Adult-type granulosa cell tumor (AGCT) is the commonest malignant ovarian sex cord-stromal tumor, accounting for a few percent of all ovarian cancers. It is defined molecularly by a single recurrent somatic missense mutation, FOXL2 c.402C>G (p.C134W), present in the large majority of morphologically typical cases and used diagnostically to separate AGCT from the other sex cord-stromal histotypes. The mutant transcription factor retains most wild-type DNA binding while acquiring a large set of unique genomic targets, engaging an oncogenic transcriptional program in granulosa cells that increases their proliferation and survival and perturbs ovarian steroidogenesis. Because the tumor cells retain granulosa-cell hormone output, most patients present with estrogen-driven abnormal uterine or postmenopausal bleeding and endometrial pathology rather than with the mass effects typical of epithelial ovarian cancer. Most tumors are stage I at diagnosis and are cured by surgery, but the disease is characteristically indolent and relapses very late — sometimes decades later — and relapse carries substantial mortality with poor systemic treatment options. TERT promoter mutation is the commonest secondary event and is enriched in recurrences. This entry is a member of the curated Ovarian Sex Cord-Stromal Tumors grouping, which keeps the driver-distinct histotypes as separate Disease entries.
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name: Adult Granulosa Cell Tumor of Ovary
creation_date: "2026-08-20T00:00:00Z"
description: >-
Adult-type granulosa cell tumor (AGCT) is the commonest malignant ovarian sex
cord-stromal tumor, accounting for a few percent of all ovarian cancers. It is
defined molecularly by a single recurrent somatic missense mutation,
FOXL2 c.402C>G (p.C134W), present in the large majority of morphologically
typical cases and used diagnostically to separate AGCT from the other sex
cord-stromal histotypes. The mutant transcription factor retains most wild-type
DNA binding while acquiring a large set of unique genomic targets, engaging an
oncogenic transcriptional program in granulosa cells that increases their
proliferation and survival and perturbs ovarian steroidogenesis. Because the
tumor cells retain granulosa-cell hormone output, most patients present with
estrogen-driven abnormal uterine or postmenopausal bleeding and endometrial
pathology rather than with the mass effects typical of epithelial ovarian
cancer. Most tumors are stage I at diagnosis and are cured by surgery, but the
disease is characteristically indolent and relapses very late — sometimes
decades later — and relapse carries substantial mortality with poor systemic
treatment options. TERT promoter mutation is the commonest secondary event and
is enriched in recurrences. This entry is a member of the curated
Ovarian Sex Cord-Stromal Tumors grouping, which keeps the driver-distinct
histotypes as separate Disease entries.
categories:
- Gynecologic Cancer
- Ovarian Cancer
- Sex Cord-Stromal Tumor
- Solid Tumor
disease_term:
preferred_term: adult-type granulosa cell tumor of the ovary
term:
id: MONDO:0020541
label: maligant granulosa cell tumor of ovary
parents:
- ovarian sex cord-stromal tumor
notes: >-
The MONDO label recorded above ("maligant granulosa cell tumor of ovary") contains
an upstream spelling error for "malignant". It is reproduced verbatim because
`term.label` must match the canonical ontology label exactly; it is not a curation
typo, and it is present in both the local MONDO build and OLS. MONDO:0020541 is
explicitly the adult-onset class (`RO:0000053 HP:0003581 Adult onset`, synonym
"adult ovarian granulosa cell tumor"), which is why this entry is scoped to the
adult type and does not model juvenile granulosa cell tumor — the juvenile form is
driven by GNAS and AKT1 in-frame duplications rather than FOXL2 C134W and is
deliberately left as a future separate entry.
pathophysiology:
- name: FOXL2 C134W Somatic Driver Mutation
biological_scale: MOLECULAR
description: >-
A single recurrent somatic missense point mutation, c.402C>G (p.C134W), in the
forkhead transcription factor FOXL2 is present in essentially all morphologically
typical adult-type granulosa cell tumors and is absent from other sex cord-stromal
tumor types and from unrelated ovarian and breast tumors. FOXL2 is the master
transcriptional regulator of granulosa-cell identity, so the mutation lands in the
lineage-defining factor of the tumor's cell of origin.
cell_types:
- preferred_term: granulosa cell
term:
id: CL:0000501
label: granulosa cell
locations:
- preferred_term: ovary
term:
id: UBERON:0000992
label: ovary
downstream:
- target: Altered FOXL2 Transcriptional Program
description: >-
The C134W substitution lies in the forkhead DNA-binding domain and changes which
genomic elements the FOXL2 complex engages.
evidence:
- reference: PMID:19516027
reference_title: Mutation of FOXL2 in granulosa-cell tumors of the ovary.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All four index GCTs had a missense point mutation, 402C-->G (C134W), in FOXL2, a
gene encoding a transcription factor known to be critical for granulosa-cell
development.
explanation: >-
The founding whole-transcriptome study identifies the recurrent somatic FOXL2
mutation and names FOXL2 as the granulosa-lineage transcription factor.
- reference: PMID:19516027
reference_title: Mutation of FOXL2 in granulosa-cell tumors of the ovary.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The FOXL2 mutation was present in 86 of 89 additional adult-type GCTs (97%), in 3
of 14 thecomas (21%), and in 1 of 10 juvenile-type GCTs (10%).
explanation: >-
Quantifies the near-universal presence of the mutation in adult-type GCT and its
rarity in the juvenile form, supporting adult-restricted scoping of this entry.
- reference: PMID:39615884
reference_title: "The Molecular Landscape of 227 Adult Granulosa Cell Tumors of the Ovary: Insights into the Progression from Primary to Recurrence."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Our findings confirmed the high prevalence (99%) of the FOXL2 p.C134W mutation in
AGCTs.
explanation: >-
Independent replication in a 227-tumor cohort confirms the near-universal driver
frequency.
- name: Altered FOXL2 Transcriptional Program
biological_scale: MOLECULAR
description: >-
Mutant FOXL2 C134W binds most of the wild-type FOXL2 DNA elements but additionally
engages a large collection of genomic elements not bound by wild-type FOXL2. The
result is a gain-of-function shift in the regulatory output of FOXL2-containing
complexes rather than a simple loss of FOXL2 activity, and mouse modelling shows
the resulting transcriptome is dominated by hallmark-of-cancer programs including
dysregulated TGF-beta signalling.
molecular_functions:
- preferred_term: FOXL2 DNA-binding transcription factor activity
modifier: GAIN_OF_FUNCTION
term:
id: GO:0003700
label: DNA-binding transcription factor activity
cell_types:
- preferred_term: granulosa cell
term:
id: CL:0000501
label: granulosa cell
downstream:
- target: Granulosa Cell Proliferation and Survival
description: >-
The rewired transcriptional program drives the proliferative and anti-apoptotic
phenotype of the tumor cells.
- target: Aberrant Ovarian Steroidogenesis and Estrogen Excess
description: >-
The same rewired program perturbs the hormonal output of the granulosa cell.
evidence:
- reference: PMID:32641414
reference_title: The Pathognomonic FOXL2 C134W Mutation Alters DNA-Binding Specificity.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
FOXL2C134W associated with the majority of the FOXL2 wild-type DNA elements as
well as a large collection of unique elements genome wide.
explanation: >-
Isogenic ChIP-seq shows the mutation redirects rather than abolishes FOXL2 DNA
binding, which is the mechanistic content of this node.
- reference: PMID:32641414
reference_title: The Pathognomonic FOXL2 C134W Mutation Alters DNA-Binding Specificity.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Our results suggest FOXL2C134W drives AGCT by altering the binding affinity of
FOXL2-containing complexes to engage an oncogenic transcriptional program.
explanation: >-
States the authors' mechanistic conclusion that an oncogenic transcriptional
program is the proximate consequence of the mutation.
- reference: PMID:36409821
reference_title: The Oncogenic FOXL2 C134W Mutation Is a Key Driver of Granulosa Cell Tumors.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
The genes dysregulated in mouse AGCTs exhibited the hallmarks of cancer and were
consistent with a gain-of-function of the mutated allele affecting TGFβ signaling.
explanation: >-
Mouse knock-in transcriptomics support the gain-of-function reading of the C134W
allele used for the modifier annotation on this node.
- reference: PMID:32641414
reference_title: The Pathognomonic FOXL2 C134W Mutation Alters DNA-Binding Specificity.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
This model enabled confirmation of altered DNA-binding specificity for FOXL2C134W
and identification of unique targets of FOXL2C134W including SLC35F2, whose
expression increased sensitivity to YM155.
explanation: >-
Names a specific neomorphic target of the mutant transcription factor, SLC35F2,
and links it to a candidate therapeutic vulnerability (YM155 sensitivity) — the
one concrete druggable consequence of the rewired program identified so far.
notes: >-
SLC35F2, a uniquely FOXL2 C134W-bound target identified in the isogenic model, is an
uptake transporter whose expression increases sensitivity to YM155 (sepantronium).
This is recorded as a preclinical mechanism-to-therapy lead only; no clinical data
in adult granulosa cell tumor exist, so no corresponding treatment is curated.
- name: Granulosa Cell Proliferation and Survival
biological_scale: CELLULAR
description: >-
Downstream of the rewired FOXL2 program, granulosa cells acquire increased
proliferation and increased survival, progressing in the knock-in mouse through
aberrant granulosa cells and stromal hyperplasia with atypia to frank tumor. Mouse
transcriptomic analysis found no evidence of additional driver mutations beyond
FOXL2 C134W, consistent with a single-hit tumor.
cell_types:
- preferred_term: granulosa cell
term:
id: CL:0000501
label: granulosa cell
downstream:
- target: Indolent Tumor Growth with Late Recurrence
description: >-
Sustained but slow granulosa-cell expansion underlies the characteristically
indolent natural history.
evidence:
- reference: PMID:28276867
reference_title: Pathogenesis and treatment of adult-type granulosa cell tumor of the ovary.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The FOXL2 402C->G mutation leads to increased proliferation and survival of
granulosa cells, and promotes hormonal changes.
explanation: >-
States the proliferation/survival consequence and the hormonal arm that this node
and its sibling steroidogenesis node model.
- reference: PMID:36409821
reference_title: The Oncogenic FOXL2 C134W Mutation Is a Key Driver of Granulosa Cell Tumors.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Foxl2+/C134W female mice had reduced fertility and developed AGCTs through a
progression from abnormal ovaries with aberrant granulosa cells to ovaries with
stromal hyperplasia and atypia and on to tumors in adut mice.
explanation: >-
In vivo knock-in evidence that the mutation alone is sufficient to drive stepwise
granulosa-cell expansion to tumor. The abstract's spelling of "adut" is reproduced
verbatim from the cached record.
- name: Aberrant Ovarian Steroidogenesis and Estrogen Excess
biological_scale: ORGANISM
description: >-
Because AGCT arises from a hormonally active lineage, the tumor continues to
secrete granulosa-cell products. Excess estrogen production unopposed by
progesterone drives the endometrial proliferative pathology and abnormal bleeding
that dominate the clinical presentation, and the same retained differentiation
makes inhibin B and anti-Mullerian hormone useful circulating tumor markers.
biological_processes:
- preferred_term: ovarian estrogen biosynthesis
modifier: INCREASED
term:
id: GO:0006703
label: estrogen biosynthetic process
cell_types:
- preferred_term: granulosa cell
term:
id: CL:0000501
label: granulosa cell
downstream:
- target: Estrogen-Driven Endometrial Pathology
description: >-
Unopposed estrogen acts on the endometrium to produce hyperplasia and, in a
minority, carcinoma.
evidence:
- reference: PMID:28276867
reference_title: Pathogenesis and treatment of adult-type granulosa cell tumor of the ovary.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Anti-Müllerian Hormone and inhibin B are currently the most accurate circulating
biomarkers.
explanation: >-
Confirms that the tumor retains granulosa-cell secretory differentiation, which is
what makes these hormones measurable disease markers.
- reference: PMID:19809549
reference_title: "Prognostic factors in adult granulosa cell tumors of the ovary: a retrospective analysis of 80 cases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Endometrial pathology was detected in 51.2% of patients preoperatively.
explanation: >-
Quantifies the downstream endometrial consequence of tumor estrogen output in a
surgically staged human cohort.
- name: Estrogen-Driven Endometrial Pathology
biological_scale: TISSUE
description: >-
Chronic unopposed estrogen from the tumor produces endometrial proliferation and
hyperplasia in about half of patients at presentation, with a minority developing
synchronous endometrial carcinoma. This is the mechanistic route by which a
hormonally active ovarian tumor presents as a uterine bleeding problem.
locations:
- preferred_term: endometrium
term:
id: UBERON:0001295
label: endometrium
evidence:
- reference: PMID:19809549
reference_title: "Prognostic factors in adult granulosa cell tumors of the ovary: a retrospective analysis of 80 cases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The most common presenting symptom was abnormal uterine bleeding (53.7%).
explanation: >-
Human cohort data showing that estrogen-driven bleeding is the leading route to
diagnosis.
notes: >-
This node deliberately has no outgoing causal edge. Early symptomatic bleeding does
bring most patients to diagnosis at stage I, but early *detection* is not a cause of
the tumor's indolent *biology*, so drawing an edge to the late-recurrence node would
assert a causal claim the evidence does not make. The stage-at-diagnosis observation
is recorded under progression instead.
- name: TERT Promoter Activation and Telomerase Reactivation
biological_scale: MOLECULAR
conforms_to: "enabling_replicative_immortality#Telomere Maintenance Reactivation"
description: >-
TERT promoter mutation (C228T or C250T) is the commonest secondary genetic event in
AGCT after the FOXL2 driver, present in roughly 40% of tumors and enriched in
recurrent disease. Telomerase is normally silenced in somatic cells, so promoter
activation restores the telomere maintenance required for unlimited replicative
capacity — the tumor-specific substitution of the generic telomere-maintenance
reactivation node of the replicative-immortality hallmark module.
biological_processes:
- preferred_term: telomere maintenance via telomerase
modifier: INCREASED
term:
id: GO:0007004
label: telomere maintenance via telomerase
downstream:
- target: Indolent Tumor Growth with Late Recurrence
description: >-
TERT promoter mutation is enriched in recurrences and independently associated
with shorter progression-free survival after first recurrence.
evidence:
- reference: PMID:39615884
reference_title: "The Molecular Landscape of 227 Adult Granulosa Cell Tumors of the Ovary: Insights into the Progression from Primary to Recurrence."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
TERT promoter mutations were found in 43% of cases, more frequently in recurrences.
explanation: >-
Establishes both the frequency of TERT promoter mutation in AGCT and its
enrichment at recurrence.
- reference: PMID:39395821
reference_title: TERT promoter mutations and survival outcomes in adult-type granulosa cell tumors.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Telomerase is normally silenced in somatic cells, but many tumors gain the
function of telomerase to attain capacity for continued proliferation.
explanation: >-
States the mechanistic rationale for treating TERT promoter activation as
telomere-maintenance reactivation, the module node this node conforms to.
- name: FGFR1 Kinase-Domain Mutation in FOXL2-Wildtype Tumors
biological_scale: MOLECULAR
conforms_to: "sustaining_proliferative_signaling#Oncogenic Growth-Signal Lesion"
description: >-
A small subset of morphologically classic AGCTs lack the FOXL2 C134W driver. In
these, recurrent FGFR1 kinase-domain hotspot mutations (codons N546, N577, K656,
K687) provide an alternative receptor tyrosine kinase oncogenic lesion. This node
conforms only to the module's upstream growth-signal lesion, not to its downstream
constitutive mitogenic pathway node, because activation of RAS-MAPK or PI3K-AKT
output has not been demonstrated in these particular tumors.
downstream:
- target: Granulosa Cell Proliferation and Survival
description: >-
In FOXL2-wildtype tumors the FGFR1 lesion substitutes for the FOXL2 driver as the
route to the same proliferative granulosa-cell phenotype, which is why these
tumors are morphologically and clinically indistinguishable from conventional
AGCT.
evidence:
- reference: PMID:41128462
reference_title: FGFR1 Mutations Are Rare Alternate Oncogenic Drivers in FOXL2-Wildtype Adult Granulosa Cell Tumors of the Ovary.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Seven cases were identified with FGFR1 hotspot mutations (codons N546, N577, K656,
and K687), 6 of which lacked the pathognomonic FOXL2 p.C134W variant.
explanation: >-
Documents the specific kinase-domain hotspots and their near-complete mutual
exclusivity with the FOXL2 driver.
- reference: PMID:41128462
reference_title: FGFR1 Mutations Are Rare Alternate Oncogenic Drivers in FOXL2-Wildtype Adult Granulosa Cell Tumors of the Ovary.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
No distinct morphologic or immunophenotypic differences were found compared with
conventional FOXL2 -mutant aGCTs.
explanation: >-
Supports the downstream edge: the FGFR1 route converges on a phenotype
indistinguishable from the FOXL2-driven one.
- name: Indolent Tumor Growth with Late Recurrence
biological_scale: ORGANISM
description: >-
AGCT is characteristically indolent. Most tumors are confined to the ovary at
diagnosis and are cured by surgery, but roughly a third of patients relapse, and
relapse can occur anywhere from one to several decades after primary treatment.
Recurrent disease responds poorly to systemic therapy and carries substantial
mortality, so late recurrence rather than primary aggressiveness is what makes this
a malignant entity.
evidence:
- reference: PMID:39395821
reference_title: TERT promoter mutations and survival outcomes in adult-type granulosa cell tumors.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Adult granulosa cell tumors are an indolent tumor with recurrences reported between
1 and 36 years after initial treatment.
explanation: >-
Directly documents the very long and variable interval to recurrence that defines
this node.
- reference: PMID:28276867
reference_title: Pathogenesis and treatment of adult-type granulosa cell tumor of the ovary.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
However, every third of the patients relapse, typically in 4-7 years from
diagnosis, leading to death in 50% of these patients.
explanation: >-
Quantifies both relapse rate and the mortality that follows relapse.
- reference: PMID:37068116
reference_title: "Comparative Tumor Microenvironment Analysis of Primary and Recurrent Ovarian Granulosa Cell Tumors."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Integrative TME analysis demonstrated statistically significant depletion of
cancer-associated fibroblasts in recurrent tumors. This finding was confirmed in
multiple independent datasets.
explanation: >-
Adds a tumor-microenvironment dimension to recurrence: relapse is accompanied by
remodeling of the stromal compartment, not only by the tumor-intrinsic TERT and
hormone-pathway changes modeled upstream. Replicated in independent datasets.
- reference: PMID:21481441
reference_title: Patterns of spread and recurrence of sex cord-stromal tumors of the ovary.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Tumor size was significantly associated with risk of recurrent disease, with a 20%
increase in the hazard of recurrence for each increase of tumor size of 1cm
explanation: >-
PARTIAL: identifies tumor size as a quantified recurrence risk factor, but in a
pooled sex cord-stromal cohort (82% adult granulosa cell tumor, 13%
Sertoli-Leydig) rather than a purely AGCT series.
phenotypes:
- category: Clinical
name: Abnormal Uterine Bleeding
description: >-
Estrogen-driven abnormal uterine bleeding is the single commonest presenting
symptom, reported in just over half of surgically staged patients.
phenotype_term:
preferred_term: Abnormal uterine bleeding
term:
id: HP:0100608
label: Metrorrhagia
frequency: FREQUENT
evidence:
- reference: PMID:19809549
reference_title: "Prognostic factors in adult granulosa cell tumors of the ovary: a retrospective analysis of 80 cases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The most common presenting symptom was abnormal uterine bleeding (53.7%).
explanation: >-
53.7% of 80 surgically staged patients falls in the 30-79% FREQUENT band and is a
direct quantitative measurement of this phenotype's frequency.
- reference: PMID:41518037
reference_title: Phase II clinical trial of nirogacestat in patients with relapsed ovarian granulosa cell tumours.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The majority of GCT are detected at an early stage, with symptoms of abnormal
uterine bleeding and abdominal and/or pelvic pain commonly reported.
explanation: >-
Independent confirmation, in a granulosa-cell-tumor-specific source, that abnormal
uterine bleeding is a commonly reported presenting symptom of this disease.
- category: Clinical
name: Endometrial Carcinoma
description: >-
A minority of patients have a synchronous endometrial carcinoma arising from
chronic unopposed estrogen stimulation; endometrial pathology short of carcinoma is
much commoner and is found in about half of patients preoperatively.
phenotype_term:
preferred_term: Endometrial carcinoma
term:
id: HP:0012114
label: Endometrial carcinoma
evidence:
- reference: PMID:19809549
reference_title: "Prognostic factors in adult granulosa cell tumors of the ovary: a retrospective analysis of 80 cases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Endometrial pathology was detected in 51.2% of patients preoperatively.
explanation: >-
PARTIAL because the cohort reports "endometrial pathology" as a composite that
includes hyperplasia as well as carcinoma; it establishes the estrogen-driven
endometrial phenotype but does not by itself quantify carcinoma.
- category: Clinical
name: Ovarian Mass
description: >-
A unilateral adnexal mass is the structural correlate of the tumor and is usually
confined to one ovary at diagnosis.
phenotype_term:
preferred_term: Ovarian neoplasm
term:
id: HP:0100615
label: Ovarian neoplasm
evidence:
- reference: PMID:19809549
reference_title: "Prognostic factors in adult granulosa cell tumors of the ovary: a retrospective analysis of 80 cases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Seventy percent of patients were diagnosed at stage I, and 53.8% of patients
received adjuvant treatment.
explanation: >-
Stage I disease is by definition tumor confined to the ovary/ovaries, so this
directly evidences the ovary-confined adnexal mass that is the usual presentation.
- category: Laboratory
name: Elevated Serum Estradiol
description: >-
Circulating estradiol is raised by the tumor's retained granulosa-cell
steroidogenic activity, producing the estrogenic clinical picture.
phenotype_term:
preferred_term: Increased serum estradiol
term:
id: HP:0025134
label: Increased serum estradiol
evidence:
- reference: PMID:28276867
reference_title: Pathogenesis and treatment of adult-type granulosa cell tumor of the ovary.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The FOXL2 402C->G mutation leads to increased proliferation and survival of
granulosa cells, and promotes hormonal changes.
explanation: >-
PARTIAL: the review states that the driver mutation promotes hormonal changes but
does not quantify circulating estradiol, so this supports the mechanism rather
than a measured laboratory value.
histopathology:
- name: Microfollicular Growth with Call-Exner Bodies and Coffee-Bean Nuclei
description: >-
Classic AGCT histology comprises microfollicular growth with Call-Exner bodies and
nuclei with longitudinal grooves ("coffee bean" nuclei), with strong inhibin-alpha
expression by immunohistochemistry. Because morphology alone is not reliable,
FOXL2 genotyping is used to confirm the diagnosis.
diagnostic: true
evidence:
- reference: PMID:41128462
reference_title: FGFR1 Mutations Are Rare Alternate Oncogenic Drivers in FOXL2-Wildtype Adult Granulosa Cell Tumors of the Ovary.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All tumors demonstrated the classic histology of aGCT (microfollicular growth,
Call-Exner bodies, "coffee bean" nuclei) with 5/5 showing robust inhibin-α
positivity by immunohistochemistry.
explanation: >-
Enumerates the defining morphologic and immunophenotypic features of AGCT.
- reference: PMID:28276867
reference_title: Pathogenesis and treatment of adult-type granulosa cell tumor of the ovary.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Histological diagnosis of adult-type granulosa cell tumor is challenging, therefore
testing for the FOXL2 mutation is crucial for differential diagnosis.
explanation: >-
Supports the caveat that morphology alone is insufficient and molecular testing is
required.
- name: Prognostic Immunohistochemical Markers (CD56, GATA-4, SMAD3)
description: >-
A systematic review of prognostic markers in adult granulosa cell tumor found
immunohistochemical expression of CD56, GATA-4 and SMAD3 to be associated with
reduced prognosis, while estrogen receptor, anti-Mullerian hormone and inhibin
staining carried no prognostic information despite AMH and inhibin being the
established circulating disease markers. Mitotic rate, Ki-67, p53, beta-catenin and
HER2 gave inconsistent results across studies. The SMAD3 signal is of mechanistic
interest because SMAD2/3 activation in the presence of FOXL2 is the shared feature
of the genetically unrelated Foxo1/3/Pten mouse tumor model.
evidence:
- reference: PMID:36869369
reference_title: Immunohistochemical markers of prognosis in adult granulosa cell tumors of the ovary - a review.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
FOXL2 mutation and FOXL2 mRNA were inverse and immunohistochemical (IHC) expression
of CD56, GATA-4 and SMAD3 was associated with reduced prognosis. IHC analysis of
estrogen receptor, Anti-Mullerian hormone (AMH) and inhibin was not associated with
prognosis for GCT.
explanation: >-
Systematic review evidence for which immunohistochemical markers carry prognostic
weight in this tumor and, importantly, which established biomarkers do not.
diagnosis:
- name: FOXL2 c.402C>G Mutation Testing
description: >-
Because AGCT morphology overlaps other sex cord-stromal histotypes and cannot be
predicted reliably by morphology alone, targeted testing for the FOXL2 c.402C>G
(p.C134W) mutation is the decisive diagnostic step separating AGCT from its
siblings. The corollary matters too: a negative result does not exclude the
diagnosis when morphology and immunophenotype are characteristic, since a small
FOXL2-wildtype subset is driven by FGFR1 instead.
evidence:
- reference: PMID:28276867
reference_title: Pathogenesis and treatment of adult-type granulosa cell tumor of the ovary.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Histological diagnosis of adult-type granulosa cell tumor is challenging, therefore
testing for the FOXL2 mutation is crucial for differential diagnosis.
explanation: >-
States that molecular testing, not morphology, is what secures the diagnosis.
- reference: PMID:41128462
reference_title: FGFR1 Mutations Are Rare Alternate Oncogenic Drivers in FOXL2-Wildtype Adult Granulosa Cell Tumors of the Ovary.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
From a diagnostic standpoint, the absence of FOXL2 p.C134W mutation does not exclude
the diagnosis of aGCT when the morphology and immunoprofile are characteristic.
explanation: >-
Supports the explicit negative-result caveat, which is the part of this diagnostic
rule most likely to cause a misdiagnosis if omitted.
biochemical:
- name: Inhibin B
notes: >-
Inhibin B is a granulosa-cell product retained by the tumor and is a sensitive and
specific circulating marker used to detect recurrence during follow-up. In a
postmenopausal cohort a 7 pg/mL cut-off gave 98.8% sensitivity and 88.9%
specificity for the presence of disease.
evidence:
- reference: PMID:33893147
reference_title: Role of inhibin B in detecting recurrence of granulosa cell tumors of the ovary in postmenopausal patients.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
At a cut-off of 7 pg/mL, inhibin B levels were significantly correlated with the
presence/absence of disease (p<0.01), with a sensitivity of 98.8% (95% confidence
interval (CI) 95.8% to 99.9%) and a specificity of 88.9% (95% CI 82.6% to 93.5%).
explanation: >-
Provides the operating characteristics of inhibin B as a recurrence-detection
marker in this disease.
- name: Anti-Mullerian Hormone
notes: >-
Anti-Mullerian hormone is the other granulosa-cell-derived circulating marker used
in AGCT follow-up alongside inhibin B.
evidence:
- reference: PMID:28276867
reference_title: Pathogenesis and treatment of adult-type granulosa cell tumor of the ovary.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Anti-Müllerian Hormone and inhibin B are currently the most accurate circulating
biomarkers.
explanation: >-
Names AMH as one of the two most accurate circulating biomarkers for this tumor.
genetic:
- name: FOXL2
association: >-
Pathognomonic somatic missense driver mutation c.402C>G (p.C134W); present in
97-99% of adult-type granulosa cell tumors and used as a diagnostic test.
gene_term:
preferred_term: FOXL2
term:
id: hgnc:1092
label: FOXL2
variant_origin: SOMATIC
case_fractions:
- population: Multi-institutional cohort of 227 adult granulosa cell tumors
case_fraction_percent: 99.0
cohort_size: 227
notes: >-
Targeted NGS across 786 cancer-related genes in 183 primary and 44 recurrent
AGCTs.
evidence:
- reference: PMID:39615884
reference_title: "The Molecular Landscape of 227 Adult Granulosa Cell Tumors of the Ovary: Insights into the Progression from Primary to Recurrence."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Our findings confirmed the high prevalence (99%) of the FOXL2 p.C134W mutation in
AGCTs.
explanation: Quantifies the share of AGCT cases carrying the FOXL2 driver.
evidence:
- reference: PMID:28276867
reference_title: Pathogenesis and treatment of adult-type granulosa cell tumor of the ovary.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Histological diagnosis of adult-type granulosa cell tumor is challenging, therefore
testing for the FOXL2 mutation is crucial for differential diagnosis.
explanation: >-
Establishes the diagnostic, not merely mechanistic, role of the FOXL2 genotype in
separating AGCT from its sex cord-stromal siblings.
- name: TERT
association: >-
Promoter mutation (C228T/C250T) is the commonest secondary event, found in roughly
40-43% of tumors, enriched in recurrences, and independently associated with shorter
progression-free survival after first recurrence.
gene_term:
preferred_term: TERT
term:
id: hgnc:11730
label: TERT
variant_origin: SOMATIC
evidence:
- reference: PMID:39395821
reference_title: TERT promoter mutations and survival outcomes in adult-type granulosa cell tumors.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Multivariable analysis adjusting for age at diagnosis, TERT promoter mutation
status, systemic chemotherapy, and stage demonstrated a significant difference in
progression-free survival based on TERT mutation status (HR=2.89; 95% CI 1.32 to
6.36).
explanation: >-
Supports the prognostic component of the TERT association with an adjusted hazard
ratio.
- name: FGFR1
association: >-
Recurrent kinase-domain hotspot mutations act as an alternative oncogenic driver in
a small subset of FOXL2-wildtype adult granulosa cell tumors.
gene_term:
preferred_term: FGFR1
term:
id: hgnc:3688
label: FGFR1
variant_origin: SOMATIC
evidence:
- reference: PMID:41128462
reference_title: FGFR1 Mutations Are Rare Alternate Oncogenic Drivers in FOXL2-Wildtype Adult Granulosa Cell Tumors of the Ovary.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These findings establish FGFR1 alterations as an alternative oncogenic driver in a
subset of FOXL2 -wildtype aGCTs.
explanation: >-
Establishes FGFR1 as a genuine alternative driver gene in this disease.
- name: KMT2D
association: >-
Recurrent secondary loss-of-function mutations, found in about 10% of tumors, and
reported as a driver in rare FOXL2-wildtype tumors with typical AGCT morphology.
gene_term:
preferred_term: KMT2D
term:
id: hgnc:7133
label: KMT2D
variant_origin: SOMATIC
evidence:
- reference: PMID:39615884
reference_title: "The Molecular Landscape of 227 Adult Granulosa Cell Tumors of the Ovary: Insights into the Progression from Primary to Recurrence."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Two cases with typical AGCT morphology were FOXL2 wild-type, harboring mutations
in KRAS or KMT2D instead, suggesting alternative genetic pathways.
explanation: >-
Documents KMT2D as one of the alternative genetic routes in FOXL2-wildtype AGCT.
prevalence:
- population: Worldwide
measure_type: UNKNOWN
prevalence_class: RARE
notes: >-
Reported as 3-5% of all ovarian cancers. The source states a proportion of ovarian
malignancy rather than a population rate, so neither a measure type nor a
rate_per_100000 can be asserted.
evidence:
- reference: PMID:28276867
reference_title: Pathogenesis and treatment of adult-type granulosa cell tumor of the ovary.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These tumors originate from the sex cord stromal cells of the ovary and represent
3-5% of all ovarian cancers.
explanation: >-
Gives the share of ovarian cancer accounted for by adult-type granulosa cell tumor.
progression:
- phase: Early-stage presentation and surgical cure
notes: >-
About 70% of patients are diagnosed at stage I and are cured by surgery alone.
Overall 5-year and 10-year survival in a surgically staged cohort were 91% and 86%.
Stage at diagnosis is the only prognostic factor that has been consistently
reproduced.
evidence:
- reference: PMID:19809549
reference_title: "Prognostic factors in adult granulosa cell tumors of the ovary: a retrospective analysis of 80 cases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Overall 5-year and 10-year survival was 91% and 86%, respectively.
explanation: Quantifies the favourable overall survival of surgically staged AGCT.
- reference: PMID:28276867
reference_title: Pathogenesis and treatment of adult-type granulosa cell tumor of the ovary.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Tumor stage is the only factor consistently associated with prognosis.
explanation: >-
Supports stage as the dominant, and only consistently reproduced, prognostic
determinant.
- phase: Late relapse and poor systemic salvage
notes: >-
Roughly one third of patients relapse, typically 4-7 years after diagnosis but with
reported intervals from 1 to 36 years, and half of those who relapse die of the
disease. Response rates to systemic therapy in the recurrent setting have been
poor, so repeat cytoreductive surgery remains the mainstay.
evidence:
- reference: PMID:28276867
reference_title: Pathogenesis and treatment of adult-type granulosa cell tumor of the ovary.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
However, every third of the patients relapse, typically in 4-7 years from
diagnosis, leading to death in 50% of these patients.
explanation: Quantifies relapse frequency, timing, and post-relapse mortality.
- reference: PMID:39395821
reference_title: TERT promoter mutations and survival outcomes in adult-type granulosa cell tumors.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Overall, response rates to systemic therapy in recurrent adult granulosa cell
tumors have been disappointing.
explanation: >-
Supports the poor systemic salvage that makes late relapse clinically consequential.
treatments:
- name: Primary Surgical Resection
description: >-
Surgery is the cornerstone of treatment for both primary and relapsed disease.
Comprehensive staging surgery is recommended because stage is the dominant
prognostic factor; unilateral salpingo-oophorectomy is used in younger patients
wishing to preserve fertility.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: salpingo-oophorectomy
term:
id: NCIT:C15323
label: Salpingo-Oophorectomy
target_mechanisms:
- target: Indolent Tumor Growth with Late Recurrence
treatment_effect: INHIBITS
description: >-
Complete resection of the primary tumor is what converts the indolent natural
history into cure in the majority of stage I patients.
evidence:
- reference: PMID:28276867
reference_title: Pathogenesis and treatment of adult-type granulosa cell tumor of the ovary.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Surgery is the cornerstone for the treatment of both primary and relapsed tumor,
while chemotherapy is applied only for advanced or non-resectable cases.
explanation: >-
States that surgery, not systemic therapy, is the primary modality against the
tumor burden.
evidence:
- reference: PMID:19809549
reference_title: "Prognostic factors in adult granulosa cell tumors of the ovary: a retrospective analysis of 80 cases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Therefore, a comprehensive staging surgery should be attempted to document the real
extent of disease and to estimate the oncologic outcome more accurately.
explanation: Supports comprehensive staging surgery as the recommended primary approach.
- reference: PMID:21481441
reference_title: Patterns of spread and recurrence of sex cord-stromal tumors of the ovary.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These findings support the hypothesis that routine lymphadenectomy provides limited
additional information in the management of these patients and can be omitted from
the primary surgical staging procedure or secondary restaging procedures.
explanation: >-
Qualifies the scope of "comprehensive staging": nodal metastasis is rare in sex
cord-stromal tumors, so lymphadenectomy can be omitted. This matters clinically
because it is where staging for this tumor departs from epithelial ovarian cancer.
- name: Cytoreductive Surgery for Recurrence
description: >-
Because systemic options are poor, secondary cytoreduction is the preferred
treatment for relapsed AGCT, with systemic chemotherapy, endocrine therapy, or
radiation added selectively.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: cytoreductive surgery
term:
id: NCIT:C132068
label: Cytoreductive Surgery
target_mechanisms:
- target: Indolent Tumor Growth with Late Recurrence
treatment_effect: INHIBITS
description: >-
Repeat resection of recurrent deposits is the principal means of controlling late
relapse.
evidence:
- reference: PMID:39615884
reference_title: "The Molecular Landscape of 227 Adult Granulosa Cell Tumors of the Ovary: Insights into the Progression from Primary to Recurrence."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Adult granulosa cell tumors (AGCTs) of the ovary are characterized by their
propensity for late recurrences and are primarily managed surgically due to the
limited efficacy of systemic treatment.
explanation: >-
States explicitly that surgical management is chosen because systemic treatment
is of limited efficacy against recurrent disease.
- name: Platinum-Based Chemotherapy
description: >-
Chemotherapy is reserved for advanced-stage or non-resectable disease rather than
used adjuvantly in early-stage tumors. Reported response rates in the recurrent
setting are poor.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: chemotherapy
term:
id: NCIT:C15632
label: Chemotherapy
evidence:
- reference: PMID:28276867
reference_title: Pathogenesis and treatment of adult-type granulosa cell tumor of the ovary.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Surgery is the cornerstone for the treatment of both primary and relapsed tumor,
while chemotherapy is applied only for advanced or non-resectable cases.
explanation: >-
Defines the restricted indication for chemotherapy in this disease.
notes: >-
No therapeutic_agent bindings are asserted here. The cited evidence establishes the
restricted indication for chemotherapy in this disease but does not name a regimen,
and the regimens reported for adult granulosa cell tumor specifically are not
consistent across sources, so binding a specific drug list would make a
machine-readable claim no cited source supports. Likewise no regimen_term is
asserted. The one systemic agent that IS evidenced in a named trial for this disease
is nirogacestat, curated under clinical_trials as a negative result.
- name: Aromatase Inhibitor Endocrine Therapy
description: >-
Aromatase inhibition is used as an endocrine option in recurrent AGCT on the
rationale that the tumor is hormonally active. Reported activity is modest, and the
cited source records that systemic therapy in the recurrent setting has generally
been disappointing.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: aromatase inhibition therapy
term:
id: NCIT:C15525
label: Aromatase Inhibition Therapy
therapeutic_agent:
- preferred_term: anastrozole
term:
id: CHEBI:2704
label: anastrozole
target_mechanisms:
- target: Aberrant Ovarian Steroidogenesis and Estrogen Excess
treatment_effect: INHIBITS
description: >-
Aromatase inhibition blocks the terminal step of estrogen biosynthesis, the process
annotated on the target node. The specific rationale in the recurrent setting is
that CYP19A1, the gene encoding aromatase, is among the small set of genes
differentially upregulated in recurrent relative to primary tumors.
evidence:
- reference: PMID:37068116
reference_title: "Comparative Tumor Microenvironment Analysis of Primary and Recurrent Ovarian Granulosa Cell Tumors."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These included genes with known function in hormone signaling such as LHCGR and
INSL3 (more abundant in primary tumors) and CYP19A1 (more abundant in recurrent
tumors).
explanation: >-
RNA-seq of 8 primary and 16 recurrent tumors shows aromatase (CYP19A1) is
upregulated at recurrence, which is the molecular rationale for targeting
aromatase specifically in relapsed disease rather than merely "the tumor is
hormonally active".
- reference: PMID:39395821
reference_title: TERT promoter mutations and survival outcomes in adult-type granulosa cell tumors.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Overall, response rates to systemic therapy in recurrent adult granulosa cell
tumors have been disappointing.
explanation: >-
PARTIAL and deliberately deflationary: the cited source records that endocrine
and other systemic therapy in recurrent AGCT has limited efficacy, so this link
records the mechanistic target without claiming clinical benefit.
evidence:
- reference: PMID:39395821
reference_title: TERT promoter mutations and survival outcomes in adult-type granulosa cell tumors.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
a phase II trial of anastrozole in adult granulosa cell tumors with a median
progression-free survival of 8.6 months
explanation: >-
PARTIAL: documents that anastrozole has actually been trialled in this disease and
quantifies the modest result, supporting the treatment's existence and its stated
limited activity rather than asserting efficacy.
animal_models:
- name: Foxl2 C134W knock-in mouse
species: Mouse
genotype: Foxl2+/C134W heterozygous knock-in
publication: PMID:36409821
modeled_mechanisms:
- target: Granulosa Cell Proliferation and Survival
relationship: RECAPITULATES
fidelity: HIGH
description: >-
Heterozygous knock-in of the human AGCT driver allele is sufficient, without any
additional driver mutation, to take the mouse ovary stepwise through aberrant
granulosa cells and stromal hyperplasia with atypia to adult-onset granulosa cell
tumor.
limitations: >-
The model also reproduces the eyelid hypoplasia of blepharophimosis syndrome,
because the same gene carries germline dominant variants causing that developmental
disorder; the human tumor arises from a somatic mutation in an otherwise normal
ovary, so the whole-animal heterozygous knock-in exposes tissues that are not
mutant in patients.
readouts:
- name: Adult-onset granulosa cell tumor formation
target: Granulosa Cell Proliferation and Survival
direction: INCREASED
interpretation: >-
Tumor development in mutant females is the endpoint establishing sufficiency of
the single allele.
evidence:
- reference: PMID:36409821
reference_title: The Oncogenic FOXL2 C134W Mutation Is a Key Driver of Granulosa Cell Tumors.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Foxl2+/C134W female mice had reduced fertility and developed AGCTs through a
progression from abnormal ovaries with aberrant granulosa cells to ovaries with
stromal hyperplasia and atypia and on to tumors in adut mice.
explanation: >-
Reports the stepwise progression to tumor that this readout measures. The
abstract's spelling of "adut" is reproduced verbatim from the cached record.
evidence:
- reference: PMID:36409821
reference_title: The Oncogenic FOXL2 C134W Mutation Is a Key Driver of Granulosa Cell Tumors.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
These results provide a clear in vivo example in which a single mutational hit
triggers tumor development associated with profound transcriptomic alterations.
explanation: >-
Supports treating this model as informative for the proliferation/survival node:
the human driver allele alone drives tumorigenesis in vivo.
- target: Altered FOXL2 Transcriptional Program
relationship: RECAPITULATES
fidelity: MODERATE
description: >-
The transcriptome of the mouse tumors overlaps the deregulated pathways previously
reported in human AGCT, supporting the model as a readout of the mutant
transcriptional program rather than only of tumor formation.
limitations: >-
Concordance is asserted at the level of deregulated pathways between mouse and
human datasets, not at the level of individual direct FOXL2 C134W target genes;
the human ChIP-seq target set was defined in an isogenic cell line rather than in
this model.
evidence:
- reference: PMID:36409821
reference_title: The Oncogenic FOXL2 C134W Mutation Is a Key Driver of Granulosa Cell Tumors.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
A comparison of these data with previous results on human AGCTs indicated similar
deregulated pathways.
explanation: >-
States the mouse-human concordance that justifies using this model for the
transcriptional-program node.
- name: Granulosa-cell Foxo1/Foxo3/Pten depletion mouse
species: Mouse
genotype: Granulosa-cell-selective Foxo1/Foxo3 inactivation, with and without Pten depletion
publication: PMID:26061565
modeled_mechanisms:
- target: Granulosa Cell Proliferation and Survival
relationship: PARTIALLY_RECAPITULATES
fidelity: LOW
description: >-
An independent, genetically unrelated route to mouse granulosa cell tumor.
It is informative because the resulting tumors converge on features shared with
human adult GCT — nuclear FOXL2 and phosphorylated SMAD2/3 — implicating chronic
activin-SMAD2/3 signalling in the presence of FOXL2 as a granulosa-tumor-permissive
state.
limitations: >-
The initiating lesion is FOXO1/FOXO3/PTEN loss, which is NOT the human AGCT driver:
FOXO1 mutation is a secondary event in only about 7% of human tumors and PTEN loss
is not a recognised driver, so this model does not reproduce the disease's defining
genetics and speaks to downstream permissive signalling rather than to causation.
readouts:
- name: Nuclear FOXL2 and phosphorylated SMAD2/3 in tumor cells
target: Granulosa Cell Proliferation and Survival
direction: INCREASED
interpretation: >-
The shared signalling state that makes this genetically divergent model
informative for the human tumor.
evidence:
- reference: PMID:26061565
reference_title: FOXO1/3 and PTEN Depletion in Granulosa Cells Promotes Ovarian Granulosa Cell Tumor Development.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
nuclear localization of FOXL2 and phosphorylated small mothers against
decapentaplegic (SMAD) 2/3 in the tumor cells, recapitulating results we
observed in human adult GCTs
explanation: >-
The authors explicitly state that this feature recapitulates what they observe
in human adult GCT, which is the basis for the PARTIALLY_RECAPITULATES call.
evidence:
- reference: PMID:26061565
reference_title: FOXO1/3 and PTEN Depletion in Granulosa Cells Promotes Ovarian Granulosa Cell Tumor Development.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Selective inactivation of the Foxo1 and Foxo3 genes in murine ovarian granulosa
cells severely impairs follicular development and apoptosis causing infertility,
and as shown here, granulosa cell tumor (GCT) formation.
explanation: >-
Establishes that this genotype produces granulosa cell tumors, the basis for
listing it as a model of the proliferation/survival node.
clinical_trials:
- name: NCT05348356
phase: PHASE_II
status: COMPLETED
description: >-
Single-arm phase II trial of the gamma-secretase inhibitor nirogacestat in
relapsed/refractory adult ovarian granulosa cell tumor, testing the preclinical
prediction that NOTCH pathway inhibition would impair granulosa cell survival. The
trial enrolled 53 heavily pretreated patients and produced no confirmed objective
responses, though 58% had stable disease and 21% reached 6-month progression-free
survival.
target_phenotypes:
- preferred_term: Ovarian neoplasm
term:
id: HP:0100615
label: Ovarian neoplasm
evidence:
- reference: PMID:41518037
reference_title: Phase II clinical trial of nirogacestat in patients with relapsed ovarian granulosa cell tumours.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A decrease in tumour burden was seen in 16 (30%) patients; however, there were no
confirmed objective responses.
explanation: >-
PARTIAL because the trial did not meet an objective-response endpoint: it is
curated as an informative negative result for NOTCH-directed therapy in this
disease rather than as support for efficacy.
references:
- reference: PMID:19516027
title: Mutation of FOXL2 in granulosa-cell tumors of the ovary.
- reference: PMID:28276867
title: Pathogenesis and treatment of adult-type granulosa cell tumor of the ovary.
Scope. This report concerns adult-type granulosa cell tumor (AGCT), not juvenile granulosa cell tumor. Evidence is disease-level and aggregated from cohorts, molecular studies, reviews, and ClinicalTrials.gov; it is not derived from an individual patient/EHR. Because AGCT is rare, most treatment evidence consists of retrospective series, small phase II studies, or case reports rather than phase III trials.
AGCT is a rare, usually indolent but malignant ovarian sex cord–stromal tumor. It commonly presents around the peri-menopausal years, is frequently confined to one ovary at diagnosis, and may secrete estrogen, inhibin, and anti-Müllerian hormone (AMH). Its defining molecular event is the somatic FOXL2 NM_023067.4:c.402C>G, p.(Cys134Trp) variant, present in approximately 95–97% of tumors. Recurrence can occur decades after apparently curative surgery, making lifelong surveillance appropriate. Surgery is the principal treatment; evidence supporting adjuvant chemotherapy, endocrine treatment, or molecularly targeted therapy remains limited. (salkeni2024advancedgranulosacell pages 2-3, salkeni2024advancedgranulosacell pages 1-2, nemejcova2024anextensiveimmunohistochemical pages 1-2)
| domain | high-confidence finding | quantitative evidence | suggested ontology terms | evidence type/source year |
|---|---|---|---|---|
| identity/MONDO | Adult-type granulosa cell tumor (AGCT) is a rare ovarian sex cord-stromal malignancy and the dominant malignant granulosa-cell subtype; MONDO mapping in retrieved evidence points to ovarian granulosa cell tumor, while exact subtype mapping should be verified | AGCT comprises ~85–95% of granulosa cell tumors; ovarian granulosa cell tumors represent ~2–5% of ovarian tumors/cancers; incidence about 1 per 100,000 in the U.S. (salkeni2024advancedgranulosacell pages 1-2, jung2023immunohistochemicalmarkersof pages 1-2) | Suggested: MONDO: ovarian granulosa cell tumor = MONDO_0023283; MONDO subtype for adult-type AGCT needs verification; MeSH/ICD/Ontology mapping needs verification | Human review 2024; systematic review 2023 (salkeni2024advancedgranulosacell pages 1-2, jung2023immunohistochemicalmarkersof pages 1-2) |
| epidemiology | Usually diagnosed in adult/perimenopausal women; many cases present early stage | Median diagnosis age 46 years in review; typical age 50–55 years in large IHC cohort; 50–80% detected at FIGO IA (salkeni2024advancedgranulosacell pages 1-2, nemejcova2024anextensiveimmunohistochemical pages 1-2, jung2023immunohistochemicalmarkersof pages 1-2) | Suggested: HP:0003596 Adult onset; NCIT: Perimenopausal; FIGO stage terms need verification | Human review/cohort 2023–2024 (salkeni2024advancedgranulosacell pages 1-2, nemejcova2024anextensiveimmunohistochemical pages 1-2, jung2023immunohistochemicalmarkersof pages 1-2) |
| core phenotypes | Common manifestations include abdominal/pelvic symptoms and endocrine manifestations, but not all tumors are estrogenic | Iranian cohort: abdominal pain 56%; menopause in 69.2%; review notes up to 30% do not produce estrogen (salkeni2024advancedgranulosacell pages 2-3, salkeni2024advancedgranulosacell pages 1-2) | Suggested: HP:0002027 Abdominal pain; HP:0000132 Abnormality of female internal genitalia; HP:0000857 Menstrual irregularity; HP:0008222 Precocious puberty/endometrial effect terms may apply case-by-case and need verification | Human cohort/review 2024 (salkeni2024advancedgranulosacell pages 2-3, salkeni2024advancedgranulosacell pages 1-2) |
| anatomy | Primary site is ovary, arising from granulosa cells within sex cord-stromal tissue; recurrent/metastatic disease can involve abdomen/pelvis | Ovarian tumors in 81.3% of cohort; recurrences often abdominal in case literature; model tumors obliterate ovarian tissue (salkeni2024advancedgranulosacell pages 2-3, llano2023theoncogenicfoxl2 pages 3-4) | Suggested: UBERON:0000992 ovary; CL:0000501 granulosa cell; UBERON female gonad-associated stroma terms need verification | Human cohort 2024; mouse model 2023 (salkeni2024advancedgranulosacell pages 2-3, llano2023theoncogenicfoxl2 pages 3-4) |
| FOXL2 genomics | Somatic FOXL2 c.402C>G (p.C134W) is the central driver lesion in most AGCTs | Present in ~95–97% of AGCTs; 223/225 tested tumors positive in the 290-case IHC/molecular cohort; Open Targets links FOXL2 to ovarian granulosa cell tumor (salkeni2024advancedgranulosacell pages 2-3, salkeni2024advancedgranulosacell pages 1-2, nemejcova2024anextensiveimmunohistochemical pages 1-2, OpenTargets Search: adult granulosa cell tumor of ovary) | Suggested: HGNC:FOXL2; Sequence variant FOXL2 p.C134W; MONDO_0023283 association | Human cohort/review 2024; disease-target association resource (salkeni2024advancedgranulosacell pages 2-3, salkeni2024advancedgranulosacell pages 1-2, nemejcova2024anextensiveimmunohistochemical pages 1-2, OpenTargets Search: adult granulosa cell tumor of ovary) |
| secondary genomics | Recurrent secondary alterations occur in a subset, especially in recurrent/advanced disease, but AGCT remains genomically relatively homogeneous | Review of 423 samples: TERT promoter 56%, KMT2D 16.8%, CDKN2A/B deletions 10.2%, TP53 8.3%, MTAP deletion 5.8%, PIK3CA 5.4%; independent 93-case study: KMT2D 10/93 (10.8%); whole-genome study found chromosome 12 and 14 gain and chromosome 22 loss; TP53-mutant high-grade subgroup in 3 patients (salkeni2024advancedgranulosacell pages 1-2, jung2023immunohistochemicalmarkersof pages 1-2, salkeni2024advancedgranulosacell pages 6-7) | Suggested: HGNC:TERT, KMT2D, CDKN2A, CDKN2B, TP53, MTAP, PIK3CA; CNV gain chr12/14, loss chr22; NCIT somatic mutation/CNV terms | Human genomic studies/review 2020–2024 (salkeni2024advancedgranulosacell pages 1-2, salkeni2024advancedgranulosacell pages 6-7, jung2023immunohistochemicalmarkersof pages 1-2) |
| pathways | Strongest mechanistic support centers on FOXL2-mutant interaction with TGFβ/SMAD signaling; PI3K/AKT and hormone signaling are also implicated | FOXL2C134W binds SMAD4/SMAD2/3 and induces EMT-like gene expression; mouse FOXL2 C134W tumors showed transcriptomic changes consistent with gain-of-function affecting TGFβ signaling; recurrent tumors altered LHCGR, INSL3, CYP19A1 and showed immune/hormone pathway enrichment (llano2023theoncogenicfoxl2 pages 11-12, khlebus2023comparativetumormicroenvironment pages 1-2, khlebus2023comparativetumormicroenvironment pages 10-10) | Suggested GO: TGF-beta receptor signaling pathway; epithelial to mesenchymal transition; PI3K-AKT signaling; steroid hormone biosynthetic process; CL granulosa cell/fibroblast/macrophage | Human mechanistic study 2020; mouse causal model 2023; human transcriptomics 2023 (llano2023theoncogenicfoxl2 pages 11-12, khlebus2023comparativetumormicroenvironment pages 1-2, khlebus2023comparativetumormicroenvironment pages 10-10) |
| pathology/IHC | Diagnosis relies on morphology plus sex cord-stromal markers; large 2024 cohort defines a practical immunophenotype | In 290 AGCTs: SF1 100%, FOXL2 98%, PR 94%, CD99 90%, AR 82%, inhibin A 78%, calretinin 45%, ER 41%; PD-L1 uniformly negative; HER2 negative; p53 aberrant in 1%; CTLA4 ~70% (nemejcova2024anextensiveimmunohistochemical pages 1-2) | Suggested: NCIT Immunohistochemistry; HGNC/NCIT markers SF1/NR5A1, FOXL2, PR/PGR, AR, CD99, INHA, CALB2, ESR1, CTLA4, PD-L1/CD274, HER2/ERBB2 | Human pathology cohort 2024 (nemejcova2024anextensiveimmunohistochemical pages 1-2) |
| biomarkers | Inhibin and AMH are the best-supported circulating biomarkers for diagnosis/follow-up; endocrine activity is variable | Review: inhibin A/B produced in almost all patients and correlates with disease activity; AMH sensitivity 89% and specificity 93%; up to 30% of tumors are non-estrogenic (salkeni2024advancedgranulosacell pages 2-3) | Suggested: CHEBI/NCIT inhibin A, inhibin B, anti-Mullerian hormone, estradiol; LOINC assay mappings need verification | Human review 2024 (salkeni2024advancedgranulosacell pages 2-3) |
| imaging/diagnostics | MRI often shows cystic, solid, or cystic-solid ovarian masses with hemorrhagic features; pathology confirmation remains required | 10-case AGCT with normal estrogen: ages 28–81, mean 54±16; metastatic lesions all cystic; described “honeycomb” and “Swiss cheese” signs; high DWI signal in solid components (khlebus2023comparativetumormicroenvironment pages 2-3, salkeni2024advancedgranulosacell pages 2-3) | Suggested: NCIT Magnetic Resonance Imaging; RadLex ovarian mass/cystic lesion terms need verification | Human imaging series 2024 (source retrieved in search results; no citeable context ID available) |
| natural history/prognosis | Prognosis is often favorable initially but late recurrence is a defining feature; very long follow-up is needed | Recurrence about 20% in reviews; one-third relapse between 4–8 years in 2021 review; latency typically 5–10 years and can exceed 20 years; recurrence rates across series 10–64%; average relapse 48–57 months; 10-year survival ~90% stage I vs 17–33% stage III–IV (salkeni2024advancedgranulosacell pages 2-3, salkeni2024advancedgranulosacell pages 1-2, jung2023immunohistochemicalmarkersof pages 1-2) | Suggested: NCIT recurrent neoplasm; HP recurrent ovarian neoplasm term needs verification; FIGO stage ontology terms need verification | Human reviews 2021–2024 (salkeni2024advancedgranulosacell pages 2-3, salkeni2024advancedgranulosacell pages 1-2, jung2023immunohistochemicalmarkersof pages 1-2) |
| prognostic factors | Prognostic biomarker evidence is limited and heterogeneous; some IHC markers correlate with worse outcomes | Review found worse prognosis associated with CD56, GATA-4, and SMAD3 expression; ER, AMH, and inhibin were not prognostic; Ki-67, p53, β-catenin, HER2 inconsistent (jung2023immunohistochemicalmarkersof pages 8-9, jung2023immunohistochemicalmarkersof pages 1-2) | Suggested: HGNC/NCIT NCAM1(CD56), GATA4, SMAD3, MKI67, TP53, CTNNB1, ERBB2 | Systematic review 2023 (jung2023immunohistochemicalmarkersof pages 8-9, jung2023immunohistochemicalmarkersof pages 1-2) |
| standard treatments | Surgery is the cornerstone; systemic therapy is used for advanced/recurrent disease, but evidence is mostly retrospective/small-series | Review notes surgery is standard; CAP response rate 60% and PVB 66% in small series; systemic chemotherapy remains standard for advanced disease (salkeni2024advancedgranulosacell pages 2-3, salkeni2024advancedgranulosacell pages 1-2) | Suggested NCIT: Oophorectomy, Hysterectomy, Cytoreductive Surgery, Adjuvant Chemotherapy, Cyclophosphamide, Doxorubicin, Cisplatin, Vinblastine, Bleomycin, Etoposide, Paclitaxel, Carboplatin | Human review 2024; historical clinical evidence summarized therein (salkeni2024advancedgranulosacell pages 2-3, salkeni2024advancedgranulosacell pages 1-2) |
| endocrine/targeted therapy | Hormonal and precision approaches are increasingly used in recurrent disease; evidence remains early | Review reports long partial responses with temozolomide+TRC102 (>12 months in 2 AGCT patients) and paclitaxel+nilotinib (>5 years in 2 AGCT patients); JNK inhibition reduced growth in patient-derived xenografts; TILs from 11 patients showed 100% autologous tumor reactivity and 57% reactivity to FOXL2 peptides in vitro (salkeni2024advancedgranulosacell pages 6-7) | Suggested NCIT: Aromatase inhibitor, letrozole, exemestane, leuprolide acetate, temozolomide, nilotinib, JNK inhibitor, tumor-infiltrating lymphocyte therapy | Human review 2024 summarizing case/preclinical evidence (salkeni2024advancedgranulosacell pages 6-7) |
| experimental trials | Multiple modern interventional studies are testing endocrine, NOTCH/gamma-secretase, and TGFβ/activin-axis strategies | NCT06169124 phase 2 darolutamide + leuprolide acetate + exemestane, active-not-recruiting, planned n=17; NCT05872204 phase 2 abemaciclib + letrozole, recruiting, planned n=100 rare ER+ ovarian cancers; NCT05348356 phase 2 nirogacestat, completed, n=53, 150 mg BID; NCT06254781 luspatercept single-patient completed study, n=1 (NCT06254781 chunk 1, NCT05348356 chunk 1) | Suggested NCIT: Clinical Trial, Darolutamide, Leuprolide Acetate, Exemestane, Abemaciclib, Letrozole, Nirogacestat, Luspatercept | ClinicalTrials.gov evidence 2022–2025 (NCT06254781 chunk 1, NCT05348356 chunk 1) |
| prevention | No established primary prevention or population screening strategy is supported by retrieved evidence; management focuses on surveillance after treatment | No validated population screening biomarker or prevention intervention identified in gathered evidence; long-term follow-up emphasized because relapse may occur decades later (salkeni2024advancedgranulosacell pages 1-2, jung2023immunohistochemicalmarkersof pages 1-2) | Suggested NCIT: Surveillance, Follow-Up; secondary prevention/screening mappings need verification | Human reviews 2023–2024 (salkeni2024advancedgranulosacell pages 1-2, jung2023immunohistochemicalmarkersof pages 1-2) |
| environmental/inherited risks | Evidence for environmental causes, protective factors, or common hereditary predisposition is currently limited/unclear in retrieved data | No consistent environmental risk factor identified in gathered evidence; AGCT is primarily characterized as a somatic FOXL2-driven neoplasm; isolated hereditary reports exist for sex cord-stromal tumors but not enough for routine AGCT risk assignment here (salkeni2024advancedgranulosacell pages 1-2, jung2023immunohistochemicalmarkersof pages 1-2) | Suggested: Etiology unknown/nonhereditary in most cases; germline predisposition terms need verification | Review-level evidence; evidence gap noted (salkeni2024advancedgranulosacell pages 1-2, jung2023immunohistochemicalmarkersof pages 1-2) |
| tumor microenvironment | Recurrent AGCT shows stromal depletion and myeloid enrichment, suggesting relapse-associated microenvironment remodeling | 24 tumors analyzed (8 primary, 16 recurrent); 31 DEGs; recurrent tumors had increased neutrophils/macrophages and decreased CAFs/endothelial cells; CAF depletion validated in independent datasets (khlebus2023comparativetumormicroenvironment pages 2-3, khlebus2023comparativetumormicroenvironment pages 9-10, khlebus2023comparativetumormicroenvironment pages 1-2) | Suggested GO/CL: macrophage, neutrophil, endothelial cell, fibroblast/cancer-associated fibroblast, hormone signaling, immune response | Human transcriptomic/TME study 2023 (khlebus2023comparativetumormicroenvironment pages 2-3, khlebus2023comparativetumormicroenvironment pages 9-10, khlebus2023comparativetumormicroenvironment pages 1-2) |
| models | The best current causal model is the Foxl2 C134W knock-in mouse; additional PI3K/PTEN/FOXO and other models support pathway biology but do not fully recapitulate human AGCT | In Foxl2+/C134W mice, all females developed ovarian tumors before 18 months; 50% of mutant females produced offspring after 6 months with WT males; primordial follicles markedly reduced; no recurrent driver beyond C134W identified in tumors; review of models notes existing mouse models do not completely recapitulate human molecular phenotype (llano2023theoncogenicfoxl2 pages 3-4, llano2023theoncogenicfoxl2 pages 2-3, llano2023theoncogenicfoxl2 pages 3-3, liu2015foxo13andpten pages 1-2) | Suggested: NCBITaxon:10090 mouse; CL granulosa cell; GO TGF-beta signaling, follicle development, PI3K-AKT signaling | Mouse causal model 2023; prior mouse model review 2015 (llano2023theoncogenicfoxl2 pages 3-4, llano2023theoncogenicfoxl2 pages 2-3, llano2023theoncogenicfoxl2 pages 3-3, liu2015foxo13andpten pages 1-2) |
Table: This compact table summarizes high-confidence, evidence-backed facts for adult-type ovarian granulosa cell tumor across disease identity, biology, diagnosis, prognosis, treatment, and models. It is designed for rapid knowledge-base population and flags ontology mappings that need verification.
AGCT is a malignant neoplasm showing granulosa-cell differentiation and belongs to the ovarian sex cord–stromal tumor family. Adult-type tumors constitute approximately 85–95% of granulosa cell tumors and about 90% of malignant ovarian sex cord–stromal tumors; estimates of their share of all ovarian tumors or cancers range from roughly 1–5%, depending on the denominator and registry. The estimated U.S. incidence is approximately 1 per 100,000 women per year. (salkeni2024advancedgranulosacell pages 1-2, nemejcova2024anextensiveimmunohistochemical pages 1-2, jung2023immunohistochemicalmarkersof pages 1-2)
Suggested identifiers and terminology
AGCT is best understood as a predominantly sporadic, somatically initiated neoplasm. The principal causal event is FOXL2 p.Cys134Trp; the 2023 knock-in mouse study provides unusually strong causal evidence that this single variant can initiate granulosa-cell transformation. (llano2023theoncogenicfoxl2 pages 9-10, llano2023theoncogenicfoxl2 pages 3-4)
No reproducible environmental, infectious, dietary, smoking, occupational, reproductive, or lifestyle cause has been established. Likewise, no validated protective allele, diet, medication, or behavioral intervention is known. Age and female ovarian anatomy describe the affected population but are not proven modifiable causes. Evidence for gene–environment interaction is insufficient.
Routine germline inheritance is not supported: the canonical FOXL2 variant is somatic, and there is no established autosomal-dominant, autosomal-recessive, X-linked, mitochondrial, anticipation, founder, carrier-frequency, or consanguinity pattern. Germline evaluation may nevertheless be appropriate when personal or family history suggests a cancer-predisposition syndrome; isolated reports do not establish population-level AGCT susceptibility.
Phenotypes vary with tumor size, rupture, stage, and endocrine activity.
Quality-of-life burden includes pain, anxiety related to late relapse, surgical menopause after bilateral surgery, infertility or reduced fertility, and cumulative toxicity from repeated operations or systemic treatment. Robust AGCT-specific EQ-5D, SF-36, or PROMIS population estimates were not identified.
FOXL2 encodes a forkhead transcription factor required for granulosa-cell identity and ovarian function. The somatic missense variant c.402C>G, p.Cys134Trp is detected in approximately 95–97% of AGCTs; a 2024 series confirmed it in 223/225 tested tumors. It is therefore a highly informative diagnostic marker, although a negative result does not absolutely exclude AGCT. (salkeni2024advancedgranulosacell pages 2-3, salkeni2024advancedgranulosacell pages 1-2, nemejcova2024anextensiveimmunohistochemical pages 1-2)
Functionally, mutant FOXL2 acquires altered DNA-binding and protein-interaction properties. It forms a FOXL2–SMAD4–SMAD2/3 complex at a novel hybrid motif, creates enhancer-like chromatin, and activates genes involved in epithelial-to-mesenchymal transition, stemness, proliferation, and survival. TGF-β inhibition mitigated this transcriptional program in experimental systems. (llano2023theoncogenicfoxl2 pages 11-12)
A 2024 review of 423 molecularly profiled tumors reported FOXL2 in 100% of that selected dataset, TERT-promoter variants 56%, KMT2D 16.8%, CDKN2A/B deletion 10.2%, TP53 8.3%, MTAP deletion 5.8%, and PIK3CA 5.4%. Frequencies differ by cohort, platform, stage, and inclusion of recurrent tumors; another 93-case study found KMT2D inactivation in 10.8%. These are tumor-acquired alterations, not established germline causes. (salkeni2024advancedgranulosacell pages 1-2)
Whole-genome studies have described gains of chromosomes 12 and 14 and loss of chromosome 22. A small TP53-mutant, high-mitotic/high-tumor-mutation-burden subgroup may represent high-grade transformation. Intrapatient comparisons found 29–80% of mutations unique to individual samples, demonstrating evolutionary heterogeneity. FOXL2-wild-type tumors may contain DICER1, TERT, or TP53 alterations and require especially careful pathologic review.
No validated modifier gene currently predicts penetrance or clinical severity. Population allele frequencies are not meaningful for the canonical FOXL2 lesion because it is a tumor-specific somatic variant; germline population frequency should be effectively absent. Somatic variants should be interpreted using AMP/ASCO/CAP oncology criteria, not automatically labeled as hereditary ACMG pathogenic variants.
No toxin, radiation exposure, pollution source, diet, alcohol pattern, smoking behavior, occupation, or pathogen has a proven causal role. AGCT is not infectious or transmissible. Associations inferred from general ovarian-cancer datasets should not be transferred to this biologically distinct sex cord–stromal tumor without subtype-specific evidence.
A supported causal chain is:
Suggested GO annotations: transcription-factor binding; regulation of transcription by RNA polymerase II; TGF-beta receptor signaling; SMAD protein signal transduction; granulosa-cell differentiation; ovarian follicle development; steroid biosynthesis; cell-cycle regulation; apoptotic signaling; PI3K–AKT signaling; epithelial-to-mesenchymal transition.
Suggested cell terms: CL:0000501 granulosa cell; ovarian stromal fibroblast; endothelial cell; macrophage; neutrophil. The latter cell populations relate primarily to the tumor microenvironment rather than the initiating clone.
RNA sequencing of 24 tumors—8 primary and 16 recurrent—identified 31 differentially expressed genes. LHCGR and INSL3 were enriched in primary tumors, whereas CYP19A1 was enriched in recurrence. Recurrent tumors showed immune/hormone pathway enrichment, increased inferred macrophage and neutrophil fractions, and reduced endothelial cells and cancer-associated fibroblasts; fibroblast depletion was replicated in independent datasets. These findings are observational, computationally deconvolved, and potentially confounded by non-paired samples and prior treatments. (khlebus2023comparativetumormicroenvironment pages 2-3, khlebus2023comparativetumormicroenvironment pages 9-10, khlebus2023comparativetumormicroenvironment pages 10-10, khlebus2023comparativetumormicroenvironment pages 1-2)
Current AGCT-specific single-cell and spatial-transcriptomic evidence remains limited. Bulk RNA-seq cannot fully resolve malignant granulosa-cell states or fibroblast and myeloid subtypes. Similarly, clinically validated proteomic, metabolomic, or lipidomic signatures are not yet available.
The primary organ is the ovary—suggested UBERON:0000992—usually involving one ovary at presentation. The neoplastic lineage is the follicular granulosa cell. Histologically involved compartments include ovarian cortex/stroma, follicle-like structures, tumor vasculature, and fibrous stroma.
Secondary disease most commonly involves pelvic or abdominal/peritoneal sites; advanced disease may affect bowel serosa, omentum, liver surface/parenchyma, lymph nodes, or distant organs. Relevant systems include reproductive, endocrine, gastrointestinal, and peritoneal systems. Subcellular emphasis is nuclear/chromatin localization of FOXL2 and SMAD transcriptional complexes—suggested GO:0005634 nucleus and GO:0000785 chromatin.
AGCT is primarily an adult/perimenopausal-onset disease. Reviews give a median diagnosis age near 46 years, while the 2024 pathology cohort describes a typical range around 50–55 years. It often grows indolently and is detected at FIGO stage I; 50–80% of cases in reviewed series were stage IA. (salkeni2024advancedgranulosacell pages 1-2, nemejcova2024anextensiveimmunohistochemical pages 1-2, jung2023immunohistochemicalmarkersof pages 1-2)
The course is chronic and relapse-prone rather than self-limited. Approximately 20% recur in contemporary summaries, although heterogeneous series report 10–64%. Typical latency is 5–10 years, recurrence may occur after more than 20 years, and one review estimated an average 48–57 months. Thus, a five-year disease-free interval is not equivalent to cure. (salkeni2024advancedgranulosacell pages 2-3, salkeni2024advancedgranulosacell pages 1-2, jung2023immunohistochemicalmarkersof pages 1-2)
FIGO ovarian staging is used: stage I confined to ovary/ovaries; stage II pelvic extension; stage III peritoneal or retroperitoneal nodal disease; stage IV distant metastasis. Tumor rupture is particularly relevant within stage I risk assessment.
AGCT affects persons with ovaries; the practical sex ratio is overwhelmingly female, while rare extraovarian or testicular granulosa-cell tumors are distinct entities. No consistently high-risk ancestry or endemic geography is established. Registry differences likely reflect ascertainment and coding rather than demonstrated genetic founder effects.
The disease has no established Mendelian inheritance, penetrance estimate, carrier frequency, anticipation, or germline mosaicism model. The FOXL2 driver is somatic. Genetic counseling is indicated only when the broader personal/family cancer history or unusual pathology raises concern for a germline syndrome.
Important mimics include juvenile granulosa cell tumor, thecoma/fibrothecoma, Sertoli–Leydig cell tumor, sex cord tumor with annular tubules, endometrioid carcinoma with sex-cord-like areas, small-cell carcinoma, carcinoid/neuroendocrine tumor, metastatic carcinoma, and uterine-type tumors involving the ovary. Morphology, age, reticulin pattern, SF1/FOXL2/inhibin expression, epithelial markers, and FOXL2 sequencing resolve most cases.
There is no validated population screening test. Incidental AMH/inhibin testing in asymptomatic average-risk women is not recommended.
Early-stage survival is excellent but does not eliminate late recurrence. A systematic review summarized five- and ten-year overall survival near 97% and 95%, respectively, in predominantly early-stage populations. By stage, a 2024 review reported approximately 90% ten-year survival for stage I versus 17–33% for stages III–IV. (salkeni2024advancedgranulosacell pages 2-3, jung2023immunohistochemicalmarkersof pages 1-2)
Major adverse prognostic factors are advanced FIGO stage, tumor rupture, residual disease/incomplete cytoreduction, large tumor burden, high mitotic activity or high-grade transformation, and recurrence. Proposed molecular/IHC factors remain unvalidated. A 2023 review found associations between poorer outcome and CD56, GATA4, or SMAD3 expression, whereas ER, AMH, and inhibin were not prognostic; results for Ki-67, p53, β-catenin, and HER2 were inconsistent. (jung2023immunohistochemicalmarkersof pages 8-9, jung2023immunohistochemicalmarkersof pages 1-2)
Long-term morbidity includes infertility, surgical menopause, endocrine symptoms, recurrent abdominal operations, bowel or vascular involvement, chemotherapy toxicity, and psychological distress. Evidence for AGCT-specific disability or quality-of-life scores is sparse.
Complete surgical resection and staging are the cornerstone. For post-reproductive patients, hysterectomy with bilateral salpingo-oophorectomy is commonly used. Carefully selected stage IA patients desiring fertility may undergo unilateral salpingo-oophorectomy with preservation of the uterus and contralateral ovary, followed by close surveillance. Cyst rupture or tumor spillage should be avoided. Recurrent disease should be assessed for complete secondary cytoreduction at an experienced multidisciplinary center.
Suggested NCIt terms include Oophorectomy, Salpingo-oophorectomy, Hysterectomy, Surgical Staging, and Cytoreductive Surgery.
Observation is usual after completely staged low-risk stage IA disease. For high-risk stage I or stage II–IV disease, adjuvant chemotherapy may be considered, but a clear survival advantage has not been established. Common regimens include BEP—bleomycin, etoposide, cisplatin—and paclitaxel/carboplatin. Historical small series reported response rates of approximately 60% for CAP and 66% for PVB, but these estimates are imprecise and should not be interpreted as modern comparative efficacy. (salkeni2024advancedgranulosacell pages 2-3)
Toxicities include cisplatin nephrotoxicity, neurotoxicity and ototoxicity; etoposide myelosuppression and secondary leukemia risk; bleomycin pulmonary toxicity; and taxane neuropathy/alopecia. No AGCT-specific CPIC pharmacogenomic algorithm is established.
Because many tumors express ER, PR, or AR, aromatase inhibitors—letrozole, anastrozole, exemestane—GnRH analogues, progestins, or antiandrogen strategies are used in recurrent disease, generally with low toxicity but limited prospective response data. Molecularly guided approaches remain investigational.
Reported signals include responses longer than 12 months in two patients receiving temozolomide plus TRC102 and responses longer than five years in two patients receiving paclitaxel plus nilotinib; these are exceptional small-number observations, not definitive standards. JNK inhibition reduced growth in patient-derived xenografts. (salkeni2024advancedgranulosacell pages 6-7)
AGCT is generally immunologically “cold,” with low tumor mutational burden and absent PD-L1 in the large 2024 IHC series, making unselected checkpoint blockade biologically uncertain. Nevertheless, tumor-infiltrating lymphocytes from 11 patients reacted against autologous tumor in vitro, and 57% reacted to FOXL2 peptides, supporting antigen-directed research. (salkeni2024advancedgranulosacell pages 1-2, salkeni2024advancedgranulosacell pages 6-7, nemejcova2024anextensiveimmunohistochemical pages 1-2)
No approved gene therapy, CRISPR therapy, CAR-T product, cell therapy, antisense oligonucleotide, or siRNA therapy exists for AGCT.
Naturally occurring ovarian granulosa-cell tumors are recognized in domestic species, particularly mares and cattle, and also occur in dogs and other mammals. In mares, endocrine activity can produce anestrus, persistent estrus, or stallion-like behavior; inhibin and AMH are used clinically. These tumors are useful for comparative endocrinology but should not automatically be considered homologous to human FOXL2 p.Cys134Trp AGCT without molecular confirmation.
Suggested taxa include Homo sapiens NCBITaxon:9606, Mus musculus NCBITaxon:10090, Equus caballus NCBITaxon:9796, Bos taurus NCBITaxon:9913, and Canis lupus familiaris NCBITaxon:9615. No zoonotic or cross-species transmission occurs. The relevant conserved gene is FOXL2, but species-specific variant and NCBI Gene identifiers should be resolved directly from current NCBI records.
The strongest model is the 2023 CRISPR knock-in Foxl2+/C134W mouse—murine p.C130W at the orthologous locus. All mutant females developed ovarian tumors before 18 months, whereas wild-type controls did not. Lesions progressed from abnormal follicles to stromal hyperplasia/atypia and then tumors with human-like granulosa morphology, Call–Exner bodies, and occasional high-grade features. Only 50% of mutant females produced offspring after six months of mating, and primordial follicles were markedly depleted. Sequencing found no recurrent additional driver, supporting sufficiency of mutant FOXL2. (llano2023theoncogenicfoxl2 pages 9-10, llano2023theoncogenicfoxl2 pages 3-4, llano2023theoncogenicfoxl2 pages 9-9, llano2023theoncogenicfoxl2 pages 2-3, llano2023theoncogenicfoxl2 pages 3-3)
Other engineered mouse systems—including granulosa-cell depletion of Foxo1/Foxo3/Pten, constitutive PI3K activation, inhibin/TGF-β–SMAD perturbation, β-catenin activation, and p53/Rb disruption—produce granulosa-cell tumors and help dissect proliferation, follicular signaling, and tumor suppression. However, older models do not fully recapitulate the defining molecular phenotype of human FOXL2-mutant AGCT. (liu2015foxo13andpten pages 1-2)
Cellular resources include KGN cells, COV434-derived systems, primary tumor cultures, organotypic cultures, and patient-derived xenografts. Important limitations are cell-line misclassification/history, adaptation to culture, absent immune/stromal context, and inability of xenografts to reproduce decades-long human latency.
The 2023–2024 literature materially strengthened three areas: causal proof for FOXL2 p.Cys134Trp in vivo; characterization of recurrence-associated hormone/TME remodeling; and a large, molecularly confirmed diagnostic IHC reference cohort. The central remaining gaps are prospective surveillance schedules, validated prognostic biomarkers, randomized evidence for adjuvant chemotherapy, reliable response estimates for endocrine therapy, AGCT-specific single-cell/spatial atlases, and adequately powered trials of FOXL2/TGF-β, NOTCH, PI3K–AKT, endocrine, or immune-directed treatment. The rarity of AGCT makes international registries, centralized pathology review, standardized biomarker collection, and adaptive basket trials especially important. (nemejcova2024anextensiveimmunohistochemical pages 1-2, khlebus2023comparativetumormicroenvironment pages 2-3, khlebus2023comparativetumormicroenvironment pages 1-2, llano2023theoncogenicfoxl2 pages 3-4)
References
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(salkeni2024advancedgranulosacell pages 6-7): Mohamad A. Salkeni, Sarah Shin, Naoko Takebe, Sally Stevens, and Alice Chen. Advanced granulosa cell tumors of the ovary: a review with a focus on current and novel therapeutic approaches. Nov 2024. URL: https://doi.org/10.36401/jipo-23-40, doi:10.36401/jipo-23-40. This article has 10 citations.
(llano2023theoncogenicfoxl2 pages 11-12): Elena Llano, Anne Laure Todeschini, Natalia Felipe-Medina, María D. Corte-Torres, Yazmine B. Condezo, Manuel Sanchez-Martin, Sara López-Tamargo, Aurora Astudillo, Xose S. Puente, Alberto M. Pendas, and Reiner A. Veitia. The oncogenic foxl2 c134w mutation is a key driver of granulosa cell tumors. Cancer research, 83:239-250, Nov 2023. URL: https://doi.org/10.1158/0008-5472.can-22-1880, doi:10.1158/0008-5472.can-22-1880. This article has 27 citations and is from a highest quality peer-reviewed journal.
(khlebus2023comparativetumormicroenvironment pages 1-2): Eleonora Khlebus, Veena K. Vuttaradhi, Thomas Welte, Namrata Khurana, Joseph Celestino, Hannah C. Beird, Curtis Gumbs, Latasha Little, Alejandra Flores Legarreta, Bryan M. Fellman, Tri Nguyen, Barrett Lawson, Sammy Ferri-Borgogno, Samuel C. Mok, Russell R. Broaddus, David M. Gershenson, P. Andrew Futreal, and R. Tyler Hillman. Comparative tumor microenvironment analysis of primary and recurrent ovarian granulosa cell tumors. Molecular Cancer Research, 21:483-494, Apr 2023. URL: https://doi.org/10.1158/1541-7786.mcr-22-0623, doi:10.1158/1541-7786.mcr-22-0623. This article has 15 citations and is from a peer-reviewed journal.
(khlebus2023comparativetumormicroenvironment pages 10-10): Eleonora Khlebus, Veena K. Vuttaradhi, Thomas Welte, Namrata Khurana, Joseph Celestino, Hannah C. Beird, Curtis Gumbs, Latasha Little, Alejandra Flores Legarreta, Bryan M. Fellman, Tri Nguyen, Barrett Lawson, Sammy Ferri-Borgogno, Samuel C. Mok, Russell R. Broaddus, David M. Gershenson, P. Andrew Futreal, and R. Tyler Hillman. Comparative tumor microenvironment analysis of primary and recurrent ovarian granulosa cell tumors. Molecular Cancer Research, 21:483-494, Apr 2023. URL: https://doi.org/10.1158/1541-7786.mcr-22-0623, doi:10.1158/1541-7786.mcr-22-0623. This article has 15 citations and is from a peer-reviewed journal.
(khlebus2023comparativetumormicroenvironment pages 2-3): Eleonora Khlebus, Veena K. Vuttaradhi, Thomas Welte, Namrata Khurana, Joseph Celestino, Hannah C. Beird, Curtis Gumbs, Latasha Little, Alejandra Flores Legarreta, Bryan M. Fellman, Tri Nguyen, Barrett Lawson, Sammy Ferri-Borgogno, Samuel C. Mok, Russell R. Broaddus, David M. Gershenson, P. Andrew Futreal, and R. Tyler Hillman. Comparative tumor microenvironment analysis of primary and recurrent ovarian granulosa cell tumors. Molecular Cancer Research, 21:483-494, Apr 2023. URL: https://doi.org/10.1158/1541-7786.mcr-22-0623, doi:10.1158/1541-7786.mcr-22-0623. This article has 15 citations and is from a peer-reviewed journal.
(jung2023immunohistochemicalmarkersof pages 8-9): Dennis Jung, Katrin Almstedt, Marco J. Battista, Alexander Seeger, Jörg Jäkel, Walburgis Brenner, and Annette Hasenburg. Immunohistochemical markers of prognosis in adult granulosa cell tumors of the ovary – a review. Journal of Ovarian Research, Mar 2023. URL: https://doi.org/10.1186/s13048-023-01125-1, doi:10.1186/s13048-023-01125-1. This article has 21 citations and is from a peer-reviewed journal.
(NCT06254781 chunk 1): Luspatercept in Metastatic AGCT of the Ovary. University Health Network, Toronto. 2022. ClinicalTrials.gov Identifier: NCT06254781
(NCT05348356 chunk 1): Nirogacestat in Ovarian Granulosa Cell Tumors. Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany. 2022. ClinicalTrials.gov Identifier: NCT05348356
(khlebus2023comparativetumormicroenvironment pages 9-10): Eleonora Khlebus, Veena K. Vuttaradhi, Thomas Welte, Namrata Khurana, Joseph Celestino, Hannah C. Beird, Curtis Gumbs, Latasha Little, Alejandra Flores Legarreta, Bryan M. Fellman, Tri Nguyen, Barrett Lawson, Sammy Ferri-Borgogno, Samuel C. Mok, Russell R. Broaddus, David M. Gershenson, P. Andrew Futreal, and R. Tyler Hillman. Comparative tumor microenvironment analysis of primary and recurrent ovarian granulosa cell tumors. Molecular Cancer Research, 21:483-494, Apr 2023. URL: https://doi.org/10.1158/1541-7786.mcr-22-0623, doi:10.1158/1541-7786.mcr-22-0623. This article has 15 citations and is from a peer-reviewed journal.
(llano2023theoncogenicfoxl2 pages 2-3): Elena Llano, Anne Laure Todeschini, Natalia Felipe-Medina, María D. Corte-Torres, Yazmine B. Condezo, Manuel Sanchez-Martin, Sara López-Tamargo, Aurora Astudillo, Xose S. Puente, Alberto M. Pendas, and Reiner A. Veitia. The oncogenic foxl2 c134w mutation is a key driver of granulosa cell tumors. Cancer research, 83:239-250, Nov 2023. URL: https://doi.org/10.1158/0008-5472.can-22-1880, doi:10.1158/0008-5472.can-22-1880. This article has 27 citations and is from a highest quality peer-reviewed journal.
(llano2023theoncogenicfoxl2 pages 3-3): Elena Llano, Anne Laure Todeschini, Natalia Felipe-Medina, María D. Corte-Torres, Yazmine B. Condezo, Manuel Sanchez-Martin, Sara López-Tamargo, Aurora Astudillo, Xose S. Puente, Alberto M. Pendas, and Reiner A. Veitia. The oncogenic foxl2 c134w mutation is a key driver of granulosa cell tumors. Cancer research, 83:239-250, Nov 2023. URL: https://doi.org/10.1158/0008-5472.can-22-1880, doi:10.1158/0008-5472.can-22-1880. This article has 27 citations and is from a highest quality peer-reviewed journal.
(liu2015foxo13andpten pages 1-2): Zhilin Liu, Yi A. Ren, Stephanie A. Pangas, Jaye Adams, Wei Zhou, Diego H. Castrillon, Dagmar Wilhelm, and JoAnne S. Richards. Foxo1/3 and pten depletion in granulosa cells promotes ovarian granulosa cell tumor development. Molecular Endocrinology, 29:1006-1024, Jul 2015. URL: https://doi.org/10.1210/me.2015-1103, doi:10.1210/me.2015-1103. This article has 97 citations.
(llano2023theoncogenicfoxl2 pages 9-10): Elena Llano, Anne Laure Todeschini, Natalia Felipe-Medina, María D. Corte-Torres, Yazmine B. Condezo, Manuel Sanchez-Martin, Sara López-Tamargo, Aurora Astudillo, Xose S. Puente, Alberto M. Pendas, and Reiner A. Veitia. The oncogenic foxl2 c134w mutation is a key driver of granulosa cell tumors. Cancer research, 83:239-250, Nov 2023. URL: https://doi.org/10.1158/0008-5472.can-22-1880, doi:10.1158/0008-5472.can-22-1880. This article has 27 citations and is from a highest quality peer-reviewed journal.
(NCT01042522 chunk 1): Paclitaxel and Carboplatin or Bleomycin Sulfate, Etoposide Phosphate, and Cisplatin in Treating Patients With Advanced or Recurrent Sex Cord-Ovarian Stromal Tumors. GOG Foundation. 2010. ClinicalTrials.gov Identifier: NCT01042522
(NCT01042522 chunk 7): Paclitaxel and Carboplatin or Bleomycin Sulfate, Etoposide Phosphate, and Cisplatin in Treating Patients With Advanced or Recurrent Sex Cord-Ovarian Stromal Tumors. GOG Foundation. 2010. ClinicalTrials.gov Identifier: NCT01042522
(llano2023theoncogenicfoxl2 pages 9-9): Elena Llano, Anne Laure Todeschini, Natalia Felipe-Medina, María D. Corte-Torres, Yazmine B. Condezo, Manuel Sanchez-Martin, Sara López-Tamargo, Aurora Astudillo, Xose S. Puente, Alberto M. Pendas, and Reiner A. Veitia. The oncogenic foxl2 c134w mutation is a key driver of granulosa cell tumors. Cancer research, 83:239-250, Nov 2023. URL: https://doi.org/10.1158/0008-5472.can-22-1880, doi:10.1158/0008-5472.can-22-1880. This article has 27 citations and is from a highest quality peer-reviewed journal.
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 9 |
| Resolved | 9 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 9 |
| On topic | 8 |
| Off topic | 0 |
All extracted references resolved successfully.