Castleman disease (etiologic types)

name: Castleman Disease
display_name: Castleman disease (etiologic types)
creation_date: "2026-08-26T00:00:00Z"
description: >-
  Castleman disease is a clinically convergent group of etiologically distinct
  lymphoproliferative disorders that share a characteristic angiofollicular
  lymph node histopathology and a downstream IL-6-driven inflammatory syndrome.
  This grouping is a curated union over the mechanistically distinct Castleman
  Disease entries - unicentric disease, HHV-8-associated multicentric disease,
  and idiopathic multicentric disease - which are deliberately kept as separate
  entries because they differ in cause, first-line therapy, and the test that
  confirms the diagnosis. POEMS-associated multicentric Castleman disease is
  historically counted as a fourth Castleman subtype but is curated inside
  POEMS_Syndrome, because its driver is the clonal plasma cell neoplasm of POEMS
  rather than anything specific to Castleman disease; it is listed here as a
  member so the historical four-way framework is not lost.
grouping_basis:
- SHARED_PHENOTYPE
- CLINICAL_CONVENTION
grouping_rationale: >-
  Grouped on a shared defining histopathology (angiofollicular lymph node
  hyperplasia) and long-standing clinical convention, NOT on a shared upstream
  mechanism: the members reach that histopathology by different routes.
  Unicentric disease is a localized stromal lesion, with recurrent somatic
  PDGFRB and IL6ST mutations, cured by resecting the single involved node.
  HHV-8-associated multicentric disease is driven by uncontrolled lytic KSHV
  replication producing a viral IL-6 homolog, and is treated by depleting the
  infected B cells with rituximab. Idiopathic multicentric disease has no known
  cause and is treated with the anti-IL-6 antibody siltuximab.
  POEMS-associated disease is driven by a clonal plasma cell neoplasm and its
  VEGF output. The members are therefore kept as separate Disease entries rather
  than merged into one umbrella entry: a single entry would have to assert a
  causal graph in which a herpesvirus infection and an unknown idiopathic
  trigger both drive the same patient's disease, and neither `Pathophysiology`,
  `Treatment` nor `Diagnosis` carries a `subtype:` discriminator that could
  scope those claims. The shared downstream IL-6 / JAK-STAT3 / acute-phase
  cascade, and the angiofollicular nodal histology it produces, are the
  convergence point common to all members.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0015564
      label: Castleman disease
    mapping_predicate: skos:closeMatch
    mapping_source: MONDO
    mapping_justification: >-
      The grouping concept corresponds closely to the MONDO Castleman disease
      class. closeMatch rather than exactMatch is used deliberately: this
      grouping's membership includes POEMS-associated disease, which dismech
      curates inside POEMS_Syndrome and which MONDO does not represent as a
      Castleman child, and it excludes MONDO:0019752 (pediatric Castleman
      disease), an age-of-onset class that cuts across the etiologic axis and is
      already flagged for obsoletion in MONDO. Membership here is the curated
      union over dismech entries and stands on its own rationale rather than
      recapitulating the MONDO hierarchy.
    consistency:
    - reference: MONDO
      consistent: INCONSISTENT
      notes: >-
        Marked INCONSISTENT for the two upstream defects named below, not
        because the members are wrong. Unicentric (MONDO:0019753) and idiopathic
        multicentric (MONDO:0035838) disease are is-a descendants of
        MONDO:0015564 as expected. First, MONDO has no term
        specific to HHV-8-associated multicentric disease: MONDO:0019754
        ("multicentric Castleman disease") is defined and classified as the
        HHV-8 form, carrying is_a MONDO:0015157 (human herpesvirus 8-related
        tumor) and an exact synonym from ORPHA:570438, so the parent class and
        the HHV-8 child are conflated. Second, and probably as a consequence,
        MONDO:0035838 is not classified under MONDO:0019754, so a query for
        descendants of "multicentric Castleman disease" returns no idiopathic
        case.
membership_criteria:
- description: >-
    A disorder belongs to the Castleman disease grouping if lymph node biopsy
    shows angiofollicular lymph node hyperplasia - abnormal germinal centers
    with mantle-zone expansion, penetrating vessels, and interfollicular
    vascular proliferation or plasmacytosis - as a defining rather than
    incidental feature of the disorder.
  criteria_semantics: NECESSARY
  logic:
    criterion_predicate: OTHER
    description: >-
      Lymph node histopathology meets the Castleman pattern (hyaline-vascular,
      plasma-cell, or mixed variant). There is no HP or GO term for the
      angiofollicular hyperplasia pattern, so this criterion cannot currently be
      expressed as a bound ontology leaf.
  evidence:
  - reference: DOI:10.1182/blood.2019000931
    reference_title: "Overview of Castleman disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Castleman disease (CD) describes a group of at least 4 disorders that share a spectrum of characteristic histopathological features but have a wide range of etiologies, presentations, treatments, and outcomes."
    explanation: >-
      States both halves of this grouping's rationale: shared histopathology as
      the membership criterion, and divergent etiology and treatment as the
      reason the members are separate entries.
- description: >-
    Membership does NOT require a shared cause, a shared first-line therapy, or
    a shared confirmatory test. Those differ between members by design, and a
    disorder is not excluded for failing to match another member on them.
  criteria_semantics: NECESSARY
  notes: >-
    Recorded as an explicit non-criterion so that a future audit does not read
    the etiologic heterogeneity of the members as a contradiction to resolve.
members:
- member: Unicentric Castleman Disease
  member_type: DISEASE
  display_name: Unicentric Castleman disease (UCD)
  disease_term:
    preferred_term: unicentric Castleman disease
    term:
      id: MONDO:0019753
      label: localized Castleman disease
  differentiating_mechanisms:
  - description: >-
      Localized to a single lymph node region, so the entire lesion and its
      stromal cytokine source are removed by resection. Recurrent somatic PDGFRB
      N666S and IL6ST mutations raise the possibility of a clonal stromal origin.
      The expanded stromal subsets are B-zone reticular cells and follicular
      dendritic cells, and VEGF expression stays confined to follicles.
    module: null
    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: The curative-resection property that distinguishes this member from all others.
- member: HHV-8-Associated Multicentric Castleman Disease
  member_type: DISEASE
  display_name: HHV-8-associated multicentric Castleman disease (HHV8+ MCD)
  disease_term:
    preferred_term: HHV-8-associated multicentric Castleman disease
  differentiating_mechanisms:
  - description: >-
      The only member with a known cause: uncontrolled lytic KSHV replication in
      plasmablasts, producing a viral IL-6 homolog that engages gp130 without
      needing the IL-6 receptor. Confirmed by HHV-8 LANA-1 immunohistochemistry,
      usually occurs with HIV co-infection, and is treated by depleting the
      infected B cells rather than by blocking the cytokine.
    evidence:
    - reference: PMID:21487108
      reference_title: "High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Castleman disease: a pilot study of virus-activated cytotoxic therapy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "It is characterized by KSHV-infected plasmablasts that frequently express lytic genes."
      explanation: Identifies the infected plasmablast that distinguishes this member.
  notes: >-
    disease_term carries no bound term: MONDO has no class for the
    HHV-8-associated form, and MONDO:0019754 is the parent of both multicentric
    arms, so binding it would claim the parent concept for one child. See the
    mapping consistency note above and the member entry's own ontology note.
- member: Idiopathic Multicentric Castleman Disease
  member_type: DISEASE
  display_name: Idiopathic multicentric Castleman disease (iMCD)
  disease_term:
    preferred_term: idiopathic multicentric Castleman disease
    term:
      id: MONDO:0035838
      label: idiopathic multicentric Castleman disease
  differentiating_mechanisms:
  - description: >-
      Multicentric and HHV-8-negative, with no identified cause. Diagnosed by
      exclusion against the international consensus criteria and treated
      first-line with the anti-IL-6 antibody siltuximab, which produces a durable
      response in about a third of patients. Carries the three clinical subtypes
      TAFRO, IPL and NOS, whose courses differ materially.
    evidence:
    - reference: DOI:10.1038/s41598-025-85193-x
      reference_title: "No evidence for active viral infection in unicentric and idiopathic multicentric Castleman disease by Viral-Track analysis"
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "While uncontrolled infection with human herpesvirus-8 (HHV-8) is responsible for the cytokine storm in a portion of multicentric CD (HHV-8-associated MCD) cases, the etiology of unicentric CD (UCD) and HHV-8-negative/idiopathic MCD (iMCD) is unknown."
      explanation: >-
        States the unknown-etiology property that distinguishes this member from
        the HHV-8-associated one.
- member: POEMS Syndrome
  member_type: DISEASE
  display_name: POEMS-associated multicentric Castleman disease (POEMS-MCD)
  disease_term:
    preferred_term: POEMS syndrome
    term:
      id: MONDO:0017364
      label: POEMS syndrome
  differentiating_mechanisms:
  - description: >-
      Driven by a clonal plasma cell neoplasm and its VEGF output rather than by
      anything specific to Castleman disease, and defined by polyradiculoneuropathy,
      a monoclonal paraprotein and sclerotic bone lesions, none of which belong to
      the other members. Outcome splits sharply on whether osteosclerotic lesions
      are present.
    evidence:
    - 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 outcome split within POEMS-associated disease and its contrast
        with the other Castleman categories.
  notes: >-
    Listed as a member for the historical four-subtype framework, but the
    Castleman manifestation is curated inside kb/disorders/POEMS_Syndrome.yaml
    (histopathology "Castleman-Type Angiofollicular Lymph Node Hyperplasia")
    rather than as a Castleman entry, because the driver is the POEMS plasma cell
    clone.
references:
- reference: PMID:39970477
  title: "Castleman's disease: one disease, multiple etiologies."
notes: >-
  This grouping replaces the former umbrella Disease entries
  kb/disorders/Castleman_Disease.yaml and
  kb/disorders/Multicentric_Castleman_Disease.yaml, which were retired when the
  concept was split. Unlike the Diabetes_Mellitus precedent, no lean umbrella
  Disease entry is retained alongside this grouping: a retained umbrella was
  exactly the duplication the split set out to remove, and the two former
  entries overlapped each other with no union record. That is a deliberate
  divergence from the diabetes pattern rather than an oversight.

  MONDO:0019752 (pediatric Castleman disease) is intentionally not a member.
  It is an age-of-onset class that cuts across the etiologic axis of this
  grouping, and it is already flagged subset:obsoletion_candidate in MONDO.
  Pediatric presentations are curated as onset and frequency detail on the
  etiologic members instead - systemic features in unicentric disease are more
  pronounced in children.