HHV-8-Associated Multicentric Castleman Disease

Complex Pathograph 12 Show in embeddings browser Castleman Disease Lymphoproliferative Disease Viral Infection

HHV-8-associated multicentric Castleman disease is the form of Castleman disease with a known cause: uncontrolled lytic replication of Kaposi sarcoma-associated herpesvirus (KSHV/HHV-8) in lymph node plasmablasts. The virus encodes a viral homolog of interleukin-6 (vIL-6) that engages gp130 directly, without needing the IL-6 receptor, so it bypasses the checkpoint that normally limits IL-6 signaling. Most cases occur in people living with HIV, though the disease also occurs in HIV-negative immunocompromised individuals. The course is remitting-relapsing, running as discrete attacks of lytic viral activity with intervening remission, and constitutional symptoms and splenomegaly are substantially more frequent than in idiopathic multicentric disease (98.6% versus 46.6%, and 89.2% versus 48.2%). Because the same uncontrolled infection also drives Kaposi sarcoma and KSHV-associated lymphoma, those malignancies frequently co-occur. First-line therapy is rituximab, which depletes the CD20-positive B cells harboring the virus and raised 5-year survival from 33% to 90%; antiretroviral therapy is given alongside for the underlying HIV infection.

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1
Mappings
6
Pathophys.
2
Histopath.
13
Phenotypes
2
Gaps
12
Pathograph
5
Medical Actions
2
Differentials
9
References
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Mappings

MONDO
MONDO:0019754 multicentric Castleman disease Not Yet Curated
skos:broadMatch MONDO MONDO: MISSING
MONDO has no class for the HHV-8-associated form, so this entry is cross-referenced to the multicentric Castleman disease parent rather than given a `disease_term` binding. broadMatch is used deliberately, not narrowMatch: MONDO:0019754 is the parent of both the HHV-8-associated and the idiopathic arms, so it is broader than this entry, and per CLAUDE.md only exactMatch and narrowMatch retire a mapped concept from the curation queue. Recording this as broadMatch keeps the anchor without claiming the parent concept as curated. A new-term request for a specific HHV-8-associated class is tracked as M1 in the Castleman split issue; rebind `disease_term` to that class when it exists and change this mapping to exactMatch.
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Discussions and Knowledge Gaps

2
What are the host genomic and molecular characteristics of HHV-8-associated MCD, which has been almost entirely left out of the sequencing studies done on unicentric and idiopathic Castleman disease?
KNOWLEDGE GAP OPEN gap_hhv8_mcd_molecular_characterization
Attached to
pathophysiology#HHV-8/KSHV Viral Pathogenesis pathophysiology#Plasma Cell / B Cell Proliferation
The recurrent somatic alleles reported in Castleman disease - PDGFRB, NCOA4, IL6ST - all come from unicentric and idiopathic series. The systematic review of Castleman molecular abnormalities notes a paucity of genetic studies for this subtype. That matters because it leaves open why only a minority of KSHV-infected, immunosuppressed people develop MCD at all, and whether host factors explain the variable rituximab response.
Proposed experiments
Paired host and viral sequencing across KSHV-infected controls
exp_hhv8_mcd_host_virus_paired_sequencing
Compare host exomes, lymph node spatial transcriptomes, and KSHV genomes between HHV-8-associated MCD, KSHV-infected people with Kaposi sarcoma but no MCD, and KSHV-infected asymptomatic carriers, matched for HIV status and CD4 count. Testing for host variants and viral strain features that segregate with the MCD phenotype is what would explain why only a minority of infected people develop it.
Would support
pathophysiology#HHV-8/KSHV Viral Pathogenesis
Supporting outcome
  • Host variants or viral strain features segregate with MCD and are absent from infected controls, nominating a susceptibility determinant.
Refuting outcome
  • MCD cases are indistinguishable from infected controls on host and viral genome, indicating the determinant is immunological or stochastic rather than genomic.
Show evidence (1 reference)
PMID:33804823 SUPPORT Human Clinical
"Interestingly, there is a paucity of genetic studies evaluating HHV-8 positive multicentric CD (HHV-8+ MCD) and POEMS-associated CD."
Names the coverage gap in a systematic review of the molecular literature.
Should rituximab be used first-line when Kaposi sarcoma co-exists with HHV-8-associated MCD, given reports that it worsens the sarcoma?
CONTROVERSY OPEN controversy_hhv8_rituximab_and_kaposi_sarcoma
Attached to
treatments#Rituximab phenotypes#Kaposi's Sarcoma
Rituximab transformed survival in this subtype and is the standard first-line therapy, but Kaposi sarcoma co-occurs frequently and its worsening on rituximab has been reported. The two conditions share a cause, so the patient who most needs B cell depletion for MCD may be the one in whom it is riskiest for KS. Combination approaches with liposomal doxorubicin, and lytic-gene-directed antiviral therapy, exist as alternatives, but the comparison has not been made in a randomized trial.
Show evidence (2 references)
DOI:10.3390/jcm14186563 SUPPORT Human Clinical
"We present four clinical cases, with concurrent KS and MCD, treated with chemotherapy and rituximab, with a satisfactory response."
Documents the concurrent presentation and a combined approach using chemotherapy together with rituximab.
PMID:21487108 SUPPORT Human Clinical
"These observations provide evidence that therapy designed to target cells with lytic KSHV replication has activity in KSHV-MCD."
Establishes lytic-gene-directed antiviral therapy as an alternative that does not deplete B cells.
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Pathophysiology

6
HHV-8/KSHV Viral Pathogenesis
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.
KSHV-infected plasmablast CL:0000980 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves KSHV-infected plasmablast, annotated with plasmablast (CL:0000980). CL:0000980 is a cell type from the Cell Ontology.
Viral process GO:0016032 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Viral process (GO:0016032). GO:0016032 is a biological process from the Gene Ontology. Lytic viral genome replication GO:0019079 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Lytic viral genome replication, annotated with viral genome replication (GO:0019079). GO:0019079 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
IL-6 / vIL-6 Overproduction
Kaposi's Sarcoma The same uncontrolled KSHV infection produces concurrent Kaposi sarcoma and KSHV-associated lymphoma in a substantial minority of patients.
Show evidence (3 references)
DOI:10.1038/s41598-025-85193-x SUPPORT Computational
"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."
Confirms HHV-8 as the etiologic driver of HHV8+ MCD specifically, while UCD and iMCD remain etiologically unexplained.
DOI:10.1038/s41598-025-85193-x SUPPORT Computational
"These results suggest that active viral infection is unlikely to be a pathological driver of UCD or iMCD."
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.
PMID:21487108 SUPPORT Human Clinical
"It is characterized by KSHV-infected plasmablasts that frequently express lytic genes."
Identifies the lytically infected plasmablast as the cell carrying the viral program in this subtype.
IL-6 / vIL-6 Overproduction
Lytically infected plasmablasts produce a viral IL-6 homolog (vIL-6) that signals through gp130 independently of the IL-6 receptor, bypassing the checkpoint that normally limits IL-6 signaling. Human IL-6 and IL-10 are also elevated, so the hypercytokinemia is a mixture of viral and host cytokine, and both fall when lytic replication is suppressed. This is the one Castleman subtype in which the source of the cytokine excess is known.
Plasma cell CL:0000786 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Plasma cell (CL:0000786). CL:0000786 is a cell type from the Cell Ontology. Vascular endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Vascular endothelial cell, annotated with endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology.
Interleukin-6 production GO:0032635 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Interleukin-6 production (GO:0032635). GO:0032635 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
JAK-STAT3 Signaling Activation
Show evidence (2 references)
DOI:10.1002/art.43269 SUPPORT Human Clinical
"Although they are all driven by excessive cytokines such as interleukin‐6 (IL‐6)"
Expert-perspective review identifies excess IL-6 as the shared driver of the multicentric forms of CD (the "they" of the quoted sentence are the MCD subtypes, of which this entry is one); IL-6 is typically normal in unicentric disease, so the quote does not establish an all-subtype claim.
PMID:21487108 SUPPORT Human Clinical
"Patients manifest inflammatory symptoms attributed to overproduction of KSHV viral IL-6, human IL-6, and human IL-6."
Attributes the inflammatory syndrome to combined viral and human cytokine overproduction. The quoted sentence repeats "human IL-6" verbatim as published; the repetition is an error in the source abstract, and the snippet is not corrected here because it must remain an exact quote.
JAK-STAT3 Signaling Activation
vIL-6 and human IL-6 both engage gp130 and activate downstream JAK kinases and STAT3 transcription factor signaling. vIL-6 does so without the IL-6 receptor, which is why anti-IL-6-receptor blockade is a poorer fit for this subtype than for the idiopathic forms, and why first-line therapy here targets the infected B cell rather than the cytokine.
Interleukin-6-mediated signaling pathway GO:0070102 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Interleukin-6-mediated signaling pathway (GO:0070102). GO:0070102 is a biological process from the Gene Ontology. ↑ INCREASED JAK-STAT signaling GO:0007259 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased JAK-STAT signaling, annotated with cell surface receptor signaling pathway via JAK-STAT (GO:0007259). GO:0007259 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Plasma Cell / B Cell Proliferation
Plasma Cell / B Cell Proliferation
JAK-STAT3 signaling drives proliferation of B cells and plasma cells within affected lymph nodes. In this subtype the expanding plasmablasts are themselves KSHV-infected and frequently express lytic viral genes, which is what makes them targetable both by anti-CD20 antibody and by lytic-gene-activated antiviral therapy.
B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology. Plasma cell CL:0000786 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Plasma cell (CL:0000786). CL:0000786 is a cell type from the Cell Ontology. Plasmablast CL:0000980 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Plasmablast (CL:0000980). CL:0000980 is a cell type from the Cell Ontology.
B cell proliferation GO:0042100 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased B cell proliferation (GO:0042100). GO:0042100 is a biological process from the Gene Ontology. ↑ INCREASED Immunoglobulin production GO:0002377 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Immunoglobulin production (GO:0002377). GO:0002377 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Angiofollicular Lymph Node Hyperplasia
Show evidence (1 reference)
PMID:21487108 SUPPORT Human Clinical
"It is characterized by KSHV-infected plasmablasts that frequently express lytic genes."
Identifies the infected plasmablast as the proliferating cell in this subtype.
Hepatic Acute-Phase Response
IL-6 and vIL-6 signaling reprogrammes hepatic protein synthesis: C-reactive protein is induced, albumin synthesis falls, and hepcidin induction restricts iron availability. Kept separate from the B-lineage arm because it acts on a different cell lineage with a different clinical read-out. C-reactive protein, albumin and platelet count all improve together when lytic viral replication is suppressed.
Hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
Acute-phase response GO:0006953 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Acute-phase response (GO:0006953). GO:0006953 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Anemia Hepcidin induction and the acute-phase response produce the anemia of inflammation.
Hypoalbuminemia Reprioritized hepatic protein synthesis during the acute-phase response lowers serum albumin.
Show evidence (1 reference)
PMID:21487108 SUPPORT Human Clinical
"At the time of best response, the patients showed significant improvements in C-reactive protein, albumin, platelets, human IL-6, IL-10, and KSHV viral load."
Shows the acute-phase outputs of this node reversing when lytic viral replication is suppressed.
Angiofollicular Lymph Node Hyperplasia
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.
Plasma cell CL:0000786 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Plasma cell (CL:0000786). CL:0000786 is a cell type from the Cell Ontology. Follicular dendritic cell CL:0000442 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Follicular dendritic cell (CL:0000442). CL:0000442 is a cell type from the Cell Ontology.
Angiogenesis GO:0001525 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Angiogenesis (GO:0001525). GO:0001525 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Generalized Lymphadenopathy
✶

Histopathology

2
Angiofollicular Lymph Node Hyperplasia, Plasma-Cell Variant
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. This is the pattern associated with iMCD-IPL and with polyclonal hypergammaglobulinemia.
Mixed Histopathologic Variant
Nodes carrying features of both the hyaline-vascular and plasma-cell patterns. In the ACCELERATE registry the histopathologic distribution across 102 adjudicated iMCD cases was hypervascular/hyaline vascular 61.8%, mixed 26.5%, and plasmacytic 6.9%; TAFRO cases were predominantly hypervascular and none were plasmacytic. The clinical significance of the histopathologic subtype is not established.
Show evidence (1 reference)
PMID:36433996 SUPPORT Human Clinical
"Patients are also classified according to histopathologic subtype, including hyaline vascular/hypervascular, plasmacytic, or mixed, though the clinical implications of defining histopathologic subtype is unclear."
States both the three-way histopathologic classification and that its clinical meaning is unresolved.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for HHV-8-Associated Multicentric Castleman Disease Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

13
Blood 1
Anemia VERY_FREQUENT HP:0001903 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anemia (HP:0001903). HP:0001903 is a phenotype from the Human Phenotype Ontology.
Anemia of inflammation, driven by the same IL-6 axis as the acute-phase response, and one of the parameters that improves when lytic replication is suppressed.
Show evidence (1 reference)
DOI:10.3324/haematol.2023.283603 SUPPORT Human Clinical
"Eighty-seven (85.3%) patients had anemia and 81 (79.4%) had hypoalbuminemia at diagnosis"
Gives the anemia frequency at diagnosis in a 102-patient adjudicated iMCD cohort.
Cardiovascular 2
Generalized Lymphadenopathy HP:0008940 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Generalized lymphadenopathy (HP:0008940). HP:0008940 is a phenotype from the Human Phenotype Ontology.
Multiple enlarged lymph node regions, which is what makes the disease multicentric. Nodes are typically bulkier than in iMCD-TAFRO and enlarge during a flare of lytic viral activity.
Show evidence (1 reference)
DOI:10.1002/art.43269 SUPPORT Human Clinical
"Unicentric CD (UCD) involves one enlarged lymph node region, whereas multicentric CD (MCD) involves multiple enlarged lymph node regions."
Lymphadenopathy is the defining clinical feature of CD; localized in UCD and generalized in MCD.
Splenomegaly FREQUENT HP:0001744 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Splenomegaly (HP:0001744). HP:0001744 is a phenotype from the Human Phenotype Ontology.
Present in 89.2% of HHV8+ MCD patients versus 48.2% of iMCD by meta-analysis - one of the two features that most sharply separates this subtype from the idiopathic form.
Show evidence (2 references)
DOI:10.1182/bloodadvances.2024013548 SUPPORT Human Clinical
"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)"
Meta-analysis quantifies splenomegaly frequencies at 48.2% in iMCD and 89.2% in HHV8+ MCD.
DOI:10.3324/haematol.2023.283603 SUPPORT Human Clinical
"A large majority of patients presented with fluid retention (84%), splenomegaly (72%), and/or hepatomegaly (60%)."
Independent registry frequency for splenomegaly at iMCD diagnosis.
Digestive 1
Hepatomegaly FREQUENT HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Part of the organomegaly that accompanies splenomegaly during an attack.
Show evidence (1 reference)
DOI:10.3324/haematol.2023.283603 SUPPORT Human Clinical
"A large majority of patients presented with fluid retention (84%), splenomegaly (72%), and/or hepatomegaly (60%)."
Gives the hepatomegaly frequency at iMCD diagnosis.
Genitourinary 1
Renal Dysfunction FREQUENT Renal insufficiency HP:0000083 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal insufficiency (HP:0000083). HP:0000083 is a phenotype from the Human Phenotype Ontology.
Reported in 17.4% of HHV8+ MCD versus 36.9% of iMCD by meta-analysis. Renal involvement is therefore real but substantially less frequent here than in the idiopathic form.
Show evidence (1 reference)
DOI:10.1182/bloodadvances.2024013548 SUPPORT Human Clinical
"Renal dysfunction was significantly more common in patients with iMCD than in patients with HHV8+ MCD before adjustment (36.9% vs 17.4%; P = .04; adjusted P = .1)."
Quantifies the iMCD/HHV8+ difference in renal dysfunction, and records that the difference did not survive multiplicity adjustment.
Integument 1
Kaposi's Sarcoma HP:0100726 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Kaposi sarcoma, annotated with Kaposi's sarcoma (HP:0100726). HP:0100726 is a phenotype from the Human Phenotype Ontology.
Kaposi sarcoma and KSHV-associated lymphoma arise from the same uncontrolled KSHV infection that drives HHV-8+ MCD and frequently co-occur with it. In a 61-patient HIV-associated MCD cohort, 7% had histologic evidence of coexisting lymphoma at MCD diagnosis, with an incidence of 28 lymphomas per 1,000 patient-years.
Show evidence (3 references)
DOI:10.3390/jcm14186563 SUPPORT Human Clinical
"Castleman disease and Kaposi sarcoma (KS) are both associated with infection by human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV). This virus plays a critical role in the pathogenesis of both conditions, particularly in immunocompromised individuals, such..."
Establishes the shared HHV-8 etiology that makes Kaposi sarcoma a co-occurring feature of this subtype rather than an unrelated comorbidity.
DOI:10.3390/jcm14186563 SUPPORT Human Clinical
"We present four clinical cases, with concurrent KS and MCD, treated with chemotherapy and rituximab, with a satisfactory response."
Documents concurrent Kaposi sarcoma and MCD in the same patients.
PMID:21555697 SUPPORT Human Clinical
"Four patients (7%) had histologic evidence of coexisting lymphoma, and one developed lymphoma 2 years after treatment. The incidence of lymphoma is 28 per 1,000 patient years."
Quantifies the concurrent KSHV-driven malignancy risk in HIV-associated MCD. Note this quote reports lymphoma specifically, not Kaposi sarcoma.
Metabolism 4
Fever VERY_FREQUENT Recurrent fever HP:0001954 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent fever (HP:0001954). HP:0001954 is a phenotype from the Human Phenotype Ontology.
Near-universal in this subtype: constitutional symptoms were present in 98.6% of HHV8+ MCD patients versus 46.6% of iMCD in a 1,998-patient meta-analysis. Fever tracks flares of lytic viral replication.
Show evidence (1 reference)
DOI:10.1182/bloodadvances.2024013548 SUPPORT INDIRECT Human Clinical
"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)"
Meta-analysis quantifies constitutional symptoms (including fever) as substantially more frequent in HHV8+ MCD than iMCD.
Hypoalbuminemia VERY_FREQUENT HP:0003073 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoalbuminemia (HP:0003073). HP:0003073 is a phenotype from the Human Phenotype Ontology.
Reflects the reprioritized hepatic protein synthesis of a sustained acute-phase response. Albumin improves alongside CRP and platelet count when lytic viral replication is suppressed.
Show evidence (1 reference)
DOI:10.3324/haematol.2023.283603 SUPPORT Human Clinical
"Eighty-seven (85.3%) patients had anemia and 81 (79.4%) had hypoalbuminemia at diagnosis"
Gives the hypoalbuminemia frequency at diagnosis in the same adjudicated iMCD cohort.
Elevated C-Reactive Protein Elevated circulating C-reactive protein concentration HP:0011227 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated C-reactive protein, annotated with Elevated circulating C-reactive protein concentration (HP:0011227). HP:0011227 is a phenotype from the Human Phenotype Ontology.
The routine marker used to follow attack activity and treatment response in this subtype, alongside plasma KSHV viral load.
Show evidence (1 reference)
DOI:10.1182/bloodadvances.2022007112 SUPPORT Human Clinical
"the median time to normalization of abnormal laboratory tests and clinical end points occurred in the following sequence: thrombocytosis, symptomatic response, elevated C-reactive protein, hypoalbuminemia, anemia, lymph node response, hyperfibrinogenemia, and elevated immunoglobulin G"
Post hoc analysis of the siltuximab trial confirms elevated CRP as one of the tracked abnormalities and places it early in the normalization sequence.
Elevated Erythrocyte Sedimentation Rate HP:0003565 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated erythrocyte sedimentation rate (HP:0003565). HP:0003565 is a phenotype from the Human Phenotype Ontology.
Constitutional 2
Night Sweats HP:0030166 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Night sweats (HP:0030166). HP:0030166 is a phenotype from the Human Phenotype Ontology.
Fatigue HP:0012378 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fatigue (HP:0012378). HP:0012378 is a phenotype from the Human Phenotype Ontology.
Growth 1
Weight Loss HP:0001824 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Weight loss (HP:0001824). HP:0001824 is a phenotype from the Human Phenotype Ontology.
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Medical Actions

5
Rituximab
Action: rituximab therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is rituximab therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: rituximab NCIT:C1702 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses rituximab (NCIT:C1702). NCIT:C1702 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
Anti-CD20 monoclonal antibody and the first-line therapy for this subtype. It depletes the CD20-positive B cells that harbor KSHV, removing the reservoir producing vIL-6. Introduction of rituximab-based treatment raised 5-year overall survival in HIV-associated MCD from 33% to 90%. Relapse occurs in a minority at a median of two years and has been successfully re-treated. Two studies reported worsening of concurrent Kaposi sarcoma on rituximab, so co-existing KS influences the choice of regimen.
Mechanism Target:
INHIBITS HHV-8/KSHV Viral Pathogenesis — Depletes the CD20-positive B cell compartment that harbors KSHV, removing the reservoir producing vIL-6.
Show evidence (3 references)
DOI:10.1182/blood.2019000931 SUPPORT Human Clinical
"The advent of effective retroviral therapy and use of rituximab in HHV8-MCD have improved outcomes in HHV8-MCD."
Authoritative Blood review establishes rituximab as outcome-improving therapy in HHV8+ MCD.
PMID:21555697 SUPPORT Human Clinical
"With rituximab-based treatment, the overall survival was 94% (95% CI, 87% to 100%) at 2 years and was 90% (95% CI, 81% to 100%) at 5 years compared with 42% (95% CI, 14% to 70%) and 33% (95% CI, 6% to 60%) in 12 patients treated before introduction of rituximab (log-rank P < .001)."
Quantifies the survival improvement attributed to rituximab in HIV-associated MCD.
PMID:21555697 SUPPORT Human Clinical
"Eight of 46 patients who achieved clinical remission suffered symptomatic, histologically confirmed MCD relapse. The median time to relapse was 2 years, and all have been successfully re-treated and are alive in remission."
Supports the relapse rate and its treatability described here.
High-Dose Zidovudine plus Valganciclovir
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: zidovudine NCIT:C947 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses zidovudine (NCIT:C947). NCIT:C947 is a therapeutic agent from the NCI Thesaurus. valganciclovir NCIT:C2629 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses valganciclovir (NCIT:C2629). NCIT:C2629 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Virus-activated cytotoxic therapy for KSHV-associated MCD. The KSHV lytic genes ORF36 and ORF21 phosphorylate ganciclovir and zidovudine to toxic moieties, so the drug pair is selectively activated inside lytically infected cells. In a 14-patient pilot, 86% attained major clinical responses with 12-month overall survival of 86%; median progression-free survival was 6 months and the main toxicity was hematologic.
Mechanism Target:
INHIBITS HHV-8/KSHV Viral Pathogenesis — Exploits the lytic viral kinases to generate cytotoxic metabolites inside KSHV-infected plasmablasts.
Show evidence (2 references)
PMID:21487108 SUPPORT Human Clinical
"We investigated an approach targeting 2 KSHV lytic genes, ORF36 and ORF21, the protein of which, respectively, phosphorylate ganciclovir and zidovudine to toxic moieties."
States the lytic-gene-activated mechanism described here.
PMID:21487108 SUPPORT Human Clinical
"A total of 86% of patients attained major clinical responses and 50% attained major biochemical responses."
Gives the pilot-study response rates quoted in the description.
Antiretroviral Therapy
Action: antiretroviral therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is antiretroviral therapy (NCIT:C94631). NCIT:C94631 is a clinical intervention from the NCI Thesaurus. Ontology label: Antiretroviral Therapy NCIT:C94631
Platform: Small molecule
Effective antiretroviral therapy is given for the underlying HIV infection in HIV-associated HHV-8+ MCD and is credited alongside rituximab with the improvement in outcomes for this subtype. It does not by itself control an MCD attack.
Show evidence (1 reference)
DOI:10.1182/blood.2019000931 SUPPORT Human Clinical
"The advent of effective retroviral therapy and use of rituximab in HHV8-MCD have improved outcomes in HHV8-MCD."
Attributes the outcome improvement jointly to antiretroviral therapy and rituximab.
Corticosteroids
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: corticosteroid CHEBI:50858 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses corticosteroid (CHEBI:50858). CHEBI:50858 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Used as an adjunct alongside rituximab-based therapy for symptom control during an attack. Corticosteroids are not disease-modifying here: the disease is driven by uncontrolled lytic viral replication, which steroids do not address, and prolonged immunosuppression is undesirable in a population that is usually HIV co-infected.
Show evidence (1 reference)
PMID:21555697 SUPPORT INDIRECT Human Clinical
"Since 2003, 49 patients with newly diagnosed MCD have been treated with rituximab with (n = 14) or without (n = 35) etoposide."
Shows that the regimens that changed outcomes in this subtype are rituximab-based rather than steroid-based. The quote does not itself address corticosteroids; their secondary role is inferred from their absence in the cohort's treatment description.
Combination Cytotoxic Chemotherapy
Action: chemotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is chemotherapy (NCIT:C15632). NCIT:C15632 is a clinical intervention from the NCI Thesaurus. Ontology label: Chemotherapy NCIT:C15632
Platform: Small molecule
Cytotoxic chemotherapy is added to rituximab in severe disease, most often as etoposide, and liposomal doxorubicin is used where Kaposi sarcoma co-exists. In the reference cohort, 14 of 49 rituximab-treated patients received etoposide alongside the antibody.
Show evidence (1 reference)
PMID:21555697 SUPPORT Human Clinical
"Since 2003, 49 patients with newly diagnosed MCD have been treated with rituximab with (n = 14) or without (n = 35) etoposide."
Documents the addition of etoposide to rituximab in this cohort.
🔬

Biochemical Markers

3
Interleukin-6 (IL-6) (Elevated)
Context: Both viral IL-6 and human IL-6 are elevated during an attack, and human IL-6 falls significantly when lytic viral replication is suppressed. Routine clinical IL-6 assays do not distinguish the viral homolog from the host cytokine, so a measured "IL-6" here is a composite of the two.
Show evidence (1 reference)
PMID:21487108 SUPPORT Human Clinical
"At the time of best response, the patients showed significant improvements in C-reactive protein, albumin, platelets, human IL-6, IL-10, and KSHV viral load."
Shows human IL-6 is elevated and falls with lytic-directed therapy, tying the cytokine to viral replication in this subtype.
C-Reactive Protein (CRP) (Elevated)
Context: Acute-phase reactant driven by IL-6 and vIL-6 signaling. Rises during an attack and falls with effective antiviral or anti-CD20 therapy, so it is the routine bedside marker of attack activity alongside plasma KSHV viral load.
KSHV/HHV-8 Viral Load (Elevated)
Context: Plasma KSHV viral load rises during HHV-8+ MCD flares and falls with effective therapy, making it a disease-activity marker specific to this subtype. Lytic-gene-directed therapy with high-dose zidovudine plus valganciclovir produced significant improvements in CRP, albumin, platelets, human IL-6, IL-10, and KSHV viral load at best response.
Show evidence (1 reference)
PMID:21487108 SUPPORT Human Clinical
"At the time of best response, the patients showed significant improvements in C-reactive protein, albumin, platelets, human IL-6, IL-10, and KSHV viral load."
Establishes KSHV viral load as a treatment-responsive disease-activity marker.
🔬

Diagnosis

3
Excisional lymph node biopsy
Diagnosis requires characteristic lymph node histopathology; there is no diagnostic serum biomarker. Excisional biopsy is preferred over core or fine needle sampling because architectural features - regressed or hyperplastic germinal centers, mantle-zone onion-skinning, penetrating vessels, interfollicular plasmacytosis - cannot be assessed on a fragment. Histology alone is not sufficient: reactive Castleman-like changes occur in autoimmune disease, lymphoma, and infection, so the findings must be combined with clinical and laboratory data.
lymph node biopsy NCIT:C51900 NCI Thesaurus (NCIT)
Results: Angiofollicular lymph node hyperplasia of hyaline-vascular, plasma-cell, or mixed type.
Show evidence (1 reference)
DOI:10.1002/art.43269 SUPPORT Human Clinical
"Patients with autoimmune disease, lymphoma, and infections can experience Castleman‐like changes in reactive lymph nodes, and thus histologic findings must be combined with clinical and laboratory findings to accurately diagnose iMCD."
States directly why histology alone cannot establish the diagnosis.
HHV-8 LANA-1 immunohistochemistry
Immunohistochemistry for the HHV-8 latency-associated nuclear antigen on the lymph node biopsy is the step that separates HHV-8-associated MCD from iMCD. This is not optional - iMCD is defined by HHV-8 negativity, and the two subtypes have different first-line therapy (rituximab versus siltuximab). HIV serology is performed alongside, since most HHV-8+ MCD occurs in HIV co-infection.
immunohistochemistry NCIT:C23020 NCI Thesaurus (NCIT)
Results: LANA-1-positive plasmablasts establish HHV-8-associated MCD; negativity is required for a diagnosis of iMCD.
Show evidence (1 reference)
DOI:10.1002/art.43269 SUPPORT Human Clinical
"MCD can be associated with excessive cytokine production due to a plasma cell neoplasm (MCD–polyneuropathy, organomegaly, endocrinopathy, monoclonal paraprotein, skin changes) or uncontrolled human herpesvirus‐8 infection (HHV‐8) (HHV‐8–positive MCD), but more than half of cases are idiopathic."
Establishes HHV-8 status as the etiologic branch point among MCD subtypes.
Cross-sectional and FDG-PET imaging
CT of the neck, chest, abdomen, and pelvis, or FDG-PET/CT, establishes whether disease is unicentric or multicentric - the single most consequential branch point in management, since unicentric disease is surgically curable. Imaging also selects the biopsy target and, in UCD, determines resectability.
positron emission tomography NCIT:C17007 NCI Thesaurus (NCIT)
Results: A single involved nodal region indicates UCD; multiple involved regions indicate MCD.
Show evidence (1 reference)
DOI:10.1002/art.43269 SUPPORT Human Clinical
"Unicentric CD (UCD) involves one enlarged lymph node region, whereas multicentric CD (MCD) involves multiple enlarged lymph node regions."
The distinction that imaging is performed to establish.
🩻

Imaging Findings

1
FDG-Avid Multicentric Lymphadenopathy
FDG-PET/CT demonstrates avid lymphadenopathy in multiple nodal stations in MCD and is used both to establish multicentricity and to select the node to biopsy. Uptake is typically moderate, and marked focal uptake in a single node raises concern for lymphomatous transformation rather than Castleman disease itself.
Pet Diagnostic
📈

Progression

1
Remitting-relapsing flares (HHV-8+ MCD)
HHV-8+ MCD runs as discrete attacks of lytic viral activity with intervening remission. Relapse after rituximab-induced remission occurred in 8 of 46 patients at a median of 2 years, and all were successfully re-treated.
Show evidence (1 reference)
PMID:21555697 SUPPORT Human Clinical
"Eight of 46 patients who achieved clinical remission suffered symptomatic, histologically confirmed MCD relapse. The median time to relapse was 2 years, and all have been successfully re-treated and are alive in remission."
Quantifies the relapse rate and its treatability in this subtype.
🦠

Infectious Agent

1
Human gammaherpesvirus 8
Kaposi sarcoma-associated herpesvirus (KSHV/HHV-8). Uncontrolled lytic replication in lymph node plasmablasts is the cause of this subtype.
Human gammaherpesvirus 8 NCBITaxon:37296 NCBI Taxonomy (NCBITaxon)
Show evidence (1 reference)
PMID:21487108 SUPPORT Human Clinical
"It is characterized by KSHV-infected plasmablasts that frequently express lytic genes."
Establishes KSHV infection of plasmablasts as the defining feature of this subtype.
⚖️

Clinical Burden

High
Before rituximab this was a rapidly fatal disease: 5-year overall survival was 33% in patients treated in the pre-rituximab era. Rituximab-based therapy raised that to 90%, so the modern burden is dominated by the relapsing course rather than by early mortality - relapse occurred in 8 of 46 patients at a median of two years, all successfully re-treated. Concurrent KSHV-driven malignancy remains a substantial risk, with lymphoma occurring at 28 cases per 1,000 patient-years, and three of four deaths in the rituximab-treated cohort occurred within 10 days of diagnosis, so late presentation is still lethal.
Show evidence (2 references)
PMID:21555697 SUPPORT Human Clinical
"With rituximab-based treatment, the overall survival was 94% (95% CI, 87% to 100%) at 2 years and was 90% (95% CI, 81% to 100%) at 5 years compared with 42% (95% CI, 14% to 70%) and 33% (95% CI, 6% to 60%) in 12 patients treated before introduction of rituximab (log-rank P < .001)."
Gives both the historical and the current survival figures behind this assessment.
PMID:21555697 SUPPORT Human Clinical
"Four of 49 rituximab-treated patients have died; three died as a result of MCD within 10 days of diagnosis, and one died as a result of lymphoma in remission of MCD."
Supports the residual early-mortality risk described here.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from HHV-8-Associated Multicentric Castleman Disease:

Lymphoma
Overlapping Features Hodgkin and non-Hodgkin lymphoma both produce lymphadenopathy with systemic symptoms and can generate reactive Castleman-like nodal changes; iMCD-NOS in particular mimics indolent lymphoma. Lymphoma is a formal exclusion in the iMCD diagnostic criteria. The relationship also runs the other way in HHV-8+ MCD, where concurrent KSHV-driven lymphoma occurs at 28 cases per 1,000 patient-years.
Show evidence (1 reference)
DOI:10.1002/art.43269 SUPPORT Human Clinical
"Patients with autoimmune disease, lymphoma, and infections can experience Castleman‐like changes in reactive lymph nodes, and thus histologic findings must be combined with clinical and laboratory findings to accurately diagnose iMCD."
Names lymphoma among the conditions producing Castleman-like reactive nodes.
Idiopathic multicentric Castleman disease MONDO:0035838
Overlapping Features The HHV-8-negative form. Clinically the two overlap heavily - both present with multicentric lymphadenopathy, constitutional symptoms, cytopenias and organ dysfunction - and the separation is made by HHV-8 LANA-1 immunohistochemistry on the node, not by the clinical picture. Getting it right changes first-line therapy from rituximab to siltuximab. Constitutional symptoms and splenomegaly are substantially more frequent here than in iMCD; renal dysfunction is less frequent.
Distinguishing Features
  • HHV-8 LANA-1-negative lymph node immunohistochemistry; no detectable plasma KSHV viral load; usually no HIV co-infection.
Show evidence (2 references)
DOI:10.1182/bloodadvances.2024013548 SUPPORT Human Clinical
"There are many similarities in the symptomatology of iMCD and HHV8+ MCD; many patients experience constitutional symptoms and organ dysfunction."
States the clinical overlap that makes the virological test, rather than the presentation, the discriminator.
DOI:10.1182/bloodadvances.2024013548 SUPPORT Human Clinical
"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)"
Quantifies the two features that do differ between the subtypes.
{ }

Source YAML

click to show 
name: HHV-8-Associated Multicentric Castleman Disease
creation_date: "2026-08-26T00:00:00Z"
category: Complex
disease_term:
  preferred_term: HHV-8-associated multicentric Castleman disease
parents:
- Castleman Disease
- Lymphoproliferative Disease
- Viral Infection
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0019754
      label: multicentric Castleman disease
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO has no class for the HHV-8-associated form, so this entry is
      cross-referenced to the multicentric Castleman disease parent rather than
      given a `disease_term` binding. broadMatch is used deliberately, not
      narrowMatch: MONDO:0019754 is the parent of both the HHV-8-associated and
      the idiopathic arms, so it is broader than this entry, and per CLAUDE.md
      only exactMatch and narrowMatch retire a mapped concept from the curation
      queue. Recording this as broadMatch keeps the anchor without claiming the
      parent concept as curated. A new-term request for a specific
      HHV-8-associated class is tracked as M1 in the Castleman split issue;
      rebind `disease_term` to that class when it exists and change this mapping
      to exactMatch.
    consistency:
    - reference: MONDO
      consistent: MISSING
      notes: >-
        The target class does not exist in MONDO. MONDO:0019754 additionally
        conflates the parent concept with the HHV-8 form - it is defined as
        "mostly results from human herpesvirus 8 (HHV8) infection", carries
        is_a MONDO:0015157 (human herpesvirus 8-related tumor) and an exact
        synonym from ORPHA:570438, while also carrying a related synonym for the
        idiopathic form. Orphanet already separates these as ORPHA:570438 and
        ORPHA:570431.
synonyms:
- HHV8+ MCD
- KSHV-associated multicentric Castleman disease
- KSHV-MCD
- Human herpesvirus-8-associated multicentric Castleman disease
infectious_agent:
- name: Human gammaherpesvirus 8
  description: >-
    Kaposi sarcoma-associated herpesvirus (KSHV/HHV-8). Uncontrolled lytic
    replication in lymph node plasmablasts is the cause of this subtype.
  infectious_agent_term:
    preferred_term: Human gammaherpesvirus 8
    term:
      id: NCBITaxon:37296
      label: Human gammaherpesvirus 8
  evidence:
  - reference: PMID:21487108
    reference_title: "High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Castleman disease: a pilot study of virus-activated cytotoxic therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is characterized by KSHV-infected plasmablasts that frequently express lytic genes."
    explanation: Establishes KSHV infection of plasmablasts as the defining feature of this subtype.
references:
- reference: DOI:10.1038/s41572-021-00317-7
  title: Castleman disease
- reference: DOI:10.3389/fmicb.2012.00073
  title: "Clinical Manifestations of Kaposi Sarcoma Herpesvirus Lytic Activation: Multicentric Castleman Disease (KSHV-MCD) and the KSHV Inflammatory Cytokine Syndrome"
- reference: DOI:10.1038/s41541-022-00535-4
  title: "KSHV (HHV8) vaccine: promises and potential pitfalls for a new anti-cancer vaccine"
- reference: DOI:10.1111/tid.70179
  title: "HHV-8/KSHV in Solid Organ Transplantation: Current Gaps of Knowledge and Future Directions"
- reference: PMID:21778341
  title: Improved outcome with rituximab in patients with HIV-associated multicentric Castleman disease.
- reference: PMID:37288720
  title: Higher rate of progression in HIV- than in HIV+ patients after rituximab for HHV8+ multicentric Castleman disease.
- reference: DOI:10.3389/ti.2023.11856
  title: Prevention of Oncogenic Gammaherpesvirinae (EBV and HHV8) Associated Disease in Solid Organ Transplant Recipients
- reference: DOI:10.3390/ijms25073775
  title: "Molecular Features of HHV8 Monoclonal Microlymphoma Associated with Kaposi Sarcoma and Multicentric Castleman Disease in an HIV-Negative Patient"
- reference: DOI:10.3390/lymphatics3030020
  title: A Review of KSHV/HHV8-Associated Neoplasms and Related Lymphoproliferative Lesions
description: >-
  HHV-8-associated multicentric Castleman disease is the form of Castleman
  disease with a known cause: uncontrolled lytic replication of Kaposi
  sarcoma-associated herpesvirus (KSHV/HHV-8) in lymph node plasmablasts. The
  virus encodes a viral homolog of interleukin-6 (vIL-6) that engages gp130
  directly, without needing the IL-6 receptor, so it bypasses the checkpoint
  that normally limits IL-6 signaling. Most cases occur in people living with
  HIV, though the disease also occurs in HIV-negative immunocompromised
  individuals. The course is remitting-relapsing, running as discrete attacks of
  lytic viral activity with intervening remission, and constitutional symptoms
  and splenomegaly are substantially more frequent than in idiopathic
  multicentric disease (98.6% versus 46.6%, and 89.2% versus 48.2%). Because the
  same uncontrolled infection also drives Kaposi sarcoma and KSHV-associated
  lymphoma, those malignancies frequently co-occur. First-line therapy is
  rituximab, which depletes the CD20-positive B cells harboring the virus and
  raised 5-year survival from 33% to 90%; antiretroviral therapy is given
  alongside for the underlying HIV infection.
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_scale: CELLULAR
  cell_types:
  - preferred_term: KSHV-infected plasmablast
    term:
      id: CL:0000980
      label: plasmablast
  biological_processes:
  - preferred_term: Viral process
    term:
      id: GO:0016032
      label: viral process
  - preferred_term: Lytic viral genome replication
    term:
      id: GO:0019079
      label: viral genome replication
    modifier: INCREASED
  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.
  - reference: PMID:21487108
    reference_title: "High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Castleman disease: a pilot study of virus-activated cytotoxic therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is characterized by KSHV-infected plasmablasts that frequently express lytic genes."
    explanation: >-
      Identifies the lytically infected plasmablast as the cell carrying the viral
      program in this subtype.
  downstream:
  - target: IL-6 / vIL-6 Overproduction
    causal_link_type: DIRECT
    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: >-
        States that uncontrolled HHV-8 infection is responsible for the cytokine
        storm in HHV-8-associated MCD, supporting this edge from viral
        pathogenesis to cytokine overproduction. The vIL-6 mechanism itself is
        not part of the quote.
  - target: Kaposi's Sarcoma
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The same uncontrolled KSHV infection produces concurrent Kaposi sarcoma and
      KSHV-associated lymphoma in a substantial minority of patients.
    evidence:
    - reference: DOI:10.3390/jcm14186563
      reference_title: "Castleman Disease and Kaposi Sarcoma: A Review of the Literature and a Case Series"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Castleman disease and Kaposi sarcoma (KS) are both associated with infection by human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV). This virus plays a critical role in the pathogenesis of both conditions, particularly in immunocompromised individuals, such as those with HIV/AIDS."
      explanation: >-
        States that the same virus is causally central to both conditions, which
        is the basis for this edge.
    - reference: PMID:21555697
      reference_title: "Clinical Features and Outcome in HIV-Associated Multicentric Castleman's Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Four patients (7%) had histologic evidence of coexisting lymphoma, and one developed lymphoma 2 years after treatment. The incidence of lymphoma is 28 per 1,000 patient years."
      explanation: >-
        Quantifies the concurrent KSHV-driven lymphoproliferative risk in this
        subtype; the same cohort is the source for the Kaposi sarcoma association.
- name: IL-6 / vIL-6 Overproduction
  conforms_to: "il6_hypercytokinemia#Sustained Interleukin-6 Oversupply"
  description: >-
    Lytically infected plasmablasts produce a viral IL-6 homolog (vIL-6) that
    signals through gp130 independently of the IL-6 receptor, bypassing the
    checkpoint that normally limits IL-6 signaling. Human IL-6 and IL-10 are
    also elevated, so the hypercytokinemia is a mixture of viral and host
    cytokine, and both fall when lytic replication is suppressed. This is the
    one Castleman subtype in which the source of the cytokine excess is known.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: Plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  - preferred_term: Vascular endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  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 excess IL-6 as the shared driver of the
      multicentric forms of CD (the "they" of the quoted sentence are the MCD
      subtypes, of which this entry is one); IL-6 is typically normal in
      unicentric disease, so the quote does not establish an all-subtype claim.
  - reference: PMID:21487108
    reference_title: "High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Castleman disease: a pilot study of virus-activated cytotoxic therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients manifest inflammatory symptoms attributed to overproduction of KSHV viral IL-6, human IL-6, and human IL-6."
    explanation: >-
      Attributes the inflammatory syndrome to combined viral and human cytokine
      overproduction. The quoted sentence repeats "human IL-6" verbatim as
      published; the repetition is an error in the source abstract, and the
      snippet is not corrected here because it must remain an exact quote.
  downstream:
  - target: JAK-STAT3 Signaling Activation
    causal_link_type: DIRECT
    evidence:
    - reference: DOI:10.1002/art.43269
      reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Although they are all driven by excessive cytokines such as interleukin‐6 (IL‐6)"
      explanation: >-
        Establishes the excess-IL-6 drive that is upstream of this edge. The quote
        does not itself mention gp130 or JAK-STAT3, so it supports the source node
        rather than the signal-transduction step asserted here.
- name: JAK-STAT3 Signaling Activation
  conforms_to: "il6_hypercytokinemia#JAK-STAT3 Activation in Responder Cells"
  description: >-
    vIL-6 and human IL-6 both engage gp130 and activate downstream JAK kinases
    and STAT3 transcription factor signaling. vIL-6 does so without the IL-6
    receptor, which is why anti-IL-6-receptor blockade is a poorer fit for this
    subtype than for the idiopathic forms, and why first-line therapy here
    targets the infected B cell rather than the cytokine.
  biological_scale: MOLECULAR
  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
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21487108
      reference_title: "High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Castleman disease: a pilot study of virus-activated cytotoxic therapy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "It is characterized by KSHV-infected plasmablasts that frequently express lytic genes."
      explanation: Identifies the infected plasmablast as the proliferating cell in this subtype.
- name: Plasma Cell / B Cell Proliferation
  conforms_to: "il6_hypercytokinemia#B-Lineage Differentiation and Immunoglobulin Output"
  description: >-
    JAK-STAT3 signaling drives proliferation of B cells and plasma cells within
    affected lymph nodes. In this subtype the expanding plasmablasts are
    themselves KSHV-infected and frequently express lytic viral genes, which is
    what makes them targetable both by anti-CD20 antibody and by
    lytic-gene-activated antiviral therapy.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: Plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  - preferred_term: Plasmablast
    term:
      id: CL:0000980
      label: plasmablast
  biological_processes:
  - preferred_term: B cell proliferation
    term:
      id: GO:0042100
      label: B cell proliferation
    modifier: INCREASED
  - preferred_term: Immunoglobulin production
    term:
      id: GO:0002377
      label: immunoglobulin production
    modifier: INCREASED
  evidence:
  - reference: PMID:21487108
    reference_title: "High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Castleman disease: a pilot study of virus-activated cytotoxic therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is characterized by KSHV-infected plasmablasts that frequently express lytic genes."
    explanation: Identifies the infected plasmablast as the proliferating cell in this subtype.
  downstream:
  - target: Angiofollicular Lymph Node Hyperplasia
    causal_link_type: DIRECT
    evidence:
    - reference: DOI:10.1002/art.43269
      reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Although they are all driven by excessive cytokines such as interleukin‐6 (IL‐6)"
      explanation: >-
        Supports the excess-IL-6 drive upstream of this edge. The quoted review
        sentence does not describe the angiofollicular histology, so the histologic
        consequence remains uncited here.
- name: Hepatic Acute-Phase Response
  conforms_to: "il6_hypercytokinemia#Hepatic Acute-Phase Reprogramming"
  description: >-
    IL-6 and vIL-6 signaling reprogrammes hepatic protein synthesis: C-reactive
    protein is induced, albumin synthesis falls, and hepcidin induction restricts
    iron availability. Kept separate from the B-lineage arm because it acts on a
    different cell lineage with a different clinical read-out. C-reactive
    protein, albumin and platelet count all improve together when lytic viral
    replication is suppressed.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: Acute-phase response
    term:
      id: GO:0006953
      label: acute-phase response
    modifier: INCREASED
  evidence:
  - reference: PMID:21487108
    reference_title: "High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Castleman disease: a pilot study of virus-activated cytotoxic therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the time of best response, the patients showed significant improvements in C-reactive protein, albumin, platelets, human IL-6, IL-10, and KSHV viral load."
    explanation: >-
      Shows the acute-phase outputs of this node reversing when lytic viral
      replication is suppressed.
  downstream:
  - target: Anemia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Hepcidin induction and the acute-phase response produce the anemia of
      inflammation.
  - target: Hypoalbuminemia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Reprioritized hepatic protein synthesis during the acute-phase response
      lowers serum albumin.
- 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.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: Plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  - preferred_term: Follicular dendritic cell
    term:
      id: CL:0000442
      label: follicular dendritic cell
  biological_processes:
  - preferred_term: Angiogenesis
    term:
      id: GO:0001525
      label: angiogenesis
    modifier: INCREASED
  downstream:
  - target: Generalized Lymphadenopathy
    causal_link_type: DIRECT
    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: >-
    Multiple enlarged lymph node regions, which is what makes the disease
    multicentric. Nodes are typically bulkier than in iMCD-TAFRO and enlarge
    during a flare of lytic viral activity.
  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
  notes: >-
    Near-universal in this subtype: constitutional symptoms were present in
    98.6% of HHV8+ MCD patients versus 46.6% of iMCD in a 1,998-patient
    meta-analysis. Fever tracks flares of lytic viral replication.
  frequency: VERY_FREQUENT
  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
    directness: INDIRECT
    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: Constitutional
  name: Weight Loss
  phenotype_term:
    preferred_term: Weight loss
    term:
      id: HP:0001824
      label: Weight loss
- category: Hematologic
  name: Anemia
  frequency: VERY_FREQUENT
  notes: >-
    Anemia of inflammation, driven by the same IL-6 axis as the acute-phase
    response, and one of the parameters that improves when lytic replication is
    suppressed.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - 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: "Eighty-seven (85.3%) patients had anemia and 81 (79.4%) had hypoalbuminemia at diagnosis"
    explanation: Gives the anemia frequency at diagnosis in a 102-patient adjudicated iMCD cohort.
- category: Hematologic
  name: Hypoalbuminemia
  frequency: VERY_FREQUENT
  notes: >-
    Reflects the reprioritized hepatic protein synthesis of a sustained
    acute-phase response. Albumin improves alongside CRP and platelet count when
    lytic viral replication is suppressed.
  phenotype_term:
    preferred_term: Hypoalbuminemia
    term:
      id: HP:0003073
      label: Hypoalbuminemia
  evidence:
  - 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: "Eighty-seven (85.3%) patients had anemia and 81 (79.4%) had hypoalbuminemia at diagnosis"
    explanation: Gives the hypoalbuminemia frequency at diagnosis in the same adjudicated iMCD cohort.
- category: Laboratory
  name: Elevated C-Reactive Protein
  diagnostic: true
  notes: >-
    The routine marker used to follow attack activity and treatment response in
    this subtype, alongside plasma KSHV viral load.
  phenotype_term:
    preferred_term: Elevated C-reactive protein
    term:
      id: HP:0011227
      label: Elevated circulating C-reactive protein concentration
  evidence:
  - reference: DOI:10.1182/bloodadvances.2022007112
    reference_title: "Siltuximab is associated with improved progression-free survival in idiopathic multicentric Castleman disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the median time to normalization of abnormal laboratory tests and clinical end points occurred in the following sequence: thrombocytosis, symptomatic response, elevated C-reactive protein, hypoalbuminemia, anemia, lymph node response, hyperfibrinogenemia, and elevated immunoglobulin G"
    explanation: >-
      Post hoc analysis of the siltuximab trial confirms elevated CRP as one of
      the tracked abnormalities and places it early in the normalization sequence.
- category: Laboratory
  name: Elevated Erythrocyte Sedimentation Rate
  phenotype_term:
    preferred_term: Elevated erythrocyte sedimentation rate
    term:
      id: HP:0003565
      label: Elevated erythrocyte sedimentation rate
- category: Abdominal
  name: Splenomegaly
  frequency: FREQUENT
  notes: >-
    Present in 89.2% of HHV8+ MCD patients versus 48.2% of iMCD by
    meta-analysis - one of the two features that most sharply separates this
    subtype from the idiopathic form.
  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.
  - 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: "A large majority of patients presented with fluid retention (84%), splenomegaly (72%), and/or hepatomegaly (60%)."
    explanation: Independent registry frequency for splenomegaly at iMCD diagnosis.
- category: Abdominal
  name: Hepatomegaly
  frequency: FREQUENT
  notes: Part of the organomegaly that accompanies splenomegaly during an attack.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - 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: "A large majority of patients presented with fluid retention (84%), splenomegaly (72%), and/or hepatomegaly (60%)."
    explanation: Gives the hepatomegaly frequency at iMCD diagnosis.
- category: Renal
  name: Renal Dysfunction
  frequency: FREQUENT
  notes: >-
    Reported in 17.4% of HHV8+ MCD versus 36.9% of iMCD by meta-analysis. Renal
    involvement is therefore real but substantially less frequent here than in
    the idiopathic form.
  phenotype_term:
    preferred_term: Renal insufficiency
    term:
      id: HP:0000083
      label: Renal insufficiency
  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: "Renal dysfunction was significantly more common in patients with iMCD than in patients with HHV8+ MCD before adjustment (36.9% vs 17.4%; P = .04; adjusted P = .1)."
    explanation: >-
      Quantifies the iMCD/HHV8+ difference in renal dysfunction, and records that
      the difference did not survive multiplicity adjustment.
- category: Neoplastic
  name: Kaposi's Sarcoma
  notes: >-
    Kaposi sarcoma and KSHV-associated lymphoma arise from the same uncontrolled
    KSHV infection that drives HHV-8+ MCD and frequently co-occur with it. In a
    61-patient HIV-associated MCD cohort, 7% had histologic evidence of
    coexisting lymphoma at MCD diagnosis, with an incidence of 28 lymphomas per
    1,000 patient-years.
  phenotype_term:
    preferred_term: Kaposi sarcoma
    term:
      id: HP:0100726
      label: Kaposi's sarcoma
  evidence:
  - reference: DOI:10.3390/jcm14186563
    reference_title: "Castleman Disease and Kaposi Sarcoma: A Review of the Literature and a Case Series"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Castleman disease and Kaposi sarcoma (KS) are both associated with infection by human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV). This virus plays a critical role in the pathogenesis of both conditions, particularly in immunocompromised individuals, such as those with HIV/AIDS."
    explanation: >-
      Establishes the shared HHV-8 etiology that makes Kaposi sarcoma a
      co-occurring feature of this subtype rather than an unrelated comorbidity.
  - reference: DOI:10.3390/jcm14186563
    reference_title: "Castleman Disease and Kaposi Sarcoma: A Review of the Literature and a Case Series"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present four clinical cases, with concurrent KS and MCD, treated with chemotherapy and rituximab, with a satisfactory response."
    explanation: Documents concurrent Kaposi sarcoma and MCD in the same patients.
  - reference: PMID:21555697
    reference_title: "Clinical Features and Outcome in HIV-Associated Multicentric Castleman's Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four patients (7%) had histologic evidence of coexisting lymphoma, and one developed lymphoma 2 years after treatment. The incidence of lymphoma is 28 per 1,000 patient years."
    explanation: >-
      Quantifies the concurrent KSHV-driven malignancy risk in HIV-associated MCD.
      Note this quote reports lymphoma specifically, not Kaposi sarcoma.
histopathology:
- 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. This is the pattern associated with iMCD-IPL and
    with polyclonal hypergammaglobulinemia.
  context: MCD
- name: Mixed Histopathologic Variant
  description: >-
    Nodes carrying features of both the hyaline-vascular and plasma-cell
    patterns. In the ACCELERATE registry the histopathologic distribution across
    102 adjudicated iMCD cases was hypervascular/hyaline vascular 61.8%, mixed
    26.5%, and plasmacytic 6.9%; TAFRO cases were predominantly
    hypervascular and none were plasmacytic. The clinical significance of the
    histopathologic subtype is not established.
  context: MCD
  evidence:
  - reference: PMID:36433996
    reference_title: CXCL13 is a predictive biomarker in idiopathic multicentric Castleman disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients are also classified according to histopathologic subtype, including hyaline vascular/hypervascular, plasmacytic, or mixed, though the clinical implications of defining histopathologic subtype is unclear."
    explanation: >-
      States both the three-way histopathologic classification and that its
      clinical meaning is unresolved.
imaging_findings:
- name: FDG-Avid Multicentric Lymphadenopathy
  modality: PET
  description: >-
    FDG-PET/CT demonstrates avid lymphadenopathy in multiple nodal stations in
    MCD and is used both to establish multicentricity and to select the node to
    biopsy. Uptake is typically moderate, and marked focal uptake in a single
    node raises concern for lymphomatous transformation rather than Castleman
    disease itself.
  diagnostic: true
biochemical:
- name: Interleukin-6 (IL-6)
  presence: Elevated
  context: >-
    Both viral IL-6 and human IL-6 are elevated during an attack, and human IL-6
    falls significantly when lytic viral replication is suppressed. Routine
    clinical IL-6 assays do not distinguish the viral homolog from the host
    cytokine, so a measured "IL-6" here is a composite of the two.
  evidence:
  - reference: PMID:21487108
    reference_title: "High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Castleman disease: a pilot study of virus-activated cytotoxic therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the time of best response, the patients showed significant improvements in C-reactive protein, albumin, platelets, human IL-6, IL-10, and KSHV viral load."
    explanation: >-
      Shows human IL-6 is elevated and falls with lytic-directed therapy, tying
      the cytokine to viral replication in this subtype.
- name: C-Reactive Protein (CRP)
  presence: Elevated
  context: >-
    Acute-phase reactant driven by IL-6 and vIL-6 signaling. Rises during an
    attack and falls with effective antiviral or anti-CD20 therapy, so it is the
    routine bedside marker of attack activity alongside plasma KSHV viral load.
- name: KSHV/HHV-8 Viral Load
  presence: Elevated
  context: >-
    Plasma KSHV viral load rises during HHV-8+ MCD flares and falls with
    effective therapy, making it a disease-activity marker specific to this
    subtype. Lytic-gene-directed therapy with high-dose zidovudine plus
    valganciclovir produced significant improvements in CRP, albumin, platelets,
    human IL-6, IL-10, and KSHV viral load at best response.
  evidence:
  - reference: PMID:21487108
    reference_title: "High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Castleman disease: a pilot study of virus-activated cytotoxic therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the time of best response, the patients showed significant improvements in C-reactive protein, albumin, platelets, human IL-6, IL-10, and KSHV viral load."
    explanation: Establishes KSHV viral load as a treatment-responsive disease-activity marker.
progression:
- phase: Remitting-relapsing flares (HHV-8+ MCD)
  notes: >-
    HHV-8+ MCD runs as discrete attacks of lytic viral activity with intervening
    remission. Relapse after rituximab-induced remission occurred in 8 of 46
    patients at a median of 2 years, and all were successfully re-treated.
  evidence:
  - reference: PMID:21555697
    reference_title: "Clinical Features and Outcome in HIV-Associated Multicentric Castleman's Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eight of 46 patients who achieved clinical remission suffered symptomatic, histologically confirmed MCD relapse. The median time to relapse was 2 years, and all have been successfully re-treated and are alive in remission."
    explanation: Quantifies the relapse rate and its treatability in this subtype.
diagnosis:
- name: Excisional lymph node biopsy
  description: >-
    Diagnosis requires characteristic lymph node histopathology; there is no
    diagnostic serum biomarker. Excisional biopsy is preferred over core or fine
    needle sampling because architectural features - regressed or hyperplastic
    germinal centers, mantle-zone onion-skinning, penetrating vessels,
    interfollicular plasmacytosis - cannot be assessed on a fragment. Histology
    alone is not sufficient: reactive Castleman-like changes occur in
    autoimmune disease, lymphoma, and infection, so the findings must be
    combined with clinical and laboratory data.
  diagnosis_term:
    preferred_term: lymph node biopsy
    term:
      id: NCIT:C51900
      label: Lymph Node Biopsy
  results: >-
    Angiofollicular lymph node hyperplasia of hyaline-vascular, plasma-cell, or
    mixed type.
  evidence:
  - reference: DOI:10.1002/art.43269
    reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with autoimmune disease, lymphoma, and infections can experience Castleman‐like changes in reactive lymph nodes, and thus histologic findings must be combined with clinical and laboratory findings to accurately diagnose iMCD."
    explanation: States directly why histology alone cannot establish the diagnosis.
- name: HHV-8 LANA-1 immunohistochemistry
  description: >-
    Immunohistochemistry for the HHV-8 latency-associated nuclear antigen on the
    lymph node biopsy is the step that separates HHV-8-associated MCD from iMCD.
    This is not optional - iMCD is defined by HHV-8 negativity, and the two
    subtypes have different first-line therapy (rituximab versus siltuximab).
    HIV serology is performed alongside, since most HHV-8+ MCD occurs in HIV
    co-infection.
  diagnosis_term:
    preferred_term: immunohistochemistry
    term:
      id: NCIT:C23020
      label: Immunohistochemistry Staining Method
  results: >-
    LANA-1-positive plasmablasts establish HHV-8-associated MCD; negativity is
    required for a diagnosis of iMCD.
  evidence:
  - reference: DOI:10.1002/art.43269
    reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MCD can be associated with excessive cytokine production due to a plasma cell neoplasm (MCD–polyneuropathy, organomegaly, endocrinopathy, monoclonal paraprotein, skin changes) or uncontrolled human herpesvirus‐8 infection (HHV‐8) (HHV‐8–positive MCD), but more than half of cases are idiopathic."
    explanation: Establishes HHV-8 status as the etiologic branch point among MCD subtypes.
- name: Cross-sectional and FDG-PET imaging
  description: >-
    CT of the neck, chest, abdomen, and pelvis, or FDG-PET/CT, establishes
    whether disease is unicentric or multicentric - the single most consequential
    branch point in management, since unicentric disease is surgically curable.
    Imaging also selects the biopsy target and, in UCD, determines resectability.
  diagnosis_term:
    preferred_term: positron emission tomography
    term:
      id: NCIT:C17007
      label: Positron Emission Tomography
  results: >-
    A single involved nodal region indicates UCD; multiple involved regions
    indicate MCD.
  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: The distinction that imaging is performed to establish.
differential_diagnoses:
- name: Lymphoma
  description: >-
    Hodgkin and non-Hodgkin lymphoma both produce lymphadenopathy with systemic
    symptoms and can generate reactive Castleman-like nodal changes; iMCD-NOS in
    particular mimics indolent lymphoma. Lymphoma is a formal exclusion in the
    iMCD diagnostic criteria. The relationship also runs the other way in
    HHV-8+ MCD, where concurrent KSHV-driven lymphoma occurs at 28 cases per
    1,000 patient-years.
  evidence:
  - reference: DOI:10.1002/art.43269
    reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with autoimmune disease, lymphoma, and infections can experience Castleman‐like changes in reactive lymph nodes, and thus histologic findings must be combined with clinical and laboratory findings to accurately diagnose iMCD."
    explanation: Names lymphoma among the conditions producing Castleman-like reactive nodes.
- name: Idiopathic multicentric Castleman disease
  description: >-
    The HHV-8-negative form. Clinically the two overlap heavily - both present
    with multicentric lymphadenopathy, constitutional symptoms, cytopenias and
    organ dysfunction - and the separation is made by HHV-8 LANA-1
    immunohistochemistry on the node, not by the clinical picture. Getting it
    right changes first-line therapy from rituximab to siltuximab. Constitutional
    symptoms and splenomegaly are substantially more frequent here than in iMCD;
    renal dysfunction is less frequent.
  disease_term:
    preferred_term: idiopathic multicentric Castleman disease
    term:
      id: MONDO:0035838
      label: idiopathic multicentric Castleman disease
  distinguishing_features:
  - >-
    HHV-8 LANA-1-negative lymph node immunohistochemistry; no detectable plasma
    KSHV viral load; usually no HIV co-infection.
  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: "There are many similarities in the symptomatology of iMCD and HHV8+ MCD; many patients experience constitutional symptoms and organ dysfunction."
    explanation: >-
      States the clinical overlap that makes the virological test, rather than
      the presentation, the discriminator.
  - 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: Quantifies the two features that do differ between the subtypes.
treatments:
- name: Rituximab
  description: >-
    Anti-CD20 monoclonal antibody and the first-line therapy for this subtype.
    It depletes the CD20-positive B cells that harbor KSHV, removing the
    reservoir producing vIL-6. Introduction of rituximab-based treatment raised
    5-year overall survival in HIV-associated MCD from 33% to 90%. Relapse
    occurs in a minority at a median of two years and has been successfully
    re-treated. Two studies reported worsening of concurrent Kaposi sarcoma on
    rituximab, so co-existing KS influences the choice of regimen.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  target_mechanisms:
  - target: HHV-8/KSHV Viral Pathogenesis
    treatment_effect: INHIBITS
    description: >-
      Depletes the CD20-positive B cell compartment that harbors KSHV, removing
      the reservoir producing vIL-6.
  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.
  - reference: PMID:21555697
    reference_title: "Clinical Features and Outcome in HIV-Associated Multicentric Castleman's Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With rituximab-based treatment, the overall survival was 94% (95% CI, 87% to 100%) at 2 years and was 90% (95% CI, 81% to 100%) at 5 years compared with 42% (95% CI, 14% to 70%) and 33% (95% CI, 6% to 60%) in 12 patients treated before introduction of rituximab (log-rank P < .001)."
    explanation: Quantifies the survival improvement attributed to rituximab in HIV-associated MCD.
  - reference: PMID:21555697
    reference_title: "Clinical Features and Outcome in HIV-Associated Multicentric Castleman's Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eight of 46 patients who achieved clinical remission suffered symptomatic, histologically confirmed MCD relapse. The median time to relapse was 2 years, and all have been successfully re-treated and are alive in remission."
    explanation: Supports the relapse rate and its treatability described here.
  treatment_term:
    preferred_term: rituximab therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
- name: High-Dose Zidovudine plus Valganciclovir
  description: >-
    Virus-activated cytotoxic therapy for KSHV-associated MCD. The KSHV lytic
    genes ORF36 and ORF21 phosphorylate ganciclovir and zidovudine to toxic
    moieties, so the drug pair is selectively activated inside lytically infected
    cells. In a 14-patient pilot, 86% attained major clinical responses with
    12-month overall survival of 86%; median progression-free survival was 6
    months and the main toxicity was hematologic.
  therapeutic_modality: SMALL_MOLECULE
  context: HHV-8+ MCD
  target_mechanisms:
  - target: HHV-8/KSHV Viral Pathogenesis
    treatment_effect: INHIBITS
    description: >-
      Exploits the lytic viral kinases to generate cytotoxic metabolites inside
      KSHV-infected plasmablasts.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: zidovudine
      term:
        id: NCIT:C947
        label: Zidovudine
    - preferred_term: valganciclovir
      term:
        id: NCIT:C2629
        label: Valganciclovir
  evidence:
  - reference: PMID:21487108
    reference_title: "High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Castleman disease: a pilot study of virus-activated cytotoxic therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We investigated an approach targeting 2 KSHV lytic genes, ORF36 and ORF21, the protein of which, respectively, phosphorylate ganciclovir and zidovudine to toxic moieties."
    explanation: States the lytic-gene-activated mechanism described here.
  - reference: PMID:21487108
    reference_title: "High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Castleman disease: a pilot study of virus-activated cytotoxic therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 86% of patients attained major clinical responses and 50% attained major biochemical responses."
    explanation: Gives the pilot-study response rates quoted in the description.
- name: Antiretroviral Therapy
  description: >-
    Effective antiretroviral therapy is given for the underlying HIV infection in
    HIV-associated HHV-8+ MCD and is credited alongside rituximab with the
    improvement in outcomes for this subtype. It does not by itself control an
    MCD attack.
  therapeutic_modality: SMALL_MOLECULE
  context: HHV-8+ MCD
  treatment_term:
    preferred_term: antiretroviral therapy
    term:
      id: NCIT:C94631
      label: Antiretroviral Therapy
  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: Attributes the outcome improvement jointly to antiretroviral therapy and rituximab.
- name: Corticosteroids
  description: >-
    Used as an adjunct alongside rituximab-based therapy for symptom control
    during an attack. Corticosteroids are not disease-modifying here: the
    disease is driven by uncontrolled lytic viral replication, which steroids do
    not address, and prolonged immunosuppression is undesirable in a population
    that is usually HIV co-infected.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
  evidence:
  - reference: PMID:21555697
    reference_title: "Clinical Features and Outcome in HIV-Associated Multicentric Castleman's Disease."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Since 2003, 49 patients with newly diagnosed MCD have been treated with rituximab with (n = 14) or without (n = 35) etoposide."
    explanation: >-
      Shows that the regimens that changed outcomes in this subtype are
      rituximab-based rather than steroid-based. The quote does not itself
      address corticosteroids; their secondary role is inferred from their
      absence in the cohort's treatment description.
- name: Combination Cytotoxic Chemotherapy
  description: >-
    Cytotoxic chemotherapy is added to rituximab in severe disease, most often
    as etoposide, and liposomal doxorubicin is used where Kaposi sarcoma
    co-exists. In the reference cohort, 14 of 49 rituximab-treated patients
    received etoposide alongside the antibody.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
  evidence:
  - reference: PMID:21555697
    reference_title: "Clinical Features and Outcome in HIV-Associated Multicentric Castleman's Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Since 2003, 49 patients with newly diagnosed MCD have been treated with rituximab with (n = 14) or without (n = 35) etoposide."
    explanation: Documents the addition of etoposide to rituximab in this cohort.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    Before rituximab this was a rapidly fatal disease: 5-year overall survival
    was 33% in patients treated in the pre-rituximab era. Rituximab-based therapy
    raised that to 90%, so the modern burden is dominated by the relapsing course
    rather than by early mortality - relapse occurred in 8 of 46 patients at a
    median of two years, all successfully re-treated. Concurrent KSHV-driven
    malignancy remains a substantial risk, with lymphoma occurring at 28 cases per
    1,000 patient-years, and three of four deaths in the rituximab-treated cohort
    occurred within 10 days of diagnosis, so late presentation is still lethal.
  evidence:
  - reference: PMID:21555697
    reference_title: "Clinical Features and Outcome in HIV-Associated Multicentric Castleman's Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With rituximab-based treatment, the overall survival was 94% (95% CI, 87% to 100%) at 2 years and was 90% (95% CI, 81% to 100%) at 5 years compared with 42% (95% CI, 14% to 70%) and 33% (95% CI, 6% to 60%) in 12 patients treated before introduction of rituximab (log-rank P < .001)."
    explanation: Gives both the historical and the current survival figures behind this assessment.
  - reference: PMID:21555697
    reference_title: "Clinical Features and Outcome in HIV-Associated Multicentric Castleman's Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four of 49 rituximab-treated patients have died; three died as a result of MCD within 10 days of diagnosis, and one died as a result of lymphoma in remission of MCD."
    explanation: Supports the residual early-mortality risk described here.
discussions:
- discussion_id: gap_hhv8_mcd_molecular_characterization
  prompt: >-
    What are the host genomic and molecular characteristics of HHV-8-associated
    MCD, which has been almost entirely left out of the sequencing studies done
    on unicentric and idiopathic Castleman disease?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#HHV-8/KSHV Viral Pathogenesis
  - pathophysiology#Plasma Cell / B Cell Proliferation
  rationale: >-
    The recurrent somatic alleles reported in Castleman disease - PDGFRB, NCOA4,
    IL6ST - all come from unicentric and idiopathic series. The systematic review
    of Castleman molecular abnormalities notes a paucity of genetic studies for
    this subtype. That matters because it leaves open why only a minority of
    KSHV-infected, immunosuppressed people develop MCD at all, and whether host
    factors explain the variable rituximab response.
  evidence:
  - reference: PMID:33804823
    reference_title: "A Review of Genetic Abnormalities in Unicentric and Multicentric Castleman Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, there is a paucity of genetic studies evaluating HHV-8 positive multicentric CD (HHV-8+ MCD) and POEMS-associated CD."
    explanation: Names the coverage gap in a systematic review of the molecular literature.
  proposed_experiments:
  - experiment_id: exp_hhv8_mcd_host_virus_paired_sequencing
    name: Paired host and viral sequencing across KSHV-infected controls
    description: >-
      Compare host exomes, lymph node spatial transcriptomes, and KSHV genomes
      between HHV-8-associated MCD, KSHV-infected people with Kaposi sarcoma but
      no MCD, and KSHV-infected asymptomatic carriers, matched for HIV status and
      CD4 count. Testing for host variants and viral strain features that
      segregate with the MCD phenotype is what would explain why only a minority
      of infected people develop it.
    would_support:
    - pathophysiology#HHV-8/KSHV Viral Pathogenesis
    supporting_outcome:
    - >-
      Host variants or viral strain features segregate with MCD and are absent
      from infected controls, nominating a susceptibility determinant.
    refuting_outcome:
    - >-
      MCD cases are indistinguishable from infected controls on host and viral
      genome, indicating the determinant is immunological or stochastic rather
      than genomic.
- discussion_id: controversy_hhv8_rituximab_and_kaposi_sarcoma
  prompt: >-
    Should rituximab be used first-line when Kaposi sarcoma co-exists with
    HHV-8-associated MCD, given reports that it worsens the sarcoma?
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - treatments#Rituximab
  - phenotypes#Kaposi's Sarcoma
  rationale: >-
    Rituximab transformed survival in this subtype and is the standard first-line
    therapy, but Kaposi sarcoma co-occurs frequently and its worsening on
    rituximab has been reported. The two conditions share a cause, so the patient
    who most needs B cell depletion for MCD may be the one in whom it is riskiest
    for KS. Combination approaches with liposomal doxorubicin, and
    lytic-gene-directed antiviral therapy, exist as alternatives, but the
    comparison has not been made in a randomized trial.
  evidence:
  - reference: DOI:10.3390/jcm14186563
    reference_title: "Castleman Disease and Kaposi Sarcoma: A Review of the Literature and a Case Series"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present four clinical cases, with concurrent KS and MCD, treated with chemotherapy and rituximab, with a satisfactory response."
    explanation: >-
      Documents the concurrent presentation and a combined approach using
      chemotherapy together with rituximab.
  - reference: PMID:21487108
    reference_title: "High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Castleman disease: a pilot study of virus-activated cytotoxic therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These observations provide evidence that therapy designed to target cells with lytic KSHV replication has activity in KSHV-MCD."
    explanation: >-
      Establishes lytic-gene-directed antiviral therapy as an alternative that
      does not deplete B cells.
notes: >-
  Scope note: this entry covers HHV-8/KSHV-associated multicentric Castleman
  disease only. It was split out of the former umbrella `Castleman_Disease`
  entry, together with `Unicentric_Castleman_Disease` and
  `Idiopathic_Multicentric_Castleman_Disease`, because those forms have
  different causes, different first-line therapy, and different confirmatory
  tests. The curated union is kept in `kb/groupings/Castleman_Disease.yaml`.

  Content gap: somatic clonality in this subtype is uncurated. KMT2D mutation
  and HHV-8-positive monoclonal microlymphoma are reported in the literature and
  would belong in a `genetic:` block, but no genomic study of this subtype has
  been mined here - see the M-numbered MONDO/coverage items in the Castleman
  split issue and the `gap_hhv8_mcd_molecular_characterization` discussion.

  Ontology note: `disease_term` deliberately carries no bound `term:`. MONDO has
  no class for the HHV-8-associated form, and the nearest candidate,
  `MONDO:0019754` (multicentric Castleman disease), is the parent of both the
  HHV-8-associated and the idiopathic arms - so binding it here would assert that
  this entry is multicentric Castleman disease in general, and would mark that
  parent concept as curated when only one of its children has been. MONDO's own
  handling of that class compounds the problem: it is defined and classified as
  the HHV-8 form, carrying `is_a MONDO:0015157` (human herpesvirus 8-related
  tumor) and an exact synonym from `ORPHA:570438`, while also carrying a related
  synonym for the idiopathic form, and that conflation is why `MONDO:0035838`
  (idiopathic MCD) is not classified under it. Following the repository rule that
  no term beats a bad one, the binding is omitted and a free-text
  `preferred_term` is kept. A request to split the MONDO class and mint a
  specific HHV-8-associated child is tracked in the dismech split issue; bind
  this entry to that term when it exists.
📚

References & Deep Research

References

9
DOI:10.1038/s41572-021-00317-7
Castleman disease
No top-level findings curated for this source.
DOI:10.3389/fmicb.2012.00073
Clinical Manifestations of Kaposi Sarcoma Herpesvirus Lytic Activation: Multicentric Castleman Disease (KSHV-MCD) and the KSHV Inflammatory Cytokine Syndrome
No top-level findings curated for this source.
DOI:10.1038/s41541-022-00535-4
KSHV (HHV8) vaccine: promises and potential pitfalls for a new anti-cancer vaccine
No top-level findings curated for this source.
DOI:10.1111/tid.70179
HHV-8/KSHV in Solid Organ Transplantation: Current Gaps of Knowledge and Future Directions
No top-level findings curated for this source.
PMID:21778341
Improved outcome with rituximab in patients with HIV-associated multicentric Castleman disease.
No top-level findings curated for this source.
PMID:37288720
Higher rate of progression in HIV- than in HIV+ patients after rituximab for HHV8+ multicentric Castleman disease.
No top-level findings curated for this source.
DOI:10.3389/ti.2023.11856
Prevention of Oncogenic Gammaherpesvirinae (EBV and HHV8) Associated Disease in Solid Organ Transplant Recipients
No top-level findings curated for this source.
DOI:10.3390/ijms25073775
Molecular Features of HHV8 Monoclonal Microlymphoma Associated with Kaposi Sarcoma and Multicentric Castleman Disease in an HIV-Negative Patient
No top-level findings curated for this source.
DOI:10.3390/lymphatics3030020
A Review of KSHV/HHV8-Associated Neoplasms and Related Lymphoproliferative Lesions
No top-level findings curated for this source.