**7. Discussion**

Human immunodeficiency virus infection (HIV) is endemic in South Africa and is associated with an increased risk of infection and malignancy, primarily as a consequence of immuno‐ deficiency [9]. The major impact of HIV on the haematological malignancies in South Africa has been in regards to an increased prevalence of Non-Hodgkin lymphoma and, more recently, Hodgkin lymphoma [34,35].

In South Africa, CD is rare. However, there has been a noticeable increase in MCD in the last five years, with more than doubling of the number of patients in the last five years, compared to the previous twenty years (see Figure 4). This is attributable to the ongoing burden of HIV, as the majority of patients in this series with MCD are HIV seropositive (86%).

There were 35 adult patients diagnosed with MCD over a 25-year period at CHBAH, a large, tertiary, public sector, University of the Witwatersrand linked hospital, located in Soweto, Johannesburg. The median age at presentation was 36 years (18–64 years), with a male to female ratio of 1.2:1. The age is similar to that described in the literature. However, in our series, there is no marked male predominance, as the major risk factor in our patients for acquisition of HIV is heterosexual contact as compared to intravenous drug use or homosexuality.

The clinical presentation of MCD is similar to that described in the literature (see Table 2). Fever, 'B' symptoms, lymphadenopathy, hepatosplenomegaly, and anaemia are commonly encountered. Pathologically, the mixed variant is seen in 94% of the patients. The mean CD4 count in the HIV seropositive patients (86%) was 257 × 106 /l, with 46% of the patients having a CD4 count of < 200 × 106 /l. Fifty three percent of the patients had newly diagnosed HIV (at the time of the diagnosis of MCD) and 47% were known to be seropositive (86% of the positive patients were on combination antiretroviral therapy). Concomitant Kaposi's sarcoma was diagnosed in 23% of patients. The HHV-8 immunostain performed on 19/21 patients with MCD in the last five years was positive in 100% of the patients (see Figure 3). Other associations are detailed in Table 2, most of these are related to coexistent HIV or HHV-8. Of note is the high prevalence of concomitant tuberculosis (43%).

A variety of treatments were used over the past twenty years, ranging from symptomatic/ supportive treatment to corticosteroids, single agent chemotherapy, combination chemother‐ apy (such as CHOP and more recently the addition of etoposide to CHOP → CHOEP), rituximab together with CHOP or CHOEP, radiotherapy, and splenectomy. Of the evaluable patients, 53% achieved a complete response to treatment and 47% manifested a partial response to treatment. As our patients have more aggressive and advanced disease, the etoposide and rituximab combinations are now being favoured. All the HIV seropositive patients receive concomitant combination antiretroviral therapy.

Long term follow up is necessary to exclude relapse and complications of the disease, such as the development of large cell lymphoma, which has a 15-fold increased incidence in patients with HIV-associated MCD [36].

### **8. Conclusion**

**6. Management**

254 Immunopathology and Immunomodulation

rituximab (375 mg/m2

and requires further evaluation.

Hodgkin lymphoma [34,35].

100% [29].

zumab) [27].

**7. Discussion**

Treatment modalities for CD include supportive care and specific modalities of treatment.

In the unicentric form of the disease, surgical resection of the localised site of the disease is usually curative. However, follow up is recommended as patients may rarely relapse or develop complications (such as an increased risk of lymphoma development) [23,26,28].

For MCD, a variety of specific treatment options are available, in addition to supportive care (such as analgesia, allopurinol, transfusion of blood and blood products where indicated). Specific treatment modalities include antiviral (anti-herpesvirus) and antiretroviral drugs where a viral association is documented, corticosteroids, monoclonal antibodies, immunomo‐

Chemotherapy has evolved from single-agent (e.g. chlorambucil) to combination chemother‐ apy (cyclophosphamide, doxorubicin, vincristine, prednisone – CHOP), to the addition of rituximab and etoposide [3,11,20,29,30,31]. Bower, 2010 [29], in his excellent review on 'How I treat HIV-associated multicentric Castleman disease', uses a combination of weekly IVI

associated MCD, with an overall 2 year survival of 85% and rituximab monotherapy (375 mg/ m2 weekly for 4 weeks) for low-risk HIV-associated MCD, with an overall 2 year survival of

For HIV-negative, HHV-8 negative MCD, other therapeutic options have been explored. This includes monoclonal antibodies directed against IL-6 (siltuximab) or the IL-6 receptor (tocili‐

Multicentric Castleman's disease (MCD) is increasingly being recognised as a relapsing and remitting disease and in the HIV-seropositive setting is not necessarily suppressed or dimin‐ ished by combination antiretroviral therapy [29]. As such, the role of both rituximab and antiherpesvirus agents such as valganciclovir have been explored as maintenance therapies [20,29,32,33]. However, the role of maintenance therapy in this disease remains controversial

Human immunodeficiency virus infection (HIV) is endemic in South Africa and is associated with an increased risk of infection and malignancy, primarily as a consequence of immuno‐ deficiency [9]. The major impact of HIV on the haematological malignancies in South Africa has been in regards to an increased prevalence of Non-Hodgkin lymphoma and, more recently,

In South Africa, CD is rare. However, there has been a noticeable increase in MCD in the last five years, with more than doubling of the number of patients in the last five years, compared

) for 4 weeks for aggressive HIV-

dulatory agents (such as thalidomide), splenectomy, and radiotherapy [29].

) with IVI etoposide (100 mg/m2

Multicentric Castleman's disease is the most common form of CD encountered in our patients at CHBAH. From being a rare disease, MCD has increased over the past few years, primarily as a result of the association of HIV, being highly seroprevalent in our patient population. The dominant clinical manifestation of MCD is lymphadenopathy. Therefore, the cause of signif‐ icant lymphadenopathy should always be defined, particularly in the setting of HIV. Most of the patients were initially suspected of having a lymphoma, while others with HIV and Kaposi's sarcoma or autoimmune haemolytic anaemia had a lymph node biopsy to define the possible cause of the lymphadenopathy in association with the KS or AIHA. The prognosis of HIV-associated MCD has improved with optimization and control of HIV replication (use of combination antiretroviral therapy), prophylaxis, and treatment of opportunistic infections, as well as etoposide and rituximab based chemotherapy. In the setting of HIV, MCD should no longer be regarded as a rare disease with a fatal outcome.
