Castleman disease (CD) is a rare, heterogeneous group of lymphoproliferative disorders that share a characteristic angiofollicular lymph node hyperplasia histopathology. CD is clinically divided by anatomic extent into unicentric Castleman disease (UCD), affecting a single lymph node region with curative surgical resection, and multicentric Castleman disease (MCD), affecting multiple regions with systemic inflammatory features. MCD is further subdivided by etiology into HHV-8/KSHV-associated MCD (driven by viral IL-6 production, often in HIV co-infection), idiopathic MCD (iMCD, of unknown etiology with dysregulated human IL-6 signaling), and POEMS- associated MCD. Across MCD subtypes, IL-6 hypercytokinemia and JAK-STAT signaling drive constitutional symptoms, lymphadenopathy, cytopenias, acute-phase response, and multi-organ dysfunction.
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name: Castleman Disease
creation_date: "2026-05-12T20:00:00Z"
updated_date: "2026-05-13T14:00:00Z"
category: Complex
disease_term:
preferred_term: Castleman disease
term:
id: MONDO:0015564
label: Castleman disease
parents:
- Lymphoproliferative Disease
description: >-
Castleman disease (CD) is a rare, heterogeneous group of lymphoproliferative
disorders that share a characteristic angiofollicular lymph node hyperplasia
histopathology. CD is clinically divided by anatomic extent into unicentric
Castleman disease (UCD), affecting a single lymph node region with curative
surgical resection, and multicentric Castleman disease (MCD), affecting
multiple regions with systemic inflammatory features. MCD is further
subdivided by etiology into HHV-8/KSHV-associated MCD (driven by viral
IL-6 production, often in HIV co-infection), idiopathic MCD (iMCD, of
unknown etiology with dysregulated human IL-6 signaling), and POEMS-
associated MCD. Across MCD subtypes, IL-6 hypercytokinemia and JAK-STAT
signaling drive constitutional symptoms, lymphadenopathy, cytopenias,
acute-phase response, and multi-organ dysfunction.
has_subtypes:
- name: Unicentric CD
display_name: Unicentric Castleman Disease (UCD)
description: >-
Localized form involving a single lymph node region. Typically presents
as an asymptomatic mass and is curable by complete surgical resection.
The hyaline-vascular histologic variant predominates. iMCD-TAFRO
further substratifies the multicentric forms (see iMCD subtype).
evidence:
- reference: DOI:10.1002/art.43269
reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Unicentric CD (UCD) involves one enlarged lymph node region, whereas multicentric CD (MCD) involves multiple enlarged lymph node regions."
explanation: Expert-perspective review defines UCD as single-region lymph node involvement.
- name: HHV-8+ MCD
display_name: HHV-8-Associated Multicentric Castleman Disease
description: >-
Multicentric form driven by Kaposi sarcoma-associated herpesvirus (KSHV/
HHV-8) infection. The virus encodes a viral homolog of IL-6 (vIL-6)
that activates JAK-STAT signaling. Predominantly affects HIV co-infected
patients but can occur in HIV-negative immunocompromised individuals.
First-line therapy is rituximab.
evidence:
- reference: DOI:10.1182/bloodadvances.2024013548
reference_title: "The clinical picture of Castleman disease: a systematic review and meta-analysis"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Castleman disease (CD) encompasses a spectrum of rare disorders, including unicentric CD (UCD), idiopathic multicentric CD (iMCD), and human herpesvirus 8–associated MCD (HHV8+ MCD)."
explanation: Meta-analysis of 1,998 patients establishes HHV8+ MCD as one of the three principal CD subtypes.
- name: iMCD
display_name: Idiopathic Multicentric Castleman Disease
description: >-
HHV-8-negative multicentric form of unknown etiology. Driven by
dysregulated endogenous human IL-6 hypercytokinemia. Subdivided into
three clinical patterns: iMCD-TAFRO (thrombocytopenia, anasarca, fever,
renal dysfunction/reticulin fibrosis, organomegaly), iMCD-IPL
(idiopathic plasmacytic lymphadenopathy with polyclonal
hypergammaglobulinemia, can mimic IgG4-related disease), and iMCD-NOS.
First-line therapy across all iMCD subtypes is the anti-IL-6 antibody
siltuximab.
evidence:
- reference: DOI:10.1002/art.43269
reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The three subtypes are iMCD–thrombocytopenia, anasarca, fever, renal dysfunction/reticulin fibrosis, organomegaly (TAFRO); iMCD–idiopathic plasmacytic lymphadenopathy (IPL); and iMCD–not otherwise specified (NOS)."
explanation: Expert-perspective review codifies the three iMCD clinical subtypes (TAFRO, IPL, NOS).
- reference: DOI:10.3324/haematol.2023.283603
reference_title: "Longitudinal, natural history study reveals the disease burden of idiopathic multicentric Castleman disease"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Idiopathic multicentric Castleman disease (iMCD) is a rare hematologic disorder with heterogeneous presentations ranging from moderate constitutional symptoms to life-threatening multiorgan system involvement."
explanation: ACCELERATE registry natural-history study confirms iMCD as a clinically heterogeneous disorder spanning mild to life-threatening presentations.
- name: POEMS-Associated MCD
description: >-
MCD occurring in the context of POEMS syndrome (polyneuropathy,
organomegaly, endocrinopathy, monoclonal protein, skin changes), a
paraneoplastic disorder of plasma cell origin.
evidence:
- reference: DOI:10.1182/blood.2019000931
reference_title: "Overview of Castleman disease"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "CD includes unicentric CD (UCD) and multicentric CD (MCD), the latter of which is divided into idiopathic MCD (iMCD), human herpes virus-8 (HHV8)-associated MCD (HHV8-MCD), and polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes (POEMS)-associated MCD (POEMS-MCD)."
explanation: Authoritative Blood review establishes the four-disorder MCD framework including POEMS-MCD as a distinct etiologic subtype.
pathophysiology:
- name: HHV-8/KSHV Viral Pathogenesis
description: >-
In HHV-8+ MCD, lytic replication of Kaposi sarcoma-associated
herpesvirus in plasmablasts produces viral IL-6 (vIL-6) and other
inflammatory mediators. vIL-6 signals through gp130 independently of
the IL-6 receptor, bypassing normal regulatory checkpoints. The disease
course is characterized by recurrent flares of lytic viral activity.
In contrast, Viral-Track analysis of UCD (n=22) and iMCD (n=19) found
no shared viral signature, indicating that active viral infection is
not a driver of the HHV-8-negative subtypes.
biological_processes:
- preferred_term: Viral process
term:
id: GO:0016032
label: viral process
evidence:
- reference: DOI:10.1038/s41598-025-85193-x
reference_title: "No evidence for active viral infection in unicentric and idiopathic multicentric Castleman disease by Viral-Track analysis"
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: "While uncontrolled infection with human herpesvirus-8 (HHV-8) is responsible for the cytokine storm in a portion of multicentric CD (HHV-8-associated MCD) cases, the etiology of unicentric CD (UCD) and HHV-8-negative/idiopathic MCD (iMCD) is unknown."
explanation: Confirms HHV-8 as the etiologic driver of HHV8+ MCD specifically, while UCD and iMCD remain etiologically unexplained.
- reference: DOI:10.1038/s41598-025-85193-x
reference_title: "No evidence for active viral infection in unicentric and idiopathic multicentric Castleman disease by Viral-Track analysis"
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: "These results suggest that active viral infection is unlikely to be a pathological driver of UCD or iMCD."
explanation: Viral-Track RNA-seq analysis rules out a shared viral driver of UCD and iMCD, supporting the distinction between HHV8+ MCD and the HHV-8-negative subtypes.
downstream:
- target: IL-6 / vIL-6 Overproduction
evidence:
- reference: DOI:10.1038/s41598-025-85193-x
reference_title: "No evidence for active viral infection in unicentric and idiopathic multicentric Castleman disease by Viral-Track analysis"
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: "While uncontrolled infection with human herpesvirus-8 (HHV-8) is responsible for the cytokine storm in a portion of multicentric CD (HHV-8-associated MCD) cases, the etiology of unicentric CD (UCD) and HHV-8-negative/idiopathic MCD (iMCD) is unknown."
explanation: HHV-8 lytic replication produces vIL-6 and triggers the cytokine storm in HHV-8+ MCD, driving downstream IL-6 / vIL-6 overproduction.
- name: IL-6 / vIL-6 Overproduction
description: >-
Dysregulated overproduction of interleukin-6 is the unifying
upstream driver of MCD. In HHV-8+ MCD, the virus produces a viral
IL-6 homolog (vIL-6) that signals through gp130 independently of
the IL-6 receptor. In iMCD, endogenous human IL-6 is overproduced
from a poorly understood trigger.
biological_processes:
- preferred_term: Interleukin-6 production
term:
id: GO:0032635
label: interleukin-6 production
modifier: INCREASED
evidence:
- reference: DOI:10.1002/art.43269
reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Although they are all driven by excessive cytokines such as interleukin‐6 (IL‐6)"
explanation: Expert-perspective review identifies IL-6 overproduction as the unifying mechanism across CD subtypes.
downstream:
- target: JAK-STAT3 Signaling Activation
evidence:
- reference: DOI:10.1002/art.43269
reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Although they are all driven by excessive cytokines such as interleukin‐6 (IL‐6)"
explanation: Excess IL-6/vIL-6 signals through gp130 to activate downstream JAK-STAT3 in target cells.
- name: JAK-STAT3 Signaling Activation
description: >-
IL-6 and vIL-6 bind gp130 and activate downstream JAK kinases and
STAT3 transcription factor signaling. This pathway is therapeutically
targeted by anti-IL-6 (siltuximab), anti-IL-6R (tocilizumab), and
JAK1/2 inhibitors (ruxolitinib).
biological_processes:
- preferred_term: Interleukin-6-mediated signaling pathway
term:
id: GO:0070102
label: interleukin-6-mediated signaling pathway
modifier: INCREASED
- preferred_term: JAK-STAT signaling
term:
id: GO:0007259
label: cell surface receptor signaling pathway via JAK-STAT
modifier: INCREASED
downstream:
- target: Plasma Cell / B Cell Proliferation and Acute-Phase Response
evidence:
- reference: DOI:10.1002/art.43269
reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Rapid onset cytokine storm with severe inflammation, anasarca, thrombocytopenia, and small volume lymphadenopathy, similar to hemophagocytic lymphohistiocytosis or sepsis, are the hallmarks of iMCD‐TAFRO."
explanation: JAK-STAT3 signaling downstream of IL-6 drives the cytokine-storm clinical picture (anasarca, thrombocytopenia, lymphadenopathy) hallmarking iMCD-TAFRO.
- name: Plasma Cell / B Cell Proliferation and Acute-Phase Response
description: >-
JAK-STAT3 signaling drives proliferation of B cells and plasma cells
within affected lymph nodes, hepatic acute-phase reactant production
(e.g., CRP), and release of vascular endothelial growth factor (VEGF)
that promotes angiogenesis. These downstream effects converge to
produce the characteristic angiofollicular lymph node hyperplasia
histology and systemic inflammatory phenotypes.
cell_types:
- preferred_term: B cell
term:
id: CL:0000236
label: B cell
- preferred_term: Plasma cell
term:
id: CL:0000786
label: plasma cell
biological_processes:
- preferred_term: B cell proliferation
term:
id: GO:0042100
label: B cell proliferation
modifier: INCREASED
- preferred_term: Acute-phase response
term:
id: GO:0006953
label: acute-phase response
modifier: INCREASED
evidence:
- reference: DOI:10.1002/art.43269
reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Rapid onset cytokine storm with severe inflammation, anasarca, thrombocytopenia, and small volume lymphadenopathy, similar to hemophagocytic lymphohistiocytosis or sepsis, are the hallmarks of iMCD‐TAFRO."
explanation: Describes the cytokine-storm hallmark of iMCD-TAFRO that follows from JAK-STAT3-driven proliferation and acute-phase response.
downstream:
- target: Angiofollicular Lymph Node Hyperplasia
evidence:
- reference: DOI:10.1002/art.43269
reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Although they are all driven by excessive cytokines such as interleukin‐6 (IL‐6)"
explanation: Excess IL-6 signaling and downstream proliferation/VEGF release produce the angiofollicular lymph node hyperplasia common to all CD subtypes.
- name: Angiofollicular Lymph Node Hyperplasia
description: >-
The unifying histopathologic feature across all CD subtypes: lymph
nodes show abnormal germinal centers (regressed/atretic in
hyaline-vascular UCD, hyperplastic with plasma cell infiltrates in
plasma-cell variant MCD), penetrating "lollipop" vessels, mantle-zone
expansion ("onion-skinning"), and interfollicular plasmacytosis and
vascular proliferation driven by IL-6 and VEGF.
cell_types:
- preferred_term: Plasma cell
term:
id: CL:0000786
label: plasma cell
biological_processes:
- preferred_term: Angiogenesis
term:
id: GO:0001525
label: angiogenesis
modifier: INCREASED
downstream:
- target: Generalized Lymphadenopathy
evidence:
- reference: DOI:10.1002/art.43269
reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Unicentric CD (UCD) involves one enlarged lymph node region, whereas multicentric CD (MCD) involves multiple enlarged lymph node regions."
explanation: Angiofollicular lymph node hyperplasia drives clinically detectable lymphadenopathy, localized in UCD and generalized in MCD.
phenotypes:
- category: Constitutional
name: Generalized Lymphadenopathy
diagnostic: true
notes: >-
Localized in UCD (single nodal region); generalized/multicentric in MCD.
phenotype_term:
preferred_term: Generalized lymphadenopathy
term:
id: HP:0008940
label: Generalized lymphadenopathy
evidence:
- reference: DOI:10.1002/art.43269
reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Unicentric CD (UCD) involves one enlarged lymph node region, whereas multicentric CD (MCD) involves multiple enlarged lymph node regions."
explanation: Lymphadenopathy is the defining clinical feature of CD; localized in UCD and generalized in MCD.
- category: Constitutional
name: Fever
subtype: HHV-8+ MCD
notes: >-
Constitutional symptoms including fever are present in 98.6% of HHV8+
MCD vs 46.6% of iMCD in a 1,998-patient meta-analysis.
phenotype_term:
preferred_term: Recurrent fever
term:
id: HP:0001954
label: Recurrent fever
evidence:
- reference: DOI:10.1182/bloodadvances.2024013548
reference_title: "The clinical picture of Castleman disease: a systematic review and meta-analysis"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "patients with HHV8+ MCD had significantly higher rates of constitutional symptoms (46.6% vs 98.6%; P = .038) and splenomegaly (48.2% vs 89.2%; P = .031)"
explanation: Meta-analysis quantifies constitutional symptoms (including fever) as substantially more frequent in HHV8+ MCD than iMCD.
- category: Constitutional
name: Night Sweats
phenotype_term:
preferred_term: Night sweats
term:
id: HP:0030166
label: Night sweats
- category: Constitutional
name: Fatigue
phenotype_term:
preferred_term: Fatigue
term:
id: HP:0012378
label: Fatigue
- category: Hematologic
name: Anemia
phenotype_term:
preferred_term: Anemia
term:
id: HP:0001903
label: Anemia
- category: Abdominal
name: Splenomegaly
phenotype_term:
preferred_term: Splenomegaly
term:
id: HP:0001744
label: Splenomegaly
evidence:
- reference: DOI:10.1182/bloodadvances.2024013548
reference_title: "The clinical picture of Castleman disease: a systematic review and meta-analysis"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "patients with HHV8+ MCD had significantly higher rates of constitutional symptoms (46.6% vs 98.6%; P = .038) and splenomegaly (48.2% vs 89.2%; P = .031)"
explanation: Meta-analysis quantifies splenomegaly frequencies at 48.2% in iMCD and 89.2% in HHV8+ MCD.
- category: Abdominal
name: Hepatomegaly
phenotype_term:
preferred_term: Hepatomegaly
term:
id: HP:0002240
label: Hepatomegaly
- category: Hematologic
name: Thrombocytopenia
subtype: iMCD
notes: >-
Hallmark feature of the iMCD-TAFRO clinical subtype.
phenotype_term:
preferred_term: Thrombocytopenia
term:
id: HP:0001873
label: Thrombocytopenia
evidence:
- reference: DOI:10.1002/art.43269
reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Rapid onset cytokine storm with severe inflammation, anasarca, thrombocytopenia, and small volume lymphadenopathy, similar to hemophagocytic lymphohistiocytosis or sepsis, are the hallmarks of iMCD‐TAFRO."
explanation: Identifies thrombocytopenia as a hallmark feature of iMCD-TAFRO.
- category: Abdominal
name: Ascites
subtype: iMCD
notes: >-
Component of the anasarca that hallmarks iMCD-TAFRO.
phenotype_term:
preferred_term: Ascites
term:
id: HP:0001541
label: Ascites
evidence:
- reference: DOI:10.1002/art.43269
reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Rapid onset cytokine storm with severe inflammation, anasarca, thrombocytopenia, and small volume lymphadenopathy, similar to hemophagocytic lymphohistiocytosis or sepsis, are the hallmarks of iMCD‐TAFRO."
explanation: Anasarca (which includes ascites) is identified as a hallmark feature of iMCD-TAFRO.
- category: Cardiovascular
name: Generalized Edema (Anasarca)
subtype: iMCD
notes: >-
Generalized edema/anasarca is a hallmark of iMCD-TAFRO.
phenotype_term:
preferred_term: Anasarca
term:
id: HP:0000969
label: Edema
evidence:
- reference: DOI:10.1002/art.43269
reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Rapid onset cytokine storm with severe inflammation, anasarca, thrombocytopenia, and small volume lymphadenopathy, similar to hemophagocytic lymphohistiocytosis or sepsis, are the hallmarks of iMCD‐TAFRO."
explanation: Anasarca is identified as a hallmark feature of iMCD-TAFRO.
- category: Renal
name: Renal Dysfunction
subtype: iMCD
notes: >-
Renal dysfunction/reticulin fibrosis is the "R" of iMCD-TAFRO; component
of the defining TAFRO pentad.
phenotype_term:
preferred_term: Renal insufficiency
term:
id: HP:0000083
label: Renal insufficiency
evidence:
- reference: DOI:10.1002/art.43269
reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The three subtypes are iMCD–thrombocytopenia, anasarca, fever, renal dysfunction/reticulin fibrosis, organomegaly (TAFRO); iMCD–idiopathic plasmacytic lymphadenopathy (IPL); and iMCD–not otherwise specified (NOS)."
explanation: Renal dysfunction/reticulin fibrosis is codified as the "R" component of the iMCD-TAFRO pentad.
histopathology:
- name: Angiofollicular Lymph Node Hyperplasia, Hyaline-Vascular Variant
description: >-
The hyaline-vascular histologic pattern predominates in UCD. Features
regressed/atretic germinal centers, penetrating radial "lollipop"
vessels with hyalinized walls, expanded "onion-skinning" mantle zones
of concentric small lymphocytes, and interfollicular vascular
proliferation. Plasmacytosis is minimal.
context: UCD
- name: Angiofollicular Lymph Node Hyperplasia, Plasma-Cell Variant
description: >-
Plasma-cell histologic variant predominates in MCD. Features
hyperplastic germinal centers, sheets of mature plasma cells in the
interfollicular zone, and increased interfollicular vascularity.
Mantle-zone onion-skinning is less prominent than in the
hyaline-vascular variant.
context: MCD
biochemical:
- name: Interleukin-6 (IL-6)
presence: Elevated
context: >-
Markedly elevated in MCD (both HHV-8+ and iMCD); typically normal in
UCD. IL-6 levels correlate with disease activity.
- name: C-Reactive Protein (CRP)
presence: Elevated
context: >-
Acute-phase reactant driven by IL-6 signaling. Elevated in MCD; useful
biomarker for disease activity and prognosis.
treatments:
- name: Surgical Resection
description: >-
Complete surgical resection is curative for unicentric Castleman
disease and is the standard first-line therapy for UCD.
treatment_term:
preferred_term: surgical procedure
term:
id: MAXO:0000004
label: surgical procedure
- name: Siltuximab
description: >-
Anti-IL-6 monoclonal antibody. FDA-approved first-line therapy across
all iMCD subtypes (TAFRO, IPL, NOS). Directly binds and neutralizes
human IL-6.
evidence:
- reference: DOI:10.1002/art.43269
reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The first‐line therapy for all subtypes of iMCD is siltuximab, an IL‐6 antagonist."
explanation: Establishes siltuximab as the cross-iMCD first-line therapy regardless of TAFRO/IPL/NOS subtyping.
treatment_term:
preferred_term: anti-IL-6 monoclonal antibody therapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: siltuximab
term:
id: NCIT:C61084
label: Siltuximab
- name: Tocilizumab
description: >-
Anti-IL-6-receptor monoclonal antibody. Approved in Japan for MCD;
recommended internationally as alternative when siltuximab is
unavailable.
treatment_term:
preferred_term: anti-IL-6 receptor monoclonal antibody therapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: tocilizumab
term:
id: NCIT:C84217
label: Tocilizumab
- name: Rituximab
description: >-
Anti-CD20 monoclonal antibody. First-line therapy for HHV-8-associated
MCD; depletes B cells that harbor HHV-8.
evidence:
- reference: DOI:10.1182/blood.2019000931
reference_title: "Overview of Castleman disease"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The advent of effective retroviral therapy and use of rituximab in HHV8-MCD have improved outcomes in HHV8-MCD."
explanation: Authoritative Blood review establishes rituximab as outcome-improving therapy in HHV8+ MCD.
treatment_term:
preferred_term: rituximab therapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: rituximab
term:
id: NCIT:C1702
label: Rituximab
- name: Sirolimus
description: >-
mTOR inhibitor under investigation for previously-treated, anti-IL-6-
refractory or intolerant iMCD; a single-arm Phase II trial
(NCT03933904) targets oral sirolimus 12-month exposure with the
Clinical Benefit Response primary endpoint.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: sirolimus
term:
id: CHEBI:9168
label: sirolimus
- name: Ruxolitinib
description: >-
JAK1/2 inhibitor under investigation as second-line therapy in iMCD
patients refractory or intolerant to anti-IL-6 therapy; multicenter
Phase II trial NCT07085039 enrolling since 2025.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: ruxolitinib
term:
id: CHEBI:66919
label: ruxolitinib
clinical_trials:
- name: NCT03933904
phase: PHASE_II
status: UNKNOWN
description: >-
A Phase II, single-arm, open-label, multi-center study of sirolimus
in previously-treated idiopathic multicentric Castleman disease.
evidence:
- reference: clinicaltrials:NCT03933904
supports: SUPPORT
snippet: "The purpose of this study is to understand the impact of sirolimus on idiopathic multicentric Castleman disease."
explanation: ClinicalTrials.gov-listed Phase II trial evaluating sirolimus in previously-treated iMCD.
- name: NCT07085039
phase: PHASE_II
status: RECRUITING
description: >-
A Phase II, single-arm, open-label, multi-center study of
ruxolitinib in adults with iMCD that has not improved with
siltuximab or tocilizumab, or who cannot take those medications.
evidence:
- reference: clinicaltrials:NCT07085039
supports: SUPPORT
snippet: "The research study is being done to look at the effects of ruxolitinib in adults with idiopathic Multicentric Castleman Disease (iMCD) that has not gotten better from taking siltuximab or tocilizumab, or who cannot take those medications."
explanation: ClinicalTrials.gov-listed Phase II trial evaluating ruxolitinib as second-line therapy in iMCD.
datasets:
Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.
Please provide a comprehensive research report on Castleman Disease covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.
For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.
Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed
Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Search first: CTD, PubMed, PheGenI, GxE databases
Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC
For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities
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For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types
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Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease
This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details
Castleman disease (CD) is a rare, nonclonal lymphoproliferative disorder characterized by distinctive lymph node histopathology and heterogeneous clinical phenotypes ranging from localized lymphadenopathy to life-threatening systemic inflammatory disease. (kobrin2026castlemandisease pages 1-3, chen2025expertperspectivediagnosis pages 1-2)
A modern, clinically actionable framework classifies CD by anatomic distribution into: - Unicentric Castleman disease (UCD): single lymph node station/region involvement. (gasljevic2025themorphologicalspectrum pages 1-3, hoffmann2024theclinicalpicture pages 1-2) - Multicentric Castleman disease (MCD): ≥2 lymph node groups with systemic inflammation. (gasljevic2025themorphologicalspectrum pages 1-3, hoffmann2024theclinicalpicture pages 1-2)
MCD is further subdivided by etiology/association into: - HHV-8/KSHV–associated MCD (HHV8+ MCD) (often with HIV or immunosuppression). (hoffmann2024theclinicalpicture pages 1-2, jitaru2026snapshotlookat pages 3-4) - Idiopathic MCD (iMCD; HHV-8 negative), which is further clinically stratified into iMCD-TAFRO, iMCD-IPL, and iMCD-NOS. (chen2025expertperspectivediagnosis pages 1-2) - POEMS-associated MCD (MCD-POEMS) linked to a plasma cell neoplasm/POEMS syndrome. (hoffmann2024theclinicalpicture pages 1-2, chen2025expertperspectivediagnosis pages 1-2)
Not found in retrieved full-text excerpts: MONDO ID, MeSH ID, Orphanet ID, OMIM ID, ICD-11 code. The accessible literature excerpts reviewed here did not include these identifiers explicitly. (kobrin2026castlemandisease pages 1-3, dispenzieri2020overviewofcastleman pages 1-2, gasljevic2025themorphologicalspectrum pages 1-3, patel2024castlemandiseasea pages 1-2)
The retrieved excerpts consistently use “Castleman disease” and subtype labels (UCD, MCD, iMCD, TAFRO, IPL, POEMS-associated MCD). (hoffmann2024theclinicalpicture pages 1-2, chen2025expertperspectivediagnosis pages 1-2, gasljevic2025themorphologicalspectrum pages 1-3)
Not found verbatim in retrieved excerpts: “angiofollicular lymph node hyperplasia,” “giant lymph node hyperplasia.” (kobrin2026castlemandisease pages 1-3, dispenzieri2020overviewofcastleman pages 1-2, patel2024castlemandiseasea pages 1-2)
The content summarized below is derived from aggregated disease-level resources (systematic review/meta-analysis, expert perspective, registry natural history), plus real-world retrospective cohorts and ClinicalTrials.gov registry records, rather than single EHR-only observations. (hoffmann2024theclinicalpicture pages 1-2, chen2025expertperspectivediagnosis pages 1-2, bustamante2024longitudinalnaturalhistory pages 1-2, jitaru2024siltuximabinidiopathic pages 1-2, NCT03933904 chunk 1)
HHV-8–associated MCD: HHV-8 infection in B cells is a direct causal driver in HHV8+ MCD and is linked to production of viral IL-6 (vIL-6) and cytokine storm biology. (jitaru2026snapshotlookat pages 3-4, fraticelli2023aclinicalhistological pages 6-10)
iMCD and UCD: The etiology of UCD and iMCD is not established. A computational virome study using Viral-Track on RNA-seq data (UCD n=22; iMCD n=19; controls n=86) concluded that active viral infection is unlikely to be a shared pathological driver of UCD or iMCD. (miller2025noevidencefor pages 1-2)
Evidence in the retrieved excerpts supports immunocompromised states (e.g., HIV) as an association particularly for HHV8+ MCD, consistent with HHV-8 biology. (hoffmann2024theclinicalpicture pages 1-2, jitaru2026snapshotlookat pages 3-4)
Robust quantitative, population-level risk factor estimates (e.g., odds ratios for sex/age/exposures) were not present in the accessible excerpts.
No specific genetic or environmental protective factors were identified in the retrieved excerpts.
Direct gene–environment interaction evidence is not provided in the accessible excerpts. However, the HHV-8 subtype illustrates a biologically plausible interaction between viral infection and host immune suppression in driving cytokine storm phenotypes. (jitaru2026snapshotlookat pages 3-4, fraticelli2023aclinicalhistological pages 6-10)
Systemic inflammatory phenotype (MCD/iMCD): MCD is described as systemic and potentially life-threatening with multifocal lymphadenopathy and systemic inflammation/constitutional symptoms; HHV8+ MCD is often more aggressive than iMCD. (hoffmann2024theclinicalpicture pages 1-2)
iMCD-TAFRO phenotype: Hallmarks include rapid-onset cytokine storm with anasarca, thrombocytopenia, and renal dysfunction/reticulin fibrosis, often resembling sepsis or HLH. (chen2025expertperspectivediagnosis pages 1-2)
iMCD-IPL phenotype: Presents with subacute/chronic lymphadenopathy, anemia of inflammation, polyclonal hypergammaglobulinemia, sometimes with increased IgG4 in serum and lymph node tissue; can be difficult to distinguish from IgG4-related disease. (chen2025expertperspectivediagnosis pages 1-2)
A 2024 systematic review/meta-analysis quantified frequencies of iMCD criteria and features across subtypes (UCD, iMCD, HHV8+ MCD), including lab abnormalities (e.g., CRP elevation, anemia, hypoalbuminemia, thrombocytopenia, hypergammaglobulinemia) and clinical symptoms (e.g., constitutional symptoms, splenomegaly, fluid accumulation). (hoffmann2024theclinicalpicture pages 1-2, hoffmann2024theclinicalpicture media e3e1d910, hoffmann2024theclinicalpicture media 14015b06)
iMCD subtype CT differences (Dec 2024): In a 20-patient iMCD CT study, compared with non-TAFRO iMCD, iMCD-TAFRO had higher frequencies of ascites (100% vs 37.5%), gallbladder wall edema (75.0% vs 12.5%), periportal collar (91.7% vs 25.0%), and anterior mediastinal infiltrative lesions (66.7% vs 12.5%). (iguchi2024computedtomographyfindings pages 1-2)
UCD ultrasound phenotype (Sep 2025): In 41 UCD patients, ultrasound frequencies included indistinct corticomedullary interface (95.12%), fatty hilum effacement (58.54%), macrocalcification (24.39%), and short linear hyperechoic foci (56.10%). (liu2025thesonographiccharacteristics pages 1-2)
A 2024 iMCD natural history analysis reported substantial morbidity and QOL impairment; QOL was assessed using EQ-5D-5L and a global health 0–100 scale, with symptom burden correlating inversely with QOL. (bustamante2024longitudinalnaturalhistory pages 6-7, bustamante2024longitudinalnaturalhistory pages 7-9)
(These HPO mappings are ontology suggestions to support KB standardization; they are not direct claims that each term is present in every patient.)
CD is generally considered nonclonal/nonmalignant rather than a monogenic disorder; however, multiple studies report somatic alterations and pathway perturbations, particularly in stromal compartments in UCD and inflammatory signaling in iMCD. (kobrin2026castlemandisease pages 1-3, fraticelli2023aclinicalhistological pages 6-10, smith2025spatialandsingle pages 1-2)
A 2025 pathology review on mimickers notes iMCD alterations in chromatin-organization genes (e.g., SETD1A, ASH1L, KMT2E, DNMT3A) and describes clonal cytogenetic changes/complex karyotypes in some hyaline vascular CD cases with chromosome 7 abnormalities. (zhang2025mimickersandassociated pages 1-3)
No robust environmental exposure or lifestyle risk/protective factor evidence was present in the retrieved excerpts.
A widely supported causal chain for multicentric/systemic forms is: 1) Trigger (HHV-8 infection for HHV8+ MCD; unknown triggers for iMCD) → 2) Cytokine dysregulation (IL-6 and other inflammatory/angiogenic mediators, including VEGF) → 3) Systemic inflammation and vascular permeability (anasarca/effusions/ascites, cytopenias, organ dysfunction) → 4) Clinical syndrome ranging from chronic inflammatory illness to critical cytokine storm (notably iMCD-TAFRO). (chen2025expertperspectivediagnosis pages 1-2, nishikori2024transcriptomeanalysisof pages 1-2, iguchi2024computedtomographyfindings pages 1-2)
A major recent advance is a 2025 Nature Communications integrated spatial proteome/transcriptome and single-nucleus RNA-seq study across UCD, iMCD, HHV8+ MCD, and reactive nodes. It concluded that CD shows expanded stromal populations and identified stromal subsets as major sources of IL-6/VEGF signaling: - CXCL13+ follicular dendritic cells (FDCs) - PDGFRA+ T-zone reticular cells (TRCs) - ACTA2+ perivascular reticular cells (PRCs) These stromal programs were linked to B-cell activation/differentiation, neovascularization, and stromal remodeling, with inferred activation of JAK–STAT, TGFβ, and MAPK signaling via ligand–receptor interactions. (smith2025spatialandsingle pages 1-2, smith2025spatialandsingle pages 6-8, smith2025spatialandsingle pages 6-6)
(These ontology mappings support KB structure; cell types and pathways are supported by single-cell/spatial evidence above.) (smith2025spatialandsingle pages 1-2, smith2025spatialandsingle pages 6-8)
iMCD ranges from moderate chronic inflammatory disease to acute, life-threatening cytokine storm. iMCD-TAFRO is characterized by rapid onset severe inflammation and can resemble sepsis/HLH. (chen2025expertperspectivediagnosis pages 1-2)
Registry-based natural history data indicate significant ongoing disease burden with defined flare dynamics; notably, iMCD-NOS patients spent a higher proportion of follow-up time in flare than iMCD-TAFRO (median 52.3% vs 18.9%). (bustamante2024longitudinalnaturalhistory pages 6-7)
Quantitative prevalence/incidence estimates were not present in the accessible excerpts. However, iMCD burden and outcome statistics from registry analyses and cohorts provide clinically relevant population-level context for severity and mortality risk. (bustamante2024longitudinalnaturalhistory pages 1-2)
CD is not typically inherited as a Mendelian trait, but rare germline predisposition has been reported in referenced literature (e.g., germline FAS mutation in a family with UCD and iMCD). (fraticelli2023aclinicalhistological pages 51-53)
Diagnosis requires lymph node histopathology integrated with clinical/laboratory findings and exclusion of mimics (autoimmune disease, infections, lymphoma, POEMS, etc.). (gasljevic2025themorphologicalspectrum pages 1-3, hoffmann2024theclinicalpicture pages 1-2, chen2025expertperspectivediagnosis pages 1-2)
For iMCD specifically, the 2017 international consensus criteria require: - Major criteria: multicentric lymphadenopathy and Castleman-consistent lymph node histopathology - Plus minor criteria and exclusion criteria. (hoffmann2024theclinicalpicture pages 1-2)
Expert guidance recommends cross-sectional imaging (CT neck-to-pelvis or PET-CT) and emphasizes obtaining an excisional lymph node biopsy when possible; fine-needle aspiration is discouraged and core biopsies can have low yield. (chen2025expertperspectivediagnosis pages 6-7)
A 2024 case report provides a direct, implementation-oriented statement on PET for biopsy targeting: “A PET scan allowed the best selection of a lymph node to be biopsied” after an initial non-diagnostic biopsy, enabling diagnosis of iMCD. (bitektine2024thevalueof pages 1-2)
A 2024 systematic review/meta-analysis synthesized frequencies of minor criteria/lab abnormalities (e.g., CRP elevation, anemia, hypoalbuminemia, thrombocytopenia, hypergammaglobulinemia) across subtypes; see Figures 3–4 in the paper. (hoffmann2024theclinicalpicture pages 1-2, hoffmann2024theclinicalpicture media e3e1d910, hoffmann2024theclinicalpicture media 14015b06)
In a 2024 longitudinal registry study, iMCD patients frequently required life-sustaining interventions during hospitalization (dialysis 27%; mechanical ventilation 17%), and post-diagnosis morbidities included acute renal failure (48%) and chronic kidney disease (15.7%). (bustamante2024longitudinalnaturalhistory pages 6-7)
In a 2024 retroperitoneal UCD surgical series (n=15), there were no perioperative deaths and no deaths or recurrences over a median follow-up of 78.5 months, supporting excellent long-term outcomes with complete resection in that anatomical context. (gao2024clinicalfeaturesand pages 1-2)
UCD: Primary treatment is typically complete surgical excision, often curative. (kobrin2026castlemandisease pages 1-3, gao2024clinicalfeaturesand pages 1-2)
iMCD: First-line therapy is IL-6 pathway inhibition, most prominently siltuximab (anti–IL-6); expert opinion frames IL-6 pathway inhibition as first-line for all iMCD subtypes. (chen2025expertperspectivediagnosis pages 1-2, jitaru2024siltuximabinidiopathic pages 1-2)
Tocilizumab (anti–IL-6R): used as an alternative option in some clinical contexts, including for HHV-8/KSHV-associated MCD in clinical trials and as an option discussed after siltuximab relapse/non-response in reviews. (jitaru2026snapshotlookat pages 8-9, NCT01441063 chunk 1)
Siltuximab real-world Europe (2017–2022; published Oct 2024): ORR 71.1% with 55.3% complete response; estimated 3-year OS ~74%; serious adverse events 16.7%. (jitaru2024siltuximabinidiopathic pages 1-2)
Siltuximab real-world China (Jul 2022–Mar 2024; published Apr 2025): ORR 59% at week 3 and 91% at week 12; in severe iMCD treated with siltuximab + bortezomib/cyclophosphamide/dexamethasone (BCD), ORR increased to 100% at week 12. (li2025realworlddataof pages 1-2, li2025realworlddataof pages 4-5)
Key ongoing/recent trials include: - Sirolimus (mTOR inhibitor) in previously treated iMCD: Phase II single-arm trial NCT03933904 (active, not recruiting). (NCT03933904 chunk 1) - Ruxolitinib (JAK1/2 inhibitor) in previously treated iMCD: Phase II trial NCT07085039 (recruiting; started 2025-12-18). (NCT07085039 chunk 1) - Tocilizumab for KSHV-associated MCD: Phase II pilot study NCT01441063 (completed; enrolled 8; tocilizumab 8 mg/kg q2 weeks up to 12 weeks; primary endpoint overall clinical benefit response). (NCT01441063 chunk 1) - Rituximab for KSHV-associated MCD in Malawi: Phase II trial NCT04585893 (active, not recruiting; rituximab 375 mg/m^2 weekly ×4; high-risk patients also received etoposide). (NCT04585893 chunk 1)
No established primary prevention strategy is supported in the retrieved excerpts. For HHV8+ MCD, prevention is indirectly related to management of HIV/immunosuppression and HHV-8 disease monitoring in relevant settings, but explicit prevention guidelines were not accessible in the excerpts used here.
No veterinary or cross-species naturally occurring Castleman disease evidence was identified in the retrieved excerpts.
While classic whole-animal models were not described in accessible excerpts, human-tissue multi-omic experimental systems represent a major “model” for mechanism discovery: - Single-nucleus RNA-seq and spatial transcriptomics/proteomics mapping of CD lymph nodes demonstrated stromal-cell programs and ligand–receptor networks driving IL-6/VEGF signaling and JAK–STAT/MAPK/TGFβ pathway signatures. (smith2025spatialandsingle pages 1-2, smith2025spatialandsingle pages 6-8)
| Subtype | Core definition | Typical triggers/associations | Hallmark clinical pattern | Hallmark pathology pattern | Key diagnostics/tests |
|---|---|---|---|---|---|
| Unicentric Castleman disease (UCD) | Localized Castleman disease involving a single lymph node station/region (hoffmann2024theclinicalpicture pages 1-2, chen2025expertperspectivediagnosis pages 1-2, gasljevic2025themorphologicalspectrum pages 1-3) | Usually no defined infectious trigger; may reflect localized stromal/FDC-related process rather than systemic cytokine disease (jitaru2026snapshotlookat pages 3-4, fraticelli2023aclinicalhistological pages 6-10) | Solitary, often indolent enlarged node or mass; minimal or no systemic inflammation in many cases (hoffmann2024theclinicalpicture pages 1-2, jitaru2026snapshotlookat pages 3-4, kobrin2026castlemandisease pages 1-3) | Most often hyaline vascular/hypervascular pattern with regressed germinal centers, onion-skin mantle zones, penetrating “lollipop” vessels, increased FDCs/vascularity (gasljevic2025themorphologicalspectrum pages 1-3) | Excisional lymph node biopsy with histopathology; CT/MRI/PET for localization and biopsy planning; exclude mimics such as lymphoma/infection (kobrin2026castlemandisease pages 1-3, chen2025expertperspectivediagnosis pages 6-7) |
| HHV-8–associated multicentric Castleman disease (HHV8+ MCD) | Multicentric systemic Castleman disease driven by KSHV/HHV-8 infection, typically involving multiple node groups (hoffmann2024theclinicalpicture pages 1-2, chen2025expertperspectivediagnosis pages 1-2, gasljevic2025themorphologicalspectrum pages 1-3) | HHV-8/KSHV infection; often associated with HIV or other immunocompromised states; viral IL-6 biology central (hoffmann2024theclinicalpicture pages 1-2, jitaru2026snapshotlookat pages 3-4) | Aggressive systemic inflammatory syndrome with multifocal lymphadenopathy, constitutional symptoms, organomegaly, cytokine-storm flares (hoffmann2024theclinicalpicture pages 1-2, jitaru2026snapshotlookat pages 3-4) | Usually plasmacytic or mixed Castleman histology with HHV-8–infected plasmablast/plasma-cell populations (jitaru2026snapshotlookat pages 3-4, fraticelli2023aclinicalhistological pages 6-10) | Lymph node biopsy plus HHV-8 testing; HIV serology and HHV-8 qPCR are key adjuncts; exclude other inflammatory/neoplastic mimics (hoffmann2024theclinicalpicture pages 1-2, chen2025expertperspectivediagnosis pages 1-2) |
| Idiopathic multicentric Castleman disease (iMCD), NOS | HHV-8–negative multicentric Castleman disease diagnosed by characteristic histopathology + multicentric lymphadenopathy + minor criteria after exclusion of mimics; NOS if not meeting TAFRO/IPL patterns (hoffmann2024theclinicalpicture pages 1-2, chen2025expertperspectivediagnosis pages 1-2) | No established cause; IL-6-driven cytokine dysregulation common, but non-IL-6 pathways also implicated (chen2025expertperspectivediagnosis pages 1-2, nishikori2024transcriptomeanalysisof pages 1-2, miller2025noevidencefor pages 1-2) | Systemic inflammation with generalized lymphadenopathy; can mimic autoimmune disease or indolent lymphoma; variable anemia, constitutional symptoms, organomegaly (chen2025expertperspectivediagnosis pages 1-2, hoffmann2024theclinicalpicture pages 1-2) | Hypervascular, plasmacytic, or mixed patterns on lymph node biopsy (hoffmann2024theclinicalpicture pages 1-2, gasljevic2025themorphologicalspectrum pages 1-3) | Consensus diagnostic workup: excisional node biopsy, cross-sectional imaging/PET-CT, inflammatory labs, and exclusion of infections, autoimmune disease, lymphoma, and POEMS (hoffmann2024theclinicalpicture pages 1-2, chen2025expertperspectivediagnosis pages 6-7) |
| iMCD-TAFRO | Clinical subtype of iMCD marked by thrombocytopenia, anasarca, fever/elevated CRP, reticulin fibrosis or renal dysfunction, and organomegaly (chen2025expertperspectivediagnosis pages 1-2, kobrin2026castlemandisease pages 1-3) | Idiopathic cytokine storm phenotype; often severe/rapid-onset; may show broader inflammatory signaling beyond IL-6 (JAK-STAT/MAPK/VEGF-related) (nishikori2024transcriptomeanalysisof pages 1-2, kobrin2026castlemandisease pages 3-5) | Rapid-onset severe inflammation with anasarca, thrombocytopenia, renal dysfunction, small-volume lymphadenopathy; can resemble HLH or sepsis (chen2025expertperspectivediagnosis pages 1-2, chen2025expertperspectivediagnosis pages 6-7) | Castleman-like lymph node changes, often with increased vascularity and atrophic follicles; marrow may show reticulin fibrosis/megakaryocytic changes (alnoor2025theevolutionand pages 3-3) | Biopsy when feasible; CT/PET often shows ascites/effusions, periportal collar, anterior mediastinal lesions, mild-moderate FDG avidity; marrow exam may support diagnosis (chen2025expertperspectivediagnosis pages 6-7, iguchi2024computedtomographyfindings pages 1-2) |
| iMCD-IPL | iMCD subtype also called idiopathic plasmacytic lymphadenopathy, defined by plasmacytic iMCD phenotype with chronic inflammatory features (chen2025expertperspectivediagnosis pages 1-2, jitaru2026snapshotlookat pages 3-4) | HHV-8 negative; often strong humoral/IL-6-associated inflammatory phenotype, sometimes overlapping with IgG4-related disease clinically (chen2025expertperspectivediagnosis pages 1-2) | Subacute/chronic lymphadenopathy, anemia of inflammation, polyclonal hypergammaglobulinemia, often increased IgG4 in serum/node tissue (chen2025expertperspectivediagnosis pages 1-2) | Plasma cell/plasmacytic histologic pattern is typical (jitaru2026snapshotlookat pages 3-4) | Excisional biopsy, serum immunoglobulins/IgG subclasses, inflammatory markers, and careful exclusion of IgG4-related disease and histiocytic/lymphoid mimics (chen2025expertperspectivediagnosis pages 1-2, hoffmann2024theclinicalpicture pages 1-2) |
| POEMS-associated MCD | Multicentric Castleman disease occurring in association with POEMS syndrome/plasma-cell neoplasm rather than idiopathic or HHV-8-driven disease (hoffmann2024theclinicalpicture pages 1-2, chen2025expertperspectivediagnosis pages 1-2, gasljevic2025themorphologicalspectrum pages 1-3) | Associated with plasma cell dyscrasia and POEMS features; VEGF-related biology emphasized in POEMS context (patel2024castlemandiseasea pages 3-4, fraticelli2023aclinicalhistological pages 15-22) | Multicentric disease with Castleman pathology plus POEMS manifestations (especially neuropathy/endocrinopathy/monoclonal plasma-cell disorder) rather than isolated cytokine syndrome alone (chen2025expertperspectivediagnosis pages 1-2, fraticelli2023aclinicalhistological pages 15-22) | Commonly plasma-cell pattern on lymph node histology (jitaru2026snapshotlookat pages 3-4, fraticelli2023aclinicalhistological pages 15-22) | Diagnose Castleman pathology plus dedicated POEMS evaluation: serum/urine monoclonal protein studies, VEGF assessment where available, and clinical assessment for neuropathy/endocrinopathy/organomegaly/skin changes (hoffmann2024theclinicalpicture pages 1-2, chen2025expertperspectivediagnosis pages 1-2) |
Table: This table summarizes the major Castleman disease subtypes, how they are defined, their typical associations, hallmark clinicopathologic features, and the main diagnostic tests used to distinguish them. It is useful as a compact reference for subtype-aware diagnosis and knowledge base curation.
| Item | Population/subtype | Design & dates | Key quantitative outcomes | URL |
|---|---|---|---|---|
| iMCD natural history (Haematologica 2024) | 102 patients with idiopathic multicentric Castleman disease; 61 iMCD-TAFRO and 41 iMCD-NOS | Longitudinal natural history registry study; published Jan 2024; median follow-up ~3.4 years (bustamante2024longitudinalnaturalhistory pages 1-2, bustamante2024longitudinalnaturalhistory pages 4-6) | Hospitalization during year around diagnosis: TAFRO median 36 days vs NOS 0 days; dialysis 27%; mechanical ventilation 17%; acute renal failure 48%; anemia 85.3%; NOS spent more time in flare than TAFRO: 52.3% vs 18.9% (bustamante2024longitudinalnaturalhistory pages 6-7, bustamante2024longitudinalnaturalhistory pages 1-2, bustamante2024longitudinalnaturalhistory pages 7-9, bustamante2024longitudinalnaturalhistory pages 4-6) | https://doi.org/10.3324/haematol.2023.283603 |
| Siltuximab real-world Europe (J Hematol 2024) | 48 adults with iMCD in Greece and Romania | Retrospective real-world cohort, Jan 2017–Dec 2022; published Oct 2024 (jitaru2024siltuximabinidiopathic pages 1-2) | Median 9 cycles; overall response rate 71.1%; complete response 55.3%; partial response 15.8%; estimated 3-year overall survival 74%; median survival 123 months; serious adverse events 16.7% (jitaru2024siltuximabinidiopathic pages 1-2) | https://doi.org/10.14740/jh1343 |
| Siltuximab real-world China (Ann Hematol 2025) | 43 consecutive iMCD patients; 18 severe cases received siltuximab+BCD | Single-center retrospective study, Jul 2022–Mar 2024; published Apr 2025 (li2025realworlddataof pages 1-2, li2025realworlddataof pages 4-5) | ORR 59% at week 3 and 91% at week 12; week-12 complete response 54% and partial response 37%; first-line siltuximab predicted better response; severe iMCD with siltuximab+BCD had ORR 50% at week 3 and 100% at week 12; mostly mild adverse events (li2025realworlddataof pages 1-2, li2025realworlddataof pages 4-5) | https://doi.org/10.1007/s00277-025-06329-7 |
| UCD retroperitoneal surgery series (Front Surg 2024) | 15 patients with retroperitoneal unicentric Castleman disease | Single-center retrospective surgical series including cases treated through Dec 2022; published Sep 2024 (gao2024clinicalfeaturesand pages 1-2) | 73.3% male; 80% age <40 years; hyaline-vascular 66.7%, mixed 33.3%; serious complications 13.3%; no perioperative deaths; median follow-up 78.5 months; no deaths or recurrences (gao2024clinicalfeaturesand pages 1-2) | https://doi.org/10.3389/fsurg.2024.1371968 |
| iMCD subtype CT imaging (JCEH 2024) | 20 iMCD patients: 12 TAFRO, 5 IPL, 3 NOS | Single-center retrospective CT study; published Dec 2024 (iguchi2024computedtomographyfindings pages 1-2) | TAFRO vs non-TAFRO: ascites 100% vs 37.5%; gallbladder wall edema 75.0% vs 12.5%; periportal collar 91.7% vs 25.0%; anterior mediastinal infiltrative lesions 66.7% vs 12.5%; para-aortic edema 83.3% vs 37.5% (trend) (iguchi2024computedtomographyfindings pages 1-2) | https://doi.org/10.3960/jslrt.24053 |
| UCD ultrasound cohort (Cancer Imaging 2025) | 41 UCD patients | Single-center retrospective preoperative ultrasound cohort, Jan 2016–Mar 2024; published Sep 2025 (liu2025thesonographiccharacteristics pages 1-2) | 100% solitary well-defined enlarged nodes with increased cortical thickness; indistinct corticomedullary interface 95.12%; asymmetric cortical thickening 41.46%; fatty hilum effacement 58.54%; macrocalcification 24.39%; short linear hyperechoic foci 56.10%; abundant flow more frequent in HV and mixed lesions (75.86% and 87.50%) than PC-type (25%) (liu2025thesonographiccharacteristics pages 1-2) | https://doi.org/10.1186/s40644-025-00937-2 |
| Sirolimus trial NCT03933904 | Previously treated HHV-8-negative iMCD refractory/relapsed after or intolerant of anti–IL-6 therapy | Phase II, single-arm, open-label University of Pennsylvania trial; started 2019-09-25; active, not recruiting (NCT03933904 chunk 1, NCT03933904 chunk 2) | Actual enrollment 7; oral sirolimus for 12 months with target trough 10–15 ng/mL; primary endpoint is positive Clinical Benefit Response at ~12 months; secondary endpoints include CHAP score, symptom score, and modified Cheson radiologic response (NCT03933904 chunk 1, NCT03933904 chunk 2) | https://clinicaltrials.gov/study/NCT03933904 |
| Ruxolitinib trial NCT07085039 | Previously treated iMCD refractory/relapsed or intolerant to anti–IL-6 therapy | Phase II, single-arm, open-label, multicenter University of Pennsylvania trial; recruiting; start 2025-12-18; estimated primary completion 2028-07-31 (NCT07085039 chunk 1, NCT07085039 chunk 2) | Estimated enrollment 14; daily oral ruxolitinib up to 1 year; primary endpoint is positive Clinical Benefit Response at 12 months; secondary endpoints include CBR at 3/6/9 months, CHAP score, 34-item symptom score, modified Cheson response, treatment retention, and grade ≥3 adverse events/SAEs (NCT07085039 chunk 1, NCT07085039 chunk 2) | https://clinicaltrials.gov/study/NCT07085039 |
| Tocilizumab KSHV-MCD trial NCT01441063 | Symptomatic KSHV/HHV-8–associated multicentric Castleman disease, largely in HIV-infected adults | Phase II, open-label, single-center NCI pilot study; start 2011-09-13; primary completion 2018-06-06; completion 2020-10-05; completed (NCT01441063 chunk 2, NCT01441063 chunk 1) | Actual enrollment 8; tocilizumab 8 mg/kg every 2 weeks up to 12 weeks; inadequate responders could add zidovudine/valganciclovir; primary endpoint overall clinical benefit response; secondary endpoints included radiographic/biochemical response, safety, 4-month PFS and OS (NCT01441063 chunk 2, NCT01441063 chunk 1) | https://clinicaltrials.gov/study/NCT01441063 |
| Rituximab Malawi trial NCT04585893 | Pathologically confirmed KSHV-associated MCD in Malawi, HIV-positive or HIV-negative adults | Phase II, single-group interventional trial; start 2021-06-22; primary completion 2024-08-30; estimated completion 2026-06-07; active, not recruiting (NCT04585893 chunk 1, NCT04585893 chunk 2) | Enrollment 15; rituximab 375 mg/m^2 weekly ×4; high-risk patients also received etoposide 100 mg/m^2 weekly ×4; primary endpoint non-hematologic grade ≥3 adverse events through ~12 weeks; secondary endpoints include overall survival, event-free survival, response rates, QoL by PROMIS Global-10, Kaposi sarcoma exacerbation, and hemoglobin change (NCT04585893 chunk 1, NCT04585893 chunk 2) | https://clinicaltrials.gov/study/NCT04585893 |
Table: This table summarizes key 2024–2025 clinical studies and active or recent trials across Castleman disease subtypes, including natural history, imaging, surgery, and systemic therapies. It is useful for quickly comparing study populations, designs, major quantitative findings, and trial status.
References
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(NCT03933904 chunk 1): Sirolimus in Previously Treated Idiopathic Multicentric Castleman Disease. University of Pennsylvania. 2019. ClinicalTrials.gov Identifier: NCT03933904
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(iguchi2024computedtomographyfindings pages 1-2): Toshihiro Iguchi, Asami Nishikori, Yasuharu Sato, Midori Filiz Nishimura, Noriko Iwaki, Katsuhide Kojima, Takashi Asahara, Fumio Otsuka, Yoshinobu Maeda, and Takao Hiraki. Computed tomography findings of idiopathic multicentric castleman disease subtypes. Journal of Clinical and Experimental Hematopathology, 64:292-296, Dec 2024. URL: https://doi.org/10.3960/jslrt.24053, doi:10.3960/jslrt.24053. This article has 5 citations.
(liu2025thesonographiccharacteristics pages 1-2): Zihan Liu, Zihan Niu, Yuhan Gao, Mengsu Xiao, Ying Wang, Qingli Zhu, and Lu Zhang. The sonographic characteristics of unicentric castleman disease - a single-center retrospective study. Cancer Imaging, Sep 2025. URL: https://doi.org/10.1186/s40644-025-00937-2, doi:10.1186/s40644-025-00937-2. This article has 0 citations and is from a peer-reviewed journal.
(bustamante2024longitudinalnaturalhistory pages 6-7): Mateo Sarmiento Bustamante, Sheila K. Pierson, Yue Ren, Adam Bagg, Joshua D. Brandstadter, Gordan Srkalovic, Natalie Mango, Daisy Alapat, Mary Jo Lechowicz, Hongzhe Li, Frits Van Rhee, Megan S. Lim, and David C. Fajgenbaum. Longitudinal, natural history study reveals the disease burden of idiopathic multicentric castleman disease. Haematologica, 109:2196-2206, Jan 2024. URL: https://doi.org/10.3324/haematol.2023.283603, doi:10.3324/haematol.2023.283603. This article has 16 citations.
(bustamante2024longitudinalnaturalhistory pages 7-9): Mateo Sarmiento Bustamante, Sheila K. Pierson, Yue Ren, Adam Bagg, Joshua D. Brandstadter, Gordan Srkalovic, Natalie Mango, Daisy Alapat, Mary Jo Lechowicz, Hongzhe Li, Frits Van Rhee, Megan S. Lim, and David C. Fajgenbaum. Longitudinal, natural history study reveals the disease burden of idiopathic multicentric castleman disease. Haematologica, 109:2196-2206, Jan 2024. URL: https://doi.org/10.3324/haematol.2023.283603, doi:10.3324/haematol.2023.283603. This article has 16 citations.
(smith2025spatialandsingle pages 1-2): David Smith, Anna Eichinger, É. Fennell, Z. Xu-Monette, Andrew Rech, Julia Wang, E. Esteva, Arta Seyedian, Xiaoxu Yang, Mei Zhang, Dan Martinez, Kai Tan, Minjie Luo, Katherine J Young, Paul G Murray, Christopher Y Park, Boris Reizis, and Vinodh Pillai. Spatial and single cell mapping of castleman disease reveals key stromal cell types and cytokine pathways. Nature Communications, Jul 2025. URL: https://doi.org/10.1038/s41467-025-61214-1, doi:10.1038/s41467-025-61214-1. This article has 11 citations and is from a highest quality peer-reviewed journal.
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(sikora2025castlemandisease—stillmore pages 7-9): Mariusz Sikora, Nel Dąbrowska-Leonik, Piotr Buda, Beata Wolska-Kuśnierz, Karina Jahnz-Różyk, Małgorzata Pac, and Ewa Więsik-Szewczyk. Castleman disease—still more questions than answers: a case report and review of the literature. Journal of Clinical Medicine, 14:2799, Apr 2025. URL: https://doi.org/10.3390/jcm14082799, doi:10.3390/jcm14082799. This article has 2 citations.
(sikora2025castlemandisease—stillmore pages 12-14): Mariusz Sikora, Nel Dąbrowska-Leonik, Piotr Buda, Beata Wolska-Kuśnierz, Karina Jahnz-Różyk, Małgorzata Pac, and Ewa Więsik-Szewczyk. Castleman disease—still more questions than answers: a case report and review of the literature. Journal of Clinical Medicine, 14:2799, Apr 2025. URL: https://doi.org/10.3390/jcm14082799, doi:10.3390/jcm14082799. This article has 2 citations.
(jitaru2026snapshotlookat pages 8-9): Ciprian Jitaru, Natalia Zlampa, Delia Dima, Anca Bojan, Mihnea Zdrenghea, Laura Urian, David Kegyes, Anamaria Bancos, Maria Santa, Andrei Ivancuta, Bobe Petrushev, Madalina Nistor, Bogdan Tigu, Catalin Constantinescu, Bogdan Fetica, Maria Puiu, Mihai‐Stefan Muresan, and Ciprian Tomuleasa. Snapshot look at castleman disease. Journal of Cellular and Molecular Medicine, Feb 2026. URL: https://doi.org/10.1111/jcmm.70961, doi:10.1111/jcmm.70961. This article has 1 citations and is from a peer-reviewed journal.
(nishikori2024transcriptomeanalysisof pages 1-2): Asami Nishikori, Midori Filiz Nishimura, Shuta Tomida, Ryota Chijimatsu, Himawari Ueta, You Cheng Lai, Yuri Kawahara, Yudai Takeda, Sayaka Ochi, Tomoka Haratake, Daisuke Ennishi, Naoya Nakamura, Shuji Momose, and Yasuharu Sato. Transcriptome analysis of the cytokine storm-related genes among the subtypes of idiopathic multicentric castleman disease. Journal of Clinical and Experimental Hematopathology : JCEH, 64:297-306, Oct 2024. URL: https://doi.org/10.3960/jslrt.24061, doi:10.3960/jslrt.24061. This article has 4 citations.
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(smith2025spatialandsingle pages 6-6): David Smith, Anna Eichinger, É. Fennell, Z. Xu-Monette, Andrew Rech, Julia Wang, E. Esteva, Arta Seyedian, Xiaoxu Yang, Mei Zhang, Dan Martinez, Kai Tan, Minjie Luo, Katherine J Young, Paul G Murray, Christopher Y Park, Boris Reizis, and Vinodh Pillai. Spatial and single cell mapping of castleman disease reveals key stromal cell types and cytokine pathways. Nature Communications, Jul 2025. URL: https://doi.org/10.1038/s41467-025-61214-1, doi:10.1038/s41467-025-61214-1. This article has 11 citations and is from a highest quality peer-reviewed journal.
(bustamante2024longitudinalnaturalhistory pages 4-6): Mateo Sarmiento Bustamante, Sheila K. Pierson, Yue Ren, Adam Bagg, Joshua D. Brandstadter, Gordan Srkalovic, Natalie Mango, Daisy Alapat, Mary Jo Lechowicz, Hongzhe Li, Frits Van Rhee, Megan S. Lim, and David C. Fajgenbaum. Longitudinal, natural history study reveals the disease burden of idiopathic multicentric castleman disease. Haematologica, 109:2196-2206, Jan 2024. URL: https://doi.org/10.3324/haematol.2023.283603, doi:10.3324/haematol.2023.283603. This article has 16 citations.
(fraticelli2023aclinicalhistological pages 51-53): S Fraticelli. A clinical, histological and transcriptomic characterization of a selected series of castleman disease's cases. Unknown journal, 2023.
(chen2025expertperspectivediagnosis pages 6-7): Luke Y.C. Chen, Lu Zhang, and David C. Fajgenbaum. Expert perspective: diagnosis and treatment of castleman disease. Arthritis & rheumatology, Jun 2025. URL: https://doi.org/10.1002/art.43269, doi:10.1002/art.43269. This article has 25 citations and is from a highest quality peer-reviewed journal.
(bitektine2024thevalueof pages 1-2): Erica Bitektine, Hamila Hagh-Daoust, René P. Michel, Stephane Isnard, and Jean-Pierre Routy. The value of a pet scan in selecting the best lymph node to biopsy, and confirming the diagnosis of idiopathic multicentric castleman disease with hlh and ebv viremia in a previously healthy adult. European Journal of Case Reports in Internal Medicine, Nov 2024. URL: https://doi.org/10.12890/2024_004908, doi:10.12890/2024_004908. This article has 2 citations.
(gao2024clinicalfeaturesand pages 1-2): Haicheng Gao, Wenjie Li, Boyuan Zou, Shibo Liu, and Chengli Miao. Clinical features and outcomes of retroperitoneal unicentric castleman disease resected as sarcomas: insights from a high-volume sarcoma center. Frontiers in Surgery, Sep 2024. URL: https://doi.org/10.3389/fsurg.2024.1371968, doi:10.3389/fsurg.2024.1371968. This article has 0 citations.
(NCT01441063 chunk 1): Robert Yarchoan. Tocilizumab for KSHV-Associated Multicentric Castleman Disease. National Cancer Institute (NCI). 2011. ClinicalTrials.gov Identifier: NCT01441063
(li2025realworlddataof pages 1-2): Si-yuan Li, Yu-han Gao, Yue Dang, Long Chang, Kai-ni Shen, Hua-cong Cai, Dan-qing Zhao, Chong Wei, Jun Feng, Lu Zhang, and Jian Li. Real-world data of siltuximab for chinese patients with imcd: combination with bcd regimen as a potential approach for severe cases. Annals of Hematology, 104:1713-1720, Apr 2025. URL: https://doi.org/10.1007/s00277-025-06329-7, doi:10.1007/s00277-025-06329-7. This article has 8 citations and is from a peer-reviewed journal.
(li2025realworlddataof pages 4-5): Si-yuan Li, Yu-han Gao, Yue Dang, Long Chang, Kai-ni Shen, Hua-cong Cai, Dan-qing Zhao, Chong Wei, Jun Feng, Lu Zhang, and Jian Li. Real-world data of siltuximab for chinese patients with imcd: combination with bcd regimen as a potential approach for severe cases. Annals of Hematology, 104:1713-1720, Apr 2025. URL: https://doi.org/10.1007/s00277-025-06329-7, doi:10.1007/s00277-025-06329-7. This article has 8 citations and is from a peer-reviewed journal.
(NCT07085039 chunk 1): Ruxolitinib in Previously Treated Idiopathic Multicentric Castleman Disease. University of Pennsylvania. 2025. ClinicalTrials.gov Identifier: NCT07085039
(NCT04585893 chunk 1): Safety and Efficacy of Rituximab for Treatment of Multicentric Castleman Disease in Malawi. UNC Lineberger Comprehensive Cancer Center. 2021. ClinicalTrials.gov Identifier: NCT04585893
(kobrin2026castlemandisease pages 3-5): Dale M. Kobrin and D. Fajgenbaum. Castleman disease. Advances in Lymphatic Medicine, Mar 2026. URL: https://doi.org/10.5772/intechopen.1009424, doi:10.5772/intechopen.1009424. This article has 0 citations.
(alnoor2025theevolutionand pages 3-3): FNU Alnoor, Nicholas C. Spies, Jyoti Kumar, Peyman Samghabadi, Oscar Silva, Matt X. Luo, Karen M. Chisholm, Jingjing Zhang, Alexandra Rangel, David Ng, Peng Li, and Robert S. Ohgami. The evolution and recent advances in diagnostic criteria for idiopathic multicentric castleman disease. American Journal of Hematology, 100:2064-2073, Aug 2025. URL: https://doi.org/10.1002/ajh.70039, doi:10.1002/ajh.70039. This article has 3 citations and is from a domain leading peer-reviewed journal.
(patel2024castlemandiseasea pages 3-4): Jay P Patel, Deep P Patel, Trishul H Amin, Rushikesh K Dave, Daksh Hardaswani, Faizanali Saiyed, and Rushita J Goswami. Castleman disease: a rare lymphoproliferative disorder with diverse clinical presentation, diagnosis, and treatment approach. Cureus, Sep 2024. URL: https://doi.org/10.7759/cureus.69149, doi:10.7759/cureus.69149. This article has 5 citations.
(fraticelli2023aclinicalhistological pages 15-22): S Fraticelli. A clinical, histological and transcriptomic characterization of a selected series of castleman disease's cases. Unknown journal, 2023.
(NCT03933904 chunk 2): Sirolimus in Previously Treated Idiopathic Multicentric Castleman Disease. University of Pennsylvania. 2019. ClinicalTrials.gov Identifier: NCT03933904
(NCT07085039 chunk 2): Ruxolitinib in Previously Treated Idiopathic Multicentric Castleman Disease. University of Pennsylvania. 2025. ClinicalTrials.gov Identifier: NCT07085039
(NCT01441063 chunk 2): Robert Yarchoan. Tocilizumab for KSHV-Associated Multicentric Castleman Disease. National Cancer Institute (NCI). 2011. ClinicalTrials.gov Identifier: NCT01441063
(NCT04585893 chunk 2): Safety and Efficacy of Rituximab for Treatment of Multicentric Castleman Disease in Malawi. UNC Lineberger Comprehensive Cancer Center. 2021. ClinicalTrials.gov Identifier: NCT04585893