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Castleman disease (CD) is a rare nonclonal lymphoproliferative disorder, also known as angiofollicular lymph-node hyperplasia or giant node hyperplasia. It was first reported in 1954 and in 1956 described by Benjamin Castleman, MD, in a case series of localized mediastinal lymph-node hyperplasia.1 Unicentric Castleman (UCD) disease presents as a localized disease affecting a single lymph node/lymph node chain. Multicentric Castleman disease (MCD) is a more widespread or generalized disease (Table 1). About 4,000 to 6,000 new cases of CD are diagnosed per year of which about 20% to 25% cases are MCD. The estimated incidence rate for CD has recently been calculated as 21 to 25 per million person-years, or about 6,000 new cases annually.2
The clinical presentation of CD often overlaps with autoimmune, infectious, or other malignant diseases. The diagnosis is confirmed by a biopsy of the affected lymph-node tissue. Interleukin-6 (IL-6) and a viral analog of IL-6 play major role in the pathogenesis by stimulating a widespread inflammatory response that results in systemic manifestations. It is often associated with HIV and human herpesvirus-8 (HHV-8) infections. Castleman disease is histologically characterized into the hyaline vascular variant, the plasma-cell variant, and the mixed form. The plasmablastic variety is associated with HIV and HHV-8 infections. The prognosis ranges from good in UCD (91% overall survival [OS] at 5 y) to poor in MCD (65% OS at 5 y).3
Treatment options range from local surgical excision to systemic treatments. Newer therapies include monoclonal antibodies against both IL-6 and CD20 and a few other targets in the inflammatory cascade. This article discusses the updated approach to diagnosis and management of CD.
Unicentric Castleman Disease
Unicentric CD is more common than MCD, presents as a localized lymph node or chain involvement, and is generally diagnosed in the third or fourth decade of life but has been reported in children. The presenting symptoms of UCD vary by site. It presents as nontender lymphadenopathy when confined to peripheral lymph nodes, whereas respiratory symptoms or bowel obstruction may be seen with lymphadenopathy in the chest/mediastinum, neck, or abdomen. The systemic
symptoms, such as fever, night sweats, and weight loss, are uncommon.
Dysplastic follicular dendritic cells characterize UCD. Histologically, it is usually classified as hyaline vascular disease with the follicles comprising small lymphocytes
and dendritic cells forming concentric rings with prominent vascularity.4,5 No association with HIV or HHV-8 has been seen.
Unicentric CD is often amenable to resection, and a complete cure can be achieved.6 Partial resection may be attempted when complete resection is not possible. Radiation therapy is offered for unresectable disease.7 In patients who are not candidates for any intervention, close long-term follow-up is recommended unless patients are symptomatic, in which case systemic treatment should be considered.
Multicentric Castleman Disease
The more widespread MCD is generally diagnosed in the fifth or sixth decade of life. It is more aggressive than UCD and presents a wide spectrum of symptoms and abnormal laboratory findings (Table 2).8
It is histologically classified into (a) plasmablastic or HHV-8 associated: It is often seen in patients with MCD infected with HIV, which can give rise to large B-cell lymphoma, known as HHV-8 plasmablastic lymphoma9; (b) plasmacytic variant has marked paracortical plasmacytosis with retained nodal architecture10; and (c) mixed MCD has abundant plasma cells with features similar to those of the hyaline-vascular variant.
Most patients with HIV-associated MCD are co-infected with HHV-8. The HHV-8 infection is also present in about 50% of HIV-negative cases.11 The incidence of HIVassociated MCD is increasing in the highly active antiretroviral therapy (HAART) era secondary to improved survival of patients infected with HIV.12 To diagnose active HIV MCD, the French Agence Nationale de Recherche sur le SIDA 117 CastlemaB trial group has described criteria based on the clinical symptoms, including fever, a raised serum C-reactive protein > 20 mg/L without any other cause, and 3 of 12 additional clinical findings described as peripheral lymphadenopathy, splenomegaly, ascites, edema, pleural effusion, cough, nasal obstruction, xerostomia, rash, central neurologic symptoms, jaundice, and autoimmune hemolytic anemia.13 The reported 2-year survival of patients who are HIV-negative is 97% compared with HIV-positive cases at 67%.14
Idiopathic MCD is diagnosed when there is no evidence of any underlying infectious, autoimmune, and neoplastic process.15
Patients with MCD are at an increased risk of developing non-Hodgkin and Hodgkin lymphoma, Kaposi sarcoma, primary effusion lymphoma, and follicular dendritic
cell sarcoma. POEMS (peripheral neuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome and paraneoplastic disease, such as paraneoplastic pemphigus myasthenia gravis, may be commonly diagnosed concurrently or sequentially with MCD.16-20
The disease course of MCD ranges from indolent to rapidly progressive, and its 5-year OS is about 65%. When associated with POEMS syndrome, the 5-year survival was estimated to be 90% with the osteosclerotic variant and 27% without osteosclerotic lesions.3 Treatment options for MCD include systemic chemotherapy, including antiviral therapy for HHV-8 positive and HAART for HIV positive and newer monoclonal antibody therapies targeting CD20 or IL-6.
Pathophysiology
Interleukin-6 plays an important role for inflammation in both UCD and MCD (Figure 1). There is dysregulation and overproduction of IL-6, which further stimulates the production of acute-phase reactants, resulting in various systemic manifestations.15,21,22 There is increased expression of IL-1 and IL-6, upregulation of IL-6 secondary to interaction of IL-1 with nuclear factor-kappa B (NF-kappa B), thus stimulating B-cell proliferation. IL-6 binding to IL-6 receptor (IL6-R) results in downstream activation of transcription Janus kinases/signal transducers and activators of the transcription pathway. This promotes the transcription of genes encoding the acute-phase reactant proteins. Hence, interfering with IL-6 transduction by blocking downstream signals are potential therapeutic targets. The mitogen-activated protein kinase cascade, the rapidly accelerated fibrosarcoma kinases, and the overexpression of the endothelial growth factor receptor (EGFR), all contribute to disease pathogenesis by promoting increased B-cell proliferation and vascular EGFR mediated angiogenesis. 23,24
In HHV-8–associated MCD, the virus replicates within lymph node plasmablasts, causing increased production of viral IL-6 analog, human IL-6, and other proinflammatory proteins resulting in B-cell and plasma-cell proliferation, increased vascular endothelial growth factor secretion and angiogenesis.25,26 The HHV-8–infected plasmablasts are marked by variable expression of CD20, and therefore, anti-CD20 is also shown to be an effective treatment. The calmodulin/calcineurin nuclear factor assists in the proliferation of HHV-8, thereby making calcineurin another potential target for the antiviral proliferation.27
Staging
The treatment decisions and prognosis for patients with CD is based on the clinical and histologic staging. The initial workup includes but is not limited to routine laboratory evaluation, imaging, and HIV and HHV-8 testing (Table 3). Routine tests of the levels of cytokines are not recommended. Other relevant tests for known disease associations should be obtained when relevant.
Treatment
Better understanding of the disease process in CD has helped to identify potential therapeutic targets (Figures 2 and 3).
For UCD, surgery is the mainstay of treatment.4,28,29 In surgically unresectable cases, radiation therapy is helpful for local disease control. Alternatively, neoadjuvant
chemotherapy and rituximab are used. Corticosteroids are generally used to treat acute exacerbations and as adjuncts to chemotherapy.
For MCD, the treatment approach depends on the HIV and HHV-8 status of the patient. For patients with HHV-8 infection, both with and without HIV co-infection, antiviral agents, such as ganciclovir, foscarnet, or cidofovir, have shown in vitro activity against HHV-8 but with limited clinical success.30 In patients infected with HIV, the aim of treating with HAART is to control the disease, prevent opportunistic infections, and improve tolerance to chemotherapy.31-33 Rituximab with or without chemotherapy is the standard treatment approach. The additional chemotherapeutic agents are used depending on the presence or absence of organ failure. This approach has improved the OS in HIV-associated MCD.34,35 Treatment with HAART does not decrease the risk of relapse in HIV MCD; therefore, the role of rituximab and antiherpesvirus agents as maintenance therapy has been explored.36 In patients who fail to respond to or relapse rapidly following rituximab monotherapy, the use of either single-agent chemotherapy with or without rituximab or antiherpesvirus therapy with high-dose zidovudine and valganciclovir is recommended.37
The cytotoxic chemotherapy with single agents, such as etoposide, vinblastine, cyclophosphamide, cladribine, chlorambucil, and liposomal doxorubicin, has been used with limited success.22 The combination chemotherapy with cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) or cyclophosphamide/vincristine/
prednisone (CVP) without rituximab has been shown to achieve durable remissions. Corticosteroids are usually administered as an initial adjunct to chemotherapy or for acute exacerbations. In patients with MCD, regardless of HIV status, the interferon therapy was found to achieve long-term remission.38,39 The interferon therapy
exerts antiviral effects via downregulation of the IL-6R and inhibition of HHV-8 replication. For patients in remission, maintenance therapy with oral valganciclovir is promising.40
Immunomodulators & Targeted Therapies
For unresectable UCD or MCD with organ failure or relapse, the use of alternativesingle-agent or combination chemotherapies with or without rituximab is recommended. Thalidomide has shown some success, probably secondary to disruption of IL-6 production.41 In cases of progression following second-line therapy, bortezomib, antiherpesvirus therapies, or IL-6–directed therapy with siltuximab or tocilizumab should be considered.
Rituximab is a monoclonal chimeric antibody that targets CD20 on B cells, thus leading to B-cell lymphodepletion via activating complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. As monotherapy, it has been shown to achieve 2-year progression-free survival in 80% of patients.42 In patients with MCD who are HIV positive, rituximab with and without chemotherapy has shown improved overall and disease-free survival of 70% to 80% at 2 years.43
Siltuximab is a chimeric human-mouse monoclonal antibody to IL-6 that has been approved for treatment of patients with MCD who are both HIV negative and HHV-8 negative.44-46 Tocilizumab targets the IL-6R. The antibody has shown improvement in a study in HIVseronegative adults with MCD.47,48
Bortezomib is a proteasome inhibitor that inhibits the NF-kappa B pathway, which induces the expression of numerous proinflammatory proteins, including IL-6. It is recommended for relapsed or refractory disease.49,50
Anakinra is a recombinant IL-1R antagonist that blocks IL-1 effects and controls disease by decreasing IL-6 production.51
Conculsion
There has been significant progress in disease diagnosis and management as more information is available about the incidence, clinical presentation, and pathophysiology of CD. The understanding of the disease pathogenesis and biology has helped to discover multiple potential therapeutic targets. Successful treatment has been achieved through targeting HHV-8 replication, CD20, and IL-6 and anti– IL-6R antibodies. Although surgical resection continues to be the
standard of therapy for UCD, the management of MCD and relapsed or refractory disease continues to evolve. Exploration of various treatment strategies in different clinical presentations is warranted.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S.
Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information
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1. Castleman B, Iverson L, Menendez VP. Localized mediastinal lymph-node hyperplasia
resembling thymoma. Cancer. 1956;9(4):822-830.
2. Munshi N, 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;56(5):1252-1260.
3. Dispenzieri A, Armitage JO, Loe MJ, et al. The clinical spectrum of Castleman’s disease. Am J Hematol. 2012;87(11):997-1002.
4. 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;29(3):670-683.
5. Cronin DM, Warnke RA. Castleman disease: an update on classification and the
spectrum of associated lesions. Adv Anat Pathol. 2009;16(4):236-246.
6. Talat N, Belgaumkar AP, Schulte KM. Surgery in Castleman’s disease: a systematic review of 404 published cases. Ann Surg. 2012;255(4):677-684.
7. Chronowski GM, Ha CS, Wilder RB, Cabanillas F, Manning J, Cox JD. Treatment of unicentric and multicentric Castleman disease and the role of radiotherapy. Cancer. 2001;92(3):670-676.
8. Herrada J, Cabanillas F, Rice L, Manning J, Pugh W. The clinical behavior of localized and multicentric Castleman disease. Ann Intern Med. 1998;128(8):657-662.
9. Dupin N, Diss TL, Kellam P, et al. HHV-8 is associated with a plasmablastic variant of Castleman disease that is linked to HHV-8-positive plasmablastic lymphoma. Blood. 2000;95(4):1406-1412.
10. Ferry JA, Harris NL. Atlas of Lymphoid Hyperplasia and Lymphoma. Philadelphia, PA: W.B. Saunders; 1997.
11. Soulier J, Grollet L, Oksenhendler E, et al. Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman’s disease. Blood. 1995;86(4):1276-1280.
12. Powles T, Stebbing J, Bazeos A, et al. The role of immune suppression and HHV-8 in the increasing incidence of HIV-associated multicentric Castleman’s disease. Ann Oncol. 2009;20(4):775-779.
13. Gérard L, Bérezné A, Galicier L, 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;25(22):3350-3356.
14. Casper C, Teltsch DY, Robinson D Jr, et al. Clinical characteristics and healthcare utilization of patients with multicentric Castleman disease. Br J Haematol. 2015;168(1):82-93.
15. Fajgenbaum DC, van Rhee F, Nabel CS. HHV-8-negative, idiopathic multicentric Castleman disease: novel insights into biology, pathogenesis, and therapy. Blood. 2014;123(19):2924-2933.
16. Larroche C, Cacoub P, Soulier J, et al. Castleman’s disease and lymphoma: report of eight cases in HIV-negative patients and literature review. Am J Hematol. 2002;69(2):119-126.
17. Dispenzieri A. POEMS syndrome: 2014 update on diagnosis, risk-stratification, and management. Am J Hematol. 2014;89(2):214-223.
18. Andhavarapu S, Jiang L. POEMS syndrome and Castleman disease. Blood. 2013;122(2):159.
19. Bélec L, Mohamed AS, Authier FJ, et al. Human herpesvirus 8 infection in patients with POEMS syndrome-associated multicentric Castleman’s disease. Blood. 1999;93(11):3643-3653.
20. Oksenhendler E, Boulanger E, Galicier L, et al. High incidence of Kaposi sarcomaassociated herpesvirus-related non-Hodgkin lymphoma in patients with HIV infection and multicentric Castleman disease. Blood. 2002;99(7):2331-2336.
21. Yoshizaki K, Matsuda T, Nishimoto N, et al. Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman’s disease. Blood. 1989;74(4):1360-1367.
22. El-Osta HE, Kurzrock R. Castleman’s disease: from basic mechanisms to molecular therapeutics. Oncologist. 2011;16(4):497-511.
23. Akula SM, Ford PW, Whitman AG, et al. B-Raf-dependent expression of vascular endothelial growth factor-A in Kaposi sarcoma-associated herpesvirus-infected human B cells. Blood. 2005;105(11):4516-4522.
24. Sun X, Chang KC, Abruzzo LV, Lai R, Younes A, Jones D. Epidermal growth factor receptor expression in follicular dendritic cells: a shared feature of follicular dendritic cell sarcoma and Castleman’s disease. Hum Pathol. 2003;34(9):835-840.
25. Adam N, Rabe B, Suthaus J, Grötzinger J, Rose-John S, Scheller J. Unraveling viral interleukin-6 binding to gp130 and activation of STAT-signaling pathways independently of the interleukin-6 receptor. J Virol. 2009;83(10):5117-5126.
26. Suda T, Katano H, Delsol G, et al. HHV-8 infection status of AIDS-unrelated and
AIDS-associated multicentric Castleman’s disease. Pathol Int. 2001;51(9):671-679.
27. Zoeteweij JP, Moses AV, Rinderknecht AS, et al. Targeted inhibition of calcineurin signaling blocks calcium-dependent reactivation of Kaposi sarcoma-associated herpesvirus. Blood. 2001;97(8):2374-2380.
28. McCarty MJ, Vukelja SJ, Banks PM, Weiss RB. Angiofollicular lymph node hyperplasia
(Castleman’s disease). Cancer Treat Rev. 1995;21(4):291-310.
29. Bowne WB, Lewis JJ, Filippa DA, et al. The management of unicentric and multicentric Castleman’s disease: a report of 16 cases and a review of the literature. Cancer. 1999;85(3):706-717.
30. Reddy D, Mitsuyasu R. HIV-associated multicentric Castleman disease. Curr Opin Oncol. 2011;23(5):475-481.
31. Aaron L, Lidove O, Yousry C, Roudiere L, Dupont B, Viard JP. Human herpesvirus 8-positive Castleman disease in human immunodeficiency virus-infected patients: the impact of highly active antiretroviral therapy. Clin Infect Dis. 2002;35(7):880-882.
32. Sprinz E, Jeffman M, Liedke P, Putten A, Schwartsmann G. Successful treatment of AIDS-related Castleman’s disease following the administration of highly active antiretroviral therapy (HAART). Ann Oncol. 2004;15(2):356-358.
33. Lee SM, Edwards SG, Chilton DN, Ramsay A, Miller RF. Highly active antiretroviral therapy alone may be an effective treatment for HIV-associated multi-centric Castleman’s disease. Haematologica. 2010;95(11):1979-1981.
34. Bower M. How I treat HIV-associated multicentric Castleman disease. Blood. 2010;116(22):4415-4421.
35. Bower M, Newsom-Davis T, Naresh K, et al. Clinical features and outcome in HIVassociated
multicentric Castleman’s disease. J Clin Oncol. 2011;29(18):2481-2486.
36. Casper C, Nichols WG, Huang ML, Corey L, Wald A. Remission of HHV-8 and HIV-associated multicentric Castleman disease with ganciclovir treatment. Blood. 2004;103(5):1632-1634.
37. Uldrick TS, Polizzotto MN, Aleman K, et al. High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Castleman disease: a pilot study of virus-activated cytotoxic therapy. Blood. 2011;117(26):6977-6986.
38. Kumari P, Schechter GP, Saini N, Benator DA. Successful treatment of human immunodeficiency virus-related Castleman’s disease with interferon-alpha. Clin Infect Dis. 2000;31(2):602-604.
39. Nord JA, Karter D. Low dose interferon-alpha therapy for HIV-associated multicentric Castleman’s disease. Int J STD AIDS. 2003;14(1):61-62.
40. Oksenhendler E. HIV-associated multicentric Castleman disease. Curr Opin HIV AIDS. 2009;4(1):16-21.
41. Jung CP, Emmerich B, Goebel FD, Bogner JR. Successful treatment of a patient with HIV-associated multicentric Castleman disease (MCD) with thalidomide. Am J Hematol. 2004;75(3):176-177.
42. Ide M, Kawachi Y, Izumi Y, Kasagi K, Ogino T. Long-term remission in HIV negative patients with multicentric Castleman’s disease using rituximab. Eur J Haematol. 2006;76(2):119-123.
43. Marcelin AG, Aaron L, Mateus C, et al. Rituximab therapy for HIV-associated Castleman disease. Blood. 2003;102(8):2786-2788.
44. Van Rhee F, Fayad L, Voorhees P, et al. Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman’s disease. J Clin Oncol. 2010;28(23):3701-3708.
45. Wong RS, Casper C, Munshi N, et al. A multicenter, randomized, doubleblind, placebo-controlled study of the efficacy and safety of siltuximab, an antiinterleukin-6 monoclonal antibody, in patients with multicentric Castleman’s disease. Blood. 2013;122(21):505.
46. Van Rhee F, Casper C, Voorhees PM, et al. An open-label, phase 2, multicenter study of the safety of long-term treatment with siltuximab (an anti-interleukin-6 monoclonal antibody) in patients with multicentric Castleman’s disease. Blood. 2013;122(21):1806.
47. Nishimoto N, Kanakura Y, Aozasa K, et al. Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease. Blood. 2005;106(8):2627-2632.
48. Müzes G, Sipos F, Csomor J, Sréter L. Successful tocilizumab treatment in a patient with human herpesvirus 8-positive and human immunodeficiency virusnegative multicentric Castleman’s disease of plasma cell type nonresponsive to rituximab-CVP therapy. APMIS. 2013;121(7):668-674.
49. Hess G, Wagner V, Kreft A, Heussel CP, Huber C. Effects of bortezomib on proinflammatory cytokine levels and transfusion dependency in a patient with multicentric Castleman disease. Br J Haematol. 2006;134(5):544-545.
50. Sobas MA, Alonso Vence N, Diaz Arias J, Bendaña Lopez A, Fraga Rodriguez M, Bello Lopez JL. Efficacy of bortezomib in refractory form of multicentric Castleman disease associated to poems syndrome (MCD-POEMS variant). Ann Hematol. 2010;89(2):217-219.
51. El-Osta H, Janku F, Kurzrock R. Successful treatment of Castleman’s disease with interleukin-1 receptor antagonist (Anakinra). Mol Cancer Ther. 2010;9(6):1485-1488.
Castleman disease (CD) is a rare nonclonal lymphoproliferative disorder, also known as angiofollicular lymph-node hyperplasia or giant node hyperplasia. It was first reported in 1954 and in 1956 described by Benjamin Castleman, MD, in a case series of localized mediastinal lymph-node hyperplasia.1 Unicentric Castleman (UCD) disease presents as a localized disease affecting a single lymph node/lymph node chain. Multicentric Castleman disease (MCD) is a more widespread or generalized disease (Table 1). About 4,000 to 6,000 new cases of CD are diagnosed per year of which about 20% to 25% cases are MCD. The estimated incidence rate for CD has recently been calculated as 21 to 25 per million person-years, or about 6,000 new cases annually.2
The clinical presentation of CD often overlaps with autoimmune, infectious, or other malignant diseases. The diagnosis is confirmed by a biopsy of the affected lymph-node tissue. Interleukin-6 (IL-6) and a viral analog of IL-6 play major role in the pathogenesis by stimulating a widespread inflammatory response that results in systemic manifestations. It is often associated with HIV and human herpesvirus-8 (HHV-8) infections. Castleman disease is histologically characterized into the hyaline vascular variant, the plasma-cell variant, and the mixed form. The plasmablastic variety is associated with HIV and HHV-8 infections. The prognosis ranges from good in UCD (91% overall survival [OS] at 5 y) to poor in MCD (65% OS at 5 y).3
Treatment options range from local surgical excision to systemic treatments. Newer therapies include monoclonal antibodies against both IL-6 and CD20 and a few other targets in the inflammatory cascade. This article discusses the updated approach to diagnosis and management of CD.
Unicentric Castleman Disease
Unicentric CD is more common than MCD, presents as a localized lymph node or chain involvement, and is generally diagnosed in the third or fourth decade of life but has been reported in children. The presenting symptoms of UCD vary by site. It presents as nontender lymphadenopathy when confined to peripheral lymph nodes, whereas respiratory symptoms or bowel obstruction may be seen with lymphadenopathy in the chest/mediastinum, neck, or abdomen. The systemic
symptoms, such as fever, night sweats, and weight loss, are uncommon.
Dysplastic follicular dendritic cells characterize UCD. Histologically, it is usually classified as hyaline vascular disease with the follicles comprising small lymphocytes
and dendritic cells forming concentric rings with prominent vascularity.4,5 No association with HIV or HHV-8 has been seen.
Unicentric CD is often amenable to resection, and a complete cure can be achieved.6 Partial resection may be attempted when complete resection is not possible. Radiation therapy is offered for unresectable disease.7 In patients who are not candidates for any intervention, close long-term follow-up is recommended unless patients are symptomatic, in which case systemic treatment should be considered.
Multicentric Castleman Disease
The more widespread MCD is generally diagnosed in the fifth or sixth decade of life. It is more aggressive than UCD and presents a wide spectrum of symptoms and abnormal laboratory findings (Table 2).8
It is histologically classified into (a) plasmablastic or HHV-8 associated: It is often seen in patients with MCD infected with HIV, which can give rise to large B-cell lymphoma, known as HHV-8 plasmablastic lymphoma9; (b) plasmacytic variant has marked paracortical plasmacytosis with retained nodal architecture10; and (c) mixed MCD has abundant plasma cells with features similar to those of the hyaline-vascular variant.
Most patients with HIV-associated MCD are co-infected with HHV-8. The HHV-8 infection is also present in about 50% of HIV-negative cases.11 The incidence of HIVassociated MCD is increasing in the highly active antiretroviral therapy (HAART) era secondary to improved survival of patients infected with HIV.12 To diagnose active HIV MCD, the French Agence Nationale de Recherche sur le SIDA 117 CastlemaB trial group has described criteria based on the clinical symptoms, including fever, a raised serum C-reactive protein > 20 mg/L without any other cause, and 3 of 12 additional clinical findings described as peripheral lymphadenopathy, splenomegaly, ascites, edema, pleural effusion, cough, nasal obstruction, xerostomia, rash, central neurologic symptoms, jaundice, and autoimmune hemolytic anemia.13 The reported 2-year survival of patients who are HIV-negative is 97% compared with HIV-positive cases at 67%.14
Idiopathic MCD is diagnosed when there is no evidence of any underlying infectious, autoimmune, and neoplastic process.15
Patients with MCD are at an increased risk of developing non-Hodgkin and Hodgkin lymphoma, Kaposi sarcoma, primary effusion lymphoma, and follicular dendritic
cell sarcoma. POEMS (peripheral neuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome and paraneoplastic disease, such as paraneoplastic pemphigus myasthenia gravis, may be commonly diagnosed concurrently or sequentially with MCD.16-20
The disease course of MCD ranges from indolent to rapidly progressive, and its 5-year OS is about 65%. When associated with POEMS syndrome, the 5-year survival was estimated to be 90% with the osteosclerotic variant and 27% without osteosclerotic lesions.3 Treatment options for MCD include systemic chemotherapy, including antiviral therapy for HHV-8 positive and HAART for HIV positive and newer monoclonal antibody therapies targeting CD20 or IL-6.
Pathophysiology
Interleukin-6 plays an important role for inflammation in both UCD and MCD (Figure 1). There is dysregulation and overproduction of IL-6, which further stimulates the production of acute-phase reactants, resulting in various systemic manifestations.15,21,22 There is increased expression of IL-1 and IL-6, upregulation of IL-6 secondary to interaction of IL-1 with nuclear factor-kappa B (NF-kappa B), thus stimulating B-cell proliferation. IL-6 binding to IL-6 receptor (IL6-R) results in downstream activation of transcription Janus kinases/signal transducers and activators of the transcription pathway. This promotes the transcription of genes encoding the acute-phase reactant proteins. Hence, interfering with IL-6 transduction by blocking downstream signals are potential therapeutic targets. The mitogen-activated protein kinase cascade, the rapidly accelerated fibrosarcoma kinases, and the overexpression of the endothelial growth factor receptor (EGFR), all contribute to disease pathogenesis by promoting increased B-cell proliferation and vascular EGFR mediated angiogenesis. 23,24
In HHV-8–associated MCD, the virus replicates within lymph node plasmablasts, causing increased production of viral IL-6 analog, human IL-6, and other proinflammatory proteins resulting in B-cell and plasma-cell proliferation, increased vascular endothelial growth factor secretion and angiogenesis.25,26 The HHV-8–infected plasmablasts are marked by variable expression of CD20, and therefore, anti-CD20 is also shown to be an effective treatment. The calmodulin/calcineurin nuclear factor assists in the proliferation of HHV-8, thereby making calcineurin another potential target for the antiviral proliferation.27
Staging
The treatment decisions and prognosis for patients with CD is based on the clinical and histologic staging. The initial workup includes but is not limited to routine laboratory evaluation, imaging, and HIV and HHV-8 testing (Table 3). Routine tests of the levels of cytokines are not recommended. Other relevant tests for known disease associations should be obtained when relevant.
Treatment
Better understanding of the disease process in CD has helped to identify potential therapeutic targets (Figures 2 and 3).
For UCD, surgery is the mainstay of treatment.4,28,29 In surgically unresectable cases, radiation therapy is helpful for local disease control. Alternatively, neoadjuvant
chemotherapy and rituximab are used. Corticosteroids are generally used to treat acute exacerbations and as adjuncts to chemotherapy.
For MCD, the treatment approach depends on the HIV and HHV-8 status of the patient. For patients with HHV-8 infection, both with and without HIV co-infection, antiviral agents, such as ganciclovir, foscarnet, or cidofovir, have shown in vitro activity against HHV-8 but with limited clinical success.30 In patients infected with HIV, the aim of treating with HAART is to control the disease, prevent opportunistic infections, and improve tolerance to chemotherapy.31-33 Rituximab with or without chemotherapy is the standard treatment approach. The additional chemotherapeutic agents are used depending on the presence or absence of organ failure. This approach has improved the OS in HIV-associated MCD.34,35 Treatment with HAART does not decrease the risk of relapse in HIV MCD; therefore, the role of rituximab and antiherpesvirus agents as maintenance therapy has been explored.36 In patients who fail to respond to or relapse rapidly following rituximab monotherapy, the use of either single-agent chemotherapy with or without rituximab or antiherpesvirus therapy with high-dose zidovudine and valganciclovir is recommended.37
The cytotoxic chemotherapy with single agents, such as etoposide, vinblastine, cyclophosphamide, cladribine, chlorambucil, and liposomal doxorubicin, has been used with limited success.22 The combination chemotherapy with cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) or cyclophosphamide/vincristine/
prednisone (CVP) without rituximab has been shown to achieve durable remissions. Corticosteroids are usually administered as an initial adjunct to chemotherapy or for acute exacerbations. In patients with MCD, regardless of HIV status, the interferon therapy was found to achieve long-term remission.38,39 The interferon therapy
exerts antiviral effects via downregulation of the IL-6R and inhibition of HHV-8 replication. For patients in remission, maintenance therapy with oral valganciclovir is promising.40
Immunomodulators & Targeted Therapies
For unresectable UCD or MCD with organ failure or relapse, the use of alternativesingle-agent or combination chemotherapies with or without rituximab is recommended. Thalidomide has shown some success, probably secondary to disruption of IL-6 production.41 In cases of progression following second-line therapy, bortezomib, antiherpesvirus therapies, or IL-6–directed therapy with siltuximab or tocilizumab should be considered.
Rituximab is a monoclonal chimeric antibody that targets CD20 on B cells, thus leading to B-cell lymphodepletion via activating complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. As monotherapy, it has been shown to achieve 2-year progression-free survival in 80% of patients.42 In patients with MCD who are HIV positive, rituximab with and without chemotherapy has shown improved overall and disease-free survival of 70% to 80% at 2 years.43
Siltuximab is a chimeric human-mouse monoclonal antibody to IL-6 that has been approved for treatment of patients with MCD who are both HIV negative and HHV-8 negative.44-46 Tocilizumab targets the IL-6R. The antibody has shown improvement in a study in HIVseronegative adults with MCD.47,48
Bortezomib is a proteasome inhibitor that inhibits the NF-kappa B pathway, which induces the expression of numerous proinflammatory proteins, including IL-6. It is recommended for relapsed or refractory disease.49,50
Anakinra is a recombinant IL-1R antagonist that blocks IL-1 effects and controls disease by decreasing IL-6 production.51
Conculsion
There has been significant progress in disease diagnosis and management as more information is available about the incidence, clinical presentation, and pathophysiology of CD. The understanding of the disease pathogenesis and biology has helped to discover multiple potential therapeutic targets. Successful treatment has been achieved through targeting HHV-8 replication, CD20, and IL-6 and anti– IL-6R antibodies. Although surgical resection continues to be the
standard of therapy for UCD, the management of MCD and relapsed or refractory disease continues to evolve. Exploration of various treatment strategies in different clinical presentations is warranted.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S.
Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information
for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to
patients.
Click here to read the digital edition.
Castleman disease (CD) is a rare nonclonal lymphoproliferative disorder, also known as angiofollicular lymph-node hyperplasia or giant node hyperplasia. It was first reported in 1954 and in 1956 described by Benjamin Castleman, MD, in a case series of localized mediastinal lymph-node hyperplasia.1 Unicentric Castleman (UCD) disease presents as a localized disease affecting a single lymph node/lymph node chain. Multicentric Castleman disease (MCD) is a more widespread or generalized disease (Table 1). About 4,000 to 6,000 new cases of CD are diagnosed per year of which about 20% to 25% cases are MCD. The estimated incidence rate for CD has recently been calculated as 21 to 25 per million person-years, or about 6,000 new cases annually.2
The clinical presentation of CD often overlaps with autoimmune, infectious, or other malignant diseases. The diagnosis is confirmed by a biopsy of the affected lymph-node tissue. Interleukin-6 (IL-6) and a viral analog of IL-6 play major role in the pathogenesis by stimulating a widespread inflammatory response that results in systemic manifestations. It is often associated with HIV and human herpesvirus-8 (HHV-8) infections. Castleman disease is histologically characterized into the hyaline vascular variant, the plasma-cell variant, and the mixed form. The plasmablastic variety is associated with HIV and HHV-8 infections. The prognosis ranges from good in UCD (91% overall survival [OS] at 5 y) to poor in MCD (65% OS at 5 y).3
Treatment options range from local surgical excision to systemic treatments. Newer therapies include monoclonal antibodies against both IL-6 and CD20 and a few other targets in the inflammatory cascade. This article discusses the updated approach to diagnosis and management of CD.
Unicentric Castleman Disease
Unicentric CD is more common than MCD, presents as a localized lymph node or chain involvement, and is generally diagnosed in the third or fourth decade of life but has been reported in children. The presenting symptoms of UCD vary by site. It presents as nontender lymphadenopathy when confined to peripheral lymph nodes, whereas respiratory symptoms or bowel obstruction may be seen with lymphadenopathy in the chest/mediastinum, neck, or abdomen. The systemic
symptoms, such as fever, night sweats, and weight loss, are uncommon.
Dysplastic follicular dendritic cells characterize UCD. Histologically, it is usually classified as hyaline vascular disease with the follicles comprising small lymphocytes
and dendritic cells forming concentric rings with prominent vascularity.4,5 No association with HIV or HHV-8 has been seen.
Unicentric CD is often amenable to resection, and a complete cure can be achieved.6 Partial resection may be attempted when complete resection is not possible. Radiation therapy is offered for unresectable disease.7 In patients who are not candidates for any intervention, close long-term follow-up is recommended unless patients are symptomatic, in which case systemic treatment should be considered.
Multicentric Castleman Disease
The more widespread MCD is generally diagnosed in the fifth or sixth decade of life. It is more aggressive than UCD and presents a wide spectrum of symptoms and abnormal laboratory findings (Table 2).8
It is histologically classified into (a) plasmablastic or HHV-8 associated: It is often seen in patients with MCD infected with HIV, which can give rise to large B-cell lymphoma, known as HHV-8 plasmablastic lymphoma9; (b) plasmacytic variant has marked paracortical plasmacytosis with retained nodal architecture10; and (c) mixed MCD has abundant plasma cells with features similar to those of the hyaline-vascular variant.
Most patients with HIV-associated MCD are co-infected with HHV-8. The HHV-8 infection is also present in about 50% of HIV-negative cases.11 The incidence of HIVassociated MCD is increasing in the highly active antiretroviral therapy (HAART) era secondary to improved survival of patients infected with HIV.12 To diagnose active HIV MCD, the French Agence Nationale de Recherche sur le SIDA 117 CastlemaB trial group has described criteria based on the clinical symptoms, including fever, a raised serum C-reactive protein > 20 mg/L without any other cause, and 3 of 12 additional clinical findings described as peripheral lymphadenopathy, splenomegaly, ascites, edema, pleural effusion, cough, nasal obstruction, xerostomia, rash, central neurologic symptoms, jaundice, and autoimmune hemolytic anemia.13 The reported 2-year survival of patients who are HIV-negative is 97% compared with HIV-positive cases at 67%.14
Idiopathic MCD is diagnosed when there is no evidence of any underlying infectious, autoimmune, and neoplastic process.15
Patients with MCD are at an increased risk of developing non-Hodgkin and Hodgkin lymphoma, Kaposi sarcoma, primary effusion lymphoma, and follicular dendritic
cell sarcoma. POEMS (peripheral neuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome and paraneoplastic disease, such as paraneoplastic pemphigus myasthenia gravis, may be commonly diagnosed concurrently or sequentially with MCD.16-20
The disease course of MCD ranges from indolent to rapidly progressive, and its 5-year OS is about 65%. When associated with POEMS syndrome, the 5-year survival was estimated to be 90% with the osteosclerotic variant and 27% without osteosclerotic lesions.3 Treatment options for MCD include systemic chemotherapy, including antiviral therapy for HHV-8 positive and HAART for HIV positive and newer monoclonal antibody therapies targeting CD20 or IL-6.
Pathophysiology
Interleukin-6 plays an important role for inflammation in both UCD and MCD (Figure 1). There is dysregulation and overproduction of IL-6, which further stimulates the production of acute-phase reactants, resulting in various systemic manifestations.15,21,22 There is increased expression of IL-1 and IL-6, upregulation of IL-6 secondary to interaction of IL-1 with nuclear factor-kappa B (NF-kappa B), thus stimulating B-cell proliferation. IL-6 binding to IL-6 receptor (IL6-R) results in downstream activation of transcription Janus kinases/signal transducers and activators of the transcription pathway. This promotes the transcription of genes encoding the acute-phase reactant proteins. Hence, interfering with IL-6 transduction by blocking downstream signals are potential therapeutic targets. The mitogen-activated protein kinase cascade, the rapidly accelerated fibrosarcoma kinases, and the overexpression of the endothelial growth factor receptor (EGFR), all contribute to disease pathogenesis by promoting increased B-cell proliferation and vascular EGFR mediated angiogenesis. 23,24
In HHV-8–associated MCD, the virus replicates within lymph node plasmablasts, causing increased production of viral IL-6 analog, human IL-6, and other proinflammatory proteins resulting in B-cell and plasma-cell proliferation, increased vascular endothelial growth factor secretion and angiogenesis.25,26 The HHV-8–infected plasmablasts are marked by variable expression of CD20, and therefore, anti-CD20 is also shown to be an effective treatment. The calmodulin/calcineurin nuclear factor assists in the proliferation of HHV-8, thereby making calcineurin another potential target for the antiviral proliferation.27
Staging
The treatment decisions and prognosis for patients with CD is based on the clinical and histologic staging. The initial workup includes but is not limited to routine laboratory evaluation, imaging, and HIV and HHV-8 testing (Table 3). Routine tests of the levels of cytokines are not recommended. Other relevant tests for known disease associations should be obtained when relevant.
Treatment
Better understanding of the disease process in CD has helped to identify potential therapeutic targets (Figures 2 and 3).
For UCD, surgery is the mainstay of treatment.4,28,29 In surgically unresectable cases, radiation therapy is helpful for local disease control. Alternatively, neoadjuvant
chemotherapy and rituximab are used. Corticosteroids are generally used to treat acute exacerbations and as adjuncts to chemotherapy.
For MCD, the treatment approach depends on the HIV and HHV-8 status of the patient. For patients with HHV-8 infection, both with and without HIV co-infection, antiviral agents, such as ganciclovir, foscarnet, or cidofovir, have shown in vitro activity against HHV-8 but with limited clinical success.30 In patients infected with HIV, the aim of treating with HAART is to control the disease, prevent opportunistic infections, and improve tolerance to chemotherapy.31-33 Rituximab with or without chemotherapy is the standard treatment approach. The additional chemotherapeutic agents are used depending on the presence or absence of organ failure. This approach has improved the OS in HIV-associated MCD.34,35 Treatment with HAART does not decrease the risk of relapse in HIV MCD; therefore, the role of rituximab and antiherpesvirus agents as maintenance therapy has been explored.36 In patients who fail to respond to or relapse rapidly following rituximab monotherapy, the use of either single-agent chemotherapy with or without rituximab or antiherpesvirus therapy with high-dose zidovudine and valganciclovir is recommended.37
The cytotoxic chemotherapy with single agents, such as etoposide, vinblastine, cyclophosphamide, cladribine, chlorambucil, and liposomal doxorubicin, has been used with limited success.22 The combination chemotherapy with cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) or cyclophosphamide/vincristine/
prednisone (CVP) without rituximab has been shown to achieve durable remissions. Corticosteroids are usually administered as an initial adjunct to chemotherapy or for acute exacerbations. In patients with MCD, regardless of HIV status, the interferon therapy was found to achieve long-term remission.38,39 The interferon therapy
exerts antiviral effects via downregulation of the IL-6R and inhibition of HHV-8 replication. For patients in remission, maintenance therapy with oral valganciclovir is promising.40
Immunomodulators & Targeted Therapies
For unresectable UCD or MCD with organ failure or relapse, the use of alternativesingle-agent or combination chemotherapies with or without rituximab is recommended. Thalidomide has shown some success, probably secondary to disruption of IL-6 production.41 In cases of progression following second-line therapy, bortezomib, antiherpesvirus therapies, or IL-6–directed therapy with siltuximab or tocilizumab should be considered.
Rituximab is a monoclonal chimeric antibody that targets CD20 on B cells, thus leading to B-cell lymphodepletion via activating complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. As monotherapy, it has been shown to achieve 2-year progression-free survival in 80% of patients.42 In patients with MCD who are HIV positive, rituximab with and without chemotherapy has shown improved overall and disease-free survival of 70% to 80% at 2 years.43
Siltuximab is a chimeric human-mouse monoclonal antibody to IL-6 that has been approved for treatment of patients with MCD who are both HIV negative and HHV-8 negative.44-46 Tocilizumab targets the IL-6R. The antibody has shown improvement in a study in HIVseronegative adults with MCD.47,48
Bortezomib is a proteasome inhibitor that inhibits the NF-kappa B pathway, which induces the expression of numerous proinflammatory proteins, including IL-6. It is recommended for relapsed or refractory disease.49,50
Anakinra is a recombinant IL-1R antagonist that blocks IL-1 effects and controls disease by decreasing IL-6 production.51
Conculsion
There has been significant progress in disease diagnosis and management as more information is available about the incidence, clinical presentation, and pathophysiology of CD. The understanding of the disease pathogenesis and biology has helped to discover multiple potential therapeutic targets. Successful treatment has been achieved through targeting HHV-8 replication, CD20, and IL-6 and anti– IL-6R antibodies. Although surgical resection continues to be the
standard of therapy for UCD, the management of MCD and relapsed or refractory disease continues to evolve. Exploration of various treatment strategies in different clinical presentations is warranted.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S.
Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information
for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to
patients.
Click here to read the digital edition.
1. Castleman B, Iverson L, Menendez VP. Localized mediastinal lymph-node hyperplasia
resembling thymoma. Cancer. 1956;9(4):822-830.
2. Munshi N, 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;56(5):1252-1260.
3. Dispenzieri A, Armitage JO, Loe MJ, et al. The clinical spectrum of Castleman’s disease. Am J Hematol. 2012;87(11):997-1002.
4. 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;29(3):670-683.
5. Cronin DM, Warnke RA. Castleman disease: an update on classification and the
spectrum of associated lesions. Adv Anat Pathol. 2009;16(4):236-246.
6. Talat N, Belgaumkar AP, Schulte KM. Surgery in Castleman’s disease: a systematic review of 404 published cases. Ann Surg. 2012;255(4):677-684.
7. Chronowski GM, Ha CS, Wilder RB, Cabanillas F, Manning J, Cox JD. Treatment of unicentric and multicentric Castleman disease and the role of radiotherapy. Cancer. 2001;92(3):670-676.
8. Herrada J, Cabanillas F, Rice L, Manning J, Pugh W. The clinical behavior of localized and multicentric Castleman disease. Ann Intern Med. 1998;128(8):657-662.
9. Dupin N, Diss TL, Kellam P, et al. HHV-8 is associated with a plasmablastic variant of Castleman disease that is linked to HHV-8-positive plasmablastic lymphoma. Blood. 2000;95(4):1406-1412.
10. Ferry JA, Harris NL. Atlas of Lymphoid Hyperplasia and Lymphoma. Philadelphia, PA: W.B. Saunders; 1997.
11. Soulier J, Grollet L, Oksenhendler E, et al. Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman’s disease. Blood. 1995;86(4):1276-1280.
12. Powles T, Stebbing J, Bazeos A, et al. The role of immune suppression and HHV-8 in the increasing incidence of HIV-associated multicentric Castleman’s disease. Ann Oncol. 2009;20(4):775-779.
13. Gérard L, Bérezné A, Galicier L, 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;25(22):3350-3356.
14. Casper C, Teltsch DY, Robinson D Jr, et al. Clinical characteristics and healthcare utilization of patients with multicentric Castleman disease. Br J Haematol. 2015;168(1):82-93.
15. Fajgenbaum DC, van Rhee F, Nabel CS. HHV-8-negative, idiopathic multicentric Castleman disease: novel insights into biology, pathogenesis, and therapy. Blood. 2014;123(19):2924-2933.
16. Larroche C, Cacoub P, Soulier J, et al. Castleman’s disease and lymphoma: report of eight cases in HIV-negative patients and literature review. Am J Hematol. 2002;69(2):119-126.
17. Dispenzieri A. POEMS syndrome: 2014 update on diagnosis, risk-stratification, and management. Am J Hematol. 2014;89(2):214-223.
18. Andhavarapu S, Jiang L. POEMS syndrome and Castleman disease. Blood. 2013;122(2):159.
19. Bélec L, Mohamed AS, Authier FJ, et al. Human herpesvirus 8 infection in patients with POEMS syndrome-associated multicentric Castleman’s disease. Blood. 1999;93(11):3643-3653.
20. Oksenhendler E, Boulanger E, Galicier L, et al. High incidence of Kaposi sarcomaassociated herpesvirus-related non-Hodgkin lymphoma in patients with HIV infection and multicentric Castleman disease. Blood. 2002;99(7):2331-2336.
21. Yoshizaki K, Matsuda T, Nishimoto N, et al. Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman’s disease. Blood. 1989;74(4):1360-1367.
22. El-Osta HE, Kurzrock R. Castleman’s disease: from basic mechanisms to molecular therapeutics. Oncologist. 2011;16(4):497-511.
23. Akula SM, Ford PW, Whitman AG, et al. B-Raf-dependent expression of vascular endothelial growth factor-A in Kaposi sarcoma-associated herpesvirus-infected human B cells. Blood. 2005;105(11):4516-4522.
24. Sun X, Chang KC, Abruzzo LV, Lai R, Younes A, Jones D. Epidermal growth factor receptor expression in follicular dendritic cells: a shared feature of follicular dendritic cell sarcoma and Castleman’s disease. Hum Pathol. 2003;34(9):835-840.
25. Adam N, Rabe B, Suthaus J, Grötzinger J, Rose-John S, Scheller J. Unraveling viral interleukin-6 binding to gp130 and activation of STAT-signaling pathways independently of the interleukin-6 receptor. J Virol. 2009;83(10):5117-5126.
26. Suda T, Katano H, Delsol G, et al. HHV-8 infection status of AIDS-unrelated and
AIDS-associated multicentric Castleman’s disease. Pathol Int. 2001;51(9):671-679.
27. Zoeteweij JP, Moses AV, Rinderknecht AS, et al. Targeted inhibition of calcineurin signaling blocks calcium-dependent reactivation of Kaposi sarcoma-associated herpesvirus. Blood. 2001;97(8):2374-2380.
28. McCarty MJ, Vukelja SJ, Banks PM, Weiss RB. Angiofollicular lymph node hyperplasia
(Castleman’s disease). Cancer Treat Rev. 1995;21(4):291-310.
29. Bowne WB, Lewis JJ, Filippa DA, et al. The management of unicentric and multicentric Castleman’s disease: a report of 16 cases and a review of the literature. Cancer. 1999;85(3):706-717.
30. Reddy D, Mitsuyasu R. HIV-associated multicentric Castleman disease. Curr Opin Oncol. 2011;23(5):475-481.
31. Aaron L, Lidove O, Yousry C, Roudiere L, Dupont B, Viard JP. Human herpesvirus 8-positive Castleman disease in human immunodeficiency virus-infected patients: the impact of highly active antiretroviral therapy. Clin Infect Dis. 2002;35(7):880-882.
32. Sprinz E, Jeffman M, Liedke P, Putten A, Schwartsmann G. Successful treatment of AIDS-related Castleman’s disease following the administration of highly active antiretroviral therapy (HAART). Ann Oncol. 2004;15(2):356-358.
33. Lee SM, Edwards SG, Chilton DN, Ramsay A, Miller RF. Highly active antiretroviral therapy alone may be an effective treatment for HIV-associated multi-centric Castleman’s disease. Haematologica. 2010;95(11):1979-1981.
34. Bower M. How I treat HIV-associated multicentric Castleman disease. Blood. 2010;116(22):4415-4421.
35. Bower M, Newsom-Davis T, Naresh K, et al. Clinical features and outcome in HIVassociated
multicentric Castleman’s disease. J Clin Oncol. 2011;29(18):2481-2486.
36. Casper C, Nichols WG, Huang ML, Corey L, Wald A. Remission of HHV-8 and HIV-associated multicentric Castleman disease with ganciclovir treatment. Blood. 2004;103(5):1632-1634.
37. Uldrick TS, Polizzotto MN, Aleman K, et al. High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Castleman disease: a pilot study of virus-activated cytotoxic therapy. Blood. 2011;117(26):6977-6986.
38. Kumari P, Schechter GP, Saini N, Benator DA. Successful treatment of human immunodeficiency virus-related Castleman’s disease with interferon-alpha. Clin Infect Dis. 2000;31(2):602-604.
39. Nord JA, Karter D. Low dose interferon-alpha therapy for HIV-associated multicentric Castleman’s disease. Int J STD AIDS. 2003;14(1):61-62.
40. Oksenhendler E. HIV-associated multicentric Castleman disease. Curr Opin HIV AIDS. 2009;4(1):16-21.
41. Jung CP, Emmerich B, Goebel FD, Bogner JR. Successful treatment of a patient with HIV-associated multicentric Castleman disease (MCD) with thalidomide. Am J Hematol. 2004;75(3):176-177.
42. Ide M, Kawachi Y, Izumi Y, Kasagi K, Ogino T. Long-term remission in HIV negative patients with multicentric Castleman’s disease using rituximab. Eur J Haematol. 2006;76(2):119-123.
43. Marcelin AG, Aaron L, Mateus C, et al. Rituximab therapy for HIV-associated Castleman disease. Blood. 2003;102(8):2786-2788.
44. Van Rhee F, Fayad L, Voorhees P, et al. Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman’s disease. J Clin Oncol. 2010;28(23):3701-3708.
45. Wong RS, Casper C, Munshi N, et al. A multicenter, randomized, doubleblind, placebo-controlled study of the efficacy and safety of siltuximab, an antiinterleukin-6 monoclonal antibody, in patients with multicentric Castleman’s disease. Blood. 2013;122(21):505.
46. Van Rhee F, Casper C, Voorhees PM, et al. An open-label, phase 2, multicenter study of the safety of long-term treatment with siltuximab (an anti-interleukin-6 monoclonal antibody) in patients with multicentric Castleman’s disease. Blood. 2013;122(21):1806.
47. Nishimoto N, Kanakura Y, Aozasa K, et al. Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease. Blood. 2005;106(8):2627-2632.
48. Müzes G, Sipos F, Csomor J, Sréter L. Successful tocilizumab treatment in a patient with human herpesvirus 8-positive and human immunodeficiency virusnegative multicentric Castleman’s disease of plasma cell type nonresponsive to rituximab-CVP therapy. APMIS. 2013;121(7):668-674.
49. Hess G, Wagner V, Kreft A, Heussel CP, Huber C. Effects of bortezomib on proinflammatory cytokine levels and transfusion dependency in a patient with multicentric Castleman disease. Br J Haematol. 2006;134(5):544-545.
50. Sobas MA, Alonso Vence N, Diaz Arias J, Bendaña Lopez A, Fraga Rodriguez M, Bello Lopez JL. Efficacy of bortezomib in refractory form of multicentric Castleman disease associated to poems syndrome (MCD-POEMS variant). Ann Hematol. 2010;89(2):217-219.
51. El-Osta H, Janku F, Kurzrock R. Successful treatment of Castleman’s disease with interleukin-1 receptor antagonist (Anakinra). Mol Cancer Ther. 2010;9(6):1485-1488.
1. Castleman B, Iverson L, Menendez VP. Localized mediastinal lymph-node hyperplasia
resembling thymoma. Cancer. 1956;9(4):822-830.
2. Munshi N, 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;56(5):1252-1260.
3. Dispenzieri A, Armitage JO, Loe MJ, et al. The clinical spectrum of Castleman’s disease. Am J Hematol. 2012;87(11):997-1002.
4. 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;29(3):670-683.
5. Cronin DM, Warnke RA. Castleman disease: an update on classification and the
spectrum of associated lesions. Adv Anat Pathol. 2009;16(4):236-246.
6. Talat N, Belgaumkar AP, Schulte KM. Surgery in Castleman’s disease: a systematic review of 404 published cases. Ann Surg. 2012;255(4):677-684.
7. Chronowski GM, Ha CS, Wilder RB, Cabanillas F, Manning J, Cox JD. Treatment of unicentric and multicentric Castleman disease and the role of radiotherapy. Cancer. 2001;92(3):670-676.
8. Herrada J, Cabanillas F, Rice L, Manning J, Pugh W. The clinical behavior of localized and multicentric Castleman disease. Ann Intern Med. 1998;128(8):657-662.
9. Dupin N, Diss TL, Kellam P, et al. HHV-8 is associated with a plasmablastic variant of Castleman disease that is linked to HHV-8-positive plasmablastic lymphoma. Blood. 2000;95(4):1406-1412.
10. Ferry JA, Harris NL. Atlas of Lymphoid Hyperplasia and Lymphoma. Philadelphia, PA: W.B. Saunders; 1997.
11. Soulier J, Grollet L, Oksenhendler E, et al. Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman’s disease. Blood. 1995;86(4):1276-1280.
12. Powles T, Stebbing J, Bazeos A, et al. The role of immune suppression and HHV-8 in the increasing incidence of HIV-associated multicentric Castleman’s disease. Ann Oncol. 2009;20(4):775-779.
13. Gérard L, Bérezné A, Galicier L, 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;25(22):3350-3356.
14. Casper C, Teltsch DY, Robinson D Jr, et al. Clinical characteristics and healthcare utilization of patients with multicentric Castleman disease. Br J Haematol. 2015;168(1):82-93.
15. Fajgenbaum DC, van Rhee F, Nabel CS. HHV-8-negative, idiopathic multicentric Castleman disease: novel insights into biology, pathogenesis, and therapy. Blood. 2014;123(19):2924-2933.
16. Larroche C, Cacoub P, Soulier J, et al. Castleman’s disease and lymphoma: report of eight cases in HIV-negative patients and literature review. Am J Hematol. 2002;69(2):119-126.
17. Dispenzieri A. POEMS syndrome: 2014 update on diagnosis, risk-stratification, and management. Am J Hematol. 2014;89(2):214-223.
18. Andhavarapu S, Jiang L. POEMS syndrome and Castleman disease. Blood. 2013;122(2):159.
19. Bélec L, Mohamed AS, Authier FJ, et al. Human herpesvirus 8 infection in patients with POEMS syndrome-associated multicentric Castleman’s disease. Blood. 1999;93(11):3643-3653.
20. Oksenhendler E, Boulanger E, Galicier L, et al. High incidence of Kaposi sarcomaassociated herpesvirus-related non-Hodgkin lymphoma in patients with HIV infection and multicentric Castleman disease. Blood. 2002;99(7):2331-2336.
21. Yoshizaki K, Matsuda T, Nishimoto N, et al. Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman’s disease. Blood. 1989;74(4):1360-1367.
22. El-Osta HE, Kurzrock R. Castleman’s disease: from basic mechanisms to molecular therapeutics. Oncologist. 2011;16(4):497-511.
23. Akula SM, Ford PW, Whitman AG, et al. B-Raf-dependent expression of vascular endothelial growth factor-A in Kaposi sarcoma-associated herpesvirus-infected human B cells. Blood. 2005;105(11):4516-4522.
24. Sun X, Chang KC, Abruzzo LV, Lai R, Younes A, Jones D. Epidermal growth factor receptor expression in follicular dendritic cells: a shared feature of follicular dendritic cell sarcoma and Castleman’s disease. Hum Pathol. 2003;34(9):835-840.
25. Adam N, Rabe B, Suthaus J, Grötzinger J, Rose-John S, Scheller J. Unraveling viral interleukin-6 binding to gp130 and activation of STAT-signaling pathways independently of the interleukin-6 receptor. J Virol. 2009;83(10):5117-5126.
26. Suda T, Katano H, Delsol G, et al. HHV-8 infection status of AIDS-unrelated and
AIDS-associated multicentric Castleman’s disease. Pathol Int. 2001;51(9):671-679.
27. Zoeteweij JP, Moses AV, Rinderknecht AS, et al. Targeted inhibition of calcineurin signaling blocks calcium-dependent reactivation of Kaposi sarcoma-associated herpesvirus. Blood. 2001;97(8):2374-2380.
28. McCarty MJ, Vukelja SJ, Banks PM, Weiss RB. Angiofollicular lymph node hyperplasia
(Castleman’s disease). Cancer Treat Rev. 1995;21(4):291-310.
29. Bowne WB, Lewis JJ, Filippa DA, et al. The management of unicentric and multicentric Castleman’s disease: a report of 16 cases and a review of the literature. Cancer. 1999;85(3):706-717.
30. Reddy D, Mitsuyasu R. HIV-associated multicentric Castleman disease. Curr Opin Oncol. 2011;23(5):475-481.
31. Aaron L, Lidove O, Yousry C, Roudiere L, Dupont B, Viard JP. Human herpesvirus 8-positive Castleman disease in human immunodeficiency virus-infected patients: the impact of highly active antiretroviral therapy. Clin Infect Dis. 2002;35(7):880-882.
32. Sprinz E, Jeffman M, Liedke P, Putten A, Schwartsmann G. Successful treatment of AIDS-related Castleman’s disease following the administration of highly active antiretroviral therapy (HAART). Ann Oncol. 2004;15(2):356-358.
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