Human Immunodeficiency Virus-Negative Castleman's Disease: Clinicopathological and Laboratory Characteristics and Outcomes in Patients Treated in a Single Institution
Authors: Hasija Nalini , Bustamante Liliana , Jaglal Michael V. , Sokol Lubomir 
Published: October 2019

Background Human Immunodeficiency Virus (HIV)-negative Castleman's Disease (HIVnegCD) is a group of rare heterogeneous polyclonal lymphoproliferative disorders of poorly understood etiopathogenesis. Several histological subtypes were previously described including hyaline-vascular, plasma-cell, mixed and plasmablastic. Unicentric Castleman's disease (UCD) is usually treated with complete surgical excision of involved lymph node(s). Multicentric Castleman's Disease (MCD) frequently manifests with generalized lymphadenopathy and systemic B-symptoms due to inflammatory hypercytokinemia. An important role of inflammatory cytokine IL-6 was previously established in MCD in experimental and clinical studies. Patients with MCD usually require systemic therapy.
Objectives Primary purpose of this study was to collect and analyze clinicopathological and laboratory characteristics and outcomes of patients with HIVnegCD treated in a single institution.
Methods Institutional review board (IRB)-approved, Health Insurance Portability and Accountability Act (HIPAA) compliant, retrospective study was conducted at Moffitt Cancer Center. Clinical and laboratory characteristics were extracted from electronic medical records and analyzed using SPSS version 22.0 statistical software.
Results We identified a total of 28 patients (pts) between 1993 and 2015. 14 pts had UCD and 14 MCD. Median age was 49 (35-87) years (UCD) and 47 (31 -79) years (MCD). Male: female ratio was 1:2.5 (UCD) and 1:1.33 (MCD). A majority of patients had a PS 0-1 in both groups (13/13 and 9/10 respectively).
Only 2/13 (15.4%) pts with UCD presented with fatigue and 2 (15.4%) had CNS symptoms. 9 of 14 (64%) pts with MCD reported fatigue and 8/14 (57.1%) presented with night sweats and anorexia. 5 of 14 pts (36%) with MCD were concurrently diagnosed with POEMS syndrome, 2 pts with MGUS and 1 pt with smoldering IgA kappa light chain restricted multiple myeloma. HIV-1/2 ELISA test was negative in all tested pts (18/18). In the remaining 10 pts the test was not available, but a longitudinal follow-up revealed no evidence of immunodeficiency or history of opportunistic infections. HHV-8 test was negative in 9 of 9 tested pts. 2 of 18 pts showed polyclonal hypergammaglobulinemia. 10 of 18 pts had soluble IL-6 tested and only 1 pt with MCD had an elevated level. C-reactive protein (CRP) was elevated in only 1 of 10 pts. Confirmatory histology slide review in our institution revealed a hyaline-vascular subtype in 4 pts with UCD and 6 pts with MCD. 10 pts had plasma-cell subtype (6 with UCD and 4 with MCD) and 2 had mixed subtype (1 each in UCD and MCD). In 6 pts, pathological diagnosis was based only on outside report due to the absence of the original histology slides or insufficient tissue for confirmatory studies. 11 of 13 pts with UCD underwent surgical excision, 1 received radiation therapy and 1 chemotherapy in the frontline settings resulting in complete response. 1 patient with UCD received anti-IL-6 monoclonal antibody for the second line therapy followed by rituximab monotherapy. This patient was the only pt with UCD demonstrating progressive disease. Management of MCD included various systemic regimens listed in Table #1. Chemotherapy regimens included chloramubucil, thalidomide, cyclophosphamide, melphalan, DT-PACE, R-CHOP and lenalidomide. Only 3 pts died and all 3 had progressive refractory MCD. 2 of the pts who died also had POEMS syndrome. Median survival was not reached, as 25 of 28 pts were alive at the time of data collection.
Conclusions This retrospective study indicated that HIVnegCD is a heterogeneous disorder with very good prognosis in patients with resectable UCD. Systemic therapy is usually required in patients with MCD. The increased frequency of malignancies associated with CD such as POEMS syndrome, multiple myeloma, and follicular dendritic cell sarcoma can have adverse impact on prognosis.
Table 1. Treatment of MCD MCD First Line Surgery 1 12 8.3% Steroids 6 12 50% Rituximab 1 12 8.3% IL-6 2 12 16.7% Chemo1 2 12 16.7% Second Line Surgery 1 8 12.5% Rituximab 2 8 25% Chemo2 1 8 12.5% Combo chemo3 2 8 25% Surgery +XRT 1 8 12.5% Auto BMT 1 8 12.5% Third Line XRT 1 5 20% IL-6 1 5 20% Chemo4 2 5 40% Combo chemo5 1 5 20% 1 Chlorambucil/Pred, Thalidomide/Dex 2 Melphalan/Pred 3 Etoposide/Ritux, Lenalidomide/Ritux 4 DT-PACE, Cyclophosphamide/Pred 5 R-CHOP

Disclosures
Sokol: Janssen Research & Development, LLC: Consultancy.