Rhabdomyosarcoma (Myogenic Soft-Tissue Sarcoma Family)

name: Rhabdomyosarcoma
display_name: Rhabdomyosarcoma (Myogenic Soft-Tissue Sarcoma Family)
creation_date: "2026-07-01T00:00:00Z"
description: >-
  Rhabdomyosarcoma (RMS) is a family of malignant soft-tissue sarcomas unified by
  skeletal-muscle (rhabdomyoblastic) differentiation: the tumor cells recapitulate
  arrested myogenesis and express myogenic transcription factors (MYOD1, myogenin)
  and structural markers (desmin). It is the most common soft-tissue sarcoma of
  childhood. Despite this shared myogenic histogenesis, the histologic subtypes
  diverge sharply by molecular driver and prognosis: fusion-positive alveolar RMS
  is driven by PAX3-FOXO1 / PAX7-FOXO1 chimeric transcription factors and carries a
  worse outcome, whereas fusion-negative embryonal RMS lacks these fusions and
  instead shows 11p15 loss of heterozygosity with IGF2 upregulation and recurrent
  RAS-pathway mutations, and generally has a more favorable prognosis. This
  grouping assembles the curated histotype Disease entries below the level of the
  MONDO taxonomy.
grouping_basis:
- SHARED_PHENOTYPE
- CLINICAL_CONVENTION
grouping_rationale: >-
  Lumped by myogenic histogenesis: every member is a malignant soft-tissue tumor
  showing skeletal-muscle (rhabdomyoblastic) differentiation with myogenic marker
  expression (MYOD1/myogenin/desmin), the unifying diagnostic feature that defines
  rhabdomyosarcoma as a clinical entity. The members are kept split as separate
  Disease entries because they are biologically and prognostically distinct along
  fusion status: fusion-positive alveolar RMS (PAX3-FOXO1 / PAX7-FOXO1) has a
  fundamentally different oncogenic driver, molecular biology, and worse prognosis
  than fusion-negative embryonal RMS (11p15 LOH / IGF2 / RAS-pathway mutations,
  better prognosis). Fusion status — not histologic pattern alone — is now the
  primary axis of clinical risk stratification, which is why the histotypes are
  curated separately rather than collapsed. The criteria are stated as NECESSARY:
  membership entails skeletal-muscle differentiation, but rhabdomyoblastic
  differentiation alone does not by itself assign a tumor to one specific member.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0005212
      label: rhabdomyosarcoma
    mapping_predicate: skos:closeMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0005212 (rhabdomyosarcoma) is the taxonomic parent under which the
      alveolar (MONDO:0009994) and embryonal (MONDO:0009993) histotypes sit, and
      it is defined as a malignant mesenchymal neoplasm arising from skeletal
      muscle — the same myogenic histogenesis that defines this grouping. A
      closeMatch (rather than exactMatch) is used because this grouping is an
      explicit curated union of the two flagship histotype Disease entries rather
      than a re-implementation of the full MONDO subtree (which also includes
      pleomorphic, spindle-cell/sclerosing, and site-specific leaf classes not
      modeled here as members).
membership_criteria:
- description: >-
    A member is a malignant soft-tissue neoplasm that exhibits skeletal-muscle
    (rhabdomyoblastic / myogenic) differentiation, evidenced histologically by
    rhabdomyoblasts and by expression of myogenic markers (MYOD1, myogenin,
    desmin). This is the unifying histogenetic feature of the rhabdomyosarcoma
    family.
  criteria_semantics: NECESSARY
  logic:
    criterion_predicate: OTHER
    description: >-
      Malignant soft-tissue neoplasm with skeletal-muscle (rhabdomyoblastic /
      myogenic) differentiation, evidenced by rhabdomyoblasts and expression of
      myogenic markers MYOD1, myogenin, and desmin (the histogenetic feature
      captured by HP:0002859, Rhabdomyosarcoma / NCIT:C3359). Modeled as an OTHER
      leaf because the member Disease entries record rhabdomyosarcoma as a
      histopathology finding rather than a self-referential phenotype descriptor,
      so the advisory evaluator returns UNKNOWN rather than verifying an HP
      phenotype fact.
members:
- member: Alveolar Rhabdomyosarcoma
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Fusion-positive histotype driven by the PAX3-FOXO1 [t(2;13)(q35;q14)] or,
      less commonly, PAX7-FOXO1 [t(1;13)(p36;q14)] chimeric transcription factor.
      The FOXO1 fusion partner (with PAX3 or PAX7) creates an aberrant
      transcription factor that reprograms enhancers, blocks terminal myogenic
      differentiation, and drives proliferation. Fusion positivity confers a
      distinctly worse prognosis and is the defining molecular contrast with
      embryonal RMS. Approximately 20% of histologically alveolar tumors are
      fusion-negative and behave like embryonal RMS.
    gene:
      preferred_term: FOXO1
      term:
        id: hgnc:3819
        label: FOXO1
- member: Embryonal Rhabdomyosarcoma
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Fusion-negative histotype and the most common subtype of rhabdomyosarcoma.
      Distinguished by loss of heterozygosity at 11p15.5 (leading to biallelic
      IGF2 overexpression) and by recurrent activating RAS-pathway mutations
      (NRAS, KRAS, HRAS in ~27% of cases) rather than a PAX-FOXO1 fusion. It
      typically affects younger children at favorable primary sites and carries a
      better prognosis than fusion-positive alveolar RMS.
    gene:
      preferred_term: NRAS
      term:
        id: hgnc:7989
        label: NRAS
notes: >-
  Umbrella-to-Grouping model for rhabdomyosarcoma (MONDO:0005212): the histotype
  members already exist as curated Disease entries, so this grouping unions them
  rather than duplicating a Disease root. The NECESSARY criterion is expressed as
  an OTHER leaf (skeletal-muscle / rhabdomyoblastic differentiation; HP:0002859,
  Rhabdomyosarcoma / NCIT:C3359) because the members encode rhabdomyosarcoma as a
  histopathology finding rather than a self-referential HP phenotype descriptor.
  The advisory membership evaluator therefore reports UNKNOWN per member, which is
  expected and advisory; the myogenic-differentiation criterion is documented in
  prose in each member's description and histopathology block.