Pathology & Oncology Research

, Volume 19, Issue 3, pp 345–351 | Cite as

Multicentric Castleman’s Disease: A Challenging Diagnosis

  • Györgyi Műzes
  • Ferenc Sipos
  • Judit Csomor
  • Lídia Sréter


Multicentric Castleman’s disease (MCD) is a sytemic disorder with flares of non-specific symptoms suggestive of a chronic inflammatory syndrome. It is typically accompanied by generalized lymphadenopathy and multiorgan involvement. Histologically, two main variants of Castleman’s disease exist, the hyalin vascular type and the plasma cell variant. Upon localization unicentric (localized), and multicentric (diffuse, systemic) subtypes can be distinguished with more different disease outcomes. Patients often exhibit acute phase reactions and several autoimmune phenomena, and are at high risk for developing malignancies. Both the idiopathic and the HHV-8-driven infectious forms of MCD represent distinct disease entities with a less favorable prognosis. The induction of human IL-6 excess via yet unknown upstream mechanisms, and overexpression of viral IL-6 by HHV-8 can pivotally influence MCD biology. Based on the role of IL-6 in pathogenesis, MCD is also designated as IL-6 lymphadenopathy. To date there are no direct therapeutic evidences, but having been translated to daily practice the main regulatory factors may serve as promising therapeutic targets.


Multicentric Castleman’s disease HHV-8 IL-6 Differential diagnosis Therapy Monoclonal antibodies 


  1. 1.
    Castleman B, Towne VW (1954) Case records of the Massachusetts General Hospital; weekly clinicopathological exercises; founded by Richard C. Cabot. N Engl J Med 251:396–400PubMedCrossRefGoogle Scholar
  2. 2.
    Herrada J, Cabanillas F, Rice L, Manning J, Pugh W (1998) The clinical behavior of localized and multicentric Castleman disease. Ann Intern Med 128:657–662PubMedCrossRefGoogle Scholar
  3. 3.
    Roca B (2009) Castleman’s disease. A review. AIDS Rev 11:3–7.PubMedGoogle Scholar
  4. 4.
    Keller AR, Hochholzer L, Castleman B (1972) Hyaline-vascular and plasma-cell types of giant lymph node hyperplasia of the mediastinum and other locations. Cancer 29:670–683PubMedCrossRefGoogle Scholar
  5. 5.
    Gaba AR, Stein RS, Sweet DL, Variakojis D (1978) Multicentric giant lymph node hyperplasia. Am J Clin Pathol 69:86–90PubMedGoogle Scholar
  6. 6.
    Peterson BA, Frizzera G (1993) Multicentric Castleman’s disease. Semin Oncol 20:636–647PubMedGoogle Scholar
  7. 7.
    Maslovsky I, Uriev L, Lugassy G (2000) The heterogeneity of Castleman disease: report of five cases and review of the literature. Am J Med Sci 320:292–295PubMedCrossRefGoogle Scholar
  8. 8.
    Waterston A, Bower M (2004) Fifty years of multicentric Castleman’s disease. Acta Oncol 43:698–704PubMedCrossRefGoogle Scholar
  9. 9.
    Frizzera G, Peterson BA, Bayrd ED, Goldman A (1985) A systemic lymphoproliferative disorder with morphologic features of Castleman’s disease: clinical findings and clinicopathologic correlations in 15 patients. J Clin Oncol 3:1202–1216PubMedGoogle Scholar
  10. 10.
    Frizzera G (2001) Atypical lymphoproliferative disorders. In: Knowles DM (ed) Neoplastic hematopathology. Lippincott, Williams and Wilkins, Philadelphia, pp 595–621Google Scholar
  11. 11.
    Collins LS, Fowler A, Tong CY, de Ruiter A (2006) Multicentric Castleman’s disease in HIV infection. Int J STD AIDS 17:19–24PubMedCrossRefGoogle Scholar
  12. 12.
    Soulier J, Grollet L, Oksenhendler E et al (1995) Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman’s disease. Blood 86:1276–1280PubMedGoogle Scholar
  13. 13.
    Cronin DM, Warnke RA (2009) Castleman disease: an update on classification and the spectrum of associated lesions. Adv Anat Pathol 16:236–246PubMedCrossRefGoogle Scholar
  14. 14.
    Shahidi H, Myers JL, Kvale PA (1995) Castleman’s disease. Mayo Clin Proc 70:969–977PubMedCrossRefGoogle Scholar
  15. 15.
    Seida A, Wada J, Morita Y et al (2004) Multicentric Castleman’s disease associated with glomerular microangiopathy and MPGN-like lesion: does vascular endothelial cell-derived growth factor play causative or protective roles in renal injury? Am J Kidney Dis 43:E3–E9PubMedCrossRefGoogle Scholar
  16. 16.
    Suneja S, Chidambaram M, Herzenberg AM, Bargman JM (2009) Kidney involvement in multicentric castleman disease. Am J Kidney Dis 53:550–554PubMedCrossRefGoogle Scholar
  17. 17.
    Guihot A, Couderc LJ, Agbalika F et al (2005) Pulmonary manifestations of multicentric Castleman’s disease in HIV infection: a clinical, biological and radiological study. Eur Respir J 26:118–125PubMedCrossRefGoogle Scholar
  18. 18.
    Weisenburger DD, Nathwani BN, Winberg CD, Rappaport H (1985) Multicentric angiofollicular lymph node hyperplasia: a clinicopathologic study of 16 cases. Hum Pathol 16:162–172PubMedCrossRefGoogle Scholar
  19. 19.
    Gessain A, Sudaka A, Brière J et al (1996) Kaposi sarcoma-associated herpes-like virus (human herpesvirus type 8) DNA sequences in multicentric Castleman’s disease: is there any relevant association in non-human immunodeficiency virus-infected patients? Blood 87:414–416PubMedGoogle Scholar
  20. 20.
    Izuchukwu IS, Tourbaf K, Mahoney MC (2003) An unusual presentation of Castleman’s disease: a case report. BMC Infect Dis 3:20PubMedCrossRefGoogle Scholar
  21. 21.
    Oksenhendler E, Duarte M, Soulier J et al (1996) Multicentric Castleman’s disease in HIV infection: a clinical and pathological study of 20 patients. AIDS 10:61–67PubMedCrossRefGoogle Scholar
  22. 22.
    Oksenhendler E, Boulanger E, Galicier L et al (2002) High incidence of Kaposi sarcoma-associated herpesvirus-related non-Hodgkin lymphoma in patients with HIV infection and multicentric Castleman disease. Blood 99:2331–2336PubMedCrossRefGoogle Scholar
  23. 23.
    Larroche C, Cacoub P, Soulier J et al (2002) Castleman’s disease and lymphoma: report of eight cases in HIV-negative patients and literature review. Am J Hematol 69:119–126PubMedCrossRefGoogle Scholar
  24. 24.
    Du MQ, Liu H, Diss TC et al (2001) Kaposi sarcoma-associated herpesvirus infects monotypic (IgM lambda) but polyclonal naive B cells in Castleman disease and associated lymphoproliferative disorders. Blood 97:2130–2136PubMedCrossRefGoogle Scholar
  25. 25.
    Dupin N, Diss TL, Kellam P et al (2000) HHV-8 is associated with a plasmablastic variant of Castleman disease that is linked to HHV-8-positive plasmablastic lymphoma. Blood 95:1406–1412PubMedGoogle Scholar
  26. 26.
    Kojima M, Nakamura S, Nishikawa M, Itoh H, Miyawaki S, Masawa N (2005) Idiopathic multicentric Castleman’s disease. A clinicopathologic and immunohistochemical study of five cases. Pathol Res Pract 201:325–332PubMedCrossRefGoogle Scholar
  27. 27.
    Kojima M, Nakamura S, Itoh H et al (1997) Systemic lupus erythematosus (SLE) lymphadenopathy presenting with histopathologic features of Castleman’ disease: a clinicopathologic study of five cases. Pathol Res Pract 193:565–571PubMedCrossRefGoogle Scholar
  28. 28.
    Ioachim HL, Cronin W, Roy M, Maya M (1990) Persistent lymphadenopathies in people at high risk for HIV infection. Clinicopathologic correlations and long-term follow-up in 79 cases. Am J Clin Pathol 93:208–218PubMedGoogle Scholar
  29. 29.
    Kojima M, Nakamura S, Shimizu K et al (2004) Clinical implication of idiopathic plasmacytic lymphadenopathy with polyclonal hypergammaglobulinemia: a report of 16 cases. Int J Surg Pathol 12:25–30PubMedCrossRefGoogle Scholar
  30. 30.
    Frizzera G, Banks PM, Massarelli G, Rosai J (1983) A systemic lymphoproliferative disorder with morphologic features of Castleman’s disease. Pathological findings in 15 patients. Am J Surg Pathol 7:211–231PubMedCrossRefGoogle Scholar
  31. 31.
    Koo CH, Nathwani BN, Winberg CD, Hill LR, Rappaport H (1984) Atypical lymphoplasmacytic and immunoblastic proliferation in lymph nodes of patients with autoimmune disease (autoimmune-disease-associated lymphadenopathy). Med (Baltimore) 63:274–290Google Scholar
  32. 32.
    Bianchi MM, Narváez J, Santo P et al (2009) Multicentric Castleman’s disease mimicking adult-onset Still’s disease. Joint Bone Spine 76:304–307PubMedCrossRefGoogle Scholar
  33. 33.
    Bonekamp D, Horton KM, Hruban RH, Fishman EK (2011) Castleman disease: the great mimic. Radiographics 31:1793–1807PubMedCrossRefGoogle Scholar
  34. 34.
    Polizzotto MN, Uldrick TS, Hu D, Yarchoan R (2012) Clinical manifestations of Kaposi sarcoma herpesvirus lytic activation: multicentric Castleman disease (KSHV-MCD) and the KSHV inflammatory cytokine syndrome. Front Microbiol 3:73PubMedCrossRefGoogle Scholar
  35. 35.
    Nishimoto N, Kishimoto T (2006) Interleukin 6: from bench to bedside. Nat Clin Pract Rheumatol 2:619–626PubMedCrossRefGoogle Scholar
  36. 36.
    Kishimoto T (2006) Interleukin-6: discovery of a pleiotropic cytokine. Arthritis Res Ther 8:S2PubMedCrossRefGoogle Scholar
  37. 37.
    Kishimoto T (1989) The biology of interleukin-6. Blood 74:1–10PubMedGoogle Scholar
  38. 38.
    Vinzio S, Ciarloni L, Schlienger JL, Rohr S, Méchine A, Goichot B (2008) Isolated microcytic anemia disclosing a unicentric Castleman disease: the interleukin-6/hepcidin pathway? Eur J Intern Med 19:367–369PubMedCrossRefGoogle Scholar
  39. 39.
    Nemeth E, Valore EV, Territo M, Schiller G, Lichtenstein A, Ganz T (2003) Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood 101:2461–2463PubMedCrossRefGoogle Scholar
  40. 40.
    Sullivan RJ, Pantanowitz L, Casper C, Stebbing J, Dezube BJ (2008) HIV/AIDS: epidemiology, pathophysiology, and treatment of Kaposi sarcoma-associated herpesvirus disease: Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman disease. Clin Infect Dis 47:1209–1215PubMedCrossRefGoogle Scholar
  41. 41.
    Moore PS, Chang Y (1995) Detection of herpesvirus-like DNA sequences in Kaposi’s sarcoma in patients with and without HIV infection. N Engl J Med 332:1181–1185PubMedCrossRefGoogle Scholar
  42. 42.
    Davis DA, Humphrey RW, Newcomb FM et al (1997) Detection of serum antibodies to a Kaposi’s sarcoma-associated herpesvirus-specific peptide. J Infect Dis 175:1071–1079PubMedCrossRefGoogle Scholar
  43. 43.
    Kedes DH, Ganem D, Ameli N, Bacchetti P, Greenblatt R (1997) The prevalence of serum antibody to human herpesvirus 8 (Kaposi sarcoma-associated herpesvirus) among HIV-seropositive and high-risk HIV-seronegative women. JAMA 277:478–481PubMedCrossRefGoogle Scholar
  44. 44.
    Pauk J, Huang ML, Brodie SJ et al (2000) Mucosal shedding of human herpesvirus 8 in men. N Engl J Med 343:1369–1377PubMedCrossRefGoogle Scholar
  45. 45.
    Regamey N, Tamm M, Wernli M et al (1998) Transmission of human herpesvirus 8 infection from renal-transplant donors to recipients. N Engl J Med 339:1358–1363PubMedCrossRefGoogle Scholar
  46. 46.
    Levi JE, Nascimento MC, Sumita LM et al (2011) Non-detection of human herpesvirus 8 (HHV-8) DNA in HHV-8-seropositive blood donors from three Brazilian regions. PLoS One 6:e23546PubMedCrossRefGoogle Scholar
  47. 47.
    Damania B (2007) DNA tumor viruses and human cancer. Trends Microbiol 15:38–44PubMedCrossRefGoogle Scholar
  48. 48.
    Fukumoto H, Kanno T, Hasegawa H, Katano H (2011) Pathology of Kaposi’s Sarcoma-Associated Herpesvirus infection. Front Microbiol 2:175PubMedCrossRefGoogle Scholar
  49. 49.
    Bélec L, Mohamed AS, Authier FJ et al (1999) Human herpesvirus 8 infection in patients with POEMS syndrome-associated multicentric Castleman’s disease. Blood 93:3643–3653PubMedGoogle Scholar
  50. 50.
    Yamasaki S, Iino T, Nakamura M et al (2003) Detection of human herpesvirus-8 in peripheral blood mononuclear cells from adult Japanese patients with multicentric Castleman’s disease. Br J Haematol 120:471–477PubMedCrossRefGoogle Scholar
  51. 51.
    Darazam IA, Mansouri SD, Karimi S et al (2010) A 25-year-old woman with cough, constitutional symptoms and lymphadenopathy. Tanaffos 9:80–83Google Scholar
  52. 52.
    Schulte KM, Talat N (2010) Castleman’s disease–a two compartment model of HHV8 infection. Nat Rev Clin Oncol 7:533–543PubMedCrossRefGoogle Scholar
  53. 53.
    Martró E, Cannon MJ, Dollard SC et al (2004) Evidence for both lytic replication and tightly regulated human herpesvirus 8 latency in circulating mononuclear cells, with virus loads frequently below common thresholds of detection. J Virol 78:11707–11714PubMedCrossRefGoogle Scholar
  54. 54.
    Neipel F, Albrecht JC, Ensser A et al (1997) Human herpesvirus 8 encodes a homolog of interleukin-6. J Virol 71:839–842PubMedGoogle Scholar
  55. 55.
    Cesarman E (2011) Gammaherpesvirus and lymphoproliferative disorders in immunocompromised patients. Cancer Lett 305:163–174PubMedCrossRefGoogle Scholar
  56. 56.
    El-Daly H, Bower M, Naresh KN (2010) Follicular dendritic cells in multicentric Castleman disease present human herpes virus type 8 (HHV8)-latent nuclear antigen 1 (LANA1) in a proportion of cases and is associated with an enhanced T-cell response. Eur J Haematol 84:133–136PubMedCrossRefGoogle Scholar
  57. 57.
    El-Osta HE, Kurzrock R (2011) Castleman’s disease: from basic mechanisms to molecular therapeutics. Oncologist 16:497–511PubMedCrossRefGoogle Scholar
  58. 58.
    Casper C (2005) The aetiology and management of Castleman disease at 50 years: translating pathophysiology to patient care. Br J Haematol 129:3–17PubMedCrossRefGoogle Scholar
  59. 59.
    Dispenzieri A, Gertz MA (2005) Treatment of Castleman’s disease. Curr Treat Options Oncol 6:255–266PubMedCrossRefGoogle Scholar
  60. 60.
    Gill PS, Loureiro C, Bernstein-Singer M, Rarick MU, Sattler F, Levine AM (1989) Clinical effect of glucocorticoids on Kaposi sarcoma related to the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 110:937–940PubMedCrossRefGoogle Scholar
  61. 61.
    Lajoie G, Kumar S, Min KW, Silva FG (1995) Renal thrombotic microangiopathy associated with multicentric Castleman’s disease. Report of two cases. Am J Surg Pathol 19:1021–1028PubMedCrossRefGoogle Scholar
  62. 62.
    Mylona EE, Baraboutis IG, Lekakis LJ, Georgiou O, Papastamopoulos V, Skoutelis A (2008) Multicentric Castleman’s disease in HIV infection: a systematic review of the literature. AIDS Rev 10:25–35PubMedGoogle Scholar
  63. 63.
    Seo HY, Kim EB, Kim JW, Shin BK, Kim SJ, Kim BS (2009) Complete remission in a patient with human herpes virus-8 negative multicentric Castleman disease using CHOP chemotherapy. Cancer Res Treat 41:104–107PubMedCrossRefGoogle Scholar
  64. 64.
    Bower M, Fox P, Fife K, Gill J, Nelson M, Gazzard B (1999) Highly active anti-retroviral therapy (HAART) prolongs time to treatment failure in Kaposi’s sarcoma. AIDS 13:2105–2111PubMedCrossRefGoogle Scholar
  65. 65.
    Zietz C, Bogner JR, Goebel FD, Löhrs U (1999) An unusual cluster of cases of Castleman’s disease during highly active antiretroviral therapy for AIDS. N Engl J Med 340:1923–1924PubMedCrossRefGoogle Scholar
  66. 66.
    Berezne A, Agbalika F, Oksenhendler E (2004) Failure of cidofovir in HIV-associated multicentric Castleman disease. Blood 103:4368–4369PubMedCrossRefGoogle Scholar
  67. 67.
    Casper C, Nichols WG, Huang ML, Corey L, Wald A (2004) Remission of HHV-8 and HIV-associated multicentric Castleman disease with ganciclovir treatment. Blood 103:1632–1634PubMedCrossRefGoogle Scholar
  68. 68.
    Bower M, Powles T, Williams S et al (2007) Brief communication: rituximab in HIV-associated multicentric Castleman disease. Ann Intern Med 147:836–839PubMedCrossRefGoogle Scholar
  69. 69.
    Gérard L, Bérezné A, Galicier L et al (2007) Prospective study of rituximab in chemotherapy-dependent human immunodeficiency virus associated multicentric Castleman’s disease: ANRS 117 CastlemaB Trial. J Clin Oncol 25:3350–3356PubMedCrossRefGoogle Scholar
  70. 70.
    Law AB, Ryan G, Lade S, Prince HM (2010) Development of Kaposi’s sarcoma after complete remission of multicentric Castlemans disease with rituximab therapy in a HHV8-positive, HIV-negative patient. Int J Hematol 91:347–348PubMedCrossRefGoogle Scholar
  71. 71.
    Nishimoto N, Sasai M, Shima Y et al (2000) Improvement in Castleman’s disease by humanized anti-interleukin-6 receptor antibody therapy. Blood 95:56–61PubMedGoogle Scholar
  72. 72.
    Nishimoto N, Kanakura Y, Aozasa K et al (2005) Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease. Blood 106:2627–2632PubMedCrossRefGoogle Scholar
  73. 73.
    Matsuyama M, Suzuki T, Tsuboi H et al (2007) Anti-interleukin-6 receptor antibody (tocilizumab) treatment of multicentric Castleman’s disease. Intern Med 46:771–774PubMedCrossRefGoogle Scholar
  74. 74.
    Higuchi T, Nakanishi T, Takada K et al (2010) A case of multicentric Castleman’s disease having lung lesion successfully treated with humanized anti-interleukin-6 receptor antibody, tocilizumab. J Korean Med Sci 25:1364–1367PubMedCrossRefGoogle Scholar
  75. 75.
    Műzes G, Sipos F, Csomor J, Sréter L (2012) Successful tocilizumab treatment in a patient with HHV8-positive and HIV-negative multicentric Castleman’s disease of plasma cell type nonresponsive to R-CVP therapy. doi:10.1111/apm.12029
  76. 76.
    van Rhee F, Fayad L, Voorhees P et al (2010) Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman’s disease. J Clin Oncol 28:3701–3708PubMedCrossRefGoogle Scholar
  77. 77.
    Starkey CR, Joste NE, Lee FC (2006) Near-total resolution of multicentric Castleman disease by prolonged treatment with thalidomide. Am J Hematol 81:303–304PubMedCrossRefGoogle Scholar
  78. 78.
    Hess G, Wagner V, Kreft A, Heussel CP, Huber C (2006) Effects of bortezomib on pro-inflammatory cytokine levels and transfusion dependency in a patient with multicentric Castleman disease. Br J Haematol 134:544–545PubMedCrossRefGoogle Scholar
  79. 79.
    Sobas MA, Alonso Vence N, Diaz Arias J, Bendaña Lopez A, Fraga Rodriguez M, Bello Lopez JL (2010) Efficacy of bortezomib in refractory form of multicentric Castleman disease associated to poems syndrome (MCD-POEMS variant). Ann Hematol 89:217–219PubMedCrossRefGoogle Scholar
  80. 80.
    Galeotti C, Tran TA, Franchi-Abella S, Fabre M, Pariente D, Koné-Paut I (2008) IL-1RA agonist (anakinra) in the treatment of multifocal castleman disease: case report. J Pediatr Hematol Oncol 30:920–924PubMedCrossRefGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2013

Authors and Affiliations

  • Györgyi Műzes
    • 1
  • Ferenc Sipos
    • 1
  • Judit Csomor
    • 2
  • Lídia Sréter
    • 1
  1. 1.2nd Department of MedicineSemmelweis UniversityBudapestHungary
  2. 2.1st Department of Pathology and Experimental OncologySemmelweis UniversityBudapestHungary

Personalised recommendations