Castleman's Disease

Background

Castleman's disease presents with marked lymph node hyperplasia. Traditionally, the disease has been subclassified on clinical grounds (solitary or multicentric presentations) and histologic appearances, including cases with a hyaline vascular pattern, plasma cell predominance, or mixed lesions. It is now increasingly clear that there are different etiologies for each of these different subtypes. The multicentric plasma cell variant is highly associated with infection by human herpesvirus 8 (HHV8), and patients have an increased risk for the development of other HHV8-associated neoplasms, including Kaposi's sarcoma and extranodal B-cell lymphoma. The solitary plasma cell/mixed variant of Castleman's disease is often seen in patients with a history of lymphoma. Overproduction of the cytokine interleukin 6, either native or virally encoded, has been hypothesized to drive plasma cell proliferation in these subtypes.

EPIDEMIOLOGY CHARACTERIZATION

SYNONYMS Angiofollicular hyperplasia
Giant lymph node hyperplasia

KOREANS

Clinicopathologic study of Castleman's disease in Korea.

Kim JE, Kim CJ, Park IA, Kim WH, Seo JW, Jang JJ, Kim CW, Park SH, Lee HS, Chi JG, Kim YI, Ham EK.

Department of Pathology, Seoul National University College of Medicine, Korea.
J Korean Med Sci 2000 Aug;15(4):393-8 Abstract quote
Castleman's disease represents an atypical lymphoproliferative disorder, infrequently associated with various immunologic abnormalities or subsequent development of malignancy such as Kaposi sarcoma, malignant lymphoma and plasmacytoma. Its clinicopathologic features depend on various etiologic factors such as Kaposi sarcoma herpesvirus (KSHV), oversecretion of IL-6, adhesion molecule and follicular dendritic cell dysplasia, etc.

To investigate the relationship of Castleman's disease (CD) and the above factors, we reviewed 22 cases of CD. Four cases of KSHV positive CD were detected, all multicentric, plasma cell type, and these cases displayed prominent vascular proliferation, characteristic 'Kaposi-like lesion'. IL-6 and CD54 positive mononuclear cells were scattered in interfollicular areas of KSHV positive cases. Follicular dendritic cell hyperplasia, vascular proliferation, expression of IL-6 and CD54 did not show any significant difference between solitary vs multicentric type, and plasma cell type vs hyaline vascular type.

Our study suggests that KSHV positive CD reveals unique pathologic features, and the probable relationship of KSHV and IL-6 and CD54 is discussed.

DISEASE ASSOCIATIONS CHARACTERIZATION

AIDS

Multicentric Castleman's disease in HIV infection: a clinical and pathological study of 20 patients.

Oksenhendler E, Duarte M, Soulier J, Cacoub P, Welker Y, Cadranel J, Cazals-Hatem D, Autran B, Clauvel JP, Raphael M.

Department of Immuno-Haematology, St Louis Hospital, Paris, France.

AIDS 1996 Jan;10(1):61-7 Abstract quote
OBJECTIVES: To describe, in a retrospective study, the clinical and pathological spectrum of multicentric Castleman's disease (MCD) in HIV infection.

PATIENTS: The diagnosis of MCD was established by lymph node biopsy in 20 HIV-infected patients. All patients had been HIV-infected by sexual contact. At diagnosis, HIV infection was asymptomatic in eight patients and Kaposi's sarcoma was present in 12. Mean +/- SD CD4+ cell count was 156 +/- 99 x 10(6)/l.

RESULTS: Patients were referred with a syndrome of fever and splenomegaly (100%), peripheral lymphadenopathy (90%), hepatomegaly (70%), severe weight loss (70%), respiratory symptoms (65%) and oedema (55%). Anaemia was a constant finding and seven (35%) patients presented with pancytopenia. Serum markers of inflammation were present in most patients: a high level of C reactive protein (90%), polyclonal hypergammaglobulinaemia (89%) and hypoalbuminaemia (56%). The histological pattern of the lymph nodes was characterized by small hyalinized germinal centres surrounded by concentric layers of small lymphocytes, vascular hyperplasia, hyalinized vessels and large interfollicular sheets of plasma cells. Five patients were classified as plasma cell type MCD and 15 as hyaline vascular/plasma cell (mixed) type. Immunophenotyping studies (n = 13) demonstrated a polyclonal B-cell process. No linkage with Epstein-Barr virus (EBV) could be demonstrated immunohistochemically using an anti-latent membrane protein-1 monoclonal antibody (n = 16) or by RNA in situ hybridization with an EBV-encoded RNA transcript-specific probe (n = 13). Remission was obtained with low-dose and usually single agent chemotherapy in 16 patients. During follow-up, non-Hodgkin's lymphoma developed in two patients and Kaposi's sarcoma in three. Fatal outcome occurred in 14 patients with a median survival of 14 months.

CONCLUSION: MCD associated with HIV infection is a distinct clinico-pathological entity that can be differentiated from other types of HIV-associated systemic lymphoproliferative disorders. It is very similar to MCD observed in non-HIV-infected patients, except for the high prevalence of pulmonary symptoms and for the stronger association with Kaposi's sarcoma. Single-agent chemotherapy with vinblastine is effective and may prolong survival.

FOLLICULAR DENDRITIC CELL SARCOMA

Development of follicular dendritic cell sarcoma in hyaline-vascular Castleman's disease of the nasopharynx: tracing its evolution by sequential biopsies.

Chan AC, Chan KW, Chan JK, Au WY, Ho WK, Ng WM.

Department of Pathology, Queen Elizabeth Hospital, Kowloon, Hong Kong.

Histopathology 2001 Jun;38(6):510-8

Hyaline-vascular Castleman's disease (HVCD) and follicular dendritic cell (FDC) sarcoma occurring in the nasopharynx are both extremely rare. We report the first case of transformation of the former into the latter as documented by sequential biopsies. The steps involved in the transformation were described in detail and the possible role of p53 studied.

METHODS AND RESULTS: The patient presented at the age of 23 years with nasopharyngeal HVCD. Hyaline- vascular Castleman's disease with FDC overgrowth was diagnosed in a recurrence 8 years later, and a frank FDC sarcoma developed at the same site 11 years after initial presentation. The patient remained disease-free 3 years after excision and adjuvant chemotherapy. The FDC sarcoma comprised swirling fascicles of spindly cells with indistinct cell borders. The tumour cells expressed the FDC markers CD21, CD35 and CNA.42 and in-situ hybridization for Epstein-Barr virus-encoded RNAs was negative. Over-expression of p53 protein was observed in the FDC sarcoma and an increased number of weakly p53-positive spindly cells could also be demonstrated in the HVCD specimen. This finding suggested a possible role of p53 in the evolution from HVCD to FDC sarcoma. Critical analysis of the literature shows that, among the 13 reported cases of FDC sarcoma associated with Castleman's disease, possible progression from the latter to the former is documented in only two cases.

CONCLUSIONS: The sequential changes observed in the current case provide further evidence to strengthen the role of HVCD as a possible precursor of FDC sarcoma. There is a possible role of p53 in the transformation process but confirmation by future studies is needed.

Follicular dendritic cell tumor and vascular neoplasm complicating hyaline-vascular Castleman's disease.

Chan JK, Tsang WY, Ng CS.

Am J Surg Pathol 1994;18:517�25. Abstract quote

The localized form of hyaline-vascular Castleman's disease may rarely be complicated by a vascular neoplasm, which appears to arise in a background of vascular hyperplasia.

We report a case complicated by follicular dendritic cell tumor, a hitherto undescribed occurrence that is expected from the presence of a "dysplastic" component of follicular dendritic cells in Castleman's disease. The patient had a large tumor mass in the mesocolon, associated with multiple small peritoneal deposits. The lesion showed typical histologic features of follicular dendritic cell tumor with storiform arrangement of spindly cells and admixture of small lymphocytes. The follicular dendritic cell nature of the tumor was confirmed by immunoreactivity with CD21 and CD35 antibodies and by ultrastructural demonstration of cell processes connected by desmosomes. Hyaline-vascular follicles were identified at the peripheral portion or occasionally scattered in the center of the tumor. Rarely, follicle-like structures were formed by tumor cells, possibly representing in situ malignant change. In addition, there was a small focus of vascular neoplasm comprising well-formed pericyte-rich small blood vessels devoid of cellular atypia.

This report of the development of follicular dendritic cell tumor in Castleman's disease therefore completes the picture in that tumors corresponding to each cell type that proliferates in Castleman's disease have now been documented.

HODGKIN'S DISEASE

Coexistence of Hodgkin's disease and giant lymph node hyperplasia of the plasma-cell type (Castleman's disease).

Abdel-Reheim FA, Koss W, Rappaport ES, Arber DA.

Department of Pathology, Scott and White Clinic, Temple, TX 76508, USA.

Arch Pathol Lab Med 1996 Jan;120(1):91-6

Coexistence of Hodgkin's disease and giant lymph node hyperplasia (Castleman's disease) is well documented in the literature. We present a unique case in which the original lymph node biopsy revealed interfollicular Hodgkin's disease (CD15+, CD30+, CD45-, Reed-Sternberg cells) with coexistent histologic features of the plasma-cell variant of Castleman's disease. The patient experienced a long-term remission following combined chemotherapy and radiation therapy. He presented at 18 years and again at 22 years later with clinical, hematologic, and histologic features of a multicentric plasma-cell variant of Castleman's disease without evidence of Hodgkin's disease.

This unique case report further strengthens the association of Castleman's disease and Hodgkin's lymphoma. Two pathogenetic mechanisms for this association have been suggested: (1) secretion of interleukin-6 by Hodgkin's Reed-Sternberg cells and histiocytes, and (2) manifestation of an abnormal immune state associated with Hodgkin's disease. These two mechanisms may, indeed, be related.

PARANEOPLASTIC PEMPHIGUS

Paraneoplastic pemphigus in association with a retroperitoneal Castleman's disease presenting with a lichen planus pemphigoides-like eruption. A case report and review of literature.

Hsiao CJ, Hsu MM, Lee JY, Chen WC, Hsieh WC.

Department of Dermatology, National Cheng-Kung University Hospital, 138 Sheng-Li Road, Tainan, Taiwan 704.

Br J Dermatol 2001 Feb;144(2):372-6 Abstract quote

A 50-year-old man presented with severe mucosal erosions of the lips, oral cavity and perianal area, a lichen planus-like eruption on the trunk and extremities and scaly plaques of the palms and soles. The clinical impression was of Stevens--Johnson syndrome, or paraneoplastic pemphigus (PNP). Histopathology revealed vacuolar interface and lichenoid dermatitis with dyskeratosis and suprabasal acantholytic vesiculation. Direct immunofluorescence showed deposition of IgG in the intercellular space and linear deposition of C3 along the basal membrane zone. Indirect immunofluorescence revealed circulating IgG with intercellular staining of the epithelium of rat urinary bladder. Western blotting demonstrated bands of 250- and 230-kDa antigens.

The clinical, histological and immunological features were consistent with the lichen planus pemphigoides variant of PNP. A retroperitoneal hyaline-vascular Castleman's disease was detected and excised. The skin lesions worsened initially after tumour resection but improved gradually, leaving extensive melanosis after cyclosporin and mycophenolate mofetil treatment.

POEMS SYNDROME

Castleman disease in POEMS syndrome with elevated interleukin-6.

Emile C, Danon F, Fermand JP, Clauvel JP.
Cancer 1993 Feb 1;71(3):874

PATHOGENESIS CHARACTERIZATION

CHROMOSOMAL ABNORMALITIES

A Chromosomal Abnormality in Hyaline Vascular Castleman's Disease Evidence for Clonal Proliferation of Dysplastic Stromal Cells

Patrick Pauwels, M.D.; Paola Dal Cin, Ph.D.; Lodewijk T. Vlasveld, M.T., Ph.D.; Roelof M. Aleva, M.D.; W. F.M. van Erp, M.D., Ph.D.; Dan Jones, M.D., Ph.D.

From Stichting PAMM, Catharina Ziekenhuis, Eindhoven, The Netherlands (P.P.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, U.S.A. (P.D.C.); Departments of Internal Medicine (L.T.V.), Pneumology (R.M.A.), and Surgery (W.F.M.v.E.), Diaconessenhuis, Eindhoven, The Netherlands; and the Department of Pathology, UT-M.D. Anderson Cancer Center, Houston, Texas (D.J.), U.S.A.

Am J Surg Pathol 2000;24:882-888 Abstract quote

The pathogenesis of the hyaline vascular variant of Castleman's disease is currently unknown; however, vascular and dendritic cell proliferations are common in this disorder.

\We report a clonal karyotypic abnormality (46,XX,t(1;16) (p11;p11), del(7)(q21q22),del(8)(q12q22)) in 15 of 20 cells obtained after short-term stromal cultures of a typical case of hyaline vascular Castleman's disease (HVCD).

There was no histologic, immunohistochemical, or genotypic evidence of a clonal lymphoid or plasma cell proliferation supporting origin of this aberration from the stromal component, possibly dendritic cells.

We re-examined 15 previous cases of HVCD and identified a spectrum of dysplastic changes in the follicular dendritic cells (FDC) of atrophic lymphoid follicles, with some cases showing expansions of FDC networks by CD21 immunostaining.

We propose that localized clonal proliferations of stromal elements, particularly follicular dendritic cells, occur in typical HVCD and likely explain the increased incidence of FDC sarcomas in these patients.

HHV-8

Kaposi sarcoma-associated herpesvirus infects monotypic (IgM lambda) but polyclonal naive B cells in Castleman disease and associated lymphoproliferative disorders.

Du MQ, Liu H, Diss TC, Ye H, Hamoudi RA, Dupin N, Meignin V, Oksenhendler E, Boshoff C, Isaacson PG.

Department of Histopathology, Royal Free and University College Medical School, University College London, London, United Kingdom.

Blood. 2001;97:2130-2136 Abstract quote

In a previous study, it was shown that the Kaposi sarcoma-associated herpesvirus (KSHV) was specifically associated with monotypic (IgMlambda) plasmablasts in multicentric Castleman disease (MCD). The plasmablasts occur as isolated cells in the mantle zone of B-cell follicles but may form microlymphoma or frank plasmablastic lymphoma.

To determine the clonality and cellular origin of the monotypic plasmablasts, the rearranged Ig genes in 13 patients with KSHV-related MCD, including 8 cases with microlymphomas and 2 with frank lymphomas, were studied.

To investigate the role of the interleukin 6 (IL-6) receptor signaling in the pathogenesis of MCD and associated lymphoproliferative disorders, viral IL-6 and human IL-6 receptor expression was examined. KSHV-positive plasmablasts were polyclonal in MCD-involved lymphoid tissues in all cases and microlymphomas in 6 of 8 cases. Monoclonal KSHV-positive plasmablasts were seen in microlymphomas of 2 cases and in both frank lymphomas. Despite their mature phenotype, KSHV-positive plasmablasts did not harbor somatic mutations in the rearranged Ig genes, indicating origination from naive B cells. Viral IL-6 was expressed in 10% to 15% of KSHV-positive plasmablasts, whereas the human IL-6 receptor was expressed in most KSHV-positive cells.

Thus, KSHV infects monotypic but polyclonal naive B cells and is associated with a range of lymphoproliferative disorders from polyclonal isolated plasmablasts and microlymphomas to monoclonal microlymphoma and frank plasmablastic lymphomas in MCD patients. Activation of the IL-6 receptor signaling pathway may play a role in differentiation of KSHV-infected naive B cells into plasmablasts and development of lymphoproliferative lesions.

Analysis of the Human Herpesvirus 8 (HHV-8) Genome and HHV-8 vIL-6 Expression in Archival Cases of Castleman Disease at Low Risk for HIV Infection

David M. Menke, MD
Amy Chadburn, MD
Ethel Cesarman, MD
Eric Green, MD
James Berenson, MD
Jonathan Said, MD
Markus Tiemann, MD
Reza Parwaresch, MD
and Stephan D. Thome, MD

Am J Clin Pathol 2002;117:268-275 Abstract quote

Lymph nodes from 44 patients with Castleman disease (CD) without risk factors for HIV infection were analyzed with polymerase chain reaction (PCR), in situ hybridization (ISH), and immunohistochemical analysis for human herpesvirus 8 (HHV-8) and viral interleukin-6 (vIL-6).

PCR detected HHV-8 genome in 2 of 4 cases; ISH detected it in 9 of 16 cases. HHV-8 vIL-6 peptides were detected in 2 of 44 cases. vIL-6� and ISH-positive cells were found in large transformed and small lymphocytes of the follicular mantle, respectively. Of 9 cases of plasma cell (PC) CD that demonstrated HHV-8 genome by PCR or ISH, 1 expressed vIL-6. Clonal populations of PCs in CD by immunohistochemical analysis or immunoelectrophoresis of serum and urine were associated with neuropathy. HHV-8 vIL-6 detection was associated with poor survival and lack of HHV-8 IL-6, with low risk for subsequent lymphoma. Although HHV-8 genome was detected in a considerable number of patients with PC CD, vIL-6 expression was infrequent.

Expression of HHV-8 vIL-6 in CD may indicate poor prognosis in patients at risk for lymphoma who may prospectively require more aggressive treatment. The lack of vIL-6 expression in CD with HHV-8 genome suggests that human IL-6 rather than vIL-6 may be the principal pathogenic cytokine.

HMGIC REARRANGEMENTS

Hyaline vascular Castleman's disease with HMGIC rearrangement in follicular dendritic cells: molecular evidence of mesenchymal tumorigenesis.

Cokelaere K, Debiec-Rychter M, De Wolf-Peeters C, Hagemeijer A, Sciot R.

Department of Pathology, University Hospital St Raphael, Katholieke Universiteit Leuven, Leuven, Belgium.
Am J Surg Pathol 2002 May;26(5):662-9 Abstract quote
Chromosomal aberrations involving chromosome segment 12q13-15 are a common finding in a variety of benign mesenchymal tumors. The target gene encodes for HMGIC, a member of the high mobility group protein family. These proteins act as architectural transcription factors. HMGIC plays a role as a common genetic denominator in benign mesenchymal tumorigenesis.

We report a case of hyaline vascular Castleman's disease with intragenic HMGIC rearrangement, due to a clonal cytogenetic aberration involving the long arm of chromosome 12 [46,XX, add(1)(q21),der(6)t(6;12) (q23;q15),add(7)(p22), -9,inv(9)(p11q13),del(12)(q15),+mar] obtained after short-term primary cultures. A combined immunocytologic-cytogenetic approach enabled us to demonstrate the exclusive presence of HMGIC rearrangement in anti-CD21 reactive follicular dendric cells.

This finding confirms that a clonal proliferation of follicular dendritic cells occurs in the hyaline vascular variant of Castleman's disease. It also provides a possible molecular pathway explaining stromal overgrowths and stromal neoplasms developing from this disorder.

INTERLEUKIN -6

Expression of interleukin-6 in Castleman's disease.

Hsu SM, Waldron JA, Xie SS, Barlogie B.

Hum Pathol 1993 Aug;24(8):833-9 Abstract quote

Although mixed forms of Castleman's disease (CD) may occur, two classically recognized forms are the angiofollicular (hyaline vascular [V]) variant and the plasma cell (P) variant. The two forms of CD differ greatly in their clinical and histopathologic manifestations. Plasma cell CD is characterized by the presence of hyperplastic germinal centers (GCs) and sheets of plasma cells in the interfollicular areas.

In this study we demonstrated an abundant expression of interleukin-6 (IL-6) in most GC B cells and in the numerous immunoblastoid B cells in the mantle zone and interfollicular areas in CD-P. Patients with CD-P also have an elevated serum IL-6 level. The increased IL-6 production is responsible for the marked plasma cell infiltration in lymph nodes and bone marrow as well as for the elevated gammaglobulin level in serum.

In contrast, CD-V is distinguished by the presence of atrophic GCs, which often are populated by cytologically atypical follicular dendritic reticulum (FDR) cells, as well as by sheets of T-zone plasmacytoid histiocytes and increased numbers of capillaries in the interfollicular areas. In contrast to the findings in CD-P, we did not observe significant expression of IL-6 in GC cells or in immunoblastoid cells in CD-V; this may account for the paucity of plasma cells in this form of CD. The reason for the atypical changes in FDR cells as well as the increases in T-zone plasmacytoid histiocytes and capillaries seen in CD-V are not known inasmuch as no cytokines, such as IL-1, IL-4, IL-6, IL-7, IL-8, IL-9, tumor necrosis factor-alpha, granulocyte-macrophage colony-stimulating factor, or granulocyte colony-stimulating factor, were detectable in tissues. It is possible that in CD-V the atypical change in FDR cells could lead to a disturbance of B-lymphocyte/FDR cell interaction and subsequently to poor development of GCs.

The study clearly indicates that the histopathologic and clinical features of CD vary greatly depending on the capacity of activated B cells to produce IL-6. However, lack of IL-6 secretion by GC cells alone cannot explain the histopathologic alterations in CD-V.

Inactivation of the IL-6 gene prevents development of multicentric Castleman's disease in C/EBP beta-deficient mice.

Screpanti I, Musiani P, Bellavia D, Cappelletti M, Aiello FB, Maroder M, Frati L, Modesti A, Gulino A, Poli V.

Dipartimento di Medicino Sperimentale c Patologia, Universita La Sapienza, Roma, Italy.
J Exp Med 1996 Oct 1;184(4):1561-6 Abstract quote.
Castleman's disease is a lymphoproliferative disorder thought to be related to deregulated production of IL-6.

We have previously shown that mice lacking the trans-acting factor C/EBP beta, a transcriptional regulator of IL-6 and a mediator of IL-6 intracellular signaling, develop a pathology nearly identical to multicentric Castleman's disease, together with increasingly high levels of circulating IL-6.

We describe here how the simultaneous inactivation of both IL-6 and C/EBP beta genes prevents the development of pathological traits of Castleman's disease observed in C/EBP beta-deficient mice. Histological and phenotypic analysis of lymph nodes and spleen of double mutant mice did not show either the lymphoadenopathy and splenomegaly or the abnormal expansion of myeloid, B and plasma cell compartments observed in C/EBP beta-/- mice, while B cell development, although delayed, was normal.

Our data demonstrate that IL-6 is essential for the development of multicentric Castleman's disease in C/EBP beta-/- mice.

LABORATORY/RADIOLOGIC/
OTHER TESTS
CHARACTERIZATION

Laboratory Markers

IL-6
Present in multicentric plasma cell type

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.

Oksenhendler E, Carcelain G, Aoki Y, Boulanger E, Maillard A, Clauvel JP, Agbalika F.

Department of Immunology and Hematology, Laboratory of Virology, Hopital Saint-Louis, Paris, France.
Blood 2000 Sep 15;96(6):2069-73 Abstract quote
Multicentric Castleman disease (MCD) is a distinct type of lymphoproliferative disorder associated with inflammatory symptoms and interleukin-6 (IL-6) dysregulation. In the context of human immunodeficiency virus (HIV) infection, MCD is associated with human herpesvirus 8 (HHV8) infection.

In a prospective study of 23 HIV-infected patients with MCD, clinical symptoms of MCD were present at 45 visits, whereas patients were in chemotherapy-induced clinical remission at 50 visits. Symptoms were associated with a high level of serum C reactive protein, high HHV8 viral load in peripheral blood mononuclear cells, and high plasma human IL-6 and IL-10 levels.

Strong correlations between plasma IL-6 and plasma IL-10 with the HHV8 viral load suggest that both cytokines may be involved in the pathogenesis of this virus-associated lymphoproliferative disorder.

GROSS APPEARANCE/
CLINICAL VARIANTS CHARACTERIZATION

General

Multicentric Plasma cell type

Hyaline vascular type

Solitary, slow-growing mass, usually in the absence of constitutional symptoms.

Most lesions are located in the mediastinum, abdomen, or neck

Less frequently associated with paraneoplastic phenomenon (for example, neuropathy) and has a benign clinical course

PEDIATRIC

Paediatric Castleman disease: report of seven cases and review of the literature.

Parez N, Bader-Meunier B, Roy CC, Dommergues JP.

Service de Pediatrie, CHU Bicetre, Le Kremlin Bicetre, France.
Eur J Pediatr 1999 Aug;158(8):631-7 Abstract quote
Castleman disease is a distinct lymphoproliferative disorder of unknown origin. Seven new cases in children are reported here and 76 cases from the paediatric literature are reviewed.

The disease has been reported in 46 females and 37 males, their age ranging from 2 months to 17 years. The disease was localized in 72 cases and multicentric in 11 cases. The hyalinovascular type was more frequently encountered (54%) than the plasma cell type (24%).

Laboratory abnormalities were more often associated with the plasma cell type and were mainly represented by anaemia and hypergammaglobulinaemia. Treatment of the localized tumour consisted of surgical excision, whereas treatment of the multicentric form was medical, comprising prednisone and other immunosuppressor drugs. The disease in the paediatric population seems to have a more favourable course than in adults.

CONCLUSION: The paediatric features of the disease suggest that Castleman disease in this population could represent an earlier form of the pathology or even suggest a benign lymphoproliferative disorder.

HISTOLOGICAL TYPES CHARACTERIZATION

General

Plasma cell type
Hyperplastic germinal centers and sheets of plasma cells in the interfollicular areas.

Hyaline vascular type

Regressed follicles with dendritic proliferation, expanded mantle zones, variable proliferation of nodal stromal elements, and increased vascularity in the interfollicular regions

Abnormal follicles with prominent penetrating arterioles and increased interfollicular vascularity, but typically has compressed/absent sinuses, more prominent mantle zone expansion, and many fewer plasma cells

PROGNOSIS AND TREATMENT CHARACTERIZATION

PROGNOSIS

Metastasis
Rare lymphomatous transformation in the hyaline vascular variant but occasionally patients develop tumors of dendritic cell or vascular origin

Lymphomatous transformation more common in hyaline vascular multicentric variant

Recurrence
Rare with hyaline vascular type

Common with multicentric type

TREATMENT
Simple excision of solitary nodules usually curative, especially in hyaline vascular type

HAART

Successful treatment of Castleman's disease with HAART in two HIV-infected patients.

Lanzafame M, Carretta G, Trevenzoli M, Lazzarini L, Vento Ercole Concia S.

Istituto di Immunologia e Malattie Infettive, Ospedale Civile Maggiore Borgo Trento, Verona, Italy.

J Infect 2000 Jan;40(1):90-1 Abstract quote

Castleman's disease is a heterogeneous group of lymphoproliferative disorders of unknown aetiology. Recently, human herpesvirus type 8 (HHV-8) has been associated with various diseases in individuals with HIV infection, including Kaposi's sarcoma, B cell non Hodgkin's lymphomas, and Castleman's disease. In Castleman's disease it has been hypothesized that HHV-8, encoding a number of various virokines, can be responsible for clinical manifestations of the disease. Previously, two reports have described a clinical recovery from HIV-associated Castleman's disease: by administration of a monoclonal antibody neutralizing human IL-6 in one case, and in another case by treatment with highly antiretroviral therapy and anti-herpesvirus therapy, following splenectomy.

We report two cases where HAART alone led to clinical recovery from Castleman's disease.In both the cases reported here, although follow-up biopsy was not performed, it is likely that the inhibition of HHV-8 replication and of virokine release, through the restoration of immunity by HAART, was the basis for the disappearance of the clinical symptoms.

ANTI-INTERLEUKIN-6 RECEPTOR (rhPM-1)

Brief report: alleviation of systemic manifestations of Castleman's disease by monoclonal anti-interleukin-6 antibody.

Beck JT, Hsu SM, Wijdenes J, Bataille R, Klein B, Vesole D, Hayden K, Jagannath S, Barlogie B.

Department of Medicine, Arkansas Cancer Research Center, University of Arkansas for Medical Sciences, Little Rock 72205.
N Engl J Med 1994 Mar 3;330(9):602-5

Increased interleukin-6 (IL-6) production in a young child with clinical and pathologic features of multicentric Castleman's disease.

Kinney MC, Hummell DS, Villiger PM, Hourigan A, Rollins-Smith L, Glick AD, Lawton AR.

Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee 37232.
J Clin Immunol 1994 Nov;14(6):382-90 Abstract quote
A 21-month-old boy presented with a papular rash, lymphoadenopathy, and splenomegaly. He developed symmetric polyarthritis, fever, and progressive glomerulonephritis. Serologies for viral agents including HIV were negative. Antinuclear antibody was transiently positive, but no anti-DNA antibodies were present. CH50 and serum C3 values were low. Biopsies of skin, kidney, bone marrow, and lymph node were obtained. There was a perivascular and periadnexal lymphocytic infiltrate in the skin, with a normal epidermis. Renal biopsy showed proliferative mesangial glomerulonephritis. Bone marrow showed an increased number of plasma cells. Lymph node showed histologic changes described in multicentric Castleman's disease including marked follicular hyperplasia, vascular proliferation, and interfollicular expansion with numerous plasma cells.

IL-6 mRNA was demonstrated in cells in the marginal zone and interfollicular regions of the node by in situ hybridization. Likewise, the serum IL-6 level was elevated during a clinical exacerbation of the patient's nephritis.

These data suggest an underlying lymphoproliferative disorder, such as Castleman's disease, with overproduction of IL-6 resulting in systemic features of the disease, including glomerulonephritis.

Improvement in Castleman's disease by humanized anti-interleukin-6 receptor antibody therapy.

Nishimoto N, Sasai M, Shima Y, Nakagawa M, Matsumoto T, Shirai T, Kishimoto T, Yoshizaki K.

Department of Medical Science I, School of Health and Sport Sciences, Osaka University, Suita-city, Osaka, Japan.

Blood 2000 Jan 1;95(1):56-61 Abstract quote

Castleman's disease, an atypical lymphoproliferative disorder, can be classified into 2 types: hyaline-vascular and plasma cell types according to the histologic features of the affected lymph nodes. The plasma cell type is frequently associated with systemic manifestations and is often refractory to systemic therapy including corticosteroids and chemotherapy, particularly in multicentric form. Dysregulated overproduction of interleukin-6 (IL-6) from affected lymph nodes is thought to be responsible for the systemic manifestations of this disease. Therefore, interference with IL-6 signal transduction may constitute a new therapeutic strategy for this disease.

We used humanized anti-IL-6 receptor antibody (rhPM-1) to treat 7 patients with multicentric plasma cell or mixed type Castleman's disease.

All patients had systemic manifestations including secondary amyloidosis in 3. With the approval of our institution's ethics committee and the consent of the patients, they were treated with 50 to 100 mg rhPM-1 either once or twice weekly. Immediately after administration of rhPM-1, fever and fatigue disappeared, and anemia as well as serum levels of C-reactive protein (CRP), fibrinogen, and albumin started to improve. After 3 months of treatment, hypergammaglobulinemia and lymphadenopathy were remarkably alleviated, as were renal function abnormalities in patients with amyloidosis. Treatment was well tolerated with only transient leukopenia. Histopathologic examination revealed reduced follicular hyperplasia and vascularity after rhPM-1 treatment.

The pathophysiologic significance of IL-6 in Castleman's disease was thus confirmed, and blockade of the IL-6 signal by rhPM-1 is thought to have potential as a new therapy based on the pathophysiologic mechanism of multicentric Castleman's disease.

Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.

Commonly Used Terms

Hematologic and Lymphatic

Last Updated 5/16/2002

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DISEASE ASSOCIATIONS	CHARACTERIZATION
AIDS
Multicentric Castleman's disease in HIV infection: a clinical and pathological study of 20 patients. Oksenhendler E, Duarte M, Soulier J, Cacoub P, Welker Y, Cadranel J, Cazals-Hatem D, Autran B, Clauvel JP, Raphael M. Department of Immuno-Haematology, St Louis Hospital, Paris, France.	AIDS 1996 Jan;10(1):61-7 Abstract quote OBJECTIVES: To describe, in a retrospective study, the clinical and pathological spectrum of multicentric Castleman's disease (MCD) in HIV infection. PATIENTS: The diagnosis of MCD was established by lymph node biopsy in 20 HIV-infected patients. All patients had been HIV-infected by sexual contact. At diagnosis, HIV infection was asymptomatic in eight patients and Kaposi's sarcoma was present in 12. Mean +/- SD CD4+ cell count was 156 +/- 99 x 10(6)/l. RESULTS: Patients were referred with a syndrome of fever and splenomegaly (100%), peripheral lymphadenopathy (90%), hepatomegaly (70%), severe weight loss (70%), respiratory symptoms (65%) and oedema (55%). Anaemia was a constant finding and seven (35%) patients presented with pancytopenia. Serum markers of inflammation were present in most patients: a high level of C reactive protein (90%), polyclonal hypergammaglobulinaemia (89%) and hypoalbuminaemia (56%). The histological pattern of the lymph nodes was characterized by small hyalinized germinal centres surrounded by concentric layers of small lymphocytes, vascular hyperplasia, hyalinized vessels and large interfollicular sheets of plasma cells. Five patients were classified as plasma cell type MCD and 15 as hyaline vascular/plasma cell (mixed) type. Immunophenotyping studies (n = 13) demonstrated a polyclonal B-cell process. No linkage with Epstein-Barr virus (EBV) could be demonstrated immunohistochemically using an anti-latent membrane protein-1 monoclonal antibody (n = 16) or by RNA in situ hybridization with an EBV-encoded RNA transcript-specific probe (n = 13). Remission was obtained with low-dose and usually single agent chemotherapy in 16 patients. During follow-up, non-Hodgkin's lymphoma developed in two patients and Kaposi's sarcoma in three. Fatal outcome occurred in 14 patients with a median survival of 14 months. CONCLUSION: MCD associated with HIV infection is a distinct clinico-pathological entity that can be differentiated from other types of HIV-associated systemic lymphoproliferative disorders. It is very similar to MCD observed in non-HIV-infected patients, except for the high prevalence of pulmonary symptoms and for the stronger association with Kaposi's sarcoma. Single-agent chemotherapy with vinblastine is effective and may prolong survival.
FOLLICULAR DENDRITIC CELL SARCOMA
Development of follicular dendritic cell sarcoma in hyaline-vascular Castleman's disease of the nasopharynx: tracing its evolution by sequential biopsies. Chan AC, Chan KW, Chan JK, Au WY, Ho WK, Ng WM. Department of Pathology, Queen Elizabeth Hospital, Kowloon, Hong Kong.	Histopathology 2001 Jun;38(6):510-8 Hyaline-vascular Castleman's disease (HVCD) and follicular dendritic cell (FDC) sarcoma occurring in the nasopharynx are both extremely rare. We report the first case of transformation of the former into the latter as documented by sequential biopsies. The steps involved in the transformation were described in detail and the possible role of p53 studied. METHODS AND RESULTS: The patient presented at the age of 23 years with nasopharyngeal HVCD. Hyaline- vascular Castleman's disease with FDC overgrowth was diagnosed in a recurrence 8 years later, and a frank FDC sarcoma developed at the same site 11 years after initial presentation. The patient remained disease-free 3 years after excision and adjuvant chemotherapy. The FDC sarcoma comprised swirling fascicles of spindly cells with indistinct cell borders. The tumour cells expressed the FDC markers CD21, CD35 and CNA.42 and in-situ hybridization for Epstein-Barr virus-encoded RNAs was negative. Over-expression of p53 protein was observed in the FDC sarcoma and an increased number of weakly p53-positive spindly cells could also be demonstrated in the HVCD specimen. This finding suggested a possible role of p53 in the evolution from HVCD to FDC sarcoma. Critical analysis of the literature shows that, among the 13 reported cases of FDC sarcoma associated with Castleman's disease, possible progression from the latter to the former is documented in only two cases. CONCLUSIONS: The sequential changes observed in the current case provide further evidence to strengthen the role of HVCD as a possible precursor of FDC sarcoma. There is a possible role of p53 in the transformation process but confirmation by future studies is needed.
Follicular dendritic cell tumor and vascular neoplasm complicating hyaline-vascular Castleman's disease. Chan JK, Tsang WY, Ng CS.	Am J Surg Pathol 1994;18:517�25. Abstract quote The localized form of hyaline-vascular Castleman's disease may rarely be complicated by a vascular neoplasm, which appears to arise in a background of vascular hyperplasia. We report a case complicated by follicular dendritic cell tumor, a hitherto undescribed occurrence that is expected from the presence of a "dysplastic" component of follicular dendritic cells in Castleman's disease. The patient had a large tumor mass in the mesocolon, associated with multiple small peritoneal deposits. The lesion showed typical histologic features of follicular dendritic cell tumor with storiform arrangement of spindly cells and admixture of small lymphocytes. The follicular dendritic cell nature of the tumor was confirmed by immunoreactivity with CD21 and CD35 antibodies and by ultrastructural demonstration of cell processes connected by desmosomes. Hyaline-vascular follicles were identified at the peripheral portion or occasionally scattered in the center of the tumor. Rarely, follicle-like structures were formed by tumor cells, possibly representing in situ malignant change. In addition, there was a small focus of vascular neoplasm comprising well-formed pericyte-rich small blood vessels devoid of cellular atypia. This report of the development of follicular dendritic cell tumor in Castleman's disease therefore completes the picture in that tumors corresponding to each cell type that proliferates in Castleman's disease have now been documented.
HODGKIN'S DISEASE
Coexistence of Hodgkin's disease and giant lymph node hyperplasia of the plasma-cell type (Castleman's disease). Abdel-Reheim FA, Koss W, Rappaport ES, Arber DA. Department of Pathology, Scott and White Clinic, Temple, TX 76508, USA.	Arch Pathol Lab Med 1996 Jan;120(1):91-6 Coexistence of Hodgkin's disease and giant lymph node hyperplasia (Castleman's disease) is well documented in the literature. We present a unique case in which the original lymph node biopsy revealed interfollicular Hodgkin's disease (CD15+, CD30+, CD45-, Reed-Sternberg cells) with coexistent histologic features of the plasma-cell variant of Castleman's disease. The patient experienced a long-term remission following combined chemotherapy and radiation therapy. He presented at 18 years and again at 22 years later with clinical, hematologic, and histologic features of a multicentric plasma-cell variant of Castleman's disease without evidence of Hodgkin's disease. This unique case report further strengthens the association of Castleman's disease and Hodgkin's lymphoma. Two pathogenetic mechanisms for this association have been suggested: (1) secretion of interleukin-6 by Hodgkin's Reed-Sternberg cells and histiocytes, and (2) manifestation of an abnormal immune state associated with Hodgkin's disease. These two mechanisms may, indeed, be related.
PARANEOPLASTIC PEMPHIGUS
Paraneoplastic pemphigus in association with a retroperitoneal Castleman's disease presenting with a lichen planus pemphigoides-like eruption. A case report and review of literature. Hsiao CJ, Hsu MM, Lee JY, Chen WC, Hsieh WC. Department of Dermatology, National Cheng-Kung University Hospital, 138 Sheng-Li Road, Tainan, Taiwan 704.	Br J Dermatol 2001 Feb;144(2):372-6 Abstract quote A 50-year-old man presented with severe mucosal erosions of the lips, oral cavity and perianal area, a lichen planus-like eruption on the trunk and extremities and scaly plaques of the palms and soles. The clinical impression was of Stevens--Johnson syndrome, or paraneoplastic pemphigus (PNP). Histopathology revealed vacuolar interface and lichenoid dermatitis with dyskeratosis and suprabasal acantholytic vesiculation. Direct immunofluorescence showed deposition of IgG in the intercellular space and linear deposition of C3 along the basal membrane zone. Indirect immunofluorescence revealed circulating IgG with intercellular staining of the epithelium of rat urinary bladder. Western blotting demonstrated bands of 250- and 230-kDa antigens. The clinical, histological and immunological features were consistent with the lichen planus pemphigoides variant of PNP. A retroperitoneal hyaline-vascular Castleman's disease was detected and excised. The skin lesions worsened initially after tumour resection but improved gradually, leaving extensive melanosis after cyclosporin and mycophenolate mofetil treatment.
POEMS SYNDROME
Castleman disease in POEMS syndrome with elevated interleukin-6. Emile C, Danon F, Fermand JP, Clauvel JP.	Cancer 1993 Feb 1;71(3):874

EPIDEMIOLOGY	CHARACTERIZATION
SYNONYMS	Angiofollicular hyperplasia Giant lymph node hyperplasia
KOREANS
Clinicopathologic study of Castleman's disease in Korea. Kim JE, Kim CJ, Park IA, Kim WH, Seo JW, Jang JJ, Kim CW, Park SH, Lee HS, Chi JG, Kim YI, Ham EK. Department of Pathology, Seoul National University College of Medicine, Korea.	J Korean Med Sci 2000 Aug;15(4):393-8 Abstract quote Castleman's disease represents an atypical lymphoproliferative disorder, infrequently associated with various immunologic abnormalities or subsequent development of malignancy such as Kaposi sarcoma, malignant lymphoma and plasmacytoma. Its clinicopathologic features depend on various etiologic factors such as Kaposi sarcoma herpesvirus (KSHV), oversecretion of IL-6, adhesion molecule and follicular dendritic cell dysplasia, etc. To investigate the relationship of Castleman's disease (CD) and the above factors, we reviewed 22 cases of CD. Four cases of KSHV positive CD were detected, all multicentric, plasma cell type, and these cases displayed prominent vascular proliferation, characteristic 'Kaposi-like lesion'. IL-6 and CD54 positive mononuclear cells were scattered in interfollicular areas of KSHV positive cases. Follicular dendritic cell hyperplasia, vascular proliferation, expression of IL-6 and CD54 did not show any significant difference between solitary vs multicentric type, and plasma cell type vs hyaline vascular type. Our study suggests that KSHV positive CD reveals unique pathologic features, and the probable relationship of KSHV and IL-6 and CD54 is discussed.

LABORATORY/RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
Laboratory Markers
IL-6	Present in multicentric plasma cell type
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. Oksenhendler E, Carcelain G, Aoki Y, Boulanger E, Maillard A, Clauvel JP, Agbalika F. Department of Immunology and Hematology, Laboratory of Virology, Hopital Saint-Louis, Paris, France.	Blood 2000 Sep 15;96(6):2069-73 Abstract quote Multicentric Castleman disease (MCD) is a distinct type of lymphoproliferative disorder associated with inflammatory symptoms and interleukin-6 (IL-6) dysregulation. In the context of human immunodeficiency virus (HIV) infection, MCD is associated with human herpesvirus 8 (HHV8) infection. In a prospective study of 23 HIV-infected patients with MCD, clinical symptoms of MCD were present at 45 visits, whereas patients were in chemotherapy-induced clinical remission at 50 visits. Symptoms were associated with a high level of serum C reactive protein, high HHV8 viral load in peripheral blood mononuclear cells, and high plasma human IL-6 and IL-10 levels. Strong correlations between plasma IL-6 and plasma IL-10 with the HHV8 viral load suggest that both cytokines may be involved in the pathogenesis of this virus-associated lymphoproliferative disorder.

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
General
Multicentric Plasma cell type
Hyaline vascular type	Solitary, slow-growing mass, usually in the absence of constitutional symptoms. Most lesions are located in the mediastinum, abdomen, or neck Less frequently associated with paraneoplastic phenomenon (for example, neuropathy) and has a benign clinical course
PEDIATRIC
Paediatric Castleman disease: report of seven cases and review of the literature. Parez N, Bader-Meunier B, Roy CC, Dommergues JP. Service de Pediatrie, CHU Bicetre, Le Kremlin Bicetre, France.	Eur J Pediatr 1999 Aug;158(8):631-7 Abstract quote Castleman disease is a distinct lymphoproliferative disorder of unknown origin. Seven new cases in children are reported here and 76 cases from the paediatric literature are reviewed. The disease has been reported in 46 females and 37 males, their age ranging from 2 months to 17 years. The disease was localized in 72 cases and multicentric in 11 cases. The hyalinovascular type was more frequently encountered (54%) than the plasma cell type (24%). Laboratory abnormalities were more often associated with the plasma cell type and were mainly represented by anaemia and hypergammaglobulinaemia. Treatment of the localized tumour consisted of surgical excision, whereas treatment of the multicentric form was medical, comprising prednisone and other immunosuppressor drugs. The disease in the paediatric population seems to have a more favourable course than in adults. CONCLUSION: The paediatric features of the disease suggest that Castleman disease in this population could represent an earlier form of the pathology or even suggest a benign lymphoproliferative disorder.

HISTOLOGICAL TYPES	CHARACTERIZATION
General
Plasma cell type	Hyperplastic germinal centers and sheets of plasma cells in the interfollicular areas.
Hyaline vascular type	Regressed follicles with dendritic proliferation, expanded mantle zones, variable proliferation of nodal stromal elements, and increased vascularity in the interfollicular regions Abnormal follicles with prominent penetrating arterioles and increased interfollicular vascularity, but typically has compressed/absent sinuses, more prominent mantle zone expansion, and many fewer plasma cells

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSIS
Metastasis	Rare lymphomatous transformation in the hyaline vascular variant but occasionally patients develop tumors of dendritic cell or vascular origin Lymphomatous transformation more common in hyaline vascular multicentric variant
Recurrence	Rare with hyaline vascular type Common with multicentric type
TREATMENT	Simple excision of solitary nodules usually curative, especially in hyaline vascular type
HAART
Successful treatment of Castleman's disease with HAART in two HIV-infected patients. Lanzafame M, Carretta G, Trevenzoli M, Lazzarini L, Vento Ercole Concia S. Istituto di Immunologia e Malattie Infettive, Ospedale Civile Maggiore Borgo Trento, Verona, Italy.	J Infect 2000 Jan;40(1):90-1 Abstract quote Castleman's disease is a heterogeneous group of lymphoproliferative disorders of unknown aetiology. Recently, human herpesvirus type 8 (HHV-8) has been associated with various diseases in individuals with HIV infection, including Kaposi's sarcoma, B cell non Hodgkin's lymphomas, and Castleman's disease. In Castleman's disease it has been hypothesized that HHV-8, encoding a number of various virokines, can be responsible for clinical manifestations of the disease. Previously, two reports have described a clinical recovery from HIV-associated Castleman's disease: by administration of a monoclonal antibody neutralizing human IL-6 in one case, and in another case by treatment with highly antiretroviral therapy and anti-herpesvirus therapy, following splenectomy. We report two cases where HAART alone led to clinical recovery from Castleman's disease.In both the cases reported here, although follow-up biopsy was not performed, it is likely that the inhibition of HHV-8 replication and of virokine release, through the restoration of immunity by HAART, was the basis for the disappearance of the clinical symptoms.
ANTI-INTERLEUKIN-6 RECEPTOR (rhPM-1)
Brief report: alleviation of systemic manifestations of Castleman's disease by monoclonal anti-interleukin-6 antibody. Beck JT, Hsu SM, Wijdenes J, Bataille R, Klein B, Vesole D, Hayden K, Jagannath S, Barlogie B. Department of Medicine, Arkansas Cancer Research Center, University of Arkansas for Medical Sciences, Little Rock 72205.	N Engl J Med 1994 Mar 3;330(9):602-5
Increased interleukin-6 (IL-6) production in a young child with clinical and pathologic features of multicentric Castleman's disease. Kinney MC, Hummell DS, Villiger PM, Hourigan A, Rollins-Smith L, Glick AD, Lawton AR. Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee 37232.	J Clin Immunol 1994 Nov;14(6):382-90 Abstract quote A 21-month-old boy presented with a papular rash, lymphoadenopathy, and splenomegaly. He developed symmetric polyarthritis, fever, and progressive glomerulonephritis. Serologies for viral agents including HIV were negative. Antinuclear antibody was transiently positive, but no anti-DNA antibodies were present. CH50 and serum C3 values were low. Biopsies of skin, kidney, bone marrow, and lymph node were obtained. There was a perivascular and periadnexal lymphocytic infiltrate in the skin, with a normal epidermis. Renal biopsy showed proliferative mesangial glomerulonephritis. Bone marrow showed an increased number of plasma cells. Lymph node showed histologic changes described in multicentric Castleman's disease including marked follicular hyperplasia, vascular proliferation, and interfollicular expansion with numerous plasma cells. IL-6 mRNA was demonstrated in cells in the marginal zone and interfollicular regions of the node by in situ hybridization. Likewise, the serum IL-6 level was elevated during a clinical exacerbation of the patient's nephritis. These data suggest an underlying lymphoproliferative disorder, such as Castleman's disease, with overproduction of IL-6 resulting in systemic features of the disease, including glomerulonephritis.
Improvement in Castleman's disease by humanized anti-interleukin-6 receptor antibody therapy. Nishimoto N, Sasai M, Shima Y, Nakagawa M, Matsumoto T, Shirai T, Kishimoto T, Yoshizaki K. Department of Medical Science I, School of Health and Sport Sciences, Osaka University, Suita-city, Osaka, Japan.	Blood 2000 Jan 1;95(1):56-61 Abstract quote Castleman's disease, an atypical lymphoproliferative disorder, can be classified into 2 types: hyaline-vascular and plasma cell types according to the histologic features of the affected lymph nodes. The plasma cell type is frequently associated with systemic manifestations and is often refractory to systemic therapy including corticosteroids and chemotherapy, particularly in multicentric form. Dysregulated overproduction of interleukin-6 (IL-6) from affected lymph nodes is thought to be responsible for the systemic manifestations of this disease. Therefore, interference with IL-6 signal transduction may constitute a new therapeutic strategy for this disease. We used humanized anti-IL-6 receptor antibody (rhPM-1) to treat 7 patients with multicentric plasma cell or mixed type Castleman's disease. All patients had systemic manifestations including secondary amyloidosis in 3. With the approval of our institution's ethics committee and the consent of the patients, they were treated with 50 to 100 mg rhPM-1 either once or twice weekly. Immediately after administration of rhPM-1, fever and fatigue disappeared, and anemia as well as serum levels of C-reactive protein (CRP), fibrinogen, and albumin started to improve. After 3 months of treatment, hypergammaglobulinemia and lymphadenopathy were remarkably alleviated, as were renal function abnormalities in patients with amyloidosis. Treatment was well tolerated with only transient leukopenia. Histopathologic examination revealed reduced follicular hyperplasia and vascularity after rhPM-1 treatment. The pathophysiologic significance of IL-6 in Castleman's disease was thus confirmed, and blockade of the IL-6 signal by rhPM-1 is thought to have potential as a new therapy based on the pathophysiologic mechanism of multicentric Castleman's disease.