Unicentric Castleman Disease

Complex MONDO:0019753 Pathograph 7 Show in embeddings browser Castleman Disease Lymphoproliferative Disease

Unicentric Castleman disease (UCD) is the localized form of Castleman disease, involving a single lymph node region and accounting for the majority of Castleman cases. It usually presents as an asymptomatic mass found incidentally or on investigation of local compressive symptoms, and complete surgical resection is generally curative, with 5-year survival around 91%. About one in five patients nonetheless has systemic symptoms or laboratory abnormalities, and these are more pronounced in children. The hyaline-vascular histologic pattern predominates: regressed germinal centers with expanded follicular dendritic cell meshworks producing the "onion-skin" mantle zones, and follicle-confined VEGF overexpression producing the penetrating "lollipop" vessels. Recurrent somatic mutations in the stromal compartment - PDGFRB N666S in about 10% of cases, and IL6ST and PDGFRB in about a third of paraneoplastic-pemphigus-associated cases - raise the possibility that UCD is a clonal stromal neoplasm rather than a reactive process, though this is not established. Paraneoplastic pemphigus with bronchiolitis obliterans is a rare but frequently fatal complication that can progress even after the Castleman lesion is removed.

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5
Pathophys.
2
Histopath.
8
Phenotypes
2
Hypotheses
3
Gaps
7
Pathograph
2
Genes
4
Medical Actions
2
Differentials
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Mechanistic Hypotheses

2
Lymph Node Stromal Cells as the Source of VEGF
stromal_cytokine_source EMERGING
Evidence balance 2 support
The cells that oversupply VEGF in unicentric Castleman disease are lymph node stromal cells - CXCL13+ follicular dendritic cells and FDCSP+/CLU+ B-zone reticular cells - rather than the hematopoietic compartment that earlier immunohistochemical work implicated. In UCD the expanded subsets and the VEGF signal are confined to follicles, which distinguishes it from the multicentric forms where T-zone and perivascular reticular cells dominate and the signal extends interfollicularly. The evidence is a single spatial multi-omic study of 22 cases with no functional perturbation, so the causal direction (stromal activation driving the lesion versus responding to it) is not established.
Pathograph links
Lymph Node Stromal Cell Activation and Expansion -> Follicular Dendritic Cell Meshwork Expansion DIRECT
Lymph Node Stromal Cell Activation and Expansion -> Stromal VEGF Overproduction and Neovascularization DIRECT
Follicular Dendritic Cell Meshwork Expansion -> Angiofollicular Lymph Node Hyperplasia DIRECT Meshwork interdigitation between concentric mantle-zone B cell layers is the proposed structural basis of onion-skinning.
Show evidence (2 references)
DOI:10.1038/s41467-025-61214-1 SUPPORT Human Clinical
"MCD is characterized by increased TRC while UCD shows increased B-reticular cells (BRC)."
Establishes that a distinct stromal subset dominates the unicentric form, the core claim of this hypothesis group.
DOI:10.1038/s41467-025-61214-1 SUPPORT Human Clinical
"Previously, prominent FDCs in CD were considered remnants of attenuated germinal centers."
States the prior interpretation this hypothesis displaces: follicular dendritic cells as passive remnants rather than activated drivers.
Clonal Somatic Stromal Mutation as a Driver of UCD
clonal_stromal_origin EMERGING
Evidence balance 2 support
Recurrent somatic mutations in the stromal compartment - notably PDGFRB N666S, and IL6ST and PDGFRB in paraneoplastic-pemphigus-associated cases - make unicentric Castleman disease at least partly a clonal stromal-cell neoplasm rather than a purely reactive process. The mutations are recurrent and enriched, and PDGFRB N666S is an activating allele in other diseases, but they are present in a minority of cases, no functional model has shown that they initiate the lymph node lesion, and their cell of origin within the node is unresolved.
Pathograph links
Somatic Stromal Cell Mutation -> Lymph Node Stromal Cell Activation and Expansion INDIRECT UNKNOWN INTERMEDIATES Under the clonal hypothesis, an activating stromal mutation is what makes the stromal compartment expand autonomously.
Show evidence (2 references)
PMID:33804823 SUPPORT Human Clinical
"specific mutations in PDGFRB N666S in 10% of unicentric CD (UCD) and NCOA4 L261F in 23% of idiopathic multicentric CD (iMCD) cases"
Quantifies the recurrent somatic allele this hypothesis rests on, and the minority frequency that keeps it from being canonical.
PMID:33804823 SUPPORT Human Clinical
"However, we continue to lack a foundational understanding of the biological mechanisms driving this disease process."
The same review states that the mechanistic significance of these genetic findings is not established, limiting the hypothesis to EMERGING status.
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Discussions and Knowledge Gaps

3
Why do some UCD patients keep constitutional symptoms after complete excision with normalized laboratory markers, and what should they be offered?
KNOWLEDGE GAP OPEN gap_ucd_persistent_symptoms_after_resection
Attached to
treatments#Surgical Resection phenotypes#Elevated C-Reactive Protein
Complete resection is described as often curative, so persisting symptoms with normal inflammatory markers after a complete excision are not explained by the current model, in which the resected node is the entire lesion and the source of the cytokine signal. Either the disease is not confined to the resected node in these patients, or the symptoms have a separate cause. The international UCD guideline names this as an open research question and offers no recommendation, so these patients are managed without evidence.
Proposed experiments
Longitudinal profiling of post-resection symptomatic UCD
exp_ucd_post_resection_longitudinal_profiling
Follow UCD patients from before resection through 24 months with serial serum proteomics (including CXCL13, IL-6, and VEGF-A), whole-body FDG-PET, and patient-reported symptom scores, comparing those with and without persisting symptoms. Sequence the resected node and any FDG-avid residual site for the same somatic alleles to test whether persistent symptoms mark occult multicentric or multifocal disease.
Would support
pathophysiology#Somatic Stromal Cell Mutation
Supporting outcome
  • Symptomatic post-resection patients show residual FDG-avid nodal tissue or a persistently elevated cytokine signature, indicating incompletely resected or multifocal disease.
Refuting outcome
  • Symptomatic and asymptomatic post-resection patients are indistinguishable on imaging and cytokine profile, pointing to a cause outside the Castleman lesion.
Show evidence (1 reference)
PMID:33284946 SUPPORT Human Clinical
"Further research is needed in UCD patients with persisting constitutional symptoms despite complete excision and normal laboratory markers."
The guideline explicitly names this as an unmet research need.
Are the recurrent somatic PDGFRB and IL6ST alleles in UCD the initiating lesion, or passengers acquired inside an already-expanding stromal population?
OPEN QUESTION OPEN gap_ucd_clonal_vs_reactive
Attached to
pathophysiology#Somatic Stromal Cell Mutation genetic#PDGFRB genetic#IL6ST
The answer decides whether UCD is a clonal stromal neoplasm or a reactive process, and therefore whether a PDGFRB inhibitor is a rational therapy for unresectable disease. PDGFRB N666S is activating in other diseases and PDGFRB marks the stromal subsets that expand here, which is suggestive. Against it: the alleles are present in a minority of cases, the cell of origin within the node has not been established, and no functional model has shown that either allele initiates the lesion.
Proposed experiments
Variant allele fraction across sorted lymph node compartments
exp_ucd_sorted_stromal_variant_allele_fraction
Sort follicular dendritic cells, B-zone and perivascular reticular cells, endothelium, B cells, T cells, and plasma cells from PDGFRB- or IL6ST-mutant UCD nodes and measure the variant allele fraction in each. A driver should be near-clonal in one stromal compartment and absent from the hematopoietic ones; a passenger should be subclonal or spread across compartments.
Would support
pathophysiology#Somatic Stromal Cell Mutation
Supporting outcome
  • The variant is near-clonal in a single stromal compartment and absent from hematopoietic cells, identifying a cell of origin.
Refuting outcome
  • The variant is subclonal or distributed across unrelated compartments, indicating it was acquired within an already-expanded population.
Show evidence (1 reference)
PMID:33804823 SUPPORT Human Clinical
"However, we continue to lack a foundational understanding of the biological mechanisms driving this disease process."
The systematic review of Castleman molecular abnormalities states that the mechanistic significance of these findings is unresolved.
Can a model system be built that reproduces the UCD lymph node lesion, and until one exists how can the stromal-activation mechanism be tested causally?
KNOWLEDGE GAP OPEN gap_ucd_no_disease_model
Attached to
pathophysiology#Lymph Node Stromal Cell Activation and Expansion pathophysiology#Follicular Dendritic Cell Meshwork Expansion pathophysiology#Stromal VEGF Overproduction and Neovascularization
Every mechanism node in this entry derives from human tissue association - spatial transcriptomics and immunohistochemistry - with no perturbation experiment behind it, because no validated model system exists. That is why the causal direction cannot be settled: stromal activation could be driving the lesion or responding to it.
Proposed experiments
Human lymphoid organoid with defined stromal perturbation
exp_ucd_lymphoid_organoid_stromal_perturbation
Build a human lymphoid organoid containing primary follicular dendritic cells, B-zone reticular cells, naive B cells, and endothelium, then perturb single stromal populations (constitutive PDGFRB N666S expression, forced VEGFA expression, lymphotoxin-beta receptor stimulation) and score for the defining tissue readouts: CD21 meshwork expansion, concentric mantle-zone B cell layering, and perifollicular neovascularization.
Would support
pathophysiology#Lymph Node Stromal Cell Activation and Expansion pathophysiology#Follicular Dendritic Cell Meshwork Expansion
Supporting outcome
  • Perturbing a single stromal population reproduces the onion-skinning and penetrating-vessel architecture, establishing stromal activation as sufficient rather than reactive.
Refuting outcome
  • No stromal perturbation reproduces the architecture, indicating the lesion requires an input absent from the organoid.
Show evidence (1 reference)
DOI:10.1038/s41467-025-61214-1 SUPPORT Human Clinical
"The absence of accurate cell culture or murine models limits functional studies of CD."
States the gap in the authors' own words.
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Pathophysiology

5
Somatic Stromal Cell Mutation
Recurrent somatic mutations are found in UCD lesional tissue. PDGFRB N666S, an activating receptor tyrosine kinase allele, is present in about 10% of cases. In paraneoplastic-pemphigus-associated UCD, whole-exome sequencing found IL6ST (encoding gp130) and PDGFRB as the most frequently mutated genes at 32% each, with IL6ST variants predicting worse overall survival. MAPK and interleukin signaling pathway abnormalities cluster in UCD, in contrast to the chromatin-organization and methylation abnormalities that cluster in idiopathic multicentric disease. Whether these alleles initiate the lesion or accumulate within it is unresolved.
Clonal Somatic Stromal Mutation as a Driver of UCD
Genetic context variant_origin: SOMATIC functional_impact_category: GAIN_OF_FUNCTION
PDGFRB N666S is an activating allele; IL6ST encodes the gp130 subunit through which IL-6 signals. PDGFRB is also the marker of the perivascular and fibroblastic reticular cells that expand in Castleman lymph nodes.
MAPK cascade GO:0000165 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased MAPK cascade (GO:0000165). GO:0000165 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Lymph Node Stromal Cell Activation and Expansion Under the clonal hypothesis, an activating stromal mutation is what makes the stromal compartment expand autonomously. Clonal Somatic Stromal Mutation as a Driver of UCD
Show evidence (3 references)
PMID:33804823 SUPPORT Human Clinical
"specific mutations in PDGFRB N666S in 10% of unicentric CD (UCD) and NCOA4 L261F in 23% of idiopathic multicentric CD (iMCD) cases"
Gives the recurrent alleles and their frequencies in each subtype.
PMID:33804823 SUPPORT Human Clinical
"Genes affecting chromatin organization and abnormalities in methylation are seen more commonly in iMCD while abnormalities within the mitogen-activated protein kinase (MAPK) and interleukin signaling pathways are more frequent in UCD."
Supports the subtype-specific pathway clustering described in this node.
PMID:37839777 SUPPORT Human Clinical
"Specifically, IL6ST and PDGFRB were the most frequently mutated genes (32%), followed by DPP6 (18%) and MUC4 (18%)."
Whole-exome sequencing of 37 PNP-associated UCD samples identifies the two recurrently mutated genes named in this node.
Lymph Node Stromal Cell Activation and Expansion
Spatial proteomic and single-nuclei transcriptomic mapping shows that the non-lymphoid stromal compartment of the UCD lymph node expands and forms microenvironments absent from reactive nodes. The subsets that expand in UCD are FDCSP+/CLU+ B-zone reticular cells and CXCL13+ follicular dendritic cells, in contrast to the T-zone and ACTA2+ perivascular reticular cells that dominate in the multicentric forms. These stromal populations, not the hematopoietic compartment, carry the highest VEGFA expression, and they activate JAK-STAT, TGF-beta, and MAPK programs. UCD follicles also show reduced cellular diversity, consistent with follicular dendritic cell predominance.
Lymph Node Stromal Cells as the Source of VEGF
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. T-zone reticular cell CL:0009105 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T-zone reticular cell, annotated with T cell zone reticular cell (CL:0009105). CL:0009105 is a cell type from the Cell Ontology. B-zone reticular cell CL:0009104 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B-zone reticular cell, annotated with B cell zone reticular cell (CL:0009104). CL:0009104 is a cell type from the Cell Ontology. Perivascular reticular cell CL:4033054 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Perivascular reticular cell, annotated with perivascular cell (CL:4033054). CL:4033054 is a cell type from the Cell Ontology. Fibroblastic reticular cell CL:0009101 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Fibroblastic reticular cell (CL:0009101). CL:0009101 is a cell type from the Cell Ontology.
Extracellular matrix remodeling GO:0030198 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Extracellular matrix remodeling, annotated with extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology. ↑ INCREASED MAPK cascade GO:0000165 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased MAPK cascade (GO:0000165). GO:0000165 is a biological process from the Gene Ontology. ↑ INCREASED TGF-beta receptor signaling GO:0007179 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased TGF-beta receptor signaling, annotated with transforming growth factor beta receptor signaling pathway (GO:0007179). GO:0007179 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Follicular Dendritic Cell Meshwork Expansion Lymph Node Stromal Cells as the Source of VEGF
Stromal VEGF Overproduction and Neovascularization Lymph Node Stromal Cells as the Source of VEGF
Show evidence (2 references)
DOI:10.1038/s41467-025-61214-1 SUPPORT Human Clinical
"CD shows increased stromal cells that form unique microenvironments."
The primary observation of stromal expansion that this node records.
DOI:10.1038/s41467-025-61214-1 SUPPORT Human Clinical
"MCD is characterized by increased TRC while UCD shows increased B-reticular cells (BRC)."
Supports the subtype-specific stromal subset assignment described here.
Follicular Dendritic Cell Meshwork Expansion
CD21+ follicular dendritic cell meshworks are larger, brighter, and more structurally complex in both UCD and MCD than in reactive lymph nodes. Interdigitation of the expanded meshwork between concentric layers of mantle zone B cells is the proposed structural basis of the "onion-skinning" appearance, and the resulting sustained antigen presentation is proposed to drive B cell activation and plasma cell differentiation. This reinterprets the prominent FDCs of Castleman histology as an active driver rather than a passive remnant of an attenuated germinal center.
Lymph Node Stromal Cells as the Source of VEGF
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. Mantle zone B cell CL:0009037 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Mantle zone B cell, annotated with lymph node mantle zone B cell (CL:0009037). CL:0009037 is a cell type from the Cell Ontology.
Germinal center formation GO:0002467 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Germinal center formation (GO:0002467). GO:0002467 is a biological process from the Gene Ontology. ↓ DECREASED Plasma cell differentiation GO:0002317 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Plasma cell differentiation (GO:0002317). GO:0002317 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Angiofollicular Lymph Node Hyperplasia Meshwork interdigitation between concentric mantle-zone B cell layers is the proposed structural basis of onion-skinning. Lymph Node Stromal Cells as the Source of VEGF
Show evidence (2 references)
DOI:10.1038/s41467-025-61214-1 SUPPORT Human Clinical
"Interaction of activated follicular dendritic cell (FDC) cytoplasmic meshworks with mantle-zone B cells is associated with B-cell activation and differentiation."
The direct observation behind this node's mechanism.
DOI:10.1038/s41467-025-61214-1 SUPPORT Human Clinical
"Previously, prominent FDCs in CD were considered remnants of attenuated germinal centers."
States the earlier interpretation that this node replaces, which is why the reinterpretation is flagged in the description.
Stromal VEGF Overproduction and Neovascularization
In UCD, VEGFA is expressed by CXCL13+ follicular dendritic cells and the expression is confined to follicles - in contrast to the multicentric forms, where perivascular and T-zone reticular cells carry the highest expression and it extends into the interfollicular space. The resulting perifollicular neovascularization and penetrating vessels are the structural basis of the diagnostic "lollipop" follicle, and hypervascularization supports the stromal remodeling and nodal expansion that make the node enlarge.
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. Blood endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Blood endothelial cell, annotated with endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology.
Vascular endothelial growth factor production GO:0010573 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Vascular endothelial growth factor production (GO:0010573). GO:0010573 is a biological process from the Gene Ontology. ↑ INCREASED 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
Angiofollicular Lymph Node Hyperplasia
Show evidence (3 references)
PMID:40593805 SUPPORT Human Clinical
"In UCD, VEGF expression was confined to the follicles, whereas MCD showed markedly elevated expression in both follicular and interfollicular regions"
States the UCD-specific spatial pattern this node records - VEGF confined to follicles - and contrasts it with the interfollicular spread seen in multicentric disease.
PMID:40593805 SUPPORT Human Clinical
"VEGF overexpression by FDCs correlated with significantly increased perifollicular neovascularization and penetrating blood vessels"
Links follicular dendritic cell VEGF output to the penetrating-vessel architecture that this node claims it produces.
PMID:31408438 SUPPORT Human Clinical
"Administration of sirolimus significantly attenuated CD8+ T cell activation and decreased VEGF-A levels."
Shows circulating VEGF-A is elevated and pharmacologically reducible in IL-6-refractory iMCD, supporting VEGF as an actionable node.
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
Localized Lymphadenopathy
✶

Histopathology

2
Angiofollicular Lymph Node Hyperplasia, Hyaline-Vascular Variant
The hyaline-vascular histologic pattern predominates in UCD. Features regressed/atretic germinal centers, penetrating radial "lollipop" vessels with hyalinized walls, expanded "onion-skinning" mantle zones of concentric small lymphocytes, and interfollicular vascular proliferation. Plasmacytosis is minimal. Spatial mapping attributes the onion-skinning to interdigitation of expanded CD21+ follicular dendritic cell meshworks between the concentric mantle-zone B cell layers, and the lollipop vessels to focal VEGF overexpression by those same follicular dendritic cells.
Show evidence (1 reference)
DOI:10.1038/s41467-025-61214-1 SUPPORT Human Clinical
"Interaction of activated follicular dendritic cell (FDC) cytoplasmic meshworks with mantle-zone B cells is associated with B-cell activation and differentiation."
Provides the cellular basis now proposed for the mantle-zone architecture described in this finding.
Expanded CD21-Positive Follicular Dendritic Cell Meshwork
CD21 immunostaining shows follicular dendritic cell meshworks of greater area, intensity, and structural complexity (image entropy) in both UCD and MCD than in reactive lymph nodes, and UCD follicles show reduced cellular diversity consistent with FDC predominance. This is an immunohistochemical correlate of the stromal-activation model rather than a routine diagnostic criterion.
Show evidence (1 reference)
DOI:10.1038/s41467-025-61214-1 SUPPORT Human Clinical
"CD shows increased stromal cells that form unique microenvironments."
Records the increased stromal content quantified by CD21 meshwork imaging in this study.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Unicentric 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

8
Blood 1
Anemia 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, seen in the symptomatic UCD minority rather than across the whole subtype, and typically reversed by resection. No UCD-specific frequency has been reported; the meta-analysis gives only the combined figure that symptoms and laboratory abnormalities are present in 20% of UCD patients.
Show evidence (1 reference)
DOI:10.1182/bloodadvances.2024013548 SUPPORT Human Clinical
"Patients with UCD had lower rates of symptoms and laboratory abnormalities, although these were present in 20% of patients and were particularly pronounced in pediatric UCD."
The UCD-population source for the symptomatic-minority framing used here. No UCD-specific anemia rate is reported, so none is asserted.
Cardiovascular 1
Localized Lymphadenopathy HP:0002716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphadenopathy (HP:0002716). HP:0002716 is a phenotype from the Human Phenotype Ontology.
The defining feature: a single enlarged lymph node region. Involvement of more than one region makes the disease multicentric and moves it out of this entry. Most often mediastinal, cervical, or abdominal, and frequently found incidentally or through local compressive symptoms.
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.
Head and Neck 1
Oral Mucosal Ulceration (Paraneoplastic Pemphigus) Oral ulcer HP:0000155 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Oral ulceration, annotated with Oral ulcer (HP:0000155). HP:0000155 is a phenotype from the Human Phenotype Ontology.
Paraneoplastic pemphigus, presenting with intractable stomatitis and intraepithelial clefting on biopsy with circulating anti-plakin antibodies, is a rare but prognostically severe complication of UCD.
Show evidence (2 references)
PMID:37839777 SUPPORT Human Clinical
"Paraneoplastic pemphigus (PNP) is a major complication associated with poor UCD prognosis."
Establishes paraneoplastic pemphigus as a recognized, prognostically adverse UCD complication.
PMID:41483625 SUPPORT Human Clinical
"Resection of the paratracheal mass revealed lymphoid tissue with follicular and interfollicular stromal changes, atretic germinal centers and thickened mantle zones, consistent with unicentric Castleman disease, stroma-rich hyaline vascular variant."
Case report documenting paraneoplastic pemphigus with oral ulceration arising from a histologically confirmed UCD mass.
Metabolism 1
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.
Present in the symptomatic UCD minority. Normalization after resection is the practical confirmation that the inflammatory syndrome has resolved; persistent constitutional symptoms with a normal CRP after complete excision are an unexplained pattern the international guideline flags as needing research.
Show evidence (1 reference)
PMID:33284946 SUPPORT Human Clinical
"Further research is needed in UCD patients with persisting constitutional symptoms despite complete excision and normal laboratory markers."
Establishes the normal-laboratory-marker-after-excision pattern described here, and that it is an open question rather than a resolved one.
Respiratory 1
Bronchiolitis Obliterans HP:0011946 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bronchiolitis obliterans (HP:0011946). HP:0011946 is a phenotype from the Human Phenotype Ontology.
The small-airway component of paraneoplastic autoimmune multiorgan syndrome. It is the feature that makes UCD-associated paraneoplastic pemphigus lethal, and it can progress to respiratory failure requiring lung transplantation even after the Castleman lesion is resected.
Show evidence (1 reference)
PMID:41483625 SUPPORT Human Clinical
"Bronchiolitis obliterans, in particular, has been identified as a marker of poor prognosis in patients with PAMS and lung transplantation often represents the only viable treatment option once the underlying neoplasm has been controlled."
Establishes bronchiolitis obliterans as the prognosis-defining complication in this setting.
Constitutional 1
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.
Part of the systemic inflammatory syndrome present in about 20% of UCD patients, and more pronounced in children. It resolves after resection in most cases.
Growth 2
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.
Part of the systemic inflammatory syndrome present in about 20% of UCD patients.
Growth Delay HP:0001510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Growth delay (HP:0001510). HP:0001510 is a phenotype from the Human Phenotype Ontology.
Symptoms and laboratory abnormalities in UCD are particularly pronounced in children, in whom the inflammatory syndrome can present as growth failure that resolves after resection.
Show evidence (1 reference)
DOI:10.1182/bloodadvances.2024013548 SUPPORT INDIRECT Human Clinical
"Patients with UCD had lower rates of symptoms and laboratory abnormalities, although these were present in 20% of patients and were particularly pronounced in pediatric UCD."
Supports the pediatric skew of systemic features in UCD. The quote does not name growth delay specifically, so it reaches this phenotype by inference from the wider category of pediatric systemic features.
🧬

Genetic Associations

2
PDGFRB
Gene: PDGFRB hgnc:8804 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PDGFRB (hgnc:8804). hgnc:8804 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (2 references)
PMID:33804823 SUPPORT Human Clinical
"specific mutations in PDGFRB N666S in 10% of unicentric CD (UCD) and NCOA4 L261F in 23% of idiopathic multicentric CD (iMCD) cases"
Gives the recurrence frequency of PDGFRB N666S in UCD.
PMID:37839777 SUPPORT Human Clinical
"Specifically, IL6ST and PDGFRB were the most frequently mutated genes (32%), followed by DPP6 (18%) and MUC4 (18%)."
Independent whole-exome confirmation of recurrent PDGFRB mutation in a UCD cohort.
IL6ST
Gene: IL6ST hgnc:6021 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is IL6ST (hgnc:6021). hgnc:6021 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (2 references)
PMID:37839777 SUPPORT Human Clinical
"Specifically, IL6ST and PDGFRB were the most frequently mutated genes (32%), followed by DPP6 (18%) and MUC4 (18%)."
Establishes IL6ST as the joint most frequently mutated gene in this cohort.
PMID:37839777 SUPPORT Human Clinical
"Finally, we classified PNP-associated UCD into 4 genomic subgroups: IL6ST, PDGFRB, IL6ST-PDGFRB, and an unknown subgroup."
Supports the proposed genomic subgrouping described in the notes.
💊

Medical Actions

4
Surgical Resection
Action: Definitive Surgical ResectionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Definitive Surgical Resection (NCIT:C154430). NCIT:C154430 is a clinical intervention from the NCI Thesaurus. NCIT:C154430
Platform: Surgery
Complete surgical resection is generally curative for unicentric Castleman disease and is the preferred first-line therapy wherever it is feasible. Asymptomatic unresectable disease may be observed rather than treated.
Mechanism Target:
INHIBITS Angiofollicular Lymph Node Hyperplasia — Removing the single involved node removes the entire lesion and, with it, the stromal cytokine source in unicentric disease.
Show evidence (2 references)
PMID:33284946 SUPPORT Human Clinical
"Complete surgical resection is often curative and is therefore the preferred first-line therapy, if possible."
International consensus guideline establishing resection as first-line UCD therapy.
PMID:33284946 SUPPORT Human Clinical
"Existing evidence supports that asymptomatic unresectable UCD may be observed."
Records the observation option for the unresectable asymptomatic case.
Siltuximab
Action: anti-IL-6 monoclonal antibody therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is anti-IL-6 monoclonal antibody therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: siltuximab NCIT:C61084 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses siltuximab (NCIT:C61084). NCIT:C61084 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
Anti-IL-6 monoclonal antibody. In unicentric disease its role is narrow: the international guideline recommends considering it for unresectable UCD in patients who have an inflammatory syndrome. It is not indicated for the typical asymptomatic resectable case. Its efficacy evidence comes from multicentric disease, where a randomised placebo-controlled trial showed durable tumour and symptomatic response in 34% of treated patients.
Show evidence (2 references)
PMID:33284946 SUPPORT Human Clinical
"The anti-interleukin-6 monoclonal antibody siltuximab should be considered for unresectable UCD patients with an inflammatory syndrome."
The guideline statement defining siltuximab's place in unicentric disease.
PMID:25042199 SUPPORT INDIRECT Human Clinical
"Durable tumour and symptomatic responses occurred in 18 (34%) of 53 patients in the siltuximab group and none of 26 in the placebo group (difference 34·0%, 95% CI 11·1-54·8, p=0·0012)."
The efficacy evidence, which comes from multicentric disease rather than UCD, so it reaches this entry's treatment claim only by extrapolation across the Castleman subtypes.
Neoadjuvant Rituximab or Corticosteroids
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. 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: Monoclonal antibody
For unresectable UCD that is symptomatic because it compresses neighbouring structures, medical therapy with rituximab or steroids can shrink the mass enough to make resection possible. This is cytoreduction to enable surgery, not definitive therapy.
Show evidence (1 reference)
PMID:33284946 SUPPORT Human Clinical
"Unresectable UCD that is symptomatic as a result of compression of vital neighboring structures may be rendered amenable to resection by medical therapy (eg, rituximab, steroids), radiotherapy, or embolization."
The guideline statement naming rituximab and steroids for this indication.
Radiotherapy or Embolization for Unresectable UCD
Action: radiation therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is radiation therapy (NCIT:C15313). NCIT:C15313 is a clinical intervention from the NCI Thesaurus. Ontology label: Radiation Therapy NCIT:C15313
Platform: Radiotherapy
Alternatives to medical cytoreduction for the same goal. Radiotherapy or arterial embolization can debulk an unresectable symptomatic mass and may render it resectable.
Show evidence (1 reference)
PMID:33284946 SUPPORT Human Clinical
"Unresectable UCD that is symptomatic as a result of compression of vital neighboring structures may be rendered amenable to resection by medical therapy (eg, rituximab, steroids), radiotherapy, or embolization."
The guideline statement naming radiotherapy and embolization for this indication.
🔬

Biochemical Markers

2
Interleukin-6 (IL-6) (Elevated)
Context: Serum IL-6 is typically normal in UCD, which is the usual laboratory contrast with the multicentric forms. It is elevated in the symptomatic minority with an inflammatory syndrome, and those are the patients for whom the international UCD guideline recommends considering siltuximab when the lesion cannot be resected.
Show evidence (1 reference)
PMID:33284946 SUPPORT INDIRECT Human Clinical
"The anti-interleukin-6 monoclonal antibody siltuximab should be considered for unresectable UCD patients with an inflammatory syndrome."
Supports the clinical relevance of an IL-6-driven inflammatory syndrome in the symptomatic UCD minority. The quote does not itself report IL-6 levels; it infers them from the fact that IL-6 blockade is the recommended therapy.
C-Reactive Protein (CRP) (Elevated)
Context: Acute-phase reactant driven by IL-6 signaling. Normal in most UCD and elevated in the symptomatic minority; when raised before resection it is the practical marker for confirming that the inflammatory syndrome has resolved afterwards.
🔬

Diagnosis

2
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.
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 confirms unicentric disease. Any additional involved region reclassifies the case as multicentric, which changes both the entity and the first-line therapy.
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
Solitary Avidly Enhancing Nodal Mass
UCD typically appears on contrast CT as a solitary, homogeneous, avidly enhancing soft-tissue mass in one nodal station, most often mediastinal, cervical, or abdominal, sometimes with branching or coarse calcification. Assessing resectability and the relation of the mass to adjacent vital structures is what determines whether first-line surgery is possible.
Ct
Show evidence (1 reference)
PMID:33284946 SUPPORT INDIRECT Human Clinical
"Unresectable UCD that is symptomatic as a result of compression of vital neighboring structures may be rendered amenable to resection by medical therapy (eg, rituximab, steroids), radiotherapy, or embolization."
Supports the clinical purpose of cross-sectional imaging in UCD - determining resectability and compression of neighboring structures. The quote does not describe the imaging appearance itself, so it bears on this finding only through the use the imaging is put to.
📈

Progression

1
Post-resection long-term survival
UCD has the best outcome of any Castleman category: 5-year overall survival was 91% in a 113-patient two-centre series, against 65% for multicentric disease without POEMS. Complete resection is generally curative and recurrence is rare. The exceptions are unresectable disease and paraneoplastic pemphigus with bronchiolitis obliterans, which can progress to respiratory failure even after the Castleman lesion is removed.
Show evidence (2 references)
PMID:22791417 SUPPORT Human Clinical
"For all patients, 2, 5, and 10-year OS was 92%, 76%, 59%, respectively."
Gives the overall survival figures quoted here.
PMID:22791417 SUPPORT Human Clinical
"(1) unicentric CD (91%); (2) multicentric CD associated with the osteosclerotic variant of POEMS syndrome (90%); (3); multicentric CD without POEMS syndrome (65%); and (4) multicentric CD with POEMS syndrome without osteosclerotic lesions (27%)."
Gives the category-specific 5-year survival stratification.
📊

Prevalence

1
United States
Annual Incidence 2.3 per 100,000 (2.1–2.5) 1–9 per 1,000,000 per year
All Castleman disease, not UCD alone - no UCD-specific incidence estimate exists. Two commercial claims databases gave 21 and 25 cases per million person-years using a lymphadenopathy-anchored case-finding algorithm (there was no CD-specific ICD-9 code at the time), reported as 2.1-2.5 per 100,000 here. About 23% of identified cases were multicentric, so roughly three-quarters of incident Castleman disease is unicentric.
Show evidence (2 references)
PMID:25120049 SUPPORT Human Clinical
"The incidence rate for CD was calculated as 21 (IMS LifeLink™) and 25 (MarketScan(®)) per million person-years."
The source incidence estimate converted to the normalized rate above.
PMID:25120049 SUPPORT Human Clinical
"Additionally, 23% of patients with CD were identified as potentially suffering from MCD."
Gives the multicentric fraction of the incident cases.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Unicentric 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.
Multicentric Castleman disease
Overlapping Features The same histopathology in more than one nodal region. This is the distinction that defines the entity and it is made by imaging, not by pathology: a node that looks identical under the microscope belongs to a different disease with a different cause and a different first-line therapy if other regions are involved. Systemic symptoms, cytopenias, and hypoalbuminemia in a patient with apparently unicentric disease should prompt a careful search for additional sites.
Distinguishing Features
  • Multiple enlarged lymph node regions on cross-sectional or FDG-PET imaging; systemic inflammatory syndrome in most rather than a minority of patients.
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."
States the anatomic criterion that separates the two entities.
{ }

Source YAML

click to show 
name: Unicentric Castleman Disease
creation_date: "2026-08-26T00:00:00Z"
category: Complex
disease_term:
  preferred_term: unicentric Castleman disease
  term:
    id: MONDO:0019753
    label: localized Castleman disease
parents:
- Castleman Disease
- Lymphoproliferative Disease
synonyms:
- UCD
- Localized Castleman disease
- Unicentric angiofollicular lymph node hyperplasia
- Hyaline-vascular Castleman disease
mechanistic_hypotheses:
- hypothesis_group_id: stromal_cytokine_source
  hypothesis_label: Lymph Node Stromal Cells as the Source of VEGF
  status: EMERGING
  description: >-
    The cells that oversupply VEGF in unicentric Castleman disease are lymph node
    stromal cells - CXCL13+ follicular dendritic cells and FDCSP+/CLU+ B-zone
    reticular cells - rather than the hematopoietic compartment that earlier
    immunohistochemical work implicated. In UCD the expanded subsets and the
    VEGF signal are confined to follicles, which distinguishes it from the
    multicentric forms where T-zone and perivascular reticular cells dominate and
    the signal extends interfollicularly. The evidence is a single spatial
    multi-omic study of 22 cases with no functional perturbation, so the causal
    direction (stromal activation driving the lesion versus responding to it) is
    not established.
  evidence:
  - reference: DOI:10.1038/s41467-025-61214-1
    reference_title: "Spatial and single cell mapping of castleman disease reveals key stromal cell types and cytokine pathways"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MCD is characterized by increased TRC while UCD shows increased B-reticular cells (BRC)."
    explanation: >-
      Establishes that a distinct stromal subset dominates the unicentric form,
      the core claim of this hypothesis group.
  - reference: DOI:10.1038/s41467-025-61214-1
    reference_title: "Spatial and single cell mapping of castleman disease reveals key stromal cell types and cytokine pathways"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Previously, prominent FDCs in CD were considered remnants of attenuated germinal centers."
    explanation: >-
      States the prior interpretation this hypothesis displaces: follicular
      dendritic cells as passive remnants rather than activated drivers.
- hypothesis_group_id: clonal_stromal_origin
  hypothesis_label: Clonal Somatic Stromal Mutation as a Driver of UCD
  status: EMERGING
  description: >-
    Recurrent somatic mutations in the stromal compartment - notably PDGFRB
    N666S, and IL6ST and PDGFRB in paraneoplastic-pemphigus-associated cases -
    make unicentric Castleman disease at least partly a clonal stromal-cell
    neoplasm rather than a purely reactive process. The mutations are recurrent
    and enriched, and PDGFRB N666S is an activating allele in other diseases, but
    they are present in a minority of cases, no functional model has shown that
    they initiate the lymph node lesion, and their cell of origin within the node
    is unresolved.
  evidence:
  - reference: PMID:33804823
    reference_title: "A Review of Genetic Abnormalities in Unicentric and Multicentric Castleman Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "specific mutations in PDGFRB N666S in 10% of unicentric CD (UCD) and NCOA4 L261F in 23% of idiopathic multicentric CD (iMCD) cases"
    explanation: >-
      Quantifies the recurrent somatic allele this hypothesis rests on, and the
      minority frequency that keeps it from being canonical.
  - reference: PMID:33804823
    reference_title: "A Review of Genetic Abnormalities in Unicentric and Multicentric Castleman Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, we continue to lack a foundational understanding of the biological mechanisms driving this disease process."
    explanation: >-
      The same review states that the mechanistic significance of these genetic
      findings is not established, limiting the hypothesis to EMERGING status.
description: >-
  Unicentric Castleman disease (UCD) is the localized form of Castleman disease,
  involving a single lymph node region and accounting for the majority of
  Castleman cases. It usually presents as an asymptomatic mass found
  incidentally or on investigation of local compressive symptoms, and complete
  surgical resection is generally curative, with 5-year survival around 91%.
  About one in five patients nonetheless has systemic symptoms or laboratory
  abnormalities, and these are more pronounced in children. The hyaline-vascular
  histologic pattern predominates: regressed germinal centers with expanded
  follicular dendritic cell meshworks producing the "onion-skin" mantle zones,
  and follicle-confined VEGF overexpression producing the penetrating "lollipop"
  vessels. Recurrent somatic mutations in the stromal compartment - PDGFRB N666S
  in about 10% of cases, and IL6ST and PDGFRB in about a third of
  paraneoplastic-pemphigus-associated cases - raise the possibility that UCD is a
  clonal stromal neoplasm rather than a reactive process, though this is not
  established. Paraneoplastic pemphigus with bronchiolitis obliterans is a rare
  but frequently fatal complication that can progress even after the Castleman
  lesion is removed.
pathophysiology:
- name: Somatic Stromal Cell Mutation
  description: >-
    Recurrent somatic mutations are found in UCD lesional tissue. PDGFRB N666S,
    an activating receptor tyrosine kinase allele, is present in about 10% of
    cases. In paraneoplastic-pemphigus-associated UCD, whole-exome sequencing
    found IL6ST (encoding gp130) and PDGFRB as the most frequently mutated genes
    at 32% each, with IL6ST variants predicting worse overall survival. MAPK and
    interleukin signaling pathway abnormalities cluster in UCD, in contrast to
    the chromatin-organization and methylation abnormalities that cluster in
    idiopathic multicentric disease. Whether these alleles initiate the lesion or
    accumulate within it is unresolved.
  biological_scale: MOLECULAR
  mechanism_confidence: HYPOTHETICAL
  genetic_context:
    variant_origin: SOMATIC
    functional_impact_category: GAIN_OF_FUNCTION
    notes: >-
      PDGFRB N666S is an activating allele; IL6ST encodes the gp130 subunit
      through which IL-6 signals. PDGFRB is also the marker of the perivascular
      and fibroblastic reticular cells that expand in Castleman lymph nodes.
  biological_processes:
  - preferred_term: MAPK cascade
    term:
      id: GO:0000165
      label: MAPK cascade
    modifier: INCREASED
  evidence:
  - reference: PMID:33804823
    reference_title: "A Review of Genetic Abnormalities in Unicentric and Multicentric Castleman Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "specific mutations in PDGFRB N666S in 10% of unicentric CD (UCD) and NCOA4 L261F in 23% of idiopathic multicentric CD (iMCD) cases"
    explanation: Gives the recurrent alleles and their frequencies in each subtype.
  - reference: PMID:33804823
    reference_title: "A Review of Genetic Abnormalities in Unicentric and Multicentric Castleman Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genes affecting chromatin organization and abnormalities in methylation are seen more commonly in iMCD while abnormalities within the mitogen-activated protein kinase (MAPK) and interleukin signaling pathways are more frequent in UCD."
    explanation: Supports the subtype-specific pathway clustering described in this node.
  - reference: PMID:37839777
    reference_title: "Whole-Exome Sequencing Reveals the Genomic Profile and IL6ST Variants as a Prognostic Biomarker of Paraneoplastic Pemphigus-Associated Unicentric Castleman Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Specifically, IL6ST and PDGFRB were the most frequently mutated genes (32%), followed by DPP6 (18%) and MUC4 (18%)."
    explanation: >-
      Whole-exome sequencing of 37 PNP-associated UCD samples identifies the two
      recurrently mutated genes named in this node.
  downstream:
  - target: Lymph Node Stromal Cell Activation and Expansion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - clonal_stromal_origin
    description: >-
      Under the clonal hypothesis, an activating stromal mutation is what makes
      the stromal compartment expand autonomously.
- name: Lymph Node Stromal Cell Activation and Expansion
  description: >-
    Spatial proteomic and single-nuclei transcriptomic mapping shows that the
    non-lymphoid stromal compartment of the UCD lymph node expands and forms
    microenvironments absent from reactive nodes. The subsets that expand in UCD
    are FDCSP+/CLU+ B-zone reticular cells and CXCL13+ follicular dendritic
    cells, in contrast to the T-zone and ACTA2+ perivascular reticular cells that
    dominate in the multicentric forms. These stromal populations, not the
    hematopoietic compartment, carry the highest VEGFA expression, and they
    activate JAK-STAT, TGF-beta, and MAPK programs. UCD follicles also show
    reduced cellular diversity, consistent with follicular dendritic cell
    predominance.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: Follicular dendritic cell
    term:
      id: CL:0000442
      label: follicular dendritic cell
  - preferred_term: T-zone reticular cell
    term:
      id: CL:0009105
      label: T cell zone reticular cell
  - preferred_term: B-zone reticular cell
    term:
      id: CL:0009104
      label: B cell zone reticular cell
  - preferred_term: Perivascular reticular cell
    term:
      id: CL:4033054
      label: perivascular cell
  - preferred_term: Fibroblastic reticular cell
    term:
      id: CL:0009101
      label: fibroblastic reticular cell
  biological_processes:
  - preferred_term: Extracellular matrix remodeling
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  - preferred_term: MAPK cascade
    term:
      id: GO:0000165
      label: MAPK cascade
    modifier: INCREASED
  - preferred_term: TGF-beta receptor signaling
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
    modifier: INCREASED
  evidence:
  - reference: DOI:10.1038/s41467-025-61214-1
    reference_title: "Spatial and single cell mapping of castleman disease reveals key stromal cell types and cytokine pathways"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CD shows increased stromal cells that form unique microenvironments."
    explanation: The primary observation of stromal expansion that this node records.
  - reference: DOI:10.1038/s41467-025-61214-1
    reference_title: "Spatial and single cell mapping of castleman disease reveals key stromal cell types and cytokine pathways"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MCD is characterized by increased TRC while UCD shows increased B-reticular cells (BRC)."
    explanation: Supports the subtype-specific stromal subset assignment described here.
  downstream:
  - target: Follicular Dendritic Cell Meshwork Expansion
    causal_link_type: DIRECT
    hypothesis_groups:
    - stromal_cytokine_source
    evidence:
    - reference: DOI:10.1038/s41467-025-61214-1
      reference_title: "Spatial and single cell mapping of castleman disease reveals key stromal cell types and cytokine pathways"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Interaction of activated follicular dendritic cell (FDC) cytoplasmic meshworks with mantle-zone B cells is associated with B-cell activation and differentiation."
      explanation: Links stromal activation to the FDC meshwork phenotype in the next node.
  - target: Stromal VEGF Overproduction and Neovascularization
    causal_link_type: DIRECT
    hypothesis_groups:
    - stromal_cytokine_source
    evidence:
    - reference: DOI:10.1038/s41467-025-61214-1
      reference_title: "Spatial and single cell mapping of castleman disease reveals key stromal cell types and cytokine pathways"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Within the follicles of both UCD and MCD, VEGF was strikingly expressed in the nuclei of FDCs with cytoplasmic CXCL13"
      explanation: >-
        Identifies activated follicular dendritic cells as the VEGF source in
        UCD as well as MCD, which is what this edge asserts.
- name: Follicular Dendritic Cell Meshwork Expansion
  description: >-
    CD21+ follicular dendritic cell meshworks are larger, brighter, and more
    structurally complex in both UCD and MCD than in reactive lymph nodes.
    Interdigitation of the expanded meshwork between concentric layers of mantle
    zone B cells is the proposed structural basis of the "onion-skinning"
    appearance, and the resulting sustained antigen presentation is proposed to
    drive B cell activation and plasma cell differentiation. This reinterprets
    the prominent FDCs of Castleman histology as an active driver rather than a
    passive remnant of an attenuated germinal center.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: Follicular dendritic cell
    term:
      id: CL:0000442
      label: follicular dendritic cell
  - preferred_term: Mantle zone B cell
    term:
      id: CL:0009037
      label: lymph node mantle zone B cell
  biological_processes:
  - preferred_term: Germinal center formation
    term:
      id: GO:0002467
      label: germinal center formation
    modifier: DECREASED
  - preferred_term: Plasma cell differentiation
    term:
      id: GO:0002317
      label: plasma cell differentiation
    modifier: INCREASED
  evidence:
  - reference: DOI:10.1038/s41467-025-61214-1
    reference_title: "Spatial and single cell mapping of castleman disease reveals key stromal cell types and cytokine pathways"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interaction of activated follicular dendritic cell (FDC) cytoplasmic meshworks with mantle-zone B cells is associated with B-cell activation and differentiation."
    explanation: The direct observation behind this node's mechanism.
  - reference: DOI:10.1038/s41467-025-61214-1
    reference_title: "Spatial and single cell mapping of castleman disease reveals key stromal cell types and cytokine pathways"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Previously, prominent FDCs in CD were considered remnants of attenuated germinal centers."
    explanation: >-
      States the earlier interpretation that this node replaces, which is why the
      reinterpretation is flagged in the description.
  downstream:
  - target: Angiofollicular Lymph Node Hyperplasia
    causal_link_type: DIRECT
    hypothesis_groups:
    - stromal_cytokine_source
    description: >-
      Meshwork interdigitation between concentric mantle-zone B cell layers is
      the proposed structural basis of onion-skinning.
- name: Stromal VEGF Overproduction and Neovascularization
  description: >-
    In UCD, VEGFA is expressed by CXCL13+ follicular dendritic cells and the
    expression is confined to follicles - in contrast to the multicentric forms,
    where perivascular and T-zone reticular cells carry the highest expression
    and it extends into the interfollicular space. The resulting perifollicular
    neovascularization and penetrating vessels are the structural basis of the
    diagnostic "lollipop" follicle, and hypervascularization supports the stromal
    remodeling and nodal expansion that make the node enlarge.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: Follicular dendritic cell
    term:
      id: CL:0000442
      label: follicular dendritic cell
  - preferred_term: Blood endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: Vascular endothelial growth factor production
    term:
      id: GO:0010573
      label: vascular endothelial growth factor production
    modifier: INCREASED
  - preferred_term: Angiogenesis
    term:
      id: GO:0001525
      label: angiogenesis
    modifier: INCREASED
  evidence:
  - reference: "PMID:40593805"
    reference_title: >-
      Spatial and single cell mapping of castleman disease reveals key stromal cell types and
      cytokine pathways.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In UCD, VEGF expression was confined to the follicles, whereas MCD showed markedly elevated expression in both follicular and interfollicular regions"
    explanation: >-
      States the UCD-specific spatial pattern this node records - VEGF confined
      to follicles - and contrasts it with the interfollicular spread seen in
      multicentric disease.
  - reference: "PMID:40593805"
    reference_title: >-
      Spatial and single cell mapping of castleman disease reveals key stromal cell types and
      cytokine pathways.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "VEGF overexpression by FDCs correlated with significantly increased perifollicular neovascularization and penetrating blood vessels"
    explanation: >-
      Links follicular dendritic cell VEGF output to the penetrating-vessel
      architecture that this node claims it produces.
  - reference: PMID:31408438
    reference_title: "Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6-blockade-refractory idiopathic multicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Administration of sirolimus significantly attenuated CD8+ T cell activation and decreased VEGF-A levels."
    explanation: >-
      Shows circulating VEGF-A is elevated and pharmacologically reducible in
      IL-6-refractory iMCD, supporting VEGF as an actionable node.
  downstream:
  - target: Angiofollicular Lymph Node Hyperplasia
    causal_link_type: DIRECT
- 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: Localized 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 hyperplasia in the single involved node is what makes it
        clinically enlarged. The quote establishes that this remains confined to
        one region in unicentric disease.
phenotypes:
- category: Constitutional
  name: Localized Lymphadenopathy
  diagnostic: true
  notes: >-
    The defining feature: a single enlarged lymph node region. Involvement of
    more than one region makes the disease multicentric and moves it out of this
    entry. Most often mediastinal, cervical, or abdominal, and frequently found
    incidentally or through local compressive symptoms.
  phenotype_term:
    preferred_term: Lymphadenopathy
    term:
      id: HP:0002716
      label: 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: Fatigue
  notes: >-
    Part of the systemic inflammatory syndrome present in about 20% of UCD
    patients, and more pronounced in children. It resolves after resection in
    most cases.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
- category: Constitutional
  name: Weight Loss
  notes: >-
    Part of the systemic inflammatory syndrome present in about 20% of UCD
    patients.
  phenotype_term:
    preferred_term: Weight loss
    term:
      id: HP:0001824
      label: Weight loss
- category: Hematologic
  name: Anemia
  notes: >-
    Anemia of inflammation, seen in the symptomatic UCD minority rather than
    across the whole subtype, and typically reversed by resection. No
    UCD-specific frequency has been reported; the meta-analysis gives only the
    combined figure that symptoms and laboratory abnormalities are present in
    20% of UCD patients.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  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 UCD had lower rates of symptoms and laboratory abnormalities, although these were present in 20% of patients and were particularly pronounced in pediatric UCD."
    explanation: >-
      The UCD-population source for the symptomatic-minority framing used here.
      No UCD-specific anemia rate is reported, so none is asserted.
- category: Laboratory
  name: Elevated C-Reactive Protein
  notes: >-
    Present in the symptomatic UCD minority. Normalization after resection is
    the practical confirmation that the inflammatory syndrome has resolved;
    persistent constitutional symptoms with a normal CRP after complete excision
    are an unexplained pattern the international guideline flags as needing
    research.
  phenotype_term:
    preferred_term: Elevated C-reactive protein
    term:
      id: HP:0011227
      label: Elevated circulating C-reactive protein concentration
  evidence:
  - reference: PMID:33284946
    reference_title: "International evidence-based consensus diagnostic and treatment guidelines for unicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Further research is needed in UCD patients with persisting constitutional symptoms despite complete excision and normal laboratory markers."
    explanation: >-
      Establishes the normal-laboratory-marker-after-excision pattern described
      here, and that it is an open question rather than a resolved one.
- category: Dermatologic
  name: Oral Mucosal Ulceration (Paraneoplastic Pemphigus)
  notes: >-
    Paraneoplastic pemphigus, presenting with intractable stomatitis and
    intraepithelial clefting on biopsy with circulating anti-plakin antibodies,
    is a rare but prognostically severe complication of UCD.
  phenotype_term:
    preferred_term: Oral ulceration
    term:
      id: HP:0000155
      label: Oral ulcer
  evidence:
  - reference: PMID:37839777
    reference_title: "Whole-Exome Sequencing Reveals the Genomic Profile and IL6ST Variants as a Prognostic Biomarker of Paraneoplastic Pemphigus-Associated Unicentric Castleman Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Paraneoplastic pemphigus (PNP) is a major complication associated with poor UCD prognosis."
    explanation: Establishes paraneoplastic pemphigus as a recognized, prognostically adverse UCD complication.
  - reference: PMID:41483625
    reference_title: "From the archives of MD Anderson Cancer Center: Paraneoplastic autoimmune multiorgan syndrome (PAMS) associated with stroma-rich Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Resection of the paratracheal mass revealed lymphoid tissue with follicular and interfollicular stromal changes, atretic germinal centers and thickened mantle zones, consistent with unicentric Castleman disease, stroma-rich hyaline vascular variant."
    explanation: >-
      Case report documenting paraneoplastic pemphigus with oral ulceration
      arising from a histologically confirmed UCD mass.
- category: Respiratory
  name: Bronchiolitis Obliterans
  notes: >-
    The small-airway component of paraneoplastic autoimmune multiorgan syndrome.
    It is the feature that makes UCD-associated paraneoplastic pemphigus lethal,
    and it can progress to respiratory failure requiring lung transplantation
    even after the Castleman lesion is resected.
  phenotype_term:
    preferred_term: Bronchiolitis obliterans
    term:
      id: HP:0011946
      label: Bronchiolitis obliterans
  evidence:
  - reference: PMID:41483625
    reference_title: "From the archives of MD Anderson Cancer Center: Paraneoplastic autoimmune multiorgan syndrome (PAMS) associated with stroma-rich Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bronchiolitis obliterans, in particular, has been identified as a marker of poor prognosis in patients with PAMS and lung transplantation often represents the only viable treatment option once the underlying neoplasm has been controlled."
    explanation: Establishes bronchiolitis obliterans as the prognosis-defining complication in this setting.
- category: Growth
  name: Growth Delay
  notes: >-
    Symptoms and laboratory abnormalities in UCD are particularly pronounced in
    children, in whom the inflammatory syndrome can present as growth failure
    that resolves after resection.
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  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 UCD had lower rates of symptoms and laboratory abnormalities, although these were present in 20% of patients and were particularly pronounced in pediatric UCD."
    explanation: >-
      Supports the pediatric skew of systemic features in UCD. The quote does not
      name growth delay specifically, so it reaches this phenotype by inference
      from the wider category of pediatric systemic features.
histopathology:
- name: Angiofollicular Lymph Node Hyperplasia, Hyaline-Vascular Variant
  description: >-
    The hyaline-vascular histologic pattern predominates in UCD. Features
    regressed/atretic germinal centers, penetrating radial "lollipop"
    vessels with hyalinized walls, expanded "onion-skinning" mantle zones
    of concentric small lymphocytes, and interfollicular vascular
    proliferation. Plasmacytosis is minimal. Spatial mapping attributes the
    onion-skinning to interdigitation of expanded CD21+ follicular dendritic cell
    meshworks between the concentric mantle-zone B cell layers, and the
    lollipop vessels to focal VEGF overexpression by those same follicular
    dendritic cells.
  context: UCD
  diagnostic: true
  evidence:
  - reference: DOI:10.1038/s41467-025-61214-1
    reference_title: "Spatial and single cell mapping of castleman disease reveals key stromal cell types and cytokine pathways"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interaction of activated follicular dendritic cell (FDC) cytoplasmic meshworks with mantle-zone B cells is associated with B-cell activation and differentiation."
    explanation: >-
      Provides the cellular basis now proposed for the mantle-zone architecture
      described in this finding.
- name: Expanded CD21-Positive Follicular Dendritic Cell Meshwork
  description: >-
    CD21 immunostaining shows follicular dendritic cell meshworks of greater
    area, intensity, and structural complexity (image entropy) in both UCD and
    MCD than in reactive lymph nodes, and UCD follicles show reduced cellular
    diversity consistent with FDC predominance. This is an immunohistochemical
    correlate of the stromal-activation model rather than a routine diagnostic
    criterion.
  evidence:
  - reference: DOI:10.1038/s41467-025-61214-1
    reference_title: "Spatial and single cell mapping of castleman disease reveals key stromal cell types and cytokine pathways"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CD shows increased stromal cells that form unique microenvironments."
    explanation: >-
      Records the increased stromal content quantified by CD21 meshwork imaging
      in this study.
imaging_findings:
- name: Solitary Avidly Enhancing Nodal Mass
  modality: CT
  description: >-
    UCD typically appears on contrast CT as a solitary, homogeneous, avidly
    enhancing soft-tissue mass in one nodal station, most often mediastinal,
    cervical, or abdominal, sometimes with branching or coarse calcification.
    Assessing resectability and the relation of the mass to adjacent vital
    structures is what determines whether first-line surgery is possible.
  evidence:
  - reference: PMID:33284946
    reference_title: "International evidence-based consensus diagnostic and treatment guidelines for unicentric Castleman disease."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Unresectable UCD that is symptomatic as a result of compression of vital neighboring structures may be rendered amenable to resection by medical therapy (eg, rituximab, steroids), radiotherapy, or embolization."
    explanation: >-
      Supports the clinical purpose of cross-sectional imaging in UCD -
      determining resectability and compression of neighboring structures. The
      quote does not describe the imaging appearance itself, so it bears on this
      finding only through the use the imaging is put to.
biochemical:
- name: Interleukin-6 (IL-6)
  presence: Elevated
  context: >-
    Serum IL-6 is typically normal in UCD, which is the usual laboratory
    contrast with the multicentric forms. It is elevated in the symptomatic
    minority with an inflammatory syndrome, and those are the patients for whom
    the international UCD guideline recommends considering siltuximab when the
    lesion cannot be resected.
  evidence:
  - reference: PMID:33284946
    reference_title: "International evidence-based consensus diagnostic and treatment guidelines for unicentric Castleman disease."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The anti-interleukin-6 monoclonal antibody siltuximab should be considered for unresectable UCD patients with an inflammatory syndrome."
    explanation: >-
      Supports the clinical relevance of an IL-6-driven inflammatory syndrome in
      the symptomatic UCD minority. The quote does not itself report IL-6 levels;
      it infers them from the fact that IL-6 blockade is the recommended
      therapy.
- name: C-Reactive Protein (CRP)
  presence: Elevated
  context: >-
    Acute-phase reactant driven by IL-6 signaling. Normal in most UCD and
    elevated in the symptomatic minority; when raised before resection it is the
    practical marker for confirming that the inflammatory syndrome has resolved
    afterwards.
prevalence:
- population: United States
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 2.3
  rate_low: 2.1
  rate_high: 2.5
  notes: >-
    All Castleman disease, not UCD alone - no UCD-specific incidence estimate
    exists. Two commercial claims databases gave 21 and 25 cases per million
    person-years using a lymphadenopathy-anchored case-finding algorithm (there
    was no CD-specific ICD-9 code at the time), reported as 2.1-2.5 per 100,000
    here. About 23% of identified cases were multicentric, so roughly
    three-quarters of incident Castleman disease is unicentric.
  evidence:
  - reference: PMID:25120049
    reference_title: "Use of a claims database to characterize and estimate the incidence rate for Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The incidence rate for CD was calculated as 21 (IMS LifeLink™) and 25 (MarketScan(®)) per million person-years."
    explanation: The source incidence estimate converted to the normalized rate above.
  - reference: PMID:25120049
    reference_title: "Use of a claims database to characterize and estimate the incidence rate for Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, 23% of patients with CD were identified as potentially suffering from MCD."
    explanation: Gives the multicentric fraction of the incident cases.
progression:
- phase: Post-resection long-term survival
  notes: >-
    UCD has the best outcome of any Castleman category: 5-year overall survival
    was 91% in a 113-patient two-centre series, against 65% for multicentric
    disease without POEMS. Complete resection is generally curative and
    recurrence is rare. The exceptions are unresectable disease and
    paraneoplastic pemphigus with bronchiolitis obliterans, which can progress to
    respiratory failure even after the Castleman lesion is removed.
  evidence:
  - reference: PMID:22791417
    reference_title: "The clinical spectrum of Castleman's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For all patients, 2, 5, and 10-year OS was 92%, 76%, 59%, respectively."
    explanation: Gives the overall survival figures quoted here.
  - reference: PMID:22791417
    reference_title: "The clinical spectrum of Castleman's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "(1) unicentric CD (91%); (2) multicentric CD associated with the osteosclerotic variant of POEMS syndrome (90%); (3); multicentric CD without POEMS syndrome (65%); and (4) multicentric CD with POEMS syndrome without osteosclerotic lesions (27%)."
    explanation: Gives the category-specific 5-year survival stratification.
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: 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 confirms unicentric disease. Any additional
    involved region reclassifies the case as multicentric, which changes both
    the entity and the first-line therapy.
  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: Multicentric Castleman disease
  description: >-
    The same histopathology in more than one nodal region. This is the
    distinction that defines the entity and it is made by imaging, not by
    pathology: a node that looks identical under the microscope belongs to a
    different disease with a different cause and a different first-line therapy
    if other regions are involved. Systemic symptoms, cytopenias, and
    hypoalbuminemia in a patient with apparently unicentric disease should
    prompt a careful search for additional sites.
  distinguishing_features:
  - >-
    Multiple enlarged lymph node regions on cross-sectional or FDG-PET imaging;
    systemic inflammatory syndrome in most rather than a minority of patients.
  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: States the anatomic criterion that separates the two entities.
genetic:
- name: PDGFRB
  gene_term:
    preferred_term: PDGFRB
    term:
      id: hgnc:8804
      label: PDGFRB
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  presence: Somatic mutation in lesional tissue
  frequency: >-
    N666S in about 10% of unicentric CD; PDGFRB among the two most frequently
    mutated genes (32%) in paraneoplastic-pemphigus-associated UCD.
  notes: >-
    N666S is an activating allele of the platelet-derived growth factor receptor
    beta, the receptor whose expression also marks the perivascular and
    fibroblastic reticular cells that expand in Castleman lymph nodes. Whether
    the mutation initiates the lesion or is acquired within an already
    proliferating stromal population has not been established, so this is
    recorded as a somatic driver candidate rather than a confirmed cause.
  evidence:
  - reference: PMID:33804823
    reference_title: "A Review of Genetic Abnormalities in Unicentric and Multicentric Castleman Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "specific mutations in PDGFRB N666S in 10% of unicentric CD (UCD) and NCOA4 L261F in 23% of idiopathic multicentric CD (iMCD) cases"
    explanation: Gives the recurrence frequency of PDGFRB N666S in UCD.
  - reference: PMID:37839777
    reference_title: "Whole-Exome Sequencing Reveals the Genomic Profile and IL6ST Variants as a Prognostic Biomarker of Paraneoplastic Pemphigus-Associated Unicentric Castleman Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Specifically, IL6ST and PDGFRB were the most frequently mutated genes (32%), followed by DPP6 (18%) and MUC4 (18%)."
    explanation: Independent whole-exome confirmation of recurrent PDGFRB mutation in a UCD cohort.
- name: IL6ST
  gene_term:
    preferred_term: IL6ST
    term:
      id: hgnc:6021
      label: IL6ST
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  presence: Somatic mutation in lesional tissue
  frequency: 32% of paraneoplastic-pemphigus-associated unicentric CD.
  notes: >-
    IL6ST encodes gp130, the signal-transducing subunit shared by IL-6 and viral
    IL-6, so a somatic IL6ST variant sits directly on the pathway the disease's
    approved therapy targets. IL6ST variants were associated with worse overall
    survival in PNP-associated UCD and defined one of four proposed genomic
    subgroups (IL6ST, PDGFRB, IL6ST-PDGFRB, unknown). The functional consequence
    of the specific variants has not been characterized.
  evidence:
  - reference: PMID:37839777
    reference_title: "Whole-Exome Sequencing Reveals the Genomic Profile and IL6ST Variants as a Prognostic Biomarker of Paraneoplastic Pemphigus-Associated Unicentric Castleman Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Specifically, IL6ST and PDGFRB were the most frequently mutated genes (32%), followed by DPP6 (18%) and MUC4 (18%)."
    explanation: Establishes IL6ST as the joint most frequently mutated gene in this cohort.
  - reference: PMID:37839777
    reference_title: "Whole-Exome Sequencing Reveals the Genomic Profile and IL6ST Variants as a Prognostic Biomarker of Paraneoplastic Pemphigus-Associated Unicentric Castleman Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Finally, we classified PNP-associated UCD into 4 genomic subgroups: IL6ST, PDGFRB, IL6ST-PDGFRB, and an unknown subgroup."
    explanation: Supports the proposed genomic subgrouping described in the notes.
treatments:
- name: Surgical Resection
  description: >-
    Complete surgical resection is generally curative for unicentric Castleman
    disease and is the preferred first-line therapy wherever it is feasible.
    Asymptomatic unresectable disease may be observed rather than treated.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Definitive Surgical Resection
    term:
      id: NCIT:C154430
      label: Definitive Surgical Resection
  target_mechanisms:
  - target: Angiofollicular Lymph Node Hyperplasia
    treatment_effect: INHIBITS
    description: >-
      Removing the single involved node removes the entire lesion and, with it,
      the stromal cytokine source in unicentric disease.
  evidence:
  - reference: PMID:33284946
    reference_title: "International evidence-based consensus diagnostic and treatment guidelines for unicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Complete surgical resection is often curative and is therefore the preferred first-line therapy, if possible."
    explanation: International consensus guideline establishing resection as first-line UCD therapy.
  - reference: PMID:33284946
    reference_title: "International evidence-based consensus diagnostic and treatment guidelines for unicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Existing evidence supports that asymptomatic unresectable UCD may be observed."
    explanation: Records the observation option for the unresectable asymptomatic case.
- name: Siltuximab
  description: >-
    Anti-IL-6 monoclonal antibody. In unicentric disease its role is narrow: the
    international guideline recommends considering it for unresectable UCD in
    patients who have an inflammatory syndrome. It is not indicated for the
    typical asymptomatic resectable case. Its efficacy evidence comes from
    multicentric disease, where a randomised placebo-controlled trial showed
    durable tumour and symptomatic response in 34% of treated patients.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  context: Unresectable UCD with an inflammatory syndrome
  treatment_term:
    preferred_term: anti-IL-6 monoclonal antibody therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: siltuximab
      term:
        id: NCIT:C61084
        label: Siltuximab
  evidence:
  - reference: PMID:33284946
    reference_title: "International evidence-based consensus diagnostic and treatment guidelines for unicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The anti-interleukin-6 monoclonal antibody siltuximab should be considered for unresectable UCD patients with an inflammatory syndrome."
    explanation: The guideline statement defining siltuximab's place in unicentric disease.
  - reference: PMID:25042199
    reference_title: "Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Durable tumour and symptomatic responses occurred in 18 (34%) of 53 patients in the siltuximab group and none of 26 in the placebo group (difference 34·0%, 95% CI 11·1-54·8, p=0·0012)."
    explanation: >-
      The efficacy evidence, which comes from multicentric disease rather than
      UCD, so it reaches this entry's treatment claim only by extrapolation
      across the Castleman subtypes.
- name: Neoadjuvant Rituximab or Corticosteroids
  description: >-
    For unresectable UCD that is symptomatic because it compresses neighbouring
    structures, medical therapy with rituximab or steroids can shrink the mass
    enough to make resection possible. This is cytoreduction to enable surgery,
    not definitive therapy.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  context: Unresectable symptomatic UCD
  treatment_term:
    preferred_term: rituximab therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
    - preferred_term: corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
  evidence:
  - reference: PMID:33284946
    reference_title: "International evidence-based consensus diagnostic and treatment guidelines for unicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Unresectable UCD that is symptomatic as a result of compression of vital neighboring structures may be rendered amenable to resection by medical therapy (eg, rituximab, steroids), radiotherapy, or embolization."
    explanation: The guideline statement naming rituximab and steroids for this indication.
- name: Radiotherapy or Embolization for Unresectable UCD
  description: >-
    Alternatives to medical cytoreduction for the same goal. Radiotherapy or
    arterial embolization can debulk an unresectable symptomatic mass and may
    render it resectable.
  therapeutic_modality: RADIOTHERAPY
  context: Unresectable symptomatic UCD
  treatment_term:
    preferred_term: radiation therapy
    term:
      id: NCIT:C15313
      label: Radiation Therapy
  evidence:
  - reference: PMID:33284946
    reference_title: "International evidence-based consensus diagnostic and treatment guidelines for unicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Unresectable UCD that is symptomatic as a result of compression of vital neighboring structures may be rendered amenable to resection by medical therapy (eg, rituximab, steroids), radiotherapy, or embolization."
    explanation: The guideline statement naming radiotherapy and embolization for this indication.
discussions:
- discussion_id: gap_ucd_persistent_symptoms_after_resection
  prompt: >-
    Why do some UCD patients keep constitutional symptoms after complete excision
    with normalized laboratory markers, and what should they be offered?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#Surgical Resection
  - phenotypes#Elevated C-Reactive Protein
  rationale: >-
    Complete resection is described as often curative, so persisting symptoms
    with normal inflammatory markers after a complete excision are not explained
    by the current model, in which the resected node is the entire lesion and the
    source of the cytokine signal. Either the disease is not confined to the
    resected node in these patients, or the symptoms have a separate cause. The
    international UCD guideline names this as an open research question and
    offers no recommendation, so these patients are managed without evidence.
  evidence:
  - reference: PMID:33284946
    reference_title: "International evidence-based consensus diagnostic and treatment guidelines for unicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Further research is needed in UCD patients with persisting constitutional symptoms despite complete excision and normal laboratory markers."
    explanation: The guideline explicitly names this as an unmet research need.
  proposed_experiments:
  - experiment_id: exp_ucd_post_resection_longitudinal_profiling
    name: Longitudinal profiling of post-resection symptomatic UCD
    description: >-
      Follow UCD patients from before resection through 24 months with serial
      serum proteomics (including CXCL13, IL-6, and VEGF-A), whole-body FDG-PET,
      and patient-reported symptom scores, comparing those with and without
      persisting symptoms. Sequence the resected node and any FDG-avid residual
      site for the same somatic alleles to test whether persistent symptoms mark
      occult multicentric or multifocal disease.
    would_support:
    - pathophysiology#Somatic Stromal Cell Mutation
    supporting_outcome:
    - >-
      Symptomatic post-resection patients show residual FDG-avid nodal tissue or
      a persistently elevated cytokine signature, indicating incompletely
      resected or multifocal disease.
    refuting_outcome:
    - >-
      Symptomatic and asymptomatic post-resection patients are indistinguishable
      on imaging and cytokine profile, pointing to a cause outside the Castleman
      lesion.
- discussion_id: gap_ucd_clonal_vs_reactive
  prompt: >-
    Are the recurrent somatic PDGFRB and IL6ST alleles in UCD the initiating
    lesion, or passengers acquired inside an already-expanding stromal
    population?
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - pathophysiology#Somatic Stromal Cell Mutation
  - genetic#PDGFRB
  - genetic#IL6ST
  rationale: >-
    The answer decides whether UCD is a clonal stromal neoplasm or a reactive
    process, and therefore whether a PDGFRB inhibitor is a rational therapy for
    unresectable disease. PDGFRB N666S is activating in other diseases and PDGFRB
    marks the stromal subsets that expand here, which is suggestive. Against it:
    the alleles are present in a minority of cases, the cell of origin within the
    node has not been established, and no functional model has shown that either
    allele initiates the lesion.
  evidence:
  - reference: PMID:33804823
    reference_title: "A Review of Genetic Abnormalities in Unicentric and Multicentric Castleman Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, we continue to lack a foundational understanding of the biological mechanisms driving this disease process."
    explanation: >-
      The systematic review of Castleman molecular abnormalities states that the
      mechanistic significance of these findings is unresolved.
  proposed_experiments:
  - experiment_id: exp_ucd_sorted_stromal_variant_allele_fraction
    name: Variant allele fraction across sorted lymph node compartments
    description: >-
      Sort follicular dendritic cells, B-zone and perivascular reticular cells,
      endothelium, B cells, T cells, and plasma cells from PDGFRB- or
      IL6ST-mutant UCD nodes and measure the variant allele fraction in each. A
      driver should be near-clonal in one stromal compartment and absent from the
      hematopoietic ones; a passenger should be subclonal or spread across
      compartments.
    would_support:
    - pathophysiology#Somatic Stromal Cell Mutation
    supporting_outcome:
    - >-
      The variant is near-clonal in a single stromal compartment and absent from
      hematopoietic cells, identifying a cell of origin.
    refuting_outcome:
    - >-
      The variant is subclonal or distributed across unrelated compartments,
      indicating it was acquired within an already-expanded population.
- discussion_id: gap_ucd_no_disease_model
  prompt: >-
    Can a model system be built that reproduces the UCD lymph node lesion, and
    until one exists how can the stromal-activation mechanism be tested causally?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Lymph Node Stromal Cell Activation and Expansion
  - pathophysiology#Follicular Dendritic Cell Meshwork Expansion
  - pathophysiology#Stromal VEGF Overproduction and Neovascularization
  rationale: >-
    Every mechanism node in this entry derives from human tissue association -
    spatial transcriptomics and immunohistochemistry - with no perturbation
    experiment behind it, because no validated model system exists. That is why
    the causal direction cannot be settled: stromal activation could be driving
    the lesion or responding to it.
  evidence:
  - reference: DOI:10.1038/s41467-025-61214-1
    reference_title: "Spatial and single cell mapping of castleman disease reveals key stromal cell types and cytokine pathways"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The absence of accurate cell culture or murine models limits functional studies of CD."
    explanation: States the gap in the authors' own words.
  proposed_experiments:
  - experiment_id: exp_ucd_lymphoid_organoid_stromal_perturbation
    name: Human lymphoid organoid with defined stromal perturbation
    description: >-
      Build a human lymphoid organoid containing primary follicular dendritic
      cells, B-zone reticular cells, naive B cells, and endothelium, then perturb
      single stromal populations (constitutive PDGFRB N666S expression, forced
      VEGFA expression, lymphotoxin-beta receptor stimulation) and score for the
      defining tissue readouts: CD21 meshwork expansion, concentric mantle-zone
      B cell layering, and perifollicular neovascularization.
    would_support:
    - pathophysiology#Lymph Node Stromal Cell Activation and Expansion
    - pathophysiology#Follicular Dendritic Cell Meshwork Expansion
    supporting_outcome:
    - >-
      Perturbing a single stromal population reproduces the onion-skinning and
      penetrating-vessel architecture, establishing stromal activation as
      sufficient rather than reactive.
    refuting_outcome:
    - >-
      No stromal perturbation reproduces the architecture, indicating the lesion
      requires an input absent from the organoid.
notes: >-
  Scope note: this entry covers the unicentric (localized) form only. It was
  split out of the former umbrella `Castleman_Disease` entry, together with
  `HHV-8-Associated_Multicentric_Castleman_Disease` and
  `Idiopathic_Multicentric_Castleman_Disease`, because those forms have
  different causes, different first-line therapy, and different confirmatory
  tests - differences that live in `pathophysiology`, `treatments` and
  `diagnosis`, none of which carry a `subtype:` discriminator. The curated union
  is kept in `kb/groupings/Castleman_Disease.yaml`.

  Evidence note: the stromal pathophysiology nodes here rest on human tissue
  association without any perturbation experiment, because no validated animal
  or cell-culture model of Castleman disease exists. That limitation is recorded
  as its own knowledge gap (gap_ucd_no_disease_model) and is why those nodes
  carry EMERGING hypothesis groups rather than being asserted as established
  mechanism.

  Ontology note: `MONDO:0019753` carries "unicentric Castleman disease" only as a
  RELATED synonym, with "localized Castleman disease" as EXACT, which is why
  `disease_term.label` reads "localized". Current clinical usage is "unicentric";
  a request to promote the synonym is tracked in the split issue.