Atlas of Genetics and Cytogenetics in Oncology and Haematology

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

Castleman's disease

Written2003-12Antonio Cuneo, Gianluigi Castoldi
Hematology Section, Department of Biomedical Sciences, University of Ferrara, Corso Giovecca 203, Ferrara, Italy
Updated2017-04Luis Miguel Juárez Salcedo, Samir Dalia
Principe de Asturias University Hospital, Madrid, Spain; (LMJS); Oncology and Hematology, Mercy Clinic Joplin, Joplin, MO, USA; (SD)

Abstract Castleman's disease are referred to a group of rare disorders that were discovered by Benjamin Castleman in 1954. The disease is more common in HIV positive patients and has been linked to human herpesvirus 8. The disease is diagnosed with excisional lymph node biopsy and carries a good prognosis. Treatment options including radiation, rituximab based therapy or monitoring.

Keywords Castleman disease

(Note : for Links provided by Atlas : click)


ICD-Morpho 9738/3 Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease
Atlas_Id 2123

Clinics and Pathology

Disease This disease was reported by Benjamin Castleman in 1954 (Castleman B, Towne V). Castleman disease is a heterogeneous cluster of disorders, with distinct unicentric CD (UCD) and multicentric CD (MCD) subtypes. Unicentric Castleman disease (UCD) is localized and carries an excellent prognosis, whereas multicentric Castleman disease (MCD) is a systemic disease occurring most commonly in the setting of HIV infection and is associated with human herpesvirus 8 and interleukin-6 (IL-6) in a significant proportion of cases.
Phenotype / cell stem origin The disease appears to be polyclonal in origin in the majority of cases, however evidence for clonal expansion was documented in some cases, possibly representing transformation into non Hodgkin's lymphoma. In approximately 1/3 of the cases studied a monoclonal IgH rearrangement was documented. A minor T-cell clone, mostly in a polyclonal background, was also documented in some cases.
Etiology The pathogenesis of Castleman disease is not fully understood; however, the central roles of interleukin (IL) 6 in UCD and both IL-6 and human herpesvirus (HHV) 8 in MCD have been well described.
Epidemiology The epidemiology of CD is difficult to characterize accurately due to its rarity and clinical heterogeneity. The incidence of CD is estimated at 21-25 cases per million person-years, with 23% of those cases potentially representing MCD (Munshi N et al.,2015).
The median age at presentation for UCD is 30-34 years. For HIV-negative MCD is 49-66 years and HIV-positive MCD between 36-40 years. The sex distribution is approximately equal, though some series have reported a male predominance, generally in the HIV-positive population. UCD also has a slight female predominance (1.4:1) (Talat N, et al., 2011; Dispenzieri A et al., 2012).
Clinics UCD may be asymptomatic at diagnosis and be incidentally discovered on chest or abdominal imaging performed for other reasons. Patients may present with painless lymphadenopathy or local anatomical symptoms varying by location. Common sites of presentation include the chest (30%), neck (23%), abdomen (20%), retroperitoneum (17%), and, rarely, the axilla (5%), groin (3%), or pelvis (2%). Intrathoracic disease is frequently found along the tracheobronchial tree or lung hila. Thoracic disease may present with cough, hemoptysis, dyspnea, or chest discomfort. Abdominal, retroperitoneal, and pelvic disease may present with abdominal or back discomfort. Disease confined to the peripheral lymph node chains, including the neck, axilla, or groin, may present with nontender lymphadenopathy.
Systemic symptoms are a common feature of MCD; these include traditional "B" symptoms such as fever, night sweats, and weight loss, as well as lymphadenopathy and hepatosplenomegaly. More severe disease phenotypes include a severe, inflammatory vascular leak syndrome where patients may develop ascites, pericardial effusions, pleural effusions, and/or peripheral edema. Hematological sings include anemia driven by IL-6 or secondary to autoimmune hemolysis, immune thrombocytopenia, and acquired factor VIII deficiency (Marsh JH et al., 1990; Marietta M et al., 2003). Bronchiolitis obliterans, glomerulonephritis, and pemphigus have also been reported, with the presence of pemphigus associated with an unfavorable prognosis (Dong Y et al., 2015) MCD may be seen in association with the POEMS syndrome, which comprises polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (Dispenzieri A et al., 2003).
Diagnosis A high index of suspicion is required in patients presenting with a compatible clinical picture, such as unifocal or generalized lymphadenopathy, splenomegaly, and/or unexplained constitutional symptoms (Chan K et al., 2016). Common laboratory findings include anemia, thrombocytopenia, hypoalbuminemia, polyclonal hypergammaglobulinemia, and elevation of acute phase reactants, such as CRP. Elevations in circulating cytokines such as IL-6 and VEGF may also be detected although not essential for diagnosis, plasma VEGF levels can be useful in distinguishing and monitoring cases of CD associated with POEMS syndrome. Although not essential for diagnosis, plasma VEGF levels can be useful in distinguishing and monitoring cases of CD associated with POEMS syndrome.
Pathology Castleman disease is a pathological diagnosis made by excisional biopsy of affected lymph node tissue. There are two variants: the hyaline-vascular and the plasma cell subtype. Most cases of UCD are histologically classified as the hyaline-vascular variant, which is characterized by increased numbers of small, hyalinized blood vessels within and between follicles with obliteration of the medullary sinuses (Soumerai J et al., 2014).
The hyaline-vascular type show greater retention of the nodal architecture with hyperplastic follicles of varying sizes and focally patent medullary sinuses. The interfollicular region may be mildly hypervascular and characteristically contains sheets of mature-appearing plasma cells. Patients with "multicentric" Castleman disease show histologic features consistent with the plasma cell subtype.
Treatment The optimal therapy for UCD is surgical excision if the mass is localized. For disease that cannot be completely excised, radiation therapy is an option due to its high rates of objective response, including complete responses in nearly one-half of reported cases (Bower M, et al., 2011).
Available treatments for the MCD variant include glucocorticoids, single-agent and combination chemotherapy, antiviral strategies, and monoclonal antibody therapies targeting CD20 or IL-6.
All patients with HIV infection and MCD should be initiated on combination antiretroviral therapy if they are not already taking it, although antiretroviral therapy alone is unlikely to independently result in a Castleman disease response. For initial systemic therapy, rituximab monotherapy has been recommended based on encouraging efficacy and safety results. Novel agents targeting interleukin 6 (Siltuximab and tocilizumab) represent exciting new additions to the treatment armamenatrium (Casper C et al., 2013). Combination chemotherapy utilized for lymphoma must be reserved to relapsed or refractory disease (Bower M, 2012).
Prognosis The prognosis of CD is variable and depends predominantly on disease subtype. As previously mentioned, patients with UCD enjoy excellent long-term outcomes if complete resection can be achieved, with 10-year overall survival rates greater than 95%.
Even in unresectable UCD cases, radiotherapy may offer good long-term response rates. %.
The HIV- and HHV-8-associated subtype of MCD has the worst prognosis, with the majority of patients in early studies dying within 2 years of diagnosis. Those patients with multicentric disease who fail to respond to steroid treatment have a serious disease.


Cytogenetics Morphological Many of the cases so far studied showed a normal karyotyope. Occasional abnormalities were found in a few patients, but none known to be a "driver" chromosome abnormality. There is growing evidence suggesting that the clonal proliferation involved dysplastic stromal cells (Chang et al., 2014).


How I treat HIV-associated multicentric Castleman disease
Bower M
Blood 2010 Nov 25;116(22):4415-21
PMID 20688959
Clinical Features and Outcome in HIV-Associated Multicentric Castleman's Disease
Bower M, Newsom-Davis T, Naresh K, Merchant S, Lee B, Gazzard B, Stebbing J, Nelson M
J Clin Oncol 2011 Jun 20;29(18):2481-6
PMID 21555697
A multicenter, randomized, double-blind, placebo-controlled study of the efficacy and safety of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with multicentric Castlemans disease.
Casper C, Munshi N, Ke X, et al.
Blood. 2013;122(21):505-505.
Remission of HHV-8 and HIV-associated multicentric Castleman disease with ganciclovir treatment.
Casper C, Nichols WG, Huang ML, Corey L, Wald A
Blood. 2004 ; 103 (5) : 1632-1634.
PMID 14615380
Case records of the Massachusetts Gener al Hospital weekly clinicopathological exercises: case 40011.
Castleman B, Towne V.
N Engl J Med. 1954;250(1):26-30.
Update and new approaches in the treatment of Castleman disease
Chan KL, Lade S, Prince HM, Harrison SJ
J Blood Med 2016 Aug 3;7:145-58
PMID 27536166
Monoclonality and cytogenetic abnormalities in hyaline vascular Castleman disease.
Chang KC, Wang YC, Hung LY, Huang WT, Tsou JH, M Jones D, Song HL, Yeh YM, Kao LY, Medeiros LJ.
Mod Pathol. 2014 Jun;27(6):823-31. doi: 10.1038/modpathol.2013.202. Epub 2013 Nov 8.
PMID 24201121
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
The American journal of surgical pathology. 2002 ; 26 (5) : 662-669.
PMID 11979097
POEMS syndrome: definitions and long-term outcome
Dispenzieri A, Kyle RA, Lacy MQ, Rajkumar SV, Therneau TM, Larson DR, Greipp PR, Witzig TE, Basu R, Suarez GA, Fonseca R, Lust JA, Gertz MA
Blood 2003 Apr 1;101(7):2496-506
PMID 12456500
Clinical and laboratory characterization of 114 cases of Castleman disease patients from a single centre: paraneoplastic pemphigus is an unfavourable prognostic factor
Dong Y, Wang M, Nong L, Wang L, Cen X, Liu W, Zhu S, Sun Y, Liang Z, Li Y, Ou J, Qiu Z, Ren H
Br J Haematol 2015 Jun;169(6):834-42
PMID 25824806
Atypical lymphoproliferative disorders.
Frizzera G
In Knowles DM (Ed) Neoplastic hemopathology IInd edition..
A case of multicentric Castleman's disease associated with advanced systemic amyloidosis treated with chemotherapy and anti-CD20 monoclonal antibody.
Gholam D, Vantelon JM, Al-Jijakli A, Bourhis JH
Annals of hematology. 2003 ; 82 (12) : 766-768.
PMID 12898190
Atypical Lymphoproliferative Diseases.
Greiner T, Armitage JO, Gross TG
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program. 2000 : 133-146.
PMID 11701539
Clonal rearrangement for immunoglobulin and T-cell receptor genes in systemic Castleman's disease. Association with Epstein-Barr virus.
Hanson CA, Frizzera G, Patton DF, Peterson BA, McClain KL, Gajl-Peczalska KJ, Kersey JH
The American journal of pathology. 1988 ; 131 (1) : 84-91.
PMID 2833104
Rituximab therapy for HIV-associated Castleman disease.
Marcelin AG, Aaron L, Mateus C, Gyan E, Gorin I, Viard JP, Calvez V, Dupin N
Blood. 2003 ; 102 (8) : 2786-2788.
PMID 12842986
Acquired haemophilia in HIV negative, HHV-8 positive multicentric Castleman's disease: a case report
Marietta M, Pozzi S, Luppi M, Bertesi M, Cappi C, Morselli M, Torelli G
Eur J Haematol 2003 Mar;70(3):181-2
PMID 12605662
Systemic Castleman's disease in association with Evan's syndrome and vitiligo
Marsh JH, Colbourn DS, Donovan V, Staszewski H
Med Pediatr Oncol 1990;18(2):169-72
PMID 2304424
Lack of cytogenetic abnormalities in Castleman's disease.
Menke DM, DeWald GW
Southern medical journal. 2001 ; 94 (5) : 472-474.
PMID 11372793
Use of a claims database to characterize and estimate the incidence rate for Castleman disease
Munshi N, Mehra M, van de Velde H, Desai A, Potluri R, Vermeulen J
Leuk Lymphoma 2015 May;56(5):1252-60
PMID 25120049
[Chromosomal abnormalities in Castleman's disease with high levels of serum interleukin-6]
Nakamura H, Nakaseko C, Ishii A, Kogure K, Kawano E, Hashimoto S, Nishimura M, Matsuura Y, Oh H, Yoshida S
[Rinsho ketsueki] The Japanese journal of clinical hematology. 1993 ; 34 (2) : 212-217.
PMID 8492420
A chromosomal abnormality in hyaline vascular Castleman's disease: evidence for clonal proliferation of dysplastic stromal cells.
Pauwels P, Dal Cin P, Vlasveld LT, Aleva RM, van Erp WF, Jones D
The American journal of surgical pathology. 2000 ; 24 (6) : 882-888.
PMID 10843293
Molecular analysis of clonality in Castleman's disease.
Soulier J, Grollet L, Oksenhendler E, Micléa JM, Cacoub P, Baruchel A, Brice P, Clauvel JP, d'Agay MF, Raphael M
Blood. 1995 ; 86 (3) : 1131-1138.
PMID 7620166
Diagnosis and management of Castleman disease
Soumerai JD, Sohani AR, Abramson JS
Cancer Control 2014 Oct;21(4):266-78
PMID 25310208
Castleman's disease: systematic analysis of 416 patients from the literature
Talat N, Schulte KM
Oncologist 2011;16(9):1316-24
PMID 21765191


This paper should be referenced as such :
Luis Miguel Juarez Salcedo, Samir Dalia
Castleman's disease
Atlas Genet Cytogenet Oncol Haematol. 2018;22(3):101-103.
Free journal version : [ pdf ]   [ DOI ]
On line version :
History of this paper:
Cuneo, A ; Castoldi, GL. Castleman's disease. Atlas Genet Cytogenet Oncol Haematol. 2004;8(2):81-82.

External links

COSMICHisto = - Site = haematopoietic_and_lymphoid_tissue (COSMIC)
arrayMap (UZH-SIB Zurich)Topo ( C42) Morph ( 9738/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Mon Aug 12 16:58:56 CEST 2019

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us