Background: Castleman disease (CD) encompasses a spectrum of rare disorders with characteristic histopathological features. Unicentric CD (UCD) is a benign, local hyperplasia of lymphoid tissue that is usually curable. Multicentric CD (MCD) manifests as a potentially life-threatening systemic disease with complex symptomatology which is mostly due to an overproduction of interleukin-6 (IL-6) or dysregulation of IL-6-related signaling pathways. From a therapeutic perspective, it is important to distinguish idiopathic MCD (iMCD) from those cases that are associated with the human herpesvirus-8 (HHV-8 + MCD). Summary: During recent years, it has become increasingly clear that even HHV-8-negative MCD is not a homogeneous entity and that there are clinically distinct variants. International consensus guidelines for diagnosis and treatment have been developed for iMCD and UCD. Key Messages: We herein summarize recent advances in diagnosis, treatment, and novel insights into the pathogenesis of this disease.

Keywords:
Castleman disease, Unicentric CD, Multicentric CD, HHV-8, Siltuximab
1.
Castleman B, Towne VW. Case records of the Massachusetts General Hospital; weekly clinicopathological exercises.
N Engl J Med
. 1954 Sep 2;251(10):396–400.
2.
Kessler E. Multicentric giant lymph node hyperplasia. A report of seven cases.
Cancer
. 1985 Nov 15;56(10):2446–51.
3.
Munshi NC, Mehra M, van de Velde H, Desai A, Potluri R, Vermeulen J. Use of a claims database to characterize and estimate the incidence rate for Castleman disease.
Leuk Lymphoma
. 2015 May;56(5):1252–60.
4.
Haap M, Wiefels J, Horger M, Hoyer A, Müssig K. Clinical, laboratory and imaging findings in Castleman’s disease – The subtype decides.
Blood Rev
. 2018 May;32(3):225–34.
5.
Mukherjee S, Martin R, Sande B, Paige JS, Fajgenbaum DC. Epidemiology and treatment patterns of idiopathic multicentric Castleman disease in the era of IL-6 directed therapy.
Blood Adv
. 2022 Jan 25;6(2):359–67.
6.
Masaki Y, Kawabata H, Fujimoto S, Kawano M, Iwaki N, Kotani T, et al. Epidemiological analysis of multicentric and unicentric Castleman disease and TAFRO syndrome in Japan.
J Clin Exp Hematop
. 2019 Dec 22;59(4):175–8.
7.
Powles T, Stebbing J, Bazeos A, Hatzimichael E, Mandalia S, Nelson M, et al. The role of immune suppression and HHV-8 in the increasing incidence of HIV-associated multicentric Castleman’s disease.
Ann Oncol
. 2009 Apr;20(4):775–9.
8.
Parez N, Bader-Meunier B, Roy CC, Dommergues JP. Paediatric Castleman disease: report of seven cases and review of the literature.
Eur J Pediatr
. 1999 Aug;158(8):631–7.
9.
Chisholm KM, Fleming MD. Histologic and laboratory characteristics of symptomatic and asymptomatic Castleman disease in the pediatric population.
Am J Clin Pathol
. 2020 May 5;153(6):821–32.
10.
Pauwels P, Dal Cin P, Vlasveld LT, Aleva RM, van Erp WF, Jones D. A chromosomal abnormality in hyaline vascular Castleman’s disease: evidence for clonal proliferation of dysplastic stromal cells.
Am J Surg Pathol
. 2000 Jun;24(6):882–8.
11.
Chang KC, Wang YC, Hung LY, Huang WT, Tsou JH, M Jones D, et al. Monoclonality and cytogenetic abnormalities in hyaline vascular Castleman disease.
Mod Pathol
. 2014 Jun;27(6):823–31.
12.
Goodman AM, Jeong AR, Phillips A, Wang HY, Sokol ES, Cohen PR, et al. Novel somatic alterations in unicentric and idiopathic multicentric Castleman disease.
Eur J Haematol
. 2021 Dec;107(6):642–9.
13.
Fajgenbaum DC, van Rhee F, Nabel CS. HHV-8-negative, idiopathic multicentric Castleman disease: novel insights into biology, pathogenesis, and therapy.
Blood
. 2014 May 8;123(19):2924–33.
14.
Pierson SK, Shenoy S, Oromendia AB, Gorzewski AM, Langan Pai RA, Nabel CS, et al. Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease.
Blood Adv
. 2021 Sep 14;5(17):3445–56.
15.
Murakami M, Johkoh T, Hayashi S, Ohshima S, Mizuki M, Nakatsuka SI, et al. Clinicopathologic characteristics of 342 patients with multicentric Castleman disease in Japan.
Mod Rheumatol
. 2020 Sep;30(5):843–51.
16.
Fajgenbaum DC. Novel insights and therapeutic approaches in idiopathic multicentric castleman disease.
Blood
. 2018 Nov 29;132(22):2323–30.
17.
Nabel CS, Sameroff S, Shilling D, Alapat D, Ruth JR, Kawano M, et al. Virome capture sequencing does not identify active viral infection in unicentric and idiopathic multicentric Castleman disease.
PLoS One
. 2019 Jun 26;14(6):e0218660.
18.
Wing A, Xu J, Meng W, Rosenfeld AM, Li EY, Wertheim G, et al. Transcriptome and unique cytokine microenvironment of Castleman disease.
Mod Pathol
. 2022;35(4):451–61.
19.
Arenas DJ, Floess K, Kobrin D, Pai RAL, Srkalovic MB, Tamakloe MA, et al. Increased mTOR activation in idiopathic multicentric Castleman disease.
Blood
. 2020 May 7;135(19):1673–84.
20.
Fajgenbaum DC, Langan RA, Japp AS, Partridge HL, Pierson SK, Singh A, et al. Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6-blockade-refractory idiopathic multicentric Castleman disease.
J Clin Invest
. 2019 Aug 13;129(10):4451–63.
21.
Pai RAL, Japp AS, Gonzalez M, Rasheed RF, Okumura M, Arenas D, et al. Type I IFN response associated with mTOR activation in the TAFRO subtype of idiopathic multicentric Castleman disease.
JCI Insight
. 2020 May 7;5(9):e135031.
22.
Li H, Wang H, Nicholas J. Detection of direct binding of human herpesvirus 8-encoded interleukin-6 (vIL-6) to both gp130 and IL-6 receptor (IL-6R) and identification of amino acid residues of vIL-6 important for IL-6R-dependent and -independent signaling.
J Virol
. 2001 Apr;75(7):3325–34.
23.
Moore PS, Boshoff C, Weiss RA, Chang Y. Molecular mimicry of human cytokine and cytokine response pathway genes by KSHV.
Science
. 1996 Dec 6;274(5293):1739–44.
24.
Oksenhendler E, Carcelain G, Aoki Y, Boulanger E, Maillard A, Clauvel JP, et al. High levels of human herpesvirus 8 viral load, human interleukin-6, interleukin-10, and C reactive protein correlate with exacerbation of multicentric castleman disease in HIV-infected patients.
Blood
. 2000 Sep 15;96(6):2069–73.
25.
Hoffmann C, Schmid H, Müller M, Teutsch C, van Lunzen J, Esser S, et al. Improved outcome with rituximab in patients with HIV-associated multicentric Castleman disease.
Blood
. 2011 Sep 29;118(13):3499–503.
26.
Haq IU, Dalla Pria A, Papanastasopoulos P, Stegmann K, Bradshaw D, Nelson M, et al. The clinical application of plasma kaposi sarcoma herpesvirus viral load as a tumour biomarker: results from 704 patients.
HIV Med
. 2016 Jan;17(1):56–61.
27.
Guihot A, Oksenhendler E, Galicier L, Marcelin AG, Papagno L, Bedin AS, et al. Multicentric Castleman disease is associated with polyfunctional effector memory HHV-8-specific CD8+ T cells.
Blood
. 2008 Feb 1;111(3):1387–95.
28.
Sbihi Z, Dossier A, Boutboul D, Galicier L, Parizot C, Emarre A, et al. iNKT and memory B-cell alterations in HHV-8 multicentric Castleman disease.
Blood
. 2017 Feb 16;129(7):855–65.
29.
Fajgenbaum DC, Uldrick TS, Bagg A, Frank D, Wu D, Srkalovic G, et al. International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease.
Blood
. 2017 Mar 23;129(12):1646–57.
30.
Keller AR, Hochholzer L, Castleman B. Hyaline-vascular and plasma-cell types of giant lymph node hyperplasia of the mediastinum and other locations.
Cancer
. 1972 Mar;29(3):670–83.
31.
Fajgenbaum DC, Wu D, Goodman A, Wong R, Chadburn A, Nasta S, et al. Insufficient evidence exists to use histopathologic subtype to guide treatment of idiopathic multicentric Castleman disease.
Am J Hematol
. 2020 Dec;95(12):1553–61.
32.
Liu AY, Nabel CS, Finkelman BS, Ruth JR, Kurzrock R, van Rhee F, et al. Idiopathic multicentric Castleman’s disease: a systematic literature review.
Lancet Haematol
. 2016 Apr;3(4):e163–75.
33.
Li Z, Lan X, Li C, Zhang Y, Wang Y, Xue W, et al. Recurrent PDGFRB mutations in unicentric Castleman disease.
Leukemia
. 2019 Apr;33(4):1035–8.
34.
You L, Lin Q, Zhao J, Shi F, Young KH, Qian W, et al. Whole-exome sequencing identifies novel somatic alterations associated with outcomes in idiopathic multicentric Castleman disease.
Br J Haematol
. 2020 Mar;188(5):e64–67.
35.
Butzmann A, Kumar J, Sridhar K, Gollapudi S, Ohgami RS. A review of genetic abnormalities in unicentric and multicentric Castleman disease.
Biology
. 2021 Mar 24;10(4):251.
36.
van Rhee F, Oksenhendler E, Srkalovic G, Voorhees P, Lim M, Dispenzieri A, et al. International evidence-based consensus diagnostic and treatment guidelines for unicentric Castleman disease.
Blood Adv
. 2020 Dec 8;4(23):6039–50.
37.
Mukherjee S, Martin R, Sande B, Glen C, Paige J, Yarlagadda S, et al. A longitudinal population level analysis of healthcare resource utilization, comorbidity, and survival in idiopathic multicentric castleman disease patients. Abstract 2059, 62nd ASH Meeting, Dec 5-8, 2020.
Blood
. 2020;136(Suppl 1):11.
38.
van Rhee F, Voorhees P, Dispenzieri A, Fosså A, Srkalovic G, Ide M, et al. International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease.
Blood
. 2018 Nov 15;132(20):2115–24.
39.
Bower M. How I treat HIV-associated multicentric Castleman disease.
Blood Nov
. 2010;25116(22):4415–21.
40.
Nishikori A, Nishimura MF, Nishimura Y, Notohara K, Satou A, Moriyama M, et al. Investigation of IgG4-positive cells in idiopathic multicentric Castleman disease and validation of the 2020 exclusion criteria for IgG4-related disease.
Pathol Int
. 2022 Jan;72(1):43–52.
41.
Sasaki T, Akiyama M, Kaneko Y, Takeuchi T. Immunoglobulin G4-related disease and idiopathic multicentric Castleman’s disease: confusable immune-mediated disorders.
Rheumatology
. 2022 Feb 2;61(2):490–501.
42.
Bower M, Pria AD, Coyle C, Nelson M, Naresh K. Diagnostic criteria schemes for multicentric Castleman disease in 75 cases.
J Acquir Immune Defic Syndr
. 2014 Feb 1;65(2):e80–2.
43.
Polizzotto MN, Uldrick TS, Wyvill KM, Aleman K, Marshall V, Wang V, et al. Clinical features and outcomes of patients with symptomatic kaposi sarcoma herpesvirus (KSHV)-associated inflammation: prospective characterization of KSHV inflammatory cytokine syndrome (KICS).
Clin Infect Dis
. 2016 Mar 15;62(6):730–8.
44.
Morra DE, Pierson SK, Shilling D, Nemat S, Appiani C, Guilfoyle M, et al. Predictors of response to anti-IL6 monoclonal antibody therapy (siltuximab) in idiopathic multicentric Castleman disease: secondary analyses of phase II clinical trial data.
Br J Haematol
. 2019 Jan;184(2):232–41.
45.
Jiang Y, Hou G, Zhu Z, Huo L, Li F, Cheng W. 18F-FDG PET/CT imaging features of patients with multicentric Castleman disease.
Nucl Med Commun
. 2021 Jul 1;42(7):833–8.
46.
Koa B, Borja AJ, Aly M, Padmanabhan S, Tran J, Zhang V, et al. Emerging role of 18F-FDG PET/CT in Castleman disease: a review.
Insights Imaging
. 2021 Mar 11;12(1):35.
47.
Talat N, Belgaumkar AP, Schulte KM. Surgery in Castleman’s disease: a systematic review of 404 published cases.
Ann Surg
. 2012 Apr;255(4):677–84.
48.
Yu L, Shi M, Cai Q, Strati P, Hagemeister F, Zhai Q, et al. A novel predictive model for idiopathic multicentric castleman disease: the International Castleman Disease Consortium Study.
Oncologist
. 2020 Nov;25(11):963–73.
49.
Oksenhendler E, Boutboul D, Fajgenbaum D, Mirouse A, Fieschi C, Malphettes M, et al. The full spectrum of Castleman disease: 273 patients studied over 20 years.
Br J Haematol
. 2018 Jan;180(2):206–16.
50.
Bower M, Newsom-Davis T, Naresh K, Merchant S, Lee B, Gazzard B, et al. Clinical features and outcome in HIV-associated multicentric Castleman’s disease.
J Clin Oncol
. 2011 Jun 20;29(18):2481–6.
51.
Zhang MY, Jia MN, Chen J, Feng J, Cao XX, Zhou DB, et al. UCD with MCD-like inflammatory state: surgical excision is highly effective.
Blood Adv
. 2021 Jan 12;5(1):122–8.
52.
Naddaf E, Dispenzieri A, Mandrekar J, Mauermann ML. Clinical spectrum of Castleman disease-associated neuropathy.
Neurology
. 2016 Dec 6;87(23):2457–62.
53.
Iwaki N, Fajgenbaum DC, Nabel CS, Gion Y, Kondo E, Kawano M, et al. Clinicopathologic analysis of TAFRO syndrome demonstrates a distinct subtype of HHV-8-negative multicentric castleman disease.
Am J Hematol
. 2016 Feb;91(2):220–6.
54.
Nishimura Y, Fajgenbaum DC, Pierson SK, Iwaki N, Nishikori A, Kawano M, et al. Validated international definition of the thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly clinical subtype (TAFRO) of idiopathic multicentric Castleman disease.
Am J Hematol
. 2021 Oct 1;96(10):1241–52.
55.
Kawabata H, Fujimoto S, Sakai T, Yanagisawa H, Kitawaki T, Nara K, et al. Patient’s age and D-dimer levels predict the prognosis in patients with TAFRO syndrome.
Int J Hematol
. 2021 Aug;114(2):179–88.
56.
Suichi T, Misawa S, Sekiguchi Y, Shibuya K, Tsuneyama A, Suzuki YI, et al. Treatment response and prognosis of POEMS syndrome coexisting with Castleman disease.
J Neurol Sci
. 2020 Jun 15;413:116771.
57.
Boutboul D, Fadlallah J, Chawki S, Fieschi C, Malphettes M, Dossier A, et al. Treatment and outcome of unicentric Castleman disease: a retrospective analysis of 71 cases.
Br J Haematol
. 2019 Jul;186(2):269–73.
58.
Mohan M, Meek JC, Meek ME, Broadwater R, Alapat D, van Rhee F. Combinatorial treatment for unresectable unicentric Castleman disease.
Eur J Haematol
. 2021 Oct;107(4):484–8.
59.
van Rhee F, Wong RS, Munshi N, Rossi JF, Ke XY, Fosså A, et al. Siltuximab for multicentric Castleman’s disease: a randomised, double-blind, placebo-controlled trial.
Lancet Oncol
. 2014 Aug;15(9):966–74.
60.
van Rhee F, Casper C, Voorhees PM, Fayad LE, Gibson D, Kanhai K, et al. Long-term safety of siltuximab in patients with idiopathic multicentric Castleman disease: a prespecified, open-label, extension analysis of two trials.
Lancet Haematol
. 2020 Mar;7(3):e209–17.
61.
Ebisawa K, Shimura A, Honda A, Masamoto Y, Nakahara F, Kurokawa M. Hemoglobin and C-reactive protein levels as predictive factors for long-term successful glucocorticoid treatment for multicentric Castleman’s disease.
Leuk Lymphoma
. 2021 Mar;62(3):614–9.
62.
Dong Y, Zhang L, Nong L, Wang L, Liang Z, Zhou D, et al. Effectiveness of rituximab-containing treatment regimens in idiopathic multicentric Castleman disease.
Ann Hematol
. 2018 Sep;97(9):1641–7.
63.
Zhang L, Zhao AL, Duan MH, Li ZY, Cao XX, Feng J, et al. Phase 2 study using oral thalidomide-cyclophosphamide-prednisone for idiopathic multicentric Castleman disease.
Blood
. 2019 Apr 18;133(16):1720–8.
64.
Killian M, Viel S, Chalayer E, Forest F, Grange S, Bonnefoy PB, et al. JAK1/2 inhibition in severe TAFRO syndrome: a case report.
Ann Int Med
. 2021 May;174(5):719–21.
65.
Lust H, Gong S, Remiker A, Rossoff J. Idiopathic multicentric Castleman disease with TAFRO clinical subtype responsive to IL-6/JAK inhibition: a pediatric case series.
Pediatr Blood Cancer
. 2021 Oct;68(10):e29261.
66.
Bower M, Powles T, Williams S, Davis TN, Atkins M, Montoto S, et al. Brief communication: rituximab in HIV-associated multicentric castleman disease.
Ann Intern Med
. 2007 Dec 18;147(12):836–9.
67.
Gérard L, Bérezné A, Galicier L, Meignin V, Obadia M, De Castro N, et al. Prospective study of rituximab in chemotherapy-dependent human immunodeficiency virus associated multicentric Castleman’s disease: ANRS 117 CastlemaB Trial.
J Clin Oncol
. 2007 Aug 1;25(22):3350–6.
68.
Bower M, Veraitch O, Szydlo R, Charles P, Kelleher P, Gazzard B, et al. Cytokine changes during rituximab therapy in HIV-associated multicentric Castleman disease.
Blood
. 2009 May 7;113(19):4521–4.
69.
Gérard L, Michot JM, Burcheri S, Fieschi C, Longuet P, Delcey V, et al. Rituximab decreases the risk of lymphoma in patients with HIV-associated multicentric Castleman disease.
Blood
. 2012 Mar 8;119(10):2228–33.
70.
Powles T, Stebbing J, Montoto S, Nelson M, Gazzard B, Orkin C, et al. Rituximab as retreatment for rituximab pretreated HIV-associated multicentric Castleman disease.
Blood
. 2007 Dec 1;110(12):4132–3.
71.
Abdallah NH, Habermann T, Buadi FK, Gertz MA, Lacy MQ, Rajkumar SV, et al. Multicentric castleman disease-a single center experience of treatment with a focus on autologous stem cell transplantation.
Am J Hematol
. 2022 Apr;97(4):401–10.
72.
Pierson SK, Khor JS, Ziglar J, Liu A, Floess K, NaPier E, et al. ACCELERATE: a patient-powered natural history study design enabling clinical and therapeutic discoveries in a rare disorder.
Cell Rep Med
. 2020 Dec 22;1(9):100158.
© 2022 S. Karger AG, Basel
2022
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.