Castleman Disease

Castleman Disease – 9 Interesting Facts

Castleman disease (CD) is a rare group of heterogeneous lymphoproliferative disorders which cause polyclonal (nonneoplastic) lymphadenopathy and characteristic histopathology of affected lymph nodes with signs and symptoms related to increased release of cytokines, especially interleukin 6^(1, 2,3,4)
CD presents in 2 different forms^(1, 2,3,4)
unicentric CD (UCD) which affects 1 lymph node
multicentric CD (MCD) which affects multiple lymph node stations
can vary in severity, and be chronic or relapsing
Subtypes include
human herpesvirus-8 (HHV-8)-associated MCD, typically associated with immunosuppressed patients, especially those coinfected with HIV
idiopathic MCD (HHV-8 and HIV negative)
management of CD is challenging due to lack of established treatment guidelines supported by evidence and absence of consensus on response criteria⁽³⁾

Synonyms

Castleman tumor
Giant lymph node hyperplasia
Giant benign lymphoma
Angiofollicular lymphoid hyperplasia
Human herpesvirus-8 (HHV-8) (Kaposi sarcoma-associated herpesvirus) multicentric CD

Types

Castleman disease (CD) has 4 histopathological variants, including^(2,3,4)
- hyaline vascular, usually associated with unicentric CD
- plasma cell-rich form
- mixed variant
- plasmablastic – associated exclusively with HHV8-associated multicentric Castleman disease
unicentric Castleman disease (UCD)^(1, 2,3)
- about 75% of cases
- solitary mass with progressive enlargement and indolent course
- presents at younger age than multicentric CD (reported median age 34 years)
- 90% of UCD reported to be associated with hyaline-vascular histopathologic type
- lymphadenopathy commonly located in mediastinum, abdomen, axillary, or cervical areas
- frequently asymptomatic and found incidentally on radiological studies
- not typically associated with HIV or HHV-8 infection
multicentric Castleman disease (MCD)^(1, 2,3,4)
- about 25% of cases
- systemic (often symptomatic) condition that can be aggressive or chronic
- presents with multiple areas of lymphadenopathy at later age than UCD (reported median age 48 years) with potential for associated malignancy
- characterized by inflammatory flares with fever, lymphadenopathy, splenomegaly, effusions, cytopenia, hypoalbuminemia, hypergammaglobulinemia, and high serum C-reactive protein
- approximately 50% of MCD associated with plasma cell histopathologic type
- MCD further classified into 2 groups
  - human herpesvirus-8 (HHV-8)-associated MCD (also called Kaposi sarcoma herpesvirus associated MCD)
    - requires presence of HHV-8 infection
    - may occur in patients with or without HIV infection
    - often associated with immunocompromised state
    - increased endogenous interleukin 6 (IL-6) production as well as viral IL-6 initiates proinflammatory state, causing symptoms and laboratory abnormalities; human IL-6 and viral IL-6 can independently or in combination cause flares of MCD
  - idiopathic (iMCD), which is HHV-8 and HIV negative and includes the following subtypes
    - classic iMCD (or iMCD not otherwise specified [iMCD-NOS]) attributed to IL-6 excess, with less intense inflammatory syndrome
    - clinical features can include
      - normal or elevated platelet count/thrombocytosis
      - hypergammaglobulinemia
      - less extreme anasarca
      - plasmacytic or mixed lymph node histopathology
    - TAFRO subtype, which is associated with
      - thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis of the bone marrow (R), and organomegaly (O)
      - more significant clinical presentation and worse outcome than classic iMCD
      - elevated vascular endothelial growth factor (VEGF) levels, and less elevated IL-6 levels than with classic iMCD
    - iMCD in association with POEMS syndrome
      - polyneuropathy, (P), organomegaly (O), endocrinopathy (E), monoclonal protein (M), and skin changes (S)
      - elevated VEGF levels
    - Reference – Hematology Am Soc Hematol Educ Program 2018 Nov 30;2018(1):318 full-text

Epidemiology

Who Is Most Affected

unicentric Castleman disease (UCD)
- typically presents at younger age (reported median age 34 years) than multicentric Castleman disease⁽²⁾
- slightly more females than males affected (Hematol Oncol Clin North Am 2018 Feb;32(1):1)
multicentric Castleman disease (MCD)⁽¹⁾
- presents at older age (reported median age 48 years) than UCD
- more males affected than females
- human herpesvirus-8-associated MCD often seen in immunocompromised patients, such as population with HIV positive status

Incidence/Prevalence

accurate epidemiological information regarding Castleman disease (CD) is lacking due to absence of International Statistical Classification of Diseases and Related Health Problems (ICD) code and formal definition of the disease until October 1, 2016 (Hematol Oncol Clin North Am 2018 Feb;32(1):1)
in United States
- incidence of idiopathic multicentric CD (iMCD) is 1,000 to 1,500 cases per year⁽³⁾
- about 50% of multicentric CD cases diagnosed each year are caused by uncontrolled human herpesvirus-8 (HHV-8) infection (Hematology Am Soc Hematol Educ Program 2018 Nov 30;2018(1):318 full-text)
in Japan, annual incidence of
- 2.4-5.8 per million for idiopathic MCD without thrombocytopenia, anasarca, fever, reticulin fibrosis of the marrow, organomegaly (TAFRO)
- 0.9-4.9 per million for idiopathic MCD with TAFRO
- Reference – Lancet Haematol 2020 Mar;7(3):e180
estimated incidence of CD in the United States
- rates derived from 2 claims databases from 2001 to 2009; IMS LifeLink Health Plan Claims Database (IMS LifeLink) and Truven Health Analytics MarketScan Commercial Claims and Encounters Database (MarketScan)
  - IMS LifeLink contained 83 million patients, of which 1,131 identified as potential patients with CD
  - MarketScan included 122 million patients, of which 1,240 identified as potential patients with CD
- potential patients with diagnosis of CD included those with diagnosis of enlargement of lymph nodes (utilization of ICD-9 code 785.6), having lymph node biopsy within 2-year follow-up period, and exclusion of other diagnosis within 1 year of or 1 year after diagnosis of lymphadenopathy (including rheumatoid arthritis, lupus, cancer, and HIV)
- about 23% identified as possibly having MCD using both databases (potential patients with CD who received chemotherapy treatment)
- estimated incidence per
  - IMS LifeLink
    - 21 per million person-years for CD
    - based on assumption that about 23% of potential patients have MCD
      - 15.9 per million person-years for unicentric CD (UCD)
      - 5.1 per million person-years for MCD
  - MarketScan
    - 24.8 per million person-years for CD
    - based on assumption that about 23% of potential patients have MCD, estimated incidence of
      - 19.1 per million person-years for UCD
      - 5.7 per million person-years for MCD
- estimated prevalence of CD (assuming median duration of disease of 2-4 years and overall United States population in 2010) per
  - IMS LifeLink, 3,139 to 6,278 cases
  - MarketScan 3,531 to 7,026 cases
- Reference – Leuk Lymphoma 2015 May;56(5):1252
similar incidence of UCD reported in China, Czechoslovakia, Japan, and New Zealand (Hematol Oncol Clin North Am 2018 Feb;32(1):1)

Risk Factors

HIV infection is associated with increased risk of developing human herpesvirus-8 positive multicentric Castleman disease (CD); estimated incidence of multicentric CD in patients with HIV 8.3 per 10,000 patient-years since 2000^(1,2,3,4)
no other established risk factors identified for idiopathic multicentric CD or unicentric CD (Hematol Oncol Clin North Am 2018 Feb;32(1):1)

Associated Conditions

CLINICIANS’ PRACTICE POINT: Many of these conditions can either be associated as part of the spectrum of multicentric Castleman disease (MCD), or present concomitantly as a distinct entity.
Kaposi sarcoma (prevalent in human herpesvirus-8 (HHV-8)/HIV-associated MCD; reported in 13% of HIV-negative MCD and up to 75% of HIV-positive MCD); most prevalent concomitant disease co-occurring with MCD⁽¹⁾
POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal-proteinemia, skin changes) syndrome seen in 11%-30% of patients with CD^(1,2,3)
B-cell non-Hodgkin lymphoma (B-NHL)⁽¹⁾
follicular dendritic cell sarcoma (10%-20% of cases reported to be associated with unicentric Castleman disease [UCD]) (⁽²⁾, Hematol Oncol Clin North Am 2018 Feb;32(1):65)
paraneoplastic pemphigus^(1,2)

Etiology and Pathogenesis

Causes

some cases (approximately 50%) of multicentric Castleman disease (MCD) are caused by uncontrolled human herpesvirus-8 (HHV-8) infection⁽³⁾
cause is unknown for other subtypes^(2,3,4)
for idiopathic MCD (iMCD)
- evidence of polyclonal lymphoproliferation, however, disease classification as an autoimmune disorder, autoinflammatory disorder, malignancy, or infectious disease is not known
- hypercytokinemia that drives iMCD could be caused by
  - pathogens – such as uncontrolled infection
  - autoimmune process – autoantibodies or autoreactive T cells associated with predisposing germline mutations
  - autoinflammatory process – germline mutations in genes regulating inflammation
  - paraneoplastic somatic mutations in monoclonal lymph node cells that lead to ectopic cytokine secretion (paraneoplastic hypothesis)
- Reference – Hematology Am Soc Hematol Educ Program 2018 Nov 30;2018(1):318 full-text

Pathogenesis

pathogenesis is not clearly understood, but excess interleukin 6 (IL-6) appears to be a driver of pathogenesis and clinical symptoms in all subtypes of Castleman disease (CD)^(1,2,4)
role of IL-6^(2,1,4)
- pleomorphic cytokine produced by various cells
- important for growth, differentiation, and survival of plasma cells and lymphocytes, which causes enlargement of lymph nodes, plasmacytic infiltration, hepatosplenomegaly
- induces proliferation of human herpesvirus-8 (HHV-8)-infected cells
- promotes secretion of vascular endothelial growth factor (VEGF), resulting in angiogenesis and vascular permeability
- drives hepcidin production during inflammatory response; overproduction of hepcidin contributes to anemia common in multicentric CD (MCD)
- deregulates humoral immune response resulting in positive antinuclear antibody assays, hemolytic anemia, and thrombocytopenia
- inhibits albumin production in liver, resulting in hypoalbuminemia
triggers for increased cytokine release, including IL-6 (within germinal centers of affected lymph nodes)^(1,2,4)
- in unicentric CD (UCD), unclear what triggers release of cytokines leading to excess IL-6
- idiopathic MCD
  - cytokine release (including IL-6) triggered for unclear reasons; potential triggers include inflammatory causes, virally driven causes, or paraneoplastic hypothesis (paraneoplastic somatic mutations in monoclonal lymph node cells that lead to ectopic cytokine secretion)
  - TAFRO subtype associated with increased levels of VEGF (and less increase in IL-6); POEMS syndrome also associated with increased levels of VEGF
  - Reference – Blood 2014 May 8;123(19):2924
- HHV-8 associated MCD
  - driven by HHV-8, also known as Kaposi sarcoma-associated herpesvirus
  - HIV infection or (more rarely) another cause of immunosuppression allows HHV-8 to evade host immune control, causing excessive cytokine production and polyclonal lymphoproliferation (Hematology Am Soc Hematol Educ Program 2018 Nov 30;2018(1):318 full-text)
  - HHV-8 encodes viral homolog of IL-6 which is released in both latent and lytic phases of infection; both endogenous human IL-6 and viral IL-6 appear to play a role in pathogenesis (Hematol Oncol Clin North Am 2018 Feb;32(1):65)
  - HHV-8 virus infects many cells, including immunoglobulin M (IgM) positive memory B-cells in germinal center of lymph node
    - induces proliferation and differentiation into plasmablastic phenotype seen in majority of MCD; these cells are polyclonal based on gene rearrangement studies
    - produces viral homologs of endogenous human regulatory proteins leading to viral persistence, inhibition of apoptosis, and release of cytokines
    - Reference – Blood 2019 Mar 14;133(11):1186

History and Physical

Clinical Presentation

presentation of Castleman disease (CD) varies by subtype and is typically nonspecific^(1,2)
often incidentally found on chest x-ray; half of both unicentric and multicentric CD localized in chest or mediastinum⁽¹⁾
unicentric CD (UCD)^(1,2,3)
- often asymptomatic
- if symptomatic, related to lymph node compression on surrounding organs
- presents with isolated lymphadenopathy
  - common sites (reported in ≥ 90% of cases) include chest, neck, abdomen, and retroperitoneum
  - less common sites (< 10% of cases) include axilla, groin, and pelvis
  - rare sites include lung, orbits, nasopharynx, spleen, and small bowel
- lymphadenopathy in
  - chest may be the cause of cough, dyspnea, hemoptysis, or chest discomfort
  - abdomen, pelvis, and retroperitoneum may result in abdominal or back discomfort, and rarely, bowel or ureteral obstruction
- mean reported size of involved lymph nodes at baseline 5.5 cm
- typically no associated lab abnormalities, especially in patients with hyaline vascular-type histology (> 95% of cases)
- patients with plasma cell-type histology (rare) may present with constitutional symptoms and lab abnormalities such as anemia, elevated erythrocyte sedimentation rate and/or C-reactive protein, hypergammaglobulinemia, and hypoalbuminemia
- Reference – Hematol Oncol Clin North Am 2018 Feb;32(1):65
multicentric CD (MCD)^(1,2,3
- severity of MCD spans a wide spectrum, some patients exhibit mild symptomatology, others experience life-threatening organ failure
- elevated cytokine levels contribute to development of “B” symptoms (fever, night sweats, weight loss)
- can present with generalized lymphadenopathy and hepatosplenomegaly
- more severe presentation may include development of ascites, pericardial effusions, pleural effusions, and/or peripheral edema (due to inflammatory vascular leak syndrome)
- can develop life-threatening cytokine storm, organ failure, and death
- other less frequent presentations may include bronchiolitis obliterans, glomerulonephritis, and pemphigus
- lab abnormalities include anemia, thrombocytopenia, and/or acquired factor VIII deficiency
- subtypes of MCD can present differently
  - TAFRO subtype – thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis of the bone marrow (R), and organomegaly (O); associated with more significant clinical presentation and worse outcome
  - classic idiopathic MCD – thrombocytosis, hypergammaglobulinemia, less extreme anasarca (features attributed to interleukin 6 excess)
  - idiopathic MCD in association with POEMS syndrome – polyneuropathy (P), organomegaly (O), endocrinopathy (E), monoclonal protein (M), and skin changes (S)
- for MCD, presence of symptomatic active disease and severity of disease can help determine course of treatment^(1,2,4)
  - National Comprehensive Cancer Network (NCCN) criteria for active disease includes
    - fever
    - increased serum C-reactive protein > 20 mg/L in absence of other cause
    - ≥ 3 of following
      - peripheral lymphadenopathy
      - splenomegaly
      - edema
      - pleural effusion
      - ascites
      - cough
      - nasal obstruction
      - xerostomia
      - rash
      - neurologic symptoms
      - jaundice
      - autoimmune hemolytic anemia
    - Reference – National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for B-Cell Lymphomas. Version 2.2023. NCCN 2023 Feb 8 from NCCN website (free registration required)
  - Castleman Disease Collaborative Network (CDCN) severity classification for idiopathic MCD; must have ≥ 2 of following to be classified as severe⁽³⁾
    - Eastern Cooperative Oncology Group (ECOG) performance status ≥ 2
    - stage IV renal dysfunction (estimated glomerular filtration rate < 30 mL/minute/1.73m², creatinine > 3 mg/dL)
    - anasarca and/or
      - ascites
      - pleural effusion
      - pericardial effusion
    - hemoglobin ≤ 8 g/dL
    - pulmonary involvement/interstitial pneumonitis with dyspnea
clinical presentation findings in analysis of 1,135 patients with CD⁽¹⁾

Table 1: Clinical Findings UCD vs. MCD

Clinical Findings	UCD (n=719)	MCD (n=416)
Lymphadenopathy	38%	65%
Fever	9.9%	51%
Weight loss	8.8%	28%
Fatigue	7.2%	21%
Night sweats	3.5%	17%
Malaise	3.5%	11%
Edema	1.5%	9.4%
Decreased appetite	3.2%	7.5%

Citation: Abbreviations: MCD, Multicentric Castleman disease; UCD, Unicentric Castleman disease.Reference -Blood Rev 2018 May;32(3):225

History

inquire about history of swelling/swollen lymph nodes^(1,2,3)
ask about any episodes of^(1,2,3)
- fevers
- night sweats
- weight loss
ask about presence of^(1,2,3)
- abdominal fullness/discomfort (due to hepatosplenomegaly)
- swelling in legs (peripheral edema)
inquire about history of^(1,2,3)
- HIV
- POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal-proteinemia, skin changes) syndrome
- unexplained anemia
- paraneoplastic pemphigus

Physical

examine for enlarged lymph nodes in node-bearing areas, including Waldeyer ring (NCCN Clinical Practice Guidelines in B-cell lymphomas. Version 2.2023. NCCN 2023 Feb 8 from NCCN website (free registration required) [free registration required])
evaluate for splenomegaly and/or hepatomegaly^(1,2,3,4)

Performance Status Evaluation

performance status used to determine severity of disease and ability of patient to tolerate certain therapies and should be used to aid treatment decisions
- Performance status evaluation such as with the Karnofsky Performance Status (KPS) scale and Eastern Cooperative Oncology Group/World Health Organization (ECOG/WHO) Performance Status Scale helps characterize the clinical features and inform management.
  - Karnofsky Performance Status (KPS) scale
    - The KPS has a total score range of 0 (dead) to 100 (normal).

Table 2: Karnofsky Performance Status Scale

Definitions	Rating	Criteria
Able to carry on normal activity; no special care needed	100	Normal; no complaints; no evidence of disease
	90	Able to carry on normal activity; minor signs or symptoms of disease
	80	Normal activity with effort; some signs or symptoms of disease
Unable to work; able to live at home and care for most personal needs; varying amount of assistance needed	70	Cares for self; unable to carry on normal activity or do active work
	60	Requires occasional assistance but able to care for most personal needs
	50	Requires considerable assistance and frequent medical care
Unable to care for self; requires equivalent of institutional or hospital care; disease may be progressing rapidly	40	Disabled; requires special care and assistance
	30	Severely disabled; hospital admission indicated, although death not imminent
	20	Very sick; hospital admission necessary; active supportive treatment necessary
	10	Moribund; fatal processes progressing rapidly
	0	Dead

Citation: References – J Gerontol 1991 Jul;46(4):M139, Cancer 1994 Apr 15;73(8):2087.

Eastern Cooperative Oncology Group/World Health Organization (ECOG/WHO) Performance Status Scale

The ECOG/WHO scale has a total score range of 0 (fully active) to 5 (dead).

Table 3: ECOG/WHO Performance Status Scale

Grade	Criteria
0	Fully active; able to carry on all predisease performance without restriction
1	Restricted in physically strenuous activity but ambulatory and able to carry out work of light or sedentary nature (such as light housework or office work)
2	Ambulatory and capable of all self-care but unable to carry out any work activities; up and about > 50% of waking hours
3	Capable of only limited self-care; confined to bed or chair > 50% of waking hours
4	Completely disabled; cannot carry on any self-care; totally confined to bed or chair
5	Dead

Citation: Abbreviations: ECOG, Eastern Cooperative Oncology Group; WHO, World Health Organization.Reference -Am J Clin Oncol 1982 Dec;5(6):649

Diagnosis

Making the Diagnosis

Castleman disease presents with clinical manifestations that are usually nonspecific, and laboratory abnormalities consistent with elevation of cytokines (interleukin 6); diagnosis is confirmed by histology of involved lymph node tissue⁽²⁾
consider diagnosis of unicentric Castleman disease (UCD) in a patient with isolated lymphadenopathy, which is usually asymptomatic without laboratory abnormalities but can be symptomatic if lymphadenopathy compresses surrounding structures^(1,2)
consider diagnosis of multicentric Castleman disease (MCD) in patient presenting with multiple sites of lymphadenopathy^(1,2,3)
- often with nonspecific constellation of B symptoms, hepatosplenomegaly, laboratory abnormalities indicative of elevated cytokine (interleukin 6), such as anemia and/or thrombocytopenia and anasarca and/or organ failure if severe
- MCD is further characterized according to human herpesvirus 8 (HHV-8) status
  - if positive, suggests HHV-8 associated MCD
  - if negative, suggests idiopathic MCD (iMCD)
diagnostic criteria for iMCD from Castleman Disease Collaborative Network (CDCN)
- must meet both major criteria and have ≥ 2 minor criteria (including ≥ 1 laboratory abnormality), and have diseases listed in the exclusion criteria ruled out
- major criteria (must have both)
  - lymph node on excisional biopsy with histopathologic features consistent with iMCD (requires grade 2 or 3 for regressive germinal centers or plasmacytosis)
    - regressed or atrophic germinal centers with expanded mantle zones with concentric rings of lymphocytes (“onion skinning”) appearance
    - prominence of follicular dendritic cells
    - hypervascularization with prominent endothelium, vessels penetrate into germinal center
    - sheet-like plasmacytosis
  - enlarged lymph node (≥ 1 cm in short-axis diameter) in ≥ 2 lymph node stations
- minor criteria (must have ≥ 2 of 11, ≥ 1 being laboratory criterion)
  - laboratory abnormalities
    - C-reactive protein (CRP) > 10 mg/L or erythrocyte sedimentation rate > 15 mm/hour, if CRP not available
    - anemia (hemoglobin < 12.5 g/dL for males, < 11.5 g/dL for females)
    - thrombocytopenia (platelet count < 150 × 10⁹/L) or thrombocytosis (platelet count > 400 × 10⁹/L)
    - hypoalbuminemia (albumin < 3.5 g/dL)
    - renal dysfunction (estimated glomerular filtration rate [GFR] < 60 mL/minute/1.73 m²)
    - proteinuria (total protein 150 mg/24 hours or 10 mg/100 mL)
    - polyclonal hypergammaglobulinemia (total gamma-globulin or immunoglobulin G >1,700 mg/dL)
  - clinical symptoms
    - constitutional symptoms (night sweats, fever, weight loss, fatigue)
    - hepatosplenomegaly
    - edema, anasarca, ascites (evidence of fluid accumulation)
    - effusions
    - cherry hemangioma or violaceous papules
    - lymphocytic interstitial pneumonitis
- Reference – Blood 2017 Mar 23;129(12):1646 full-text
imaging studies may be nonspecific but show enlarged lymph nodes, organomegaly, or localized nodal masses
biopsy showing histological features of Castleman disease confirms the diagnosis; histological variants include
- hyaline vascular (typically associated with UCD)
- plasma cell-rich (commonly associated with iMCD)
- mixed variant (evidence of hyaline vascular changes and plasma cell variant seen in iMCD)
- plasmablastic (associated with HHV-8 MCD)
identification of associated subtypes and related conditions can guide treatment decisions, including⁽²⁾
- TAFRO
- POEMS
- occult Kaposi sarcoma
- Reference – National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for B-Cell Lymphomas. Version 2.2023. NCCN 2023 Feb 8 from NCCN website (free registration required)

Differential Diagnosis

consider lymphadenopathy due to various conditions⁽²⁾
- malignancy, such as
  - lymphomas, including follicular lymphoma, marginal zone lymphoma, Hodgkin Lymphoma (HL), other Non-Hodgkin Lymphoma (NHL)
  - plasmacytoma/multiple myeloma
- infectious causes
  - HIV, Epstein-Barr virus (EBV), tuberculosis
  - toxoplasma lymphadenitis
- autoimmune diseases
  - rheumatoid arthritis, systemic lupus erythematosus
  - immunoglobulin G4 (IgG4)-related disease
- Reference – Blood 2017 Mar 23;129(12):1646 full-text
Castleman Disease Collaborative Network (CDCN) exclusion criteria (to rule out conditions that present similarly to idiopathic multicentric Castleman disease) for diagnosis of idiopathic multicentric Castleman disease
- infectious conditions
  - HHV-8
  - EBV-lymphoproliferative disorders, such as infectious mononucleosis or chronic active EBV infection
  - uncontrolled infections such as cytomegalovirus, toxoplasmosis, HIV, or active tuberculosis causing inflammation and adenopathy
- autoimmune/autoinflammatory conditions (requires full diagnosis; detection of autoimmune antibodies is not sufficient for exclusion)
  - systemic lupus erythematosus
  - rheumatoid arthritis
  - juvenile idiopathic arthritis
  - adult-onset Still disease
  - autoimmune lymphoproliferative syndrome
- malignancy or lymphoproliferative disorders diagnosed before or at the same time of iMCD diagnosis
  - Hodgkin lymphoma or non-Hodgkin lymphoma
  - multiple myeloma
  - primary lymph node plasmacytoma
  - follicular dendritic cell sarcoma
  - POEMS syndrome
- Reference – Blood 2017 Mar 23;129(12):1646 full-text

Testing Overview

perform physical exam with attention to lymph node areas
obtain blood tests to establish baseline organ function, exclude other diagnoses (such as monoclonal gammopathy of uncertain significance [MGUS, which is associated with POEMS syndrome] or multiple myeloma), and measure inflammatory and cytokine markers
collect urine for testing, including urine electrophoresis with immunofixation, serum light chains, quantitative immunoglobulins to exclude MGUS or multiple myeloma
perform lymph node biopsy (excisional or incisional biopsy preferred) of affected lymph node(s) to establish diagnosis and histological variant
imaging with whole body positron emission tomography/computed tomography (PET/CT) scan (preferred) or CT of chest, abdomen, and pelvis with contrast of diagnostic quality to further assess lymphadenopathy and identify suitable biopsy targets
for multicentric Castleman disease (MCD), to help determine course of treatment
- assess for criteria for active disease (NCCN Category 2A)
- evaluate performance status (NCCN Category 2A)

Recommendations From Professional Organizations

guidance on workup for Castleman disease by National Comprehensive Cancer Network (NCCN) and idiopathic multicentric Castleman disease by the Castleman Disease Collaborative Network (CDCN)

Table 4: Castleman Disease Workup Guidance

Testing	NCCN Recommendations for Castleman Disease (all NCCN Category 2A)	CDCN Recommendations for Idiopathic Multicentric Castleman Disease
Blood tests	CBC with differentialCMPLDHCRPESRBeta-2 microglobulinSerum protein electrophoresisSerum light chainsQuantitative immunoglobulins	CBCCMPCRPESRSerum light chainsQuantitative immunoglobulinsAlbuminFerritinIL-6IL-2 receptorVEGFANA and rheumatoid factorFibrinogenRenal and liver function
Serum viral studies	HIV ELISAHHV-8 by PCRHepatitis B (due to risk of reactivation with immunotherapy and chemotherapy)EBV by PCR	HIVHHV-8 by PCR
Lymph node biopsy	EBER to rule out EBVLANA-1 to confirm presence of HHV-8Kappa/lambdaIHC for CD20, CD3, CD5, CD138	EBER to rule out EBVLANA-1 to confirm presence of HHV-8Determine histopathologic variant
Urine studies	Electrophoresis with immunofixation	NA
Imaging	Whole body PET/CT (preferred) or CT of chest, abdomen, and pelvis	Whole body PET/CT or CT of neck, chest, abdomen, and pelvis
Additional studies in select patients	Molecular analysis for immunoglobulin and TCR gene rearrangementsAdditional IHC panel evaluating Ki-67 index, Ig heavy chains, CD10, BCL2, BCL6, cyclin D1, CD21, CD23, CD38, IRF4/MUM1, PAX5Flow cytometry for cell surface markers including kappa/lambda, CD19, CD20, CD5, CD23, CD10Screening for Kaposi sarcoma if HHV-8 or HIV positiveBone marrow biopsy and aspirateNeck CT with contrastEchocardiogram or MUGA scan if anthracycline or anthracenedione-based regimen is plannedPregnancy testing in persons of child- bearing age if chemotherapy or radiation is plannedIgG4, sIL6, sIL10, VEGF, uric acid, ferritin (acute phase reactant monitoring during therapy)Hepatitis C testingWork-up for POEMS syndrome in those with concurrent polyneuropathy and monoclonal plasma cell disorder	Bone marrow biopsyEchocardiogramPulmonary function tests

Citation: Abbreviations: ANA, antinuclear antibody test; CBC, complete blood count; CDCN, Castleman Disease Collaborative Network; CMP, comprehensive metabolic panel; CRP, C-reactive protein; CT, computed tomography; EBER, Epstein-Barr encoded RNA; EBV, Epstein-Barr virus; ELISA, enzyme-linked immunosorbent assay; ESR, erythrocyte sedimentation rate; Ig, immunoglobulin; IHC, immunohistochemistry; IL, interleukin; LANA-1, latency-associated nuclear antigen -1; LDH, lactate dehydrogenase; MUGA, multigated acquisition; NA, not applicable; NCCN, National Comprehensive Cancer Network; PCR, polymerase chain reaction; PET, positron emission tomography; sIL, soluble interleukin; VEGF, vascular endothelial growth factor. Reference -2NCCN website

Blood Tests

blood tests help establish baseline organ function, exclude other diagnoses, and measure inflammatory and cytokine markers associated with Castleman disease (CD)⁽³⁾
to establish baseline organ function, obtain^(1,2,3,4)
- complete blood count – may show anemia and/or thrombocytopenia
  - 50% of patients with multicentric Castleman disease (MCD) reported to present with anemia
  - 19% of patients with unicentric Castleman disease (UCD) present with anemia
- comprehensive metabolic panel, including evaluation of renal and liver function
tests to exclude or suggest other or additional diagnoses^(2,3,4)
- serum protein electrophoresis, beta-2 microglobulin, and free light chains to exclude monoclonal gammopathy of uncertain significance (MGUS, which is associated with POEMS syndrome) or multiple myeloma
  - 41% of patients with MCD present with abnormal protein electrophoresis
  - 13% of patients with UCD present with abnormal protein electrophoresis
- HIV panel including enzyme-linked immunosorbent assay (ELISA)
- human herpesvirus-8 (HHV-8) DNA by polymerase chain reaction (PCR) – indicative of actively replicating HHV-8; should not be used solely to diagnose HHV-8-associated MCD but HHV-8 should be histologically confirmed
- Epstein-Barr virus DNA quantitation by PCR
to measure systemic inflammatory response mostly all related to interleukin 6 (IL-6), measure⁽⁴⁾
- C-reactive protein (CRP) – commonly elevated and considered a surrogate marker for IL-6 activityerythrocyte sedimentation rate (ESR) – measured if CRP is not availableferritin – may be reducedfibrinogen – elevated fibrinogen levels together with systemic inflammatory response may lead to development of deep vein thrombosis and other thromboembolic eventsIL-6 levelsoluble IL-2 receptor – increased IL-6 levels lead to increased levels of soluble IL-2 receptorlactate dehydrogenase (LDH) – may be elevatedvascular endothelial growth factor (VEGF) – increased secretion VEGF as a result of increased IL-6 promotes angiogenesis and vascular permeabilityantinuclear antibody (ANA)- positive in response to IL-6 dysregulation of humoral immune responsealbumin – reduced due to IL-6 inhibition of hepatic albumin production

Table 5: Common Laboratory Findings in UCD Compared to MCD in Analysis of 1,135 Patients With Castleman Disease

Laboratory Findings	UCD (n=719)	MCD (n=416)	p Value
Anemia	19%	57%	< 0.0001
Thrombocytopenia	1.1%	17%	< 0.0001
Thrombocytosis	5%	5.5%	Not significant
Leukocytosis	6.8%	9.4%	Not significant
Leukopenia	1.7%	4.6%	0.0039
Decreased renal function	0.83%	7.7%	< 0.0001
Elevated liver enzymes	2.2%	4.6%	0.0279
Low albumin	4.2%	14%	< 0.0001
Elevated LDH	0.28%	0.48%	Not significant
Elevated ESR	18%	31%	< 0.0001
Elevated CRP	6.1%	19%	< 0.0001
Abnormal serum protein electrophoresis	13%	41%	< 0.0001
Elevated ferritin	0.97%	3.8%	0.0009
Low ferritin	0.42%	0.72%	Not significant

Citation: Abbreviations: CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; LDH, lactate dehydrogenase; MCD, Multicentric Castleman disease; UCD, Unicentric Castleman disease.

Urine Studies

consider urine electrophoresis with immunofixation to help evaluate for presence of monoclonal gammopathy of uncertain significance (which is part of POEMS syndrome) or multiple myeloma ^(3,4)

Imaging Studies

imaging findings can be nonspecific and may demonstrate^(2,3)
- lymphadenopathy
- organomegaly
- sclerotic bony lesions
- pulmonary infiltrates
chest x-ray may incidentally reveal lymphadenopathy as part of workup for alternate condition (in most of these cases, the diagnosis will not be Castleman disease [CD]); findings on x-ray that are consistent with Castleman disease (in particular unicentric CD [UCD]) may include
- solitary mediastinal, hilar, or lung mass
- associated pleural effusion
- Reference – Hematol Oncol Clin North Am 2018 Feb;32(1):65
computed tomography (CT) or CT-positron emission tomography (PET) scan
- CT of neck, chest, abdomen, pelvis, or whole body CT is typically the modality of choice to evaluate sites of lymphadenopathy⁽³⁾
- either CT or PET can be used to^(2,3)
  - determine extent of lymphadenopathy
  - identify suitable biopsy targets
  - monitor treatment response
- in PET evaluation, standardized uptake value max (SUVmax) of > 6 may suggest alternate diagnosis, such as lymphoma⁽³⁾
- in UCD (which is mostly hyaline vascular variant), affected lymph node may appear
  - solitary and noninvasive (reported in 50% of cases), or as dominant infiltrative mass with associated lymphadenopathy (reported in 40% of cases), or matted lymphadenopathy without associated mass (reported in 10% of cases)
  - homogenous intense contrast enhancement typically involving thorax
  - hypodense to isodense to skeletal muscle on noncontrast CT
  - intralesional or diffuse calcifications may be observed
  - Reference – Hematol Oncol Clin North Am 2018 Feb;32(1):65, Radiographics 2011 Oct;31(6):1793
- in multicentric CD (typically plasma cell variant), findings on CT may include
  - diffuse lymphadenopathy involving several regions, including hilar, mediastinal, thoracic, abdominal, pelvic, or cervical lymphadenopathy
  - heterogenous less avid enhancement indicative of necrosis or intralesional fibrosis (especially in tumors > 5 cm), typically with abdominal and pelvic involvement
  - diffuse centrilobular pulmonary parenchymal nodular opacities may suggest associated lymphocytic interstitial pneumonitis
  - intralesional or diffuse calcifications less common
  - human herpesvirus 8-associated CD often indistinguishable radiographically from plasma cell CD
  - Reference – Radiographics 2011 Oct;31(6):1793
other imaging modalities that may be helpful in evaluation of CD include
- magnetic resonance imaging, which shows extent of tumor and allows visualization of adjacent structure
- ultrasound, which has been used to assess peripheral, abdominal, or pelvic lesions
- Reference – Hematol Oncol Clin North Am 2018 Feb;32(1):65

Biopsy and Pathology

Lymph Node Biopsy

excisional lymph node biopsy is preferred method and is used to establish diagnosis and histological variant^(2,3)
CLINICIANS’ PRACTICE POINT: Lymph node biopsy is the most critical of the diagnostic tests. An excisional lymph node biopsy should be performed, if at all possible. A core biopsy is sometimes adequate, but fine needle aspiration is typically not adequate for diagnosis and should be avoided.
other methods of biopsy not recommended
- core needle biopsy may or may not be accurate
- fine needle aspirate not typically suitable for initial diagnosis
- Reference – National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for B-Cell Lymphomas. Version 2.2023. NCCN 2023 Feb 8 from NCCN website (free registration required)
determination of histological variants^(1,2)
- characteristics of hyaline vascular variant
  - usually presents as unicentric, involving a single or group of thoracic lymph node(s); almost 90% of unicentric Castleman disease cases reported to be of hyaline vascular type
  - multiple groupings of atypical or dysplastic follicular dendritic cells or atrophic follicles
  - follicles have radially penetrating vessels and are within mantle cell lymphocytes
  - lymphocytes form “onion skin” layers
  - perivascular hyalinization featured
  - associated with vascular tumor, dendritic cell sarcoma
- characteristics of plasma cell-rich variant
  - commonly multicentric Castleman disease (MCD) and presents with constitutional symptoms
  - associated with cytopenias, hypergammaglobulinemia, splenomegaly, and increased interleukin 6 (IL-6) levels
  - preserved architecture of node; variable follicular hyperplasia with paracortical plasmacytosis without follicular dysplasia or atypia
  - features are usually nonspecific and variable; often diagnosis of exclusion
  - given variability in histological pattern, features also seen in many other conditions such as HIV-associated lymphadenopathy, autoimmune disease, B-cell lymphomas, or plasmacytic tumors
  - plasmablastic subtype of plasma cell-rich variant
    - human herpesvirus-8 (HHV-8) and HIV associated
    - immunoglobulin M (IgM)-positive plasmablasts in mantle zone of affected lymph nodes
    - usually lambda light chain restricted
    - risk of progression to large B-cell lymphoma
- characteristics of mixed-pattern variant – plasma cell-rich variant that also presents with some hyaline vascular changes (considered plasma-cell rich variant)
consider performing on tissue
- immunohistochemical staining for latency-associated nuclear antigen (LANA)⁽²⁾
  - LANA mediates upregulation of IL-6 transcription
  - used to detect the presence of HHV-8 within lymph node sections
  - can help to exclude diagnosis of idiopathic/HHV-8 negative MCD
- Epstein-Barr encoding region (EBER) in situ hybridization to rule out EBV infection⁽³⁾

Bone Marrow Biopsy

bone marrow evaluation may be useful to evaluate for⁽³⁾
- reticulin fibrosis of bone marrow (seen in TAFRO subtype)
- plasma cell dyscrasias such as multiple myeloma and monoclonal gammopathy of uncertain significance (MGUS)

Management

when treating a patient with Castleman disease, consider^(1,2,3,4)
- various manifestations of the disease, including lymphadenopathy/organomegaly, severity of other symptoms (fatigue, anorexia, fever), presence of organ failure, and laboratory test abnormalities
- kinetics of response to treatment
  - with anti-interleukin 6 (IL-6) therapy, clinical and laboratory parameters often resolve after 3-4 doses, while reduction in lymph node size may take longer to resolve
  - with chemotherapeutic agents, rapid resolution of lymphadenopathy and symptoms is possible (but associated with various toxicities)
  - regardless of type of therapy, symptoms associated with vascular leak syndrome (ascites, effusions) may take months to resolve
treatment strategies according to disease type
- unicentric Castleman disease
  - surgically resectable disease
    - complete surgical resection of the lymph node is preferred modality of treatment
    - if complete resection or incomplete resection but asymptomatic, continue observation for recurrent disease
  - surgically unresectable disease (or incomplete resection and symptomatic)
    - consider one of following as first-line therapy
      - radiation therapy
      - rituximab with or without prednisone with or without cyclophosphamide
      - embolization
    - after first-line treatment, determine if surgically resectable
      - perform complete resection if possible and observe for recurrence of disease
      - if incomplete resection or surgically unresectable, offer one of first-line therapies not given
  - see Treatment of Relapsed/Refractory UCD for further information
- multicentric Castleman disease (MCD)
  - evaluate for disease severity and criteria of active disease and determine HIV and human herpesvirus-8 (HHV-8) status
  - if idiopathic MCD (HIV-1 and HHV-8 negative)
    - with no organ failure, offer one of following
      - siltuximab with or without corticosteroids as preferred option for plasmacytic/mixed histology
      - tocilizumab with or without corticosteroids
      - rituximab with or without corticosteroids
      - thalidomide, cyclophosphamide, and prednisone for hyaline vascular histology
    - with organ failure, offer
      - siltuximab with high-dose corticosteroids
      - tocilizumab with high-dose corticosteroids
  - if HHV-8 positive MCD (regardless of HIV status)
    - with no organ failure, offer one of
      - rituximab (preferred regimen) with or without liposomal doxorubicin with or without prednisone
      - zidovudine plus ganciclovir/valganciclovir
    - with organ failure, consider
      - combination chemotherapy regimens with or without rituximab
      - rituximab as monotherapy if not candidate for combination therapy
    - observe for response, if no response or relapsed disease, treat as refractory disease
    - see Treatment of Relapsed/Refractory MCD for further information
- in patients with MCD with more limited lymph node involvement (regional/oligocentric CD) without associated constitutional symptoms or proinflammatory marker abnormalities, consider management similar to unicentric CD (UCD)⁽⁴⁾
assessing treatment response
- no clear consensus criteria for treatment response
- treatment is assessed by evaluating
  - improvement in biochemical values such as C-reactive protein, hemoglobin, albumin, and glomerular filtration rate (markers of inflammatory response and organ function)
  - reduction in lymph node size
  - improvement in other symptoms
additional treatment considerations are required in patients also presenting with TAFRO and POEMS
See Recommendations from Professional Organizations for more detailed guidance and corresponding grades of recommendations

Recommendations From Professional Organizations

Treatment of Unicentric Castleman Disease

Initial Treatment of Unicentric Castleman Disease

National Comprehensive Cancer Network (NCCN) recommendations (NCCN Category 2A)
- surgically resectable disease
  - if complete resection, continue observation for recurrent disease
  - if incomplete resection and asymptomatic, continue observation for recurrent disease
  - if incomplete resection and symptomatic, manage as surgically unresectable
- surgically unresectable disease
  - consider one of following as first-line therapy
    - radiation therapy
    - rituximab with or without prednisone, with or without cyclophosphamide
    - embolization
  - after first-line treatment, determine if surgically resectable
    - if resectable, perform complete resection if possible and observe for recurrence of disease
    - if incomplete resection or surgically unresectable, offer one of first-line therapies not given
  - Reference – National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for B-Cell Lymphomas. Version 2.2023 NCCN 2023 Feb 8 from NCCN website (free registration required)

Treatment of Relapsed/Refractory Unicentric Castleman Disease

for relapsed or refractory disease consider (NCCN Category 2A)
- repeat biopsy of lymph node to determine if transformation to diffuse large B-cell lymphoma, other malignancy, or infection
- one of the following as therapeutic option
  - local therapy with surgery or radiation therapy or embolization (if appropriate)
  - systemic therapy with rituximab with or without prednisone, with or without cyclophosphamide
  - siltuximab/tocilizumab for patients with human herpesvirus-8 (HHV-8) and HIV negative status
- Reference – National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for B-Cell Lymphomas. Version 2.2023 NCCN 2023 Feb 8 from NCCN website (free registration required)

Treatment of Multicentric Castleman Disease

Initial Treatment of Multicentric Castleman Disease

NCCN recommendations (NCCN Category 2A)
- if active disease present but no organ failure, determine HIV and HHV-8 status
  - if HHV-8 negative and HIV-1 negative
    - offer siltuximab as preferred regimen for plasmacytic/mixed histology – if response, continue until progression
    - consider thalidomide, cyclophosphamide, and prednisone for hyaline vascular histology
    - consider rituximab with or without prednisone – if response, observe and retreat at time of progression
    - if no response or relapsed disease, treat with alternate primary treatment not used for first-line treatment
  - if HHV-8 positive (with positive or negative HIV-1 status)
    - preferred regimen is rituximab
    - other options include
      - rituximab with or without liposomal doxorubicin with or without prednisone
      - zidovudine plus ganciclovir/valganciclovir
    - if response, continue to observe for recurrent or relapsed disease
    - if no response, treat with alternate treatment not used for first-line treatment
- fulminant HHV-8 positive disease with or without organ failure
  - offer one of following combination therapies with or without rituximab
    - CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)
    - CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone)
    - CVP (cyclophosphamide, vincristine, prednisone)
    - liposomal doxorubicin
  - if not candidate for combination therapy, offer rituximab as monotherapy
  - observe for response, if no response or relapsed disease, treat as relapsed disease
- Reference – National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for B-Cell Lymphomas. Version 2.2023 NCCN 2023 Feb 8 from NCCN website (free registration required)
International Working Group and Castleman Disease Collaborative Network (CDCN) recommendations for idiopathic multicentric CD (iMCD)⁽³⁾
- non-severe iMCD (disease without evidence of organ failure)
  - anti-interleukin 6 (IL-6) therapy is the treatment of choice
    - offer siltuximab 11 mg/kg every 3 weeks (CDCN Category 1)
    - if siltuximab not available, consider tocilizumab 8 mg/kg every 2 weeks (CDCN Category 2A)
    - consider adjunctive corticosteroid for initial disease control
      - for indolent disease – prednisone 1 mg/kg or equivalent for 4-8 weeks with gradual taper (CDCN Category 2B)
      - for symptomatic disease – methylprednisolone 2 mg/kg or equivalent with more gradual taper
  - alternate option is rituximab 375 mg/m² per week for 4-8 doses (CDCN Category 2B) for patients who do not have cytokine-driven symptoms or who are not appropriate for indefinite anti-IL-6 monoclonal antibody therapy
  - if partial or complete response, continue therapy with
    - siltuximab with or without steroids (CDCN Category 1)
    - tocilizumab with or without steroids (CDCN Category 2A)
  - if inadequate response, treat as refractory disease
- severe iMCD (disease with evidence of organ failure)
  - offer siltuximab (11 mg/kg IV every week for 1 month then every 3 weeks) plus high-dose steroids (methylprednisolone 500 mg/day orally) (CDCN Category 1)
  - consider tocilizumab plus high-dose steroids (CDCN Category 2A)
  - if no response within 1 week to siltuximab treatment, or evidence of clinical deterioration, consider combination therapy with either (CDCN Category 2B)
    - R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)
    - CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone)
    - CVP (cyclophosphamide, vincristine, prednisone)
    - VDT-ACE-R (bortezomib, dexamethasone, thalidomide, doxorubicin, cyclophosphamide, etoposide, rituximab)
    - etoposide/cyclophosphamide-containing regimens
  - refer to clinician/center with expertise in management of CD

Treatment of Relapsed/Refractory Multicentric Castleman Disease

NCCN recommendations for (NCCN Category 2A)
- relapsed/refractory disease in patients with asymptomatic active disease without organ failure
  - in relapsed disease, treat with alternate primary treatment option not tried before as part of initial treatment
  - in refractory or progressive disease, offer single agent therapy with 1 of
    - etoposide (oral or IV)
    - vinblastine
    - liposomal doxorubicin
  - in patients with HHV-8 positive status, offer single agent therapy as above with or without ganciclovir/valganciclovir
- refractory or progressive disease in patients with fulminant disease and organ failure
  - offer combination therapy with or without rituximab, if not given previously, with one of following
    - CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)
    - CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone)
    - CVP (cyclophosphamide, vincristine, prednisone)
    - liposomal doxorubicin
- assess response
  - if no response, treat with alternate combination therapy not yet given with or without rituximab
  - if response, observe for disease recurrence; treat with maintenance valganciclovir if HHV-8 positive
- if multiple relapsed/refractory disease, consider
  - repeat biopsy of lymph node to determine if transformation to diffuse large B-cell lymphoma, other malignancy, or development of opportunistic infections
  - alternate single-agent therapy
  - combination therapy with one of following
    - bortezomib with or without rituximab
    - tocilizumab
    - anakinra
    - thalidomide with or without rituximab
    - lenalidomide with or without rituximab
    - high-dose zidovudine plus valganciclovir
  - autologous hematopoietic stem cell transplantation (in select patients)
  - Reference – National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for B-Cell Lymphomas. Version 2.2023 NCCN 2023 Feb 8 from NCCN website (free registration required)
International Working Group and CDCN recommendations for⁽³⁾
- refractory or progressive idiopathic multicentric Castleman disease in nonsevere patients (no organ failure)
  - perform evaluation of diagnosis in patients who fail to respond to first-line therapy; rule out alternative diagnosis such as lymphoma
  - consider rituximab plus steroids with or without immunomodulatory agent (thalidomide, cyclosporine A, sirolimus, anakinra, or bortezomib) (CDCN Category 2B)
    - if partial or complete response, continue with therapy
    - if response is inadequate, consider consultation with expert and treatment with immunomodulatory agent such as thalidomide, cyclosporine A, sirolimus, anakinra, or bortezomib
- refractory or progressive disease in severe disease (presence of organ failure)
  - combination chemotherapy for 1 cycle with one of following (CDCN Category 2B)
    - R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)
    - R-VDT-PACE (rituximab, bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide)
    - etoposide plus cyclophosphamide plus rituximab
  - further treatment should be individualized in consultation with an expert

Medications

Anti-interleukin 6 (IL-6) Therapy

anti-IL-6 therapy (siltuximab and tocilizumab) are treatment options for patients with idiopathic multicentric Castleman disease (iMCD)^(1,2,3,4)
anti-IL-6 therapy considerations^(3,4)
- not lympholytic, but neutralizes growth and survival stimuli of lymphocytes
- patients with clinical and biochemical manifestations demonstrating inflammatory syndrome are most likely to benefit
- response often rapid and can be seen after 3-4 doses; changes in size of lymph nodes may take longer (reported median time to lymph node response 5 months)
- often combined with corticosteroid therapy, which is later tapered
- lab abnormalities associated with disease manifestations (hemoglobin, C-reactive protein, erythrocyte sedimentation rate, and albumin) should improve as clinical symptoms improve; should be followed weekly at the start, then biweekly until normalization
- can cause spurious elevation of IL-6 levels (and symptoms) in serum for 18-24 months following last dose, therefore IL-6 levels should not be used to monitor response
- treatment with anti-IL-6 therapy is not curative; extended or indefinite treatment should be considered
siltuximab
- chimeric monoclonal antibody that binds to human IL-6 (but not viral IL-6) and prevents its binding to both the soluble and membrane-bound IL-6 receptors⁽⁴⁾
- approved in the United States, Canada, and Europe, among other countries, for treatment of idiopathic MCD^(2,3)
- dose⁽³⁾
  - 11 mg/kg IV every 3 weeks for nonsevere iMCD
  - 11 mg/kg IV every week for 1 month, then every 3 weeks for severe iMCD
- generally well tolerated; commonly reported adverse events include pruritus, upper respiratory infection, fatigue, maculopapular rash, and peripheral edema⁽²⁾
- few serious infections without any cumulative toxicity or treatment discontinuations reported among 19 patients treated with siltuximab for up to 7 years (Oncotarget 2015 Oct 6;6(30):30408 full-text)
- evidence for siltuximab
  - siltuximab associated with greater rate of response in patients with symptomatic idiopathic (HIV- and HHV-8 negative) multicentric Castleman disease receiving supportive care (level 2 [mid-level] evidence)
    - based on small randomized trial
    - 79 adults (median age 48 years) with HIV negative/human herpesvirus-8 (HHV-8) negative symptomatic MCD randomized to siltuximab (11 mg/kg IV every 3 weeks) plus best supportive care vs. placebo plus best supportive care
    - patients assigned to siltuximab discontinued at time of first treatment failure (defined as sustained increase in disease-related symptoms lasting ≥ 3 weeks or new or worsening symptoms); patients assigned to placebo could crossover to receive siltuximab plus best supportive care at time of first treatment failure
    - median follow-up 14 months
    - response defined as durable tumor and symptomatic response
    - comparing siltuximab vs. placebo
      - response in 34% vs. 0% (p = 0.0012, NNT 3); duration of response in siltuximab group 383 days
      - grade ≥ 3 adverse events (fatigue, night sweats, anemia) 47% vs. 54% (no p value reported)
    - durable tumor and symptomatic response to siltuximab differed by histological variant; response in
      - 0% of patients with hyaline vascular subtype
      - 61% of patients with plasmacytic variant
      - 45% of patients with mixed variant
    - 6% of patients in siltuximab group reported serious adverse events including lower respiratory tract infection, anaphylactic reaction, and sepsis
    - Reference – Lancet Oncol 2014 Aug;15(9):966, editorial can be found in Lancet Oncol 2014 Aug;15(9):910
  - 60% of adults on long-term siltuximab (up to 6 years) reported to experience ≥ grade 3 adverse events, with hypertension being most common in adults with idiopathic multicentric Castleman disease (level 3 [lacking direct] evidence)
    - based on uncontrolled trial
    - 60 adults (median age 45 years, 67% male) with symptomatic iMCD (19 from phase 1 uncontrolled trial and 41 from phase 2 randomized trial above), who completed the trials without progression on siltuximab, continued to received siltuximab 11 mg/kg IV every 3 weeks for up to 6 years
    - patients showing partial response or complete response for > 6 months could switch to every 6 weeks dosing
    - 18 patients discontinued treatment prior to study completion due to change in treatment location, rather than study centers (8 adults), progressive disease (2 adults), adverse events (2 adults), and other reasons (6 adults)
    - grade ≥ 3 adverse events (reported in 60%); most frequent grade ≥ 3 events included
      - hypertension in 13%
      - fatigue in 8%
      - nausea in 7%
      - neutropenia in 7%
      - vomiting in 5%
    - Reference – Lancet Haematol 2020 Mar;7(3):e180
  - siltuximab reported to induce overall response in 33% of 9 patients with relapsed/refractory Castleman disease in case series (Hematol Oncol 2018 Oct;36(4):689)
tocilizumab^(1,2)
- recombinant humanized monoclonal antibody that binds to soluble and membrane bound IL-6 receptors and blocks IL-6 binding and intracellular signaling^(2,4)
- approved for use for iMCD in Japan⁽²⁾
- dose 8 mg/kg every 2 weeks for nonsevere iMCD without evidence of organ failure⁽³⁾
- reported adverse events are mostly transient and mild and include upper respiratory infections, pruritus, malaise, pharyngitis, diarrhea, and infusion reactions⁽²⁾
- evidence for tocilizumab
  - tocilizumab reported to decrease lymph node size measurements and improve lab abnormalities and symptoms in adults with plasma cell or mixed variant HIV negative multicentric Castleman disease (level 3 [lacking direct] evidence)
    - based on uncontrolled trial
    - 28 adults (median age 38 years) with plasma-cell or mixed variant HIV-negative MCD received tocilizumab 8 mg/kg IV every 2 weeks
    - at 16 weeks of treatment compared to baseline
      - among 23 patients with affected lymph nodes > 10 mm, lymph node decreased in mean short-axis length from 13.5 mm to 9.1 mm (no p value reported); 30% reduction observed at 1 year (p < 0.001)
      - hemoglobin level increased from 92 g/L to 120 g/L (p < 0.001)
      - erythrocyte sedimentation rate (ESR) decreased from 114 mm/hour to 48 mm/hour (p < 0.001)
      - mean body mass index (BMI) improved from 21.6 kg/m² to 23.1 kg/m² (p < 0.001)
      - general fatigue score measured by visual analog scale decreased from 29.9 to 17.7 (p = 0.008)
    - during median treatment duration of 65 weeks, adverse reaction reported in 96% but no severe adverse reactions reported; common adverse events included
      - common cold (and symptoms related to common cold) in 57.1%
      - transient, mild infusion reactions in 50% (21 infusion reactions total)
    - Reference – Blood 2005 Oct 15;106(8):2627
  - tocilizumab reported to be effective in improving lymphadenopathy, laboratory parameters, and symptoms in
    - 2 adults with HIV/HHV-8 positive MCD in case series (J Hematol Oncol 2014 Jan 17;7:10 full-text)
    - 3 adults with plasma cell MCD in case series (Intern Med 2007;46(11):771 full-text)
    - 2 pediatric patients with MCD in case series (Mol Cancer Ther 2012 Aug;11(8):1623 full-text)

Rituximab

rituximab^(1,2,3,4)
- humanized monoclonal antibody to CD20 (and HHV-8 replicates within CD20 expressing plasmablasts)^(2,4)
- reported to decrease risk of transformation to lymphoma^(2,4)
- can be used as limited duration monotherapy or in combination with chemotherapy for MCD (both idiopathic and HIV/HHV-8 positive)^(1,2,3,4)
- in HIV-positive patients, single agent rituximab reported to achieve remissions in majority of patients^(1,2)
- reported toxicities are mostly mild; reactivation of Kaposi sarcoma and hepatitis B has been observed (major adverse events) as well as infusion-related reactions⁽²⁾
evidence for rituximab
- rituximab-based regimens associated with increased survival compared to regimens not containing rituximab in adults with HIV-associated multicentric Castleman disease (level 2 [mid-level] evidence)
  - based on retrospective cohort study
  - 52 adults (mean age 42 years, 99% male) with HIV-associated MCD treated with rituximab-based therapy (monotherapy or in combination with chemotherapy), chemotherapy (with or without viral therapy), or antiviral therapy were followed for median 2.26 years
  - 19 patients died; median estimated overall survival (from HIV MCD diagnosis to death from any cause or last evaluation) 6.2 years
  - comparing rituximab-based therapy (with or without chemotherapy) vs. chemotherapy (with antiviral agents)
    - estimated overall survival, not reached vs. 5.1 years (p = 0.03)
    - sustained complete remission in 91% vs. 41% (p < 0.01)
  - Reference – Blood 2011 Sep 29;118(13):3499
- administration of rituximab following discontinuation of chemotherapy reported to induce sustained remission in 92% of adults with chemotherapy-dependent HIV-associated multicentric Castleman disease (level 3 [lacking direct] evidence)
  - based on uncontrolled trial
  - 24 adults (median age 43.5 years, 88% men) with stable (not active) chemotherapy-dependent HIV-associated MCD treated with rituximab 375 mg/m² IV once weekly for 4 weeks
    - rituximab started within 6-10 days of discontinuation of chemotherapy
    - stable chemotherapy-dependent disease defined as when
      - treated with chemotherapy for > 3 months with clinical response
      - experienced ≥ 1 recurrence of MCD flare (fever, ≥ 1 other related symptoms, and increased C-reactive protein in absence of any other cause) after trial of discontinuation of chemotherapy
  - at day 60, sustained remission (defined as absence of MCD flares) in 92%
  - at 1 year
    - sustained remission in 71%
    - relapse in 16%
    - overall survival in 92%
    - disease-free survival in 77%
  - infection adverse events were mild to moderate and mild exacerbations of Kaposi sarcoma reported in 8 out of 12 patients with history of Kaposi sarcoma
  - Reference – CastlemaB trial (J Clin Oncol 2007 Aug 1;25(22):3350)
- rituximab therapy may decrease risk of developing non-Hodgkin lymphoma compared to regimens without rituximab in patients with HHV-8-positive multicentric Castleman disease (level 2 [mid-level] evidence)
  - based on retrospective cohort study
  - 113 adults (median age 43 years) with HHV-8 associated MCD received therapy with rituximab (42% of patients) or regimens not containing rituximab and followed for mean 4.2 years
    - all patients received single agent chemotherapy as first-line treatment
    - rituximab regimen included 375 mg/m²once weekly for 4 weeks
  - 16% patients overall developed lymphoma (1 patient in rituximab group)
  - comparing rituximab vs. no rituximab (no p value reported)
    - 5-year probability of developing non-Hodgkin lymphoma 3% vs. 31%
    - 2-year overall survival 93.2% vs. 67.9%
    - 5-year overall survival 90.2% vs. 47.3%
  - rituximab associated with reduced risk of non-Hodgkin lymphoma compared to no rituximab after propensity score matching for history of disease, baseline laboratory parameters, and other clinical factors (hazard ratio 0.09, 95% CI 0.01-0.7)
  - Reference – Blood 2012 Mar 8;119(10):2228

Combination Chemotherapy Regimens

cytotoxic chemotherapy sometimes utilized for CD, but evidence is limited and results on efficacy reported to vary^(2,3,4)
more often used in MCD; if used in unicentric CD, goal is to reduce size of lymph node to allow successful surgical resection⁽²⁾
often, regimens are based off of those used for non-Hodgkin lymphoma, including^(2,3,4)
- low-dose single agent chemotherapy such as etoposide or vinblastine (alleviates symptoms, but without long-term disease control)
- combination therapy regimens (often with rituximab) used for more aggressive disease (such as CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisolone] or CVAD [cyclophosphamide, vincristine, adriamycin, etoposide])
aggressive intervention with combination chemotherapy can be considered in severe MCD if⁽³⁾
- rapid clinical deterioration and/or poor performance status
- no response to IL-6 antibodies within 1 week
- treatment failure to both IL-6 monoclonal antibodies and rituximab
given toxicities and potential treatment failures, consider chemotherapy regimens only if progression to severe disease or failure of multiple treatment options^(3,4)
liposomal doxorubicin plus rituximab reported to induce complete clinical response in 88% of patients with HHV-8 associated multicentric Castleman disease (level 3 [lacking direct] evidence)
- based on uncontrolled trial
- 17 adults with HIV-positive HHV-8 (Kaposi sarcoma)-associated MCD received liposomal doxorubicin 20 mg/m² IV plus rituximab 375 mg/m² IV weekly every 3 weeks for median 4 cycles
- 15 of 17 received consolidation therapy with interferon-alfa or high-dose zidovudine/ valganciclovir after completion of doxorubicin plus rituximab, 2 received liposomal doxorubicin alone or after 4 months of high-dose zidovudine/valganciclovir for treatment of progressive Kaposi sarcoma
- median follow-up 58 months
- treatment response defined by National Cancer Institute’s Kaposi sarcoma herpesvirus-associated multicentric Castleman disease (NCI KSHV-MCD) criteria
  - complete clinical response – full resolution of clinical symptoms lasting 1 cycle
  - complete biochemical response – normalization of hemoglobin, platelet, albumin, sodium, and C-reactive protein values lasting 1 cycle
  - complete radiographic response
    - reduction of lymph node size to < 1.5 cm in greatest transverse dimension with < 1 cm for lymph nodes measuring 1.1-1.5 cm at baseline or 75% reduction in sum product of diameters
    - reduction of spleen size to < 12 cm greatest dimension, no pleural effusions
- at completion of liposomal doxorubicin plus rituximab cycles
  - complete clinical response in 88%
  - complete biochemical response in 76%
  - complete radiographic response of lymph nodes in 76%
  - complete radiographic response of spleen in 47%
  - significant improvement from baseline in HHV-8 viral load (p = 0.0002), IL-6 level (p = 0.0026), hemoglobin (p < 0.0001), albumin, and C-reactive protein (p = 0.0013)
- at 12 months (after doxorubicin plus rituximab and during consolidation)
  - overall survival 93.8%
  - event-free survival 81.6%
- common adverse events included infusion events (70%), neutropenia (24% with grade 3-4), and anemia (12% with grade 3-4)
- Reference – Blood 2014 Dec 4;124(24):3544 full-text
- CLINICIANS’ PRACTICE POINT: Full description of NCI KSHV-MCD criteria can be found in Blood 2011 Jun 30;117(26):6977 full-text
combination chemotherapy with cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) reported to induce clinical response but not complete response in 10 patients with HIV-negative MCD in case series (Med Oncol 2013 Mar;30(1):492)

Corticosteroids

corticosteroids^(1,2,3,4)
- often used in conjunction with chemotherapy and other regimens
- reduce replication of proinflammatory cytokines and chemokines, adhesion molecules, and key enzymes such as interleukin 2, interleukin 6, and tumor necrosis factor α (TNFα) (Lancet Haematol 2016 Apr;3(4):e163)
- can provide symptom relief, but typically at high doses and cannot be sustained for long periods
- relapse of disease can occur at time of steroid tapering
dosing when used in combination with anti-interleukin 6 therapy for idiopathic multicentric Castleman disease⁽³⁾
- no evidence of organ failure (nonsevere)
  - if indolent disease, prednisone 1 mg/kg or equivalent for 4-8 weeks with gradual taper
  - if symptomatic disease, methylprednisolone 2 mg/kg or equivalent with more gradual taper
- evidence of organ failure (severe) – methylprednisolone 500 mg/day orally

Antiviral Therapy

some antiviral therapies (for example, zidovudine, valganciclovir, ganciclovir) reported to improve clinical symptoms and viral loads in patients with HHV-8 positive MCD⁽²⁾
not known exactly how antiviral therapy can be utilized as part of treatment of HHV-8-positive MCD; possibilities include⁽²⁾
- combination of high-dose zidovudine plus valganciclovir – results in clinical response in majority of patients but may be accompanied by hematological toxicity
- valganciclovir or ganciclovir in combination with rituximab and/or chemotherapy or as maintenance therapy after initial treatment
high-dose zidovudine plus valganciclovir reported to induce major clinical response in 86% of patients with HIV/HHV-8 positive multicentric Castleman disease (level 3 [lacking direct] evidence)
- based on uncontrolled trial
- 14 adults (median age 41 years, 93% men) with HIV-positive HHV-8 positive MCD treated with zidovudine 600 mg orally every 6 hours plus valganciclovir 900 mg orally every 12 hours for 7 days every 21-day cycle and continued as long as there was clinical benefit (median 8.5 cycles)
- median follow-up 42.8 months
- major clinical responses in 86% (defined as symptom-free disease plus partial response [by ≥ 50%] or better for 1 cycle)
- major biochemical response in 50% (defined as partial response or better [≥ 50% improvement in laboratory values such as hemoglobin, platelets, albumin, sodium and C-reactive protein for 1 cycle])
- median overall survival 86%
- median progression-free survival, 6 months
- significant improvement from baseline in HHV-8 viral load (p = 0.021), IL-6 level (p = 0.027), albumin, and C-reactive protein (p = 0.0085)
- Reference – Blood 2011 Jun 30;117(26):6977 full-text
ganciclovir reported to induce clinical response and decrease in HHV-8 plasma viremia in 3 patients with HIV/HHV-8 positive MCD in case series (Blood 2004 Mar 1;103(5):1632)

Other Medications

Anti-interleukin 1 (IL-1) Therapy

anakinra^(2,3)
- IL-1 receptor antagonist
- IL-1 stimulates or promotes production of IL-6; blocking IL-1, in theory, will disrupt IL-6-driven properties of Castleman disease
- option for relapsed/refractory Castleman disease
- limited evidence for use, mostly anecdotal
anakinra reported to improve symptoms and laboratory parameters in
- 61-year-old woman with refractory Castleman disease in case report (Mol Cancer Ther 2010 Jun;9(6):1485 full-text)
- 13-year-old boy with relapsed mixed-type multicentric Castleman disease in case report (J Pediatr Hematol Oncol 2008 Dec;30(12):920)

Other Immunomodulatory and Immunosuppressive Agents

other agents used for management of relapsed or refractory Castleman disease with varying success include bortezomib, thalidomide, and lenalidomide^(1,2,3)
immunomodulatory and immunosuppressive agents associated with less toxicity than chemotherapy⁽³⁾
limited evidence for use of these medications, which can be used as single agent or as part of combination therapy with other agents^(2,3)
thalidomide
- downregulates IL-6 expression and modulates vascular endothelial growth factor (VEGF)⁽³⁾
- thalidomide plus cyclophosphamide plus prednisone reported to induce durable tumor and symptom response in 48% of adults with idiopathic multicentric Castleman disease (level 3 [lacking direct] evidence)
  - based on uncontrolled trial
  - 25 adults (median age 40 years) with newly diagnosed idiopathic MCD received treatment with thalidomide, cyclophosphamide, and prednisone (TCP) and followed for median 14 months
    - 40% with hyaline vascular variant
    - 44% with plasmacytic variant
    - 16% with mixed variant
  - all patients received following regimen for 2 years or until treatment failure
    - thalidomide 100 mg orally once daily for year 1 and year 2
    - cyclophosphamide 300 mg/m² orally weekly on days 1, 8, 15, and 22 of a 4-week cycle for year 1
    - prednisone 1 mg/kg orally twice weekly on days 1 and 2, days 8 and 9, days 15 and 16, and days 22 and 23 of a 4-week cycle for year 1
  - at 24 weeks
    - durable tumor and symptomatic disease response in 48%
    - stable disease in 12%
    - treatment failure in 40%
  - comparing disease characteristics at 24 weeks vs. baseline
    - interleukin 6 level 10.6 pg/mL vs. 21.3 pg/mL (not significant)
    - erythrocyte sedimentation rate 60.5 mm/hour vs. 97.5 mm/hour (p = 0.03)
    - albumin 37 g/L vs. 32 g/L (p = 0.002)
    - immunoglobulin (Ig)G level 18.9 g/L vs. 25.9 g/L (p = 0.001)
  - Reference – Blood 2019 Apr 18;133(16):1720, editorial can be found in Blood 2019 Apr 18;133(16):1697
- thalidomide plus rituximab with or without subsequent thalidomide maintenance reported to induce response in 91% of patients with multicentric Castleman disease (level 3 [lacking direct] evidence)
  - based on case series
  - 11 adults (median age 43 years) with MCD (10 with HHV-8 MCD) received treatment with thalidomide plus rituximab and followed for median 22 months
  - all patients received
    - rituximab 375 mg/m²IV weekly for 4 weeks
    - thalidomide 100 mg/day orally for 4 weeks
  - thalidomide was continued as a single agent for median duration of 3 months in 81%
  - complete response (resolution of constitutional symptoms and complete regression of lymphadenopathy and/or organomegaly) in 91%
  - median progression-free survival 34.3 months
  - no significant difference in progression-free survival between thalidomide maintenance and no maintenance
  - Reference – Br J Haematol 2012 Aug;158(3):421
- thalidomide-containing regimen reported to induce response in 33-year-old man with HHV-8 positive/HIV positive MCD in case report (Am J Hematol 2004 Mar;75(3):176)
- single-agent thalidomide reported to induce clinical response in 37-year old woman with MCD in case report (Am J Hematol 2003 May;73(1):48)
bortezomib
- proteasome inhibitor that preferentially targets plasma cells, also inhibits the NF-kappaB pathway, which is a transcription factor involved in production of IL-6 (⁽⁴⁾, Lancet Haematol 2016 Apr;3(4):163)
- bortezomib reported to induce response in 49-year-old man with refractory MCD and POEMS syndrome in case report (Ann Hematol 2010 Feb;89(2):217)
- bortezomib plus thalidomide reported to induce clinical response in 16-year-old male with relapsed mixed-hyaline vascular and plasma cell variant multicentric CD in case report (Blood Cancer J 2015 Mar 20;5:e298)
lenalidomide
- functional and structural analog of thalidomide
- lenalidomide reported to induce clinical response in 3 patients with relapsed/refractory HIV-negative/HHV-8 negative MCD in case series (Front Med 2017 Jun;11(2):287)
- lenalidomide reported to induce improvement in lymph node size and symptoms in 46-year-old man with refractory MCD in case report (Leuk Lymphoma 2012 Oct;53(10):2089)

Surgery and Procedures

for unicentric Castleman disease (UCD)^(1,2,4)
- complete surgical resection of the affected lymph node is the preferred treatment modality
- complete surgical resection of affected lymph node can be curative; with complete resection, reported 10-year overall survival rate > 95%
- if not resectable
  - debulking surgery possible for symptom control or compression of surrounding organs by lymphadenopathy; sometimes followed by second surgery for resection
  - primary treatment includes either radiation therapy, rituximab with or without prednisone with or without cyclophosphamide, or embolization with goal to decrease lymph node size (to become more easily resectable)
- surgery reported to induce complete response in 91% of patients with unicentric Castleman disease (level 3 [lacking direct] evidence)
  - based on case series
  - 71 patients (median age at diagnosis 35 years) with UCD were treated with variety of modalities and followed for median 22 months
  - overall 5-year survival 98.4 %
  - complete response (no remaining tumor and no clinical or biochemical abnormality) in 91% of 47 patients who had surgery alone
  - Reference – Br J Haematol 2019 Jul;186(2):269
for multicentric Castleman disease^(1, 4)
- surgery not typically performed
- splenectomy can be considered for disease-related hemolytic anemia that has failed conventional therapy

Hematopoietic Stem Cell Transplant (HSCT)

autologous and allogeneic HSCT reported in only few cases with mixed results and performed as last treatment option⁽³⁾
patients with multicentric Castleman disease (MCD) and associated POEMS syndrome could be considered for autologous HSCT given aggressiveness of disease⁽⁴⁾
consider autologous HSCT in patients with multiple relapsed or refractory MCD as option after chemoresponsiveness to most recent pre-HSCT therapy (National Comprehensive Cancer Network [NCCN] Clinical Practice Guidelines for B-Cell Lymphomas. Version 2.2023 NCCN 2023 Feb 8 from NCCN website (free registration required)
autologous HSCT reported to induce response in
- 52-year-old male with relapsed MCD in case report (Int J Hematol 2011 May;93(5):677)
- 39-year-old woman with refractory MCD in case report (Clin Nephrol 2007 Sep;68(3):171)

Radiation Therapy

for unicentric Castleman disease (UCD)^(2,4)
- consider radiation therapy as alternative treatment option in unresectable cases
- acute and late toxicities are possible following treatment; continue observation for late-onset toxicities (Hematol Oncol Clin North Am 2018 Feb;32(1):65)
- 82% overall survival reported at 20 months after radiotherapy even in unresectable cases
- reported radiotherapy doses range from 27 to 60 Gy (mostly 40-45 Gy) (Hematol Oncol Clin North Am 2018 Feb;32(1):65)
- radiation therapy reported to induce complete response in 50% of patients with unicentric Castleman disease (level 3 [lacking direct] evidence)
  - based on case series
  - 71 patients (median age at diagnosis 35 years) with UCD were treated with variety of modalities and followed for median 22 months
  - overall 5-year survival 98.4 %
  - complete response (no remaining tumor and no clinical or biochemical abnormality) in 50% of 8 patients who had radiation therapy alone
  - Reference – Br J Haematol 2019 Jul;186(2):269
for multicentric Castleman disease⁽⁴⁾
- essentially no role for radiation therapy
- consider local radiotherapy for patients with coexisting POEMS syndrome and localized bony lesions

Management Considerations for TAFRO and POEMS Syndrome

unclear whether syndromes are distinct clinical entities or part of idiopathic multicentric Castleman disease (iMCD) spectrum^(2,3,4)
TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis of the bone marrow, and organomegaly)
- often aggressive clinical course and worse outcomes; often requires multiple therapies⁽⁴⁾
- treatments commonly used include corticosteroids (TAFRO associated with increased corticosteroid refractoriness), anti-interleukin 6 (IL-6) therapy, chemotherapy, and cyclosporin A^(3,4)
- Castleman Disease Collaborative Network (CDCN) suggested treatment strategy⁽³⁾
  - same treatment strategy as for other cases of iMCD that involves treatment with anti-IL-6 therapy with or without corticosteroids
  - cyclosporine A can be considered for refractory symptoms; reported to be beneficial for persistent ascites and thrombocytopenia
- alternate treatment strategies
  - high-dose corticosteroid (for example, methylprednisolone pulse treatment 500-1,000 mg/day for 3 days if urgent, or prednisolone 1 mg/kg/day for 2 weeks, followed by taper)
  - consider cyclosporine A if refractory or dependent on corticosteroids (suggested initial dose 3-5 mg/kg/day in 2 divided doses per day); target serum cyclosporine A concentration 150-250 ng/mL
  - consider tocilizumab or rituximab if refractory disease or contraindication to cyclosporine
  - consider thrombopoietin receptor agonists (romiplostim or eltrombopag) if thrombocytopenia is persistent
  - Reference – Int J Hematol 2016 Jun;103(6):686
POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)^(3,4)
- sometimes require treatment for POEMS syndrome as well as for MCD
- in patients with POEMS and iMCD
  - anti-IL-6 therapy or rituximab treatment may be beneficial, but polyneuropathy associated with POEMS syndrome does not appear to respond to anti-IL-6 therapy
  - not routinely performed but, autologous hematopoietic stem cell transplantation can be considered
- for POEMS
  - radiation therapy is a treatment option for patients with isolated osteosclerotic bone lesions without disseminated bone marrow involvement
  - for patients with disseminated bone marrow involvement, systemic therapy is needed (combination of chemotherapy, radiation, and immunotherapy are indicated)
- Reference – Am J Hematol 2017 Aug;92(8):814 full-text

Monitoring Treatment Response

historically there has been lack of cohesive criteria for treatment response⁽³⁾
response to treatment is assessed by evaluation of biochemical values, lymph node size, and symptoms
- laboratory markers evaluated for treatment response (markers of inflammatory response and organ function) include⁽³⁾
  - C-reactive protein
  - hemoglobin
  - albumin
  - glomerular filtration rate
- lymph node evaluation can be done by multiple assessments (no current cohesive criteria for Castleman disease), including
  - revised Lugano criteria with modification for cutaneous lesions; see Staging in Diffuse Large B-cell Lymphoma for details
  - Cheson criteria for lymph node response (J Clin Oncol 2007 Feb 10;25(5):579)
  - iMCD symptom score per Castleman Disease Collaborative Network (CDCN)
- symptoms assessed per National Cancer Institute Common Terminology Criteria of Adverse Events include
  - fatigue
  - anorexia
  - fever
  - weight
CDCN treatment response criteria for idiopathic multicentric Castleman disease (iMCD)⁽³⁾
- complete response
  - biochemical (includes C-reactive protein, hemoglobin, albumin, and glomerular filtration rate) – normalization of all values compared with baseline
  - lymph nodes – normalization of previously enlarged lymph node(s)
  - symptoms – normalization to baseline in 4 categories (fatigue, anorexia, fever, and weight)
- partial response
  - biochemical – 50%-99% improvement in all values
  - lymph nodes – ≥ 50% decrease in previously enlarged lymph node(s)
  - symptoms – improvement in all 4 categories, but not back to baseline
- stable disease
  - biochemical – < 50% improvement or < 25% worsening in all laboratory values
  - lymph nodes – no partial or complete response in previously enlarged lymph node(s)
  - symptoms – improvement in ≥ 1 (but not all) symptoms
- progressive disease
  - biochemical – > 25% worsening in any of laboratory values
  - lymph nodes – >25% increase in size
  - symptoms – any symptoms that are worse on ≥ 2 evaluations 4 weeks apart
frequency of monitoring⁽³⁾
- with severe presentation, daily monitoring initially necessary
- for less severe presentation, assessment of clinical symptoms and laboratory values evaluated weekly, then biweekly until maximum benefit has been achieved
- radiological assessment of lymph nodes with computed tomography
  - starting at 6 weeks after initiation of treatment
  - every 3 months until maximum response has occurred
  - frequency can then be reduced to every 6-12 months

Complications

reactivation of Kaposi sarcoma (KS)
- in multicentric Castleman disease (MCD) up to 75% of HIV-positive patients and up to 13% without HIV reported to have flare of KS⁽¹⁾
- rituximab and/or prednisone reported to be associated with reactivation of KS⁽²⁾
- liposomal doxorubicin is considered therapy for KS and often used as part of combination management (NCCN Clinical Practice Guidelines for B-cell lymphomas. Version 1.2020. NCCN 2020 Jan 22 from NCCN website [free registration required])
transformation to lymphoma
- 71% of all reported cases of Castleman disease-associated lymphomas are non-Hodgkin lymphoma (NHL); also reports of transformation to Hodgkin lymphoma⁽¹⁾
- both unicentric (UCD) and MCD can sometimes progress to non-Hodgkin lymphoma but more common in MCD^(1,4)
- prognostic factors for malignant transformation^(2,4)
  - human herpesvirus-8 (HHV-8) positive MCD associated with increased risk of development of NHL
  - administration of rituximab to HHV-8 positive MCD may decrease risk of transformation to lymphoma
other complications associated with MCD
- autoimmune hemolytic anemia^(2, 4)
- immune thrombocytopenia^(2, 4
- renal failure (due to thrombotic microangiopathy, and in those with TAFRO syndrome)^(3,4)
- pulmonary involvement/lymphocytic interstitial pneumonitis, which can lead to pulmonary fibrosis if not managed⁽³⁾
- acquired factor VIII deficiency⁽²⁾
- other less common complications include⁽²⁴⁾
  - bronchiolitis obliterans
  - glomerulonephritis

Prognosis

prognosis of Castleman disease (CD) is variable and depends on multiple factors
- unicentric CD (UCD) vs. multicentric CD (MCD)
  - UCD
    - reported 10-year survival rate > 95% after complete resection⁽²⁾
    - poorer outcomes associated with incomplete resection of tumor; reported overall survival at 20 months 82% after radiotherapy in unresectable cases⁽²⁾
    - in cohort of 497 patients with UCD (91% treated surgically), at mean follow-up of 28 months⁽¹⁾
      - death in 5.6%
      - stable or progressive disease in 20%
      - remission in 75%
  - MCD
    - can range from persistent chronic condition to rapid progression and death within weeks⁽¹⁾
    - human herpes virus 8 (HHV-8 positive) MCD associated with the worst outcomes, with majority of deaths reported within 2 years of diagnosis in studies prior to introduction of rituximab to therapy; 94% 2-year survival reported when treated with rituximab⁽²⁾
    - among patients with idiopathic MCD receiving various types of therapy, reported 2-year overall survival 88%⁽⁴⁾
    - in cohort of 324 patients with MCD (received various drug therapy), at mean follow-up of 28 months⁽¹⁾
      - death in 28%
      - stable or progressive disease in 43%
      - remission in 30%
  - idiopathic multicentric Castleman disease associated with decreased progression-free survival compared to unicentric Castleman disease (UCD)
    - based on cohort study
    - 74 adults with Castleman disease (43 with UCD, 31 with idiopathic MCD) were assessed
    - 46 patients with mean follow-up of 65 months included in survival analysis
    - idiopathic MCD associated with decreased survival (hazard ratio 0.236, 95% CI 0.07-0.791) compared to UCD
    - Reference – Blood 2017 Mar 23;129(12):1658 full-text, editorial can be found in Blood 2017 Mar 23;129(12):1570
- TAFRO subtype of MCD often associated with severe clinical presentation and worse outcomes⁽³⁾
- presence of paraneoplastic pemphigus associated with increased mortality in patients with Castleman disease
  - based on cohort study
  - 114 patients (median age 35 years, 53.5% male) with Castleman disease (45.6% with MCD, 54.4% with UCD) were followed for 37 months
  - 32% diagnosed with paraneoplastic pemphigus (86% had UCD)
  - 3-year survival rate 57.6% of patients with paraneoplastic pemphigus vs. 88.3% of patients without paraneoplastic pemphigus
  - paraneoplastic pemphigus associated with increased mortality (hazard ratio 4.76, 95% CI 1.09-20.84) compared to no paraneoplastic pemphigus
  - Reference – Br J Haematol 2015 Jun;169(6):834

Prevention and Screening

not applicable

Guidelines and Resources

Guidelines

International Guidelines

International, evidence-based consensus treatment guidelines on idiopathic multicentric Castleman disease can be found in Blood 2018 Nov 15;132(20):2115 full-text
International evidence-based consensus diagnostic criteria on HHV-8-negative/idiopathic multicentric Castleman disease can be found in Blood 2017 Mar 23;129(12):1646 full-text

United States Guidelines

Castleman Disease Collaborative Network (CDCN) treatment guidelines on idiopathic multicentric castleman disease can be found at CDCN Sep 2018
National Comprehensive Cancer Network (NCCN) statement on mitigating the impacts of anticancer drug shortages can be found at NCCN 2023 Jun 7 PDF
National Comprehensive Cancer Network Guidelines (NCCN) on B-Cell Lymphomas and Castleman Disease can be found at NCCN website (free registration required)
expert consensus statement on blocking interleukin-6 receptor and interleukin-6 in inflammatory conditions can be found in Ann Rheum Dis 2023 Jun;82(6):773
American Society of Clinical Oncology (ASCO) position on prioritization of antineoplastic agents in limited supply for first intervention can be found at ASCO, accessed 2023 Jun 13

United Kingdom Guidelines

British Society for Haematology (BSH) guideline on management of Castleman disease can be found in Br J Haematol 2021 Nov;195(3):328

Review Articles

review of diagnostic criteria for Castleman disease can be found at Br J Haematol 2018 Jan;180(2):206, editorial can be found in Br J Haematol 2018 Jan;180(2):173
review of diagnostic approach to Castleman disease can be found at Hematol Oncol Clin North Am 2018 Feb;32(1):53
HHV-8/HIV associated multicentric Castleman disease
- review of treatment of HHV-8/HIV associated multicentric Castleman disease can be found at Blood 2010 Nov 25;116(22):4415
- review of HIV associated multicentric Castleman disease can be found at Curr Opin Oncol 2011 Sep;23(5):475 full-text
idiopathic multicentric Castleman disease
- review of clinical features, treatment, and outcomes can be found at Lancet Haematol 2016 Apr;3(4):e163, editorial can be found in Lancet Haematol 2016 Apr;3(4):e150
- novel insights and therapeutic approaches in idiopathic multicentric Castleman disease can be found at Blood 2018 Nov 29;132(22):2323 full-text
review of pathogenesis of Castleman disease can be found at Hematol Oncol Clin North Am 2018 Feb;32(1):11
review of pathology of Castleman disease can be found at Surg Pathol Clin 2019 Sep;12(3):849
review of surgery in Castleman disease can be found in Ann Surg 2012 Apr;255(4):677
TAFRO syndrome
- review of TAFRO syndrome can be found at Blood 2018 Nov 15;132(20):2109
- proposed diagnostic criteria, disease severity, classification, and treatment strategy for TAFRO syndrome can be found at Int J Hematol 2016 Jun;103(6):686
review of diagnosis and management of POEMS syndrome can be found at Am J Hematol 2019 Jul;94(7):812

MEDLINE Search

to search MEDLINE for (Castleman disease) with targeted search (Clinical Queries), click therapy, diagnosis, or prognosis

Patient Information

information from Castleman Disease Collaborative Network
handout from National Organization for Rare Disorders (NORD)
information from Genetic and Rare Diseases Information Center

References

Haap M, Wiefels J, Horger M, Hoyer A, Müssig K. Clinical, laboratory and imaging findings in Castleman’s disease – The subtype decides. Blood Rev. 2018 May;32(3):225-234.
Chan KL, Lade S, Prince HM, Harrison SJ. Update and new approaches in the treatment of Castleman disease. J Blood Med. 2016;7:145-58 full-text.
van Rhee F, Voorhees P, Dispenzieri A, et al. International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease. Blood. 2018 Nov 15;132(20):2115-2124 full-text, editorial can be found in Blood 2018 Nov 15;132(20):2109.
van Rhee F, Greenway A, Stone K. Treatment of Idiopathic Castleman Disease. Hematol Oncol Clin North Am. 2018 Feb;32(1):89-106.

Castleman Disease – 9 Interesting Facts

Synonyms

Types

Epidemiology

Who Is Most Affected

Incidence/Prevalence

Risk Factors

Associated Conditions

Etiology and Pathogenesis

Causes

Pathogenesis

History and Physical

Clinical Presentation

History

Physical

Performance Status Evaluation

Diagnosis

Making the Diagnosis

Differential Diagnosis

Testing Overview

Recommendations From Professional Organizations

Blood Tests

Urine Studies

Imaging Studies

Biopsy and Pathology

Lymph Node Biopsy

Bone Marrow Biopsy

Management

Recommendations From Professional Organizations

Treatment of Unicentric Castleman Disease

Initial Treatment of Unicentric Castleman Disease

Treatment of Relapsed/Refractory Unicentric Castleman Disease

Treatment of Multicentric Castleman Disease

Initial Treatment of Multicentric Castleman Disease

Treatment of Relapsed/Refractory Multicentric Castleman Disease

Medications

Anti-interleukin 6 (IL-6) Therapy

Rituximab

Combination Chemotherapy Regimens

Corticosteroids

Antiviral Therapy

Other Medications

Anti-interleukin 1 (IL-1) Therapy

Other Immunomodulatory and Immunosuppressive Agents

Surgery and Procedures

Hematopoietic Stem Cell Transplant (HSCT)

Radiation Therapy

Management Considerations for TAFRO and POEMS Syndrome

Monitoring Treatment Response

Complications

Prognosis

Prevention and Screening

Guidelines and Resources

Guidelines

International Guidelines

United States Guidelines

United Kingdom Guidelines

Review Articles

MEDLINE Search

Patient Information

References

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