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 HIV-MCD 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). According to a review on 84 cases with HIV-MCD, life expectancy of the patients seems to have significantly improved in the era of combination ART (mortality rate of only 29% when compared to 75% in the pre-HAART era). During recent years, prognosis further improved, mainly due to the increased use of the monoclonal antibody rituximab (Hoffmann 2011, Michot 2011).

Pathogenesis

The pathogenesis of the disease is not completely understood. There is a close association to HHV-8, and as a result about half of the patients also have KS. Lymph nodes involved by HIV-MCD are often involved by KS (Naresh 2008). HHV-8 encodes a homologue of IL-6 (viral IL-6) that has been shown to be biologically active in several assays and whose activities mirror those of its mammalian counterparts. In particular IL-6 and IL-10 are elevated with close association to the HHV-8 viral load (Oksenhendler 2000). Viral IL-6 mediates its effects through the gp130 signal transducer, but signaling is not dependent on the structurally related IL-6 receptor subunit of the receptor-signal transducer complex (Moore 1996, Li 2001, Suthaus 2010). It is postulated that viral IL-6 thus has a broader spectrum of potential target cells than human IL-6. This may be reflected by the clinically impressive “cytokine storms” which are observed periodically in patients suffering from HIV-MCD. HHV8-infected plasmablasts localise to the mantle zones of the lymphoid follicles (El Daly 2010). Of note, there are reports of MCD cases negative for HHV-8-infection (Seo 2009) but also of an interleukin-6-related systemic inflammatory syndrome in HIV-infected patients with HHV-8 but without MMCD (Uldrick 2010). In these cases, the pathogenesis remains unclear.

It remains also unclear, why only a small proportion of patients with active HIV/HHV-8 coinfection develops HIV-MCD. It should be noted that the extent of immunodeficiency varies significantly in these patients. We and others have seen MCD patients with a normal immune status and low viral load (Powles 2009). Moreover, ART does not appear to protect against HIV-MCD. In our own cohort of 52 patients, the majority of the patients with HIV-MCD were already on ART and had a viral load of less than 400 copies/ml at the time of diagnosis (Hoffmann 2011). It is also of note that HIV-MCD, unlike KS, is not associated with a lack of HHV-8-specific CD8 T cells or limitation of their functional profile (Guihot 2008). There is also evidence that the incidence of HIV-MCD is increasing. It appears to occur more frequently in older HIV-positive individuals with well-preserved immune function (Powles 2009).

Progression to malignant lymphoma (often HHV-8-associated entities such as PEL or plasmablastic subtypes) 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). However, in patients treated with rituximab, the lymphoma risk appears to be significant lower than in patients treated with conventional chemotherapies (Hoffmann 2011, Michot 2011).

Signs and symptoms

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. Almost all patients complain of weakness and severe malaise. There is always massive splenomegaly. Hepatomegaly (70%), respiratory symptoms (65%) and edema with hypoalbuminemia (55%) are also seen in the majority of cases. 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.

The extent of symptoms is very variable and may fluctuate considerably. Many patients report on “Castleman episodes”, lasting from a few days to one or two weeks. Between these episodes, most patients do again relatively well for weeks or even months. In most patients leaving untreated for HIV-MC, however, the frequency of the episodic flares is increasing over time.

Diagnosis

The diagnosis is made histologically after lymph node extirpation – providing that the pathologist knows what HIV-MCD looks like. 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.

Clinicians should explicitly indicate their suspicion. It is possible that a significant proportion of cases are never correctly diagnosed. In every case of episodic flares of B-symptoms, splenomegaly, lymphadenopathy and elevated CRP the diagnosis of HIV-MCD must be considered.  HIV alone rarely causes such severe illness! In the case of the symptoms described above, the pathological diagnosis of HIV-associated lymphadenopathy should thus not be accepted too easily.

Ultrasound reveals hepatosplenomegaly. Laboratory tests show hypoalbuminemia and hypergammaglobulinemia. There is often significant anemia which may be hemolytic, often reflecting pancytopenia or hemophagocytic syndrome (Stebbing 2009).

In our experience, CRP is a useful parameter for monitoring the activity of HIV-MCD and observing the effectiveness of MCD treatment.. During an episodic flare, CRP levels of more than 100 mg/l can bee seen. Between the episodes, however, CRP is often reaching normal ranges. In some patients, clinical symptoms are preceeded by elevated CRP levels. Treatment success is reflected by sustained decrease of CRP. Determining the HHV-8-DNA level may also be useful in diagnosing and for following up (Marcelin 2007, Stebbing 2011).

Treatment

At present, there is no widely accepted recommendation for a specific treatment for MCD. However, something has to be done quickly as the course of disease can be extremely fulminant. According to newer data, we believe that the use of rituximab is the treatment of choice in HIV-infected patients with MCD (see below). Some experts advocate rituximab monotherapy for good performance status patients without organ involvement and rituximab with chemotherapy for more aggressive disease (Bower 2010). ART 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 ART, leading to the suspicion that the inflammatory component of MCD may be increased by immune reconstitution (Zietz 1999).

Apart from ART, there are numerous, very diverse forms of therapy. However, no option has been tested in randomized, controlled trials. Another problem lies also within the countless case reports, where a probable positive “publication bias” has to be taken into account.

Rituximab: this monoclonal antibody against CD20-expressing cells is also used in B cell lymphomas (see above). It has been speculated that rituximab is effective in HIV-MCD by eliminating or reducing the pool of HHV-8 infected B cells which are localized mainly in the mantle zone of lymph nodes. Rituximab has being tried with success in several patients with HIV-MCD (Corbellino 2001, Marcelin 2003, Casquero 2006). More recently, at least two larger studies came to encouraging results. In a French study, 16/24 patients with HIV-MCD reached a complete remission of clinical symptoms after four cycles of rituximab (Gérard 2006). The overall survival (OS) after one year was 92% and the disease-free survival (DFS) was 74%. In a British study, 20/21 patients achieved a clinical remission with rituximab, and 14/21 patients showed a radiological response (Bower 2007). After two years, OS and DFS were 95% and 79%, respectively. CRP, immune globulins, cytokines such as IL-5, IL-6 or IL-10 and HHV-8-viremia decreased after treatment (Bower 2009). In our cohort, rituximab markedly improved prognosis in HIV-infected patients with MCD, compared to patients receiving chemotherapy only (Hoffmann 2011).

Rituximab is usually given at a dose 375 mg per m2 body surface, once weekly over four weeks. Attention should be paid to a good hydration of the patients. Rituximab is usually well tolerated. The main adverse event seems to be a reactivation of KS, which is seen in up to a third of the cases (Bower 2007).

Rituximab is also effective as retreatment for rituximab pretreated HIV-MCD (Powles 2007). Based on the data published to date and on our own experiences we would consider rituximab to be the first option in patients with HIV-MCD. However, there also some case reports in which rituximab was not successful (Neuville 2005, Buchler 2008). For these cases, other therapeutical approaches are to be discussed in the following briefly.

Valgancyclovir: promising approach as this antiviral agent may act against HHV-8. As shown by a randomized trial, valgancyclovir significantly reduces the frequency and quantity of HHV-8 replication (Casper 2008). More recently, preliminary data suggest that valgancyclovir (combined with high-dose AZT) is active in HIV-MCD. Of 14 patients, 12 had “clinical improvement”, showing a decline of inflammatory markers such as CRP, IL-6 and HHV-8 viremia (Uldrich 2011). However, in our own cohort we were unable to confirm these findings (Hoffmann 2011). According to some experts, valgancyclovir may have a role as maintenance therapy in the future (Bower 2010). In contrast, antiviral therapy with foscarnet or cidofovir had no benefit (Coty 2003, Senanayake 2003, Berezne 2004).

Chemotherapy: 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, Kotb 2006). Even CHOP standard chemotherapy can help, but does not seem to significantly prolong survival.

Splenectomy: may be appropriate in severe cases. It is speculated that IL-6 production is reduced and that a large reservoir of HHV-8 is removed through the splenectomy. 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).

Anti-IL-6 receptor antibodies: In HIV-negative patients, very optimistic data from Japan have been published, in which patients were successfully treated with anti-IL-6 receptor antibodies such as tocilizumab (Nishimoto 2005, Matsuyama 2007). In Europe, tocilizumab has been approved in 2009 for treatment of rheumatoid arthritis. There are no data in patients with HIV-MCD.

Thalidomide: This drug is believed to inhibit cytokine dysregulation as well as the inflammatory component of MCD. Case reports in HIV-MCD exist (Lee 2003, Jung 2004). It should be noted that thalidomide has been associated with venous thrombo-embolic events, including deep venous thrombosis and pulmonary emboli. Anticoagulation during thalidomide administration is mandatory. We have seen two patients developing pulmonary emboli despite anticoagulation. Therefore we would not recommend the use of thalidomide in HIV-MCD.

Other immune therapies: For interferon, there are positive as well as negative examples (Coty 2003, Nord 2003). Steroids have no effect on MCD.

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Filed under 13. Malignant Lymphomas, Multicentirc Castleman's Disease (MCD), Part 3 - AIDS

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