scholarly journals Characteristics and outcomes of KSHV-associated multicentric Castleman disease with or without other KSHV diseases

2021 ◽  
Vol 5 (6) ◽  
pp. 1660-1670
Author(s):  
Ramya Ramaswami ◽  
Kathryn Lurain ◽  
Mark N. Polizzotto ◽  
Irene Ekwede ◽  
Kirsta Waldon ◽  
...  
Keyword(s):  
Primary Effusion Lymphoma ◽  
Treatment Options ◽  
Kaposi Sarcoma ◽  
Progression Free Survival ◽  
The United States ◽  
Castleman Disease ◽  
High Dose ◽  
People Living With Hiv ◽  
Multicentric Castleman Disease ◽  
Associated Diseases

Abstract Kaposi sarcoma (KS)-associated herpesvirus (KSHV)–associated multicentric Castleman disease (MCD) is a relapsing and remitting systemic lymphoproliferative disorder characterized by severe inflammatory symptoms most common among people living with HIV (PLWH). Patients with KSHV-MCD may present with concurrent KSHV-associated diseases, such as KS and/or primary effusion lymphoma (PEL). We evaluated clinical and immunologic characteristics, the effects of concurrent KSHV malignancies, and treatments from the largest prospective natural history study of participants with KSHV-MCD within the United States. Treatment options administered at investigator discretion included high-dose zidovudine with valganciclovir (AZT/VGC), rituximab, or rituximab with liposomal doxorubicin (R-Dox) during KSHV-MCD flares. Survival analyses and prognostic factors were explored for all participants. Sixty-two participants with HIV were enrolled, including 20 with KSHV-MCD alone, 34 with KSHV-MCD and KS, 1 with KSHV-MCD and PEL, and 7 with all KSHV-associated diseases. Forty-four percent of KSHV-MCD diagnoses were made at our institution. Forty-four participants received rituximab-based therapies, 20 of whom had maintenance AZT/VGC or interferon. Participants receiving R-Dox and then maintenance AZT/VGC had the highest 5-year progression-free survival (89%). Cytokine profiles during KSHV-MCD flares did not differ by the presence of concurrent KSHV-associated diseases. The 10-year survival was 71% (95% confidence interval [CI], 56% to 82%) for all participants. A concurrent diagnosis of PEL negatively impacted survival (PEL hazard ratio, 5.4; 95% CI, 1.8 to 16.8). KSHV-MCD is an underdiagnosed condition among PLWH, including those with KS. KSHV-MCD has an excellent prognosis with appropriate treatment. Physicians should be alert for patients with multiple KSHV diseases, which impact optimal treatment and survival outcomes. This study was registered at www.clinicaltrials.gov as #NCT00099073.

scholarly journals High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Castleman disease: a pilot study of virus-activated cytotoxic therapy

Blood ◽  
2011 ◽  
Vol 117 (26) ◽  
pp. 6977-6986 ◽  
Author(s):  
Thomas S. Uldrick ◽  
Mark N. Polizzotto ◽  
Karen Aleman ◽  
Deirdre O'Mahony ◽  
Kathleen M. Wyvill ◽  
...  
Keyword(s):  
Pilot Study ◽  
Kaposi Sarcoma ◽  
Progression Free Survival ◽  
Castleman Disease ◽  
Response Criteria ◽  
Target Cells ◽  
High Dose ◽  
Multicentric Castleman Disease ◽  
Best Response ◽  
Lytic Genes

Kaposi sarcoma herpesvirus (KSHV)–associated multicentric Castleman disease (MCD) is a lymphoproliferative disorder most commonly observed in HIV-infected patients. It is characterized by KSHV-infected plasmablasts that frequently express lytic genes. Patients manifest inflammatory symptoms attributed to overproduction of KSHV viral IL-6, human IL-6, and human IL-6. There is no standard therapy and no established response criteria. We investigated an approach targeting 2 KSHV lytic genes, ORF36 and ORF21, the protein of which, respectively, phosphorylate ganciclovir and zidovudine to toxic moieties. In a pilot study, 14 HIV-infected patients with symptomatic KSHV-MCD received high-dose zidovudine (600 mg orally every 6 hours) and the oral prodrug, valganciclovir (900 mg orally every 12 hours). Responses were evaluated using new response criteria. A total of 86% of patients attained major clinical responses and 50% attained major biochemical responses. Median progression-free survival was 6 months. With 43 months of median follow-up, overall survival was 86% at 12 months and beyond. At the time of best response, the patients showed significant improvements in C-reactive protein, albumin, platelets, human IL-6, IL-10, and KSHV viral load. The most common toxicities were hematologic. These observations provide evidence that therapy designed to target cells with lytic KSHV replication has activity in KSHV-MCD. This trial was registered at www.clinicaltrials.gov as #NCT00099073.

Detection of viral interleukin-6 in Kaposi sarcoma–associated herpesvirus–linked disorders

Blood ◽  
2001 ◽  
Vol 97 (7) ◽  
pp. 2173-2176 ◽  
Author(s):  
Yoshiyasu Aoki ◽  
Robert Yarchoan ◽  
Kathleen Wyvill ◽  
Shin-ichiro Okamoto ◽  
Richard F. Little ◽  
...  
Keyword(s):  
United States ◽  
Interleukin 6 ◽  
Blood Donors ◽  
Primary Effusion Lymphoma ◽  
Kaposi Sarcoma ◽  
The United States ◽  
Castleman Disease ◽  
Hiv Status ◽  
Hiv Patients ◽  
Multicentric Castleman Disease

Abstract Expression of a viral interleukin-6 (vIL-6) has been detected in certain Kaposi sarcoma (KS)–associated herpesvirus positive (KSHV+) lesions. The release of vIL-6 systemically and its contribution to the pathogenesis of HIV-related malignancies was studied. Serum vIL-6 was detected in 13 (38.2%) of 34 HIV+ patients with KS, in 6 (85.7%) of 7 HIV+patients with primary effusion lymphoma (PEL) and/or multicentric Castleman disease (MCD), and in 18 (60.0%) of 30 HIV+, mostly homosexual, individuals without KS, MCD, or PEL. By contrast, serum vIL-6 was detected in only 3 (23.1%) of 13 patients with classic KS, 1 (2.5%) of 40 blood donors from the United States, and 4 (19.0%) of 21 blood donors from Italy. Circulating vIL-6 levels were associated with HIV+ status (P < .0001). However, within the HIV+ cohort, serum vIL-6 levels were not associated with the occurrence of KSHV-associated malignancies (P = .43).

scholarly journals KSHV- and EBV-associated germinotropic lymphoproliferative disorder

Blood ◽  
2002 ◽  
Vol 100 (9) ◽  
pp. 3415-3418 ◽  
Author(s):  
Ming-Qing Du ◽  
Tim C. Diss ◽  
Hongxiang Liu ◽  
Hongtao Ye ◽  
Rifat A. Hamoudi ◽  
...  
Keyword(s):  
Lymphoproliferative Disorder ◽  
Gene Rearrangement ◽  
Primary Effusion Lymphoma ◽  
Kaposi Sarcoma ◽  
Castleman Disease ◽  
Lymphoproliferative Disorders ◽  
Multicentric Castleman Disease ◽  
Tissue Sections ◽  
Response To Chemotherapy ◽  
Ig Heavy Chain

Abstract Kaposi sarcoma–associated herpesvirus (KSHV) is known to be associated with 3 distinct lymphoproliferative disorders: primary effusion lymphoma (PEL), multicentric Castleman disease (MCD), and MCD-associated plasmablastic lymphoma. We report 3 cases of a previously undescribed KSHV-associated lymphoproliferative disorder. The disease presented as localized lymphadenopathy and showed a favorable response to chemotherapy or radiotherapy. Histologically, the lymphoproliferation is characterized by plasmablasts that preferentially involved germinal centers of the lymphoid follicles, forming confluent aggregates. They were negative for CD20, CD27, CD79a, CD138, BCL6, and CD10 but showed monotypic κ or λ light chain. Clusters of CD10+CD20+ residual follicle center cells were identified in some of the follicles. The plasmablasts were positive for both KSHV and EBV, and most of them also expressed viral interleukin-6 (vIL-6). Unexpectedly, molecular analysis of whole tissue sections or microdissected KSHV-positive aggregates demonstrated a polyclonal or oligoclonal pattern of immunoglobulin (Ig) gene rearrangement. The plasmablasts showed somatic mutation and intraclonal variation in the rearranged Ig genes, and one case expressed switched Ig heavy chain (IgA), suggesting that they originated from germinal center B cells. We propose calling this distinctive entity “KSHV-associated germinotropic lymphoproliferative disorder.”

scholarly journals Latent KSHV infection increases the vascular permeability of human endothelial cells

Blood ◽  
2011 ◽  
Vol 118 (19) ◽  
pp. 5344-5354 ◽  
Author(s):  
Christophe Guilluy ◽  
Zhigang Zhang ◽  
Prasanna M. Bhende ◽  
Lisa Sharek ◽  
Ling Wang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vascular Permeability ◽  
Latent Infection ◽  
Primary Effusion Lymphoma ◽  
Kaposi Sarcoma ◽  
Castleman Disease ◽  
Cell Junctions ◽  
Paracrine Factors ◽  
Kshv Infection ◽  
Multicentric Castleman Disease

Abstract Kaposi sarcoma–associated herpesvirus (KSHV) is associated with 3 different human malignancies: Kaposi sarcoma (KS), primary effusion lymphoma, and multicentric Castleman disease. The KS lesion is driven by KSHV-infected endothelial cells and is highly dependent on autocrine and paracrine factors for survival and growth. We report that latent KSHV infection increases the vascular permeability of endothelial cells. Endothelial cells with latent KSHV infection display increased Rac1 activation and activation of its downstream modulator, p21-activated kinase 1 (PAK1). The KSHV-infected cells also exhibit increases in tyrosine phosphorylation of vascular endothelial (VE)–cadherin and β-catenin, whereas total levels of these proteins remained unchanged, suggesting that latent infection disrupted endothelial cell junctions. Consistent with these findings, we found that KSHV-infected endothelial cells displayed increased permeability compared with uninfected endothelial cells. Knockdown of Rac1 and inhibition of reactive oxygen species (ROS) resulted in decreased permeability in the KSHV-infected endothelial cells. We further demonstrate that the KSHV K1 protein can activate Rac1. Rac1 was also highly activated in KSHV-infected endothelial cells and KS tumors. In conclusion, KSHV latent infection increases Rac1 and PAK1 activity in endothelial cells, resulting in the phosphorylation of VE-cadherin and β-catenin and leading to the disassembly of cell junctions and to increased vascular permeability of the infected endothelial cells.

scholarly journals Kaposi sarcoma–associated herpesvirus/human herpesvirus 8–associated lymphoproliferative disorders

Blood ◽  
2019 ◽  
Vol 133 (11) ◽  
pp. 1186-1190 ◽  
Author(s):  
Eric Oksenhendler ◽  
David Boutboul ◽  
Lionel Galicier
Keyword(s):  
B Cells ◽  
Primary Effusion Lymphoma ◽  
Human Herpesvirus ◽  
Kaposi Sarcoma ◽  
Castleman Disease ◽  
Lymphoproliferative Disorders ◽  
Human Herpesvirus 8 ◽  
Herpesvirus 8 ◽  
Multicentric Castleman Disease ◽  
Infected Cells

Abstract Kaposi sarcoma–associated herpesvirus/human herpesvirus 8 is associated with multicentric Castleman disease (MCD) and primary effusion lymphoma (PEL). In MCD, infected B cells, although polyclonal, express a monotypic immunoglobulin Mλ phenotype, probably through editing toward λ light chain in mature B cells. They are considered to originate from pre–germinal center (GC) naive B cells. Both viral and human interleukin-6 contribute to the plasmacytic differentiation of these cells, and viral replication can be observed in some infected cells. PEL cells are clonal B cells considered as GC/post-GC B cells. One can also hypothesize that they originate from the same infected naive B cells and that additional factors could be responsible for their peculiar phenotype.

scholarly journals HIV-associated multicentric Castleman disease: a report of 19 cases at an oncology institution

2020 ◽  
Vol 31 (4) ◽  
pp. 318-325 ◽  
Author(s):  
P Volkow-Fernández ◽  
C Lome-Maldonado ◽  
H Quintero-Buenrostro ◽  
B Islas-Muñoz ◽  
P Cornejo-Juárez
Keyword(s):  
Clinical Characteristics ◽  
Plasma Cells ◽  
Kaposi Sarcoma ◽  
Castleman Disease ◽  
People Living With Hiv ◽  
Multicentric Castleman Disease ◽  
Positron Emission ◽  
Systemic Symptoms ◽  
Clinical Records ◽  
Living With Hiv

The aim of this study is to describe the clinical characteristics and outcome of multicentric Castleman disease (MCD) in HIV-infected patients at an oncological referral center in Mexico. Clinical records at the HIV-AIDS clinic of all patients diagnosed with MCD from 1994 to 2018 were reviewed. There were 19 patients, mean age was 31.3 ± 8.4 years, and 17 (89.5%) were males. Fifteen patients (79%) had also Kaposi sarcoma (KS). Main clinical characteristics were multiple lymphadenopathy (95%), systemic symptoms (63%), and hepatosplenomegaly (50%). Computed tomography scan and 2-[18F]-fluoro-2-deoxy-d-glucose positron emission tomography showed multiple lymphadenopathy, inversion of the liver:spleen uptake ratio, with an increase in SUVmax (5.7). The histopathology report described plasma cells in 58%, mixed type in 26%, and hyaline vascular in 16%. Eleven patients (57.9%) received different chemotherapy regimens. Seven patients died (36.8%): four related to MCD progression or chemotherapy complications, median survival was eight months. For those patients who survived, median, follow-up was 28 months (p < 0.001). The incidence of MCD in people living with HIV is probably underestimated. In patients with lymphadenopathy, B symptoms, deranged inflammatory markers, and/or disseminated KS, a biopsy of an enlarged lymph node is warranted, and the histology should be reviewed by an experienced pathologist.

scholarly journals How I treat HHV8/KSHV-related diseases in posttransplant patients

Blood ◽  
2012 ◽  
Vol 120 (20) ◽  
pp. 4150-4159 ◽  
Author(s):  
Giovanni Riva ◽  
Mario Luppi ◽  
Patrizia Barozzi ◽  
Fabio Forghieri ◽  
Leonardo Potenza
Keyword(s):  
Primary Effusion Lymphoma ◽  
Bone Marrow Failure ◽  
Clinical Manifestations ◽  
Human Herpesvirus ◽  
Calcineurin Inhibitors ◽  
Kaposi Sarcoma ◽  
Mtor Inhibitors ◽  
Castleman Disease ◽  
Diagnostic Features ◽  
Multicentric Castleman Disease

Abstract Posttransplantation human herpesvirus-8 (HHV8)/Kaposi sarcoma herpesvirus (KSHV) primary infection and/or reactivations are associated with uncommon and sometimes fatal, neoplastic, and non-neoplastic diseases. HHV8-related clinical manifestations notably range from Kaposi sarcoma (KS) to either primary effusion lymphoma or multicentric Castleman disease B-cell malignancies, and from polyclonal HHV8-positive plasmacytic lymphoproliferative disorders to bone marrow failure and peripheral cytopenias, associated or not with hemophagocytic syndromes, and to acute hepatitis syndromes. We reviewed the patient series reported in the literature and summarized clinical management aspects, in terms of diagnosis, follow-up, and treatment. We described typical clinical presentations and histopathologic diagnostic features of these diseases, and we discussed the role of HHV8-specific serologic, molecular, and immunologic assays, particularly focusing on recent data from HHV8-specific T-cell monitoring in posttransplantation KS patients. We finally discussed actual therapeutic options, namely, the reduction or discontinuation of immunosuppressive therapy or the switch from calcineurin inhibitors to mTOR inhibitors, as alternatives to antineoplastic chemotherapy, along with the use of antiherpesvirus agents as prophylactic or therapeutic measures, and treatment with rituximab in posttrans-plantation multicentric Castleman disease patients and non-neoplastic HHV8-associated syndromes.

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