Malignant Ovarian Sex Cord-Stromal Tumors

name: Ovarian Sex Cord-Stromal Tumors
display_name: Malignant Ovarian Sex Cord-Stromal Tumors
creation_date: "2026-08-20T00:00:00Z"
description: >-
  Malignant ovarian sex cord-stromal tumor is not a single disease but a curated
  union of tumors that share an ovarian non-epithelial, non-germ-cell origin from
  the granulosa, theca, Sertoli, Leydig and stromal fibroblast lineages, and that
  share a hormone-producing clinical signature and a comparatively favourable
  prognosis. They differ fundamentally in their driver lesion, their cell of
  origin, their age distribution, and the direction of their steroid output, and
  are therefore modelled as separate Disease entries rather than bundled into one
  entity. This grouping records the histotype framework and the lump/keep-split
  rationale over those distinct entries.

  Scope warning for future curators: despite the short `name`, this grouping is
  restricted to the MALIGNANT ovarian sex cord-stromal tumors, as the
  `display_name`, the MONDO:0018172 mapping, and the NECESSARY membership
  criterion all state. Benign or borderline sex cord-stromal neoplasms — ovarian
  fibroma, thecoma, sclerosing stromal tumor, and well-differentiated
  Sertoli-Leydig cell tumor — are OUT of scope and must not be added as members.
grouping_basis:
- CLINICAL_CONVENTION
- SHARED_PHENOTYPE
grouping_rationale: >-
  The members are lumped by anatomic site, non-epithelial gonadal-stromal lineage,
  and a shared hormone-excess presentation — that is, by clinical and
  histopathological convention — NOT by a shared mechanism, which is exactly why
  they are kept as separate Disease entries. This follows the directly parallel
  Epithelial_Ovarian_Cancer precedent, which makes the same argument for the
  epithelial histotypes of the same organ.

  The driver lesions here are not merely different, they are mutually exclusive
  within a single tumor: adult granulosa cell tumor is defined by the somatic
  FOXL2 c.402C>G (p.C134W) mutation, present in 97-99% of cases and used as a
  diagnostic test, with TERT promoter mutation as the commonest secondary event;
  malignant Sertoli-Leydig cell tumor is defined by somatic missense mutation at
  the metal-binding residues of the DICER1 RNase IIIb catalytic centre, a
  hypomorphic allele that reprograms mature miRNA output to a 3p-biased
  repertoire, frequently on a germline DICER1 loss-of-function background. A
  single molecular series of Sertoli-Leydig cell tumors found DICER1 and FOXL2
  mutations to be mutually exclusive. A lumped umbrella entry would therefore
  assert a causal graph false of every patient in it. The two members also differ
  in hormone direction (estrogenic versus androgenic), in age (postmenopausal
  versus second and third decades), and in whether a heritable cancer-predisposition
  syndrome is implicated.

  Scope, and what is deliberately absent. MONDO:0018172 has four children. Only two
  are curated as members here, because only two have enough evidenced mechanism to
  carry distinctive pathophysiology nodes. Ovarian gonadoblastoma (MONDO:0002697),
  which arises in a dysgenetic gonad carrying Y-chromosome material (GBY locus,
  TSPY), and theca steroid-producing cell malignant tumor of ovary NFS
  (MONDO:0020543), whose own Orphanet-derived definition describes it as being of
  unknown histological lineage, are noted as future members to be added when a
  mechanism-bearing entry can be written for each. Creating stub entries for them
  now would violate the promotion rule that an entity with no distinctive
  pathophysiology node should not be split out speculatively. Juvenile granulosa
  cell tumor, driven by GNAS and AKT1 in-frame duplications rather than FOXL2
  C134W, is likewise a future member; MONDO:0020541 is explicitly the adult-onset
  class, so the curated granulosa member covers the adult form only.

  The membership criterion is NECESSARY (being a member entails a malignant primary
  ovarian sex cord-stromal neoplasm), used to audit listed members. It is
  deliberately not SUFFICIENT, because ovarian sex cord-stromal origin alone does
  not assign a specific histotype and does not by itself identify which of the
  mutually exclusive driver arms a tumor belongs to.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0018172
      label: malignant sex cord stromal tumor of ovary
    mapping_predicate: skos:closeMatch
    mapping_source: MONDO
    mapping_justification: >-
      closeMatch rather than exactMatch: this grouping is the curated union of the
      malignant ovarian sex cord-stromal histotypes, closely aligned with the MONDO
      class (which MONDO itself tags `disease_grouping` and
      `ordo_group_of_disorders`) but scoped to the two curated mechanism-bearing
      member entries. Two of the four MONDO children — ovarian gonadoblastoma and
      theca steroid-producing cell malignant tumor NFS — are noted future members
      and are not yet curated, so the grouping does not currently cover the full
      MONDO descendant set.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        Both listed members are direct is-a children of MONDO:0018172
        (MONDO:0020541 maligant granulosa cell tumor of ovary; MONDO:0020542
        malignant Sertoli-Leydig cell tumor of ovary). The grouping is narrower
        than the MONDO class rather than inconsistent with it: coverage is
        incomplete (2 of 4 children) but nothing asserted here falls outside the
        MONDO subtree.
membership_criteria:
- description: >-
    A member is a malignant primary neoplasm of the ovary arising from the sex cord
    or gonadal stromal lineages (granulosa, theca, Sertoli, Leydig, or stromal
    fibroblast) rather than from ovarian/tubal surface epithelium or from germ
    cells, and manifests as an ovarian neoplasm.
  criteria_semantics: NECESSARY
  logic:
    operator: AND
    operands:
    - criterion_predicate: HAS_PHENOTYPE
      description: The member manifests an ovarian neoplasm.
      phenotype_term:
        preferred_term: Ovarian neoplasm
        term:
          id: HP:0100615
          label: Ovarian neoplasm
    - criterion_predicate: OTHER
      description: >-
        Sex cord or gonadal stromal lineage (granulosa, theca, Sertoli, Leydig, or
        stromal fibroblast), excluding epithelial and germ cell origin. Carried as
        OTHER because the unifying feature is histogenetic lineage and anatomic
        site convention rather than a single shared gene, phenotype, or mechanism
        module — the members' drivers are in fact mutually exclusive.
members:
- member: Adult Granulosa Cell Tumor of Ovary
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Defined by the somatic FOXL2 c.402C>G (p.C134W) driver, present in 97-99% of
      adult-type tumors and used diagnostically. The mutant transcription factor
      retains most wild-type DNA binding while engaging a large set of unique
      genomic elements, producing a gain-of-function oncogenic transcriptional
      program in the granulosa lineage. Presents in an older, typically
      postmenopausal population with ESTROGEN excess — abnormal uterine or
      postmenopausal bleeding and endometrial pathology — and follows an indolent
      course with characteristically late relapse, up to decades after primary
      surgery. TERT promoter mutation is the commonest secondary event and is
      enriched in recurrences. Sporadic; no heritable predisposition syndrome.
    gene:
      preferred_term: FOXL2
      term:
        id: hgnc:1092
        label: FOXL2
    modifier: GAIN_OF_FUNCTION
- member: Malignant Sertoli-Leydig Cell Tumor of Ovary
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Defined by somatic missense mutation restricted to the metal-binding residues
      of the DICER1 RNase IIIb catalytic centre — a hypomorphic allele that retains
      RNase IIIa activity while losing 5p-strand cleavage, reprogramming the mature
      miRNA repertoire to a 3p-biased profile with derepression of 5p-miRNA targets.
      Mutually exclusive with the FOXL2 driver of the granulosa member. Presents in
      the second and third decades with ANDROGEN excess (hirsutism, hair loss,
      amenorrhea/oligomenorrhea), and is confined to the moderately/poorly
      differentiated and retiform tumors; well-differentiated SLCT is DICER1
      wild-type. A substantial fraction arise on a germline DICER1 loss-of-function
      background, so unlike the granulosa member this tumor is a sentinel neoplasm
      of an autosomal dominant cancer-predisposition syndrome with surveillance and
      cascade-testing implications.
    gene:
      preferred_term: DICER1
      term:
        id: hgnc:17098
        label: DICER1
    modifier: DECREASED