, some very optimistic data from Japan has been published, in which 7 patients were successfully treated with anti-IL-6 receptor antibodies (Nishimoto 2000). Another new approach, supported by an encouraging number of case studies, is thalidomide, which is believed to inhibit cytokine dysregulation as well as the inflammatory component of MCD (Lee 2003, Jung 2004). In contrast, steroids have no effect on MCD.

Immunochemotherapy - well-tolerated chemotherapies such as vincristine (2 mg i.v. as a bolus at 14-day intervals) or oral etoposide (50 mg daily) have proven effective according to several reports as well as our own experience (Scott 2001). Even CHOP chemotherapy can help, but does not seem to significantly prolong survival. Rituximab, a monoclonal antibody against CD20-expressing cells, which is also used in B cell lymphomas (see above), is being tried in several patients (Corbellino 2001, Marcelin 2003, Marrache 2003, Kofteridis 2004). In a study on 5 HIV patients with MCD, remission was achieved in 3 (Marcelin 2003). However, there are also reports in which rituximab has no effect (Casquero 2005, Neuville 2005).

Splenectomy - in severe cases, splenectomy may be appropriate. In a series of 40 patients, the median survival following splenectomy was 28 versus 12 months (Oksenhendler 2002). According to a US team, the symptoms were improved in 10/10 patients following splenectomy (Coty 2003). Why this should occur, is currently unclear. It is speculated that IL-6 production is reduced and that a large reservoir of HHV-8 is removed through the splenectomy.

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