Diagnosis and Management of Castleman Disease

Multicentric Castleman Disease

Epidemiology

MCD commonly presents in the sixth decade of life, although patients with HIV infection tend to present at a younger age.^4,25,32 A slight male predominance is seen in MCD. HIV infection is an important risk factor for MCD, and all patients with HIV-associated MCD are coinfected with HHV-8. HHV-8 infection is present in approximately 50% of HIV-negative cases of MCD and varies with the HHV-8 seroprevalence of the population.

Large population studies have revealed an in­creased incidence of HIV-associated MCD since the introduction of antiretroviral therapy, which is in con­trast to the marked decline in incidence of HIV-as­sociated Kaposi sarcoma.³³

The mechanism of this increase is unclear, but such an increase may reflect improved survival rates, longstanding immune dys­regulation associated with long-term HIV infection, or an increased awareness of the disease among health care professionals.

Clinical Presentation

Systemic inflammatory manifestations characterize the vast majority of patients with MCD who present with fevers, night sweats, weight loss, and fatigue.^4,25,32 Physical examination is typically notable for general­ized lymphadenopathy and hepatosplenomegaly, and many patients have evidence of fluid retention with lower extremity edema, pleural and pericardial effu­sions, and abdominal ascites.

Common hematological abnormalities include anemia, elevated inflammato­ry markers, hypergammaglobulinemia, and hypoal­buminemia. Systemic symptoms and hematological abnormalities have been shown to correspond to elevated inflammatory markers and cytokine levels, particularly IL-6 and IL-10.

The natural history of MCD is variable. Some patients may present with indolent disease and very slow progression over months to years, while others will experience a relapsing-remitting course or an acute and fulminant disease that can be fatal within weeks; the latter courses are more common in pa­tients with HIV-associated MCD.^34,35

HIV-associated MCD may also concurrently or sequentially present with other concomitant malignancies, including Ka­posi sarcoma or primary effusion lymphoma, each of which share an HHV-8–mediated pathogenesis. Kaposi sarcoma may be identified in 72% of HIV-re­lated MCD cases at diagnosis and may be seen in HIV-negative MCD, although at a far lower rate.³³

Patients are also at significant risk for diffuse large B-cell lymphoma, which may arise directly out of HHV-8–positive MCD; therefore, one must consider the possibility of a second malignancy at the time of diagnosis and perform a thorough skin exam­ination for cutaneous Kaposi sarcoma, as well as consider biopsying bulky or visceral locations seen on imaging studies for staging that may constitute a distinct histology from Castleman disease.

Repeat biopsy should also be considered at progression or relapse to evaluate for lymphomatous transformation. Patients with HIV-associated MCD will often present with a low CD4 count, so concomitant opportunistic infections must also be considered at diagnosis and during the course of illness, including Pneumocystis jiroveci, Toxoplasma gondii, cytomegalovirus, and mycobacterial infections, among others.

Treatment

Treatment options for MCD are based on few non­randomized prospective studies, small case series, and expert opinion; therefore, the body of evidence must be interpreted with caution. Available treatments include glucocorticoids, single-agent and combination chemotherapy, antiviral strategies, and monoclonal antibody therapies targeting CD20 or IL-6.

Antiretroviral Therapy: All patients with HIV infection and MCD should be initiated on combination antiretroviral therapy if they are not already taking it, although antiretroviral therapy alone is unlikely to independently result in a Castleman disease response. The risk of developing MCD is not influenced by the use of combination antiretroviral therapy or by the CD4 count at the time of diagnosis.³³

However, independent of MCD, the initiation of combination antiretroviral therapy can prevent further consequences of poorly controlled HIV, including opportunistic infections and malignancies, and allows for the safe administration of chemotherapy due to immune reconstitution.

Pa­tients should be monitored for immune reconstitution inflammatory syndrome, including an exacerbation of MCD and concurrent Kaposi sarcoma.³⁶

Glucocorticoids: Glucocorticoids have activity as monotherapy in MCD and may offer short-term control of symptoms, but complete remissions are rare and are generally short-lived. Twenty-one cases of MCD treated with glucocorticoids alone have been described in case reports and small case series, and responses were observed in approximately 80% of patients.^4,32,37-42

None of these reported cases were known to be positive for HIV. Given the delayed response to rituximab monotherapy, glucocorticoid pulses may be helpful as an initial adjunct for acutely symptomatic disease. In these patients, prednisone 1 mg/kg daily or its equivalent may be added to rit­uximab until systemic inflammatory symptoms are adequately controlled and then tapered off.

Cytotoxic Chemotherapy: Various agents have been used as single-agent chemotherapy in the treatment of MCD, although data are limited to few case reports and small case series. These include oral etoposide,⁵ vinblastine,⁴³ cyclophosphamide,³² cladribine,^44,45 chlorambucil,³² and liposomal doxoru­bicin.^46,47

Responses following these agents are often short-lived and symptoms may rapidly recur following the completion of therapy. Single-agent chemother­apies are often administered at doses and schedules routinely used to treat patients with lymphoma.

Etopo­side may be administered at a dose of 50 or 100 mg by mouth daily on days 1 through 7 of a 14-day cycle until maximal response, or 100 mg/m² intravenously once weekly for 4 weeks, and can be used with a maintenance schedule to prolong remission duration.

Vinblastine may be administered at a dose of 4 to 6 mg/m² every 2 weeks until maximal response, and it can be used with a maintenance schedule in the absence of significant toxicity.

Combination chemotherapy with cyclophospha­mide/doxorubicin/vincristine/prednisone (CHOP) or cyclophosphamide/vincristine/prednisone (CVP) without rituximab have produced durable remissions in small case series of patients with MCD,^{4,25,32,46,48,49} although many patients will progress or experience infectious toxicities.

These data are primarily from be­fore the introduction of rituximab, and the impact of rituximab in combination with chemotherapy in these patients is unknown. Our practice is to include ritux­imab for most patients and to administer chemother­apy at doses and schedules typical for patients with lymphoma, but infectious risk is increased; therefore, caution and attention to supportive care are required, particularly in patients with low CD4 counts.

Dose reductions may be necessary on the basis of interactions with antiretroviral therapy, because pro­tease inhibitors and non-nucleoside reverse transcrip­tase inhibitors are metabolized by the CYP450 system, which is either induced or inhibited by many che­motherapeutic agents, including cyclophosphamide, doxorubicin, etoposide, vinblastine, and vincristine.