Adult Granulosa Cell Tumor of the Ovary: Disease Characteristics Report

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.

Executive summary

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)

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.

1. Disease information

Definition and classification

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

• MONDO: MONDO:0023283, ovarian granulosa cell tumor; MONDO:0006036 is the broader granulosa cell tumor. A dedicated adult-type child term should be verified in the target ontology release. Open Targets maps ovarian granulosa cell tumor to MONDO:0023283. (OpenTargets Search: adult granulosa cell tumor of ovary)
• Synonyms: adult-type granulosa cell tumor; adult granulosa cell tumor; ovarian adult granulosa cell tumor; AGCT; aGCT; adult-type ovarian granulosa cell tumour.
• Category: rare malignant ovarian sex cord–stromal/endocrine neoplasm.
• ICD-10-CM: generally coded by behavior and ovarian site, most often C56.- for malignant ovarian neoplasm; morphology-specific registry coding is preferable. ICD-11 and ICD-O-3 morphology/site codes should be checked against the locally implemented release rather than inferred from text literature.
• MeSH: Granulosa Cell Tumor and Ovarian Neoplasms.
• No AGCT-specific OMIM entry establishing a Mendelian disorder was identified. FOXL2 has an OMIM disease relationship with blepharophimosis syndrome, but that germline disorder must not be conflated with the usual somatic FOXL2-mutant AGCT.

2. Etiology, risk, and protective factors

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.

3. Phenotypes

Phenotypes vary with tumor size, rupture, stage, and endocrine activity.

• Pelvic or abdominal pain/fullness: common presenting symptom; a 2013–2023 Iranian cohort reported abdominal pain in 56%. Suggested HPO: HP:0002027 Abdominal pain, HP:0031507 Pelvic pain. Severity ranges from mild pressure to acute pain from hemorrhage or rupture.
• Adnexal/pelvic mass and abdominal distension: generally progressive until diagnosis. Suggested HPO: HP:0000149 Ovarian mass and HP:0003270 Abdominal distention, subject to ontology-version verification.
• Abnormal uterine bleeding or menstrual irregularity: caused by estrogenic stimulation in many reproductive-age or postmenopausal patients. Suggested HPO: HP:0000132 Abnormal uterine bleeding, HP:0000858 Menstrual irregularity.
• Postmenopausal bleeding/endometrial proliferation: clinically important because prolonged unopposed estrogen may cause endometrial hyperplasia or carcinoma. Suggested HPO: postmenopausal bleeding and endometrial hyperplasia terms, with IDs verified locally.
• Precocious puberty: characteristic mainly of juvenile GCT and uncommon in adult-type disease; it should not be treated as a core AGCT phenotype.
• Laboratory abnormalities: elevated inhibin B, inhibin A, AMH, or estradiol. Up to 30% of tumors may not produce estrogen, so normal estrogen does not exclude AGCT. AMH has reported sensitivity of 89% and specificity of 93% in the summarized literature. Suggested HPO: abnormal circulating inhibin/AMH/estradiol terms where available. (salkeni2024advancedgranulosacell pages 2-3)

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.

4. Genetic and molecular information

Central driver

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)

Secondary alterations

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.

5. Environmental information

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.

6. Mechanism and pathophysiology

A supported causal chain is:

1. Upstream somatic event: FOXL2 p.Cys134Trp arises in an ovarian granulosa cell.
2. Transcriptional rewiring: mutant FOXL2 changes DNA-site selection and hijacks SMAD4/SMAD2/3.
3. Pathway disturbance: TGF-β/activin signaling, steroidogenesis, apoptosis, cell-cycle control, EMT-like programs, and PI3K–AKT cross-talk become dysregulated.
4. Cellular phenotype: sustained granulosa-cell survival/proliferation, altered follicular organization, stromal remodeling, endocrine secretion, and eventual invasive tumor growth.
5. Clinical manifestations: ovarian mass, pain/rupture, estrogen-mediated uterine effects, and—after clonal evolution—late abdominal or pelvic recurrence. (llano2023theoncogenicfoxl2 pages 11-12, llano2023theoncogenicfoxl2 pages 9-10, llano2023theoncogenicfoxl2 pages 3-4)

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.

Molecular profiling and tumor microenvironment

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.

7. Anatomical structures affected

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.

8. Temporal development

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.

9. Inheritance and population

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.

10. Diagnostics

Recommended workflow

1. Clinical evaluation: pelvic/abdominal symptoms, menstrual or postmenopausal bleeding, endocrine manifestations, fertility goals, and prior AGCT history.
2. Imaging: pelvic ultrasound initially; contrast CT for staging; MRI for lesion characterization or surgical planning. AGCT may be solid, cystic, or mixed with hemorrhage. A 2024 ten-case MRI series of estrogen-normal AGCT described T2-hyperintense cystic areas, diffusion restriction in solid components, hemorrhagic fluid levels, and occasional “honeycomb” or “Swiss-cheese” appearance; these are supportive, not diagnostic.
3. Serum biomarkers: inhibin B ± inhibin A, AMH, and estradiol. CA-125 is nonspecific. Baseline values are valuable for longitudinal surveillance.
4. Histopathology: variable diffuse, trabecular, insular, microfollicular, or cystic growth; grooved “coffee-bean” nuclei and Call–Exner bodies are classic but neither uniformly present nor individually specific.
5. Immunohistochemistry: in a 290-tumor 2024 cohort, positivity was SF1 100%, FOXL2 98%, PR 94%, CD99 90%, AR 82%, inhibin A 78%, calretinin 45%, and ER 41%. Tumors were microsatellite stable and uniformly PD-L1- and HER2-negative; aberrant p53 occurred in only 1%. (nemejcova2024anextensiveimmunohistochemical pages 1-2)
6. Tumor molecular testing: targeted FOXL2 c.402C>G testing is useful in morphologically difficult cases. Broader NGS can investigate FOXL2-wild-type, high-grade, recurrent, or treatment-refractory tumors. WES/WGS is not required routinely; CMA, karyotyping, FISH, mitochondrial testing, and repeat-expansion assays have no standard diagnostic role.

Differential diagnosis

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.

11. Outcomes and prognosis

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.

12. Treatment

Surgery

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.

Systemic therapy

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.

Endocrine and targeted treatment

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)

Trials and real-world development

• NCT06169124: phase II darolutamide + leuprolide + exemestane for recurrent ovarian GCT; active, not recruiting; 17 participants.
• NCT05872204: phase II abemaciclib + letrozole in ER-positive rare ovarian cancers; recruiting; planned enrollment 100.
• NCT05348356: completed phase II nirogacestat, a gamma-secretase/NOTCH-pathway inhibitor, 150 mg twice daily; 53 recurrent AGCT participants; results were not available in the retrieved record. (NCT05348356 chunk 1)
• NCT06254781: completed single-patient luspatercept study targeting activin receptor–SMAD2/3 signaling; 1 mg/kg subcutaneously every three weeks. (NCT06254781 chunk 1)
• NCT01042522: randomized phase II paclitaxel/carboplatin versus BEP in advanced or recurrent sex cord–stromal tumors; 63 participants; primary endpoint progression-free survival. (NCT01042522 chunk 1, NCT01042522 chunk 7)
• Additional completed studies include paclitaxel (NCT00006227) and bevacizumab (NCT00748657).

No approved gene therapy, CRISPR therapy, CAR-T product, cell therapy, antisense oligonucleotide, or siRNA therapy exists for AGCT.

13. Prevention

• Primary prevention: none established; no vaccine, prophylactic drug, validated lifestyle modification, or risk-reducing surgery is recommended for average-risk women specifically to prevent AGCT.
• Secondary prevention: no population screening program. Prompt investigation of postmenopausal bleeding, endocrine abnormalities, or persistent adnexal masses may permit earlier diagnosis but is not AGCT-specific screening.
• Tertiary prevention: complete initial resection, avoidance of rupture, surveillance with symptoms/examination, imaging when indicated, and serial inhibin B/AMH when informative. Follow-up should extend beyond 10 years and often lifelong because relapse may occur after 20 years. (salkeni2024advancedgranulosacell pages 1-2, jung2023immunohistochemicalmarkersof pages 1-2)
• Counseling: discuss fertility preservation before definitive surgery or gonadotoxic chemotherapy. Routine cascade testing, prenatal testing, or preimplantation testing for somatic FOXL2 p.Cys134Trp is not appropriate.

14. Other species and natural disease

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.

15. Model organisms and experimental systems

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.

Evidence appraisal and knowledge gaps

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)

Key recent sources and links

• Llano et al., Cancer Research, published November 2023, “The oncogenic FOXL2 C134W mutation is a key driver of granulosa cell tumors,” DOI: https://doi.org/10.1158/0008-5472.CAN-22-1880. (llano2023theoncogenicfoxl2 pages 3-4)
• Khlebus et al., Molecular Cancer Research, published April 2023, DOI: https://doi.org/10.1158/1541-7786.MCR-22-0623. (khlebus2023comparativetumormicroenvironment pages 1-2)
• Jung et al., Journal of Ovarian Research, published March 2023, DOI: https://doi.org/10.1186/s13048-023-01125-1. (jung2023immunohistochemicalmarkersof pages 1-2)
• Němejcová et al., Virchows Archiv, published June 2024, DOI: https://doi.org/10.1007/s00428-024-03854-0. (nemejcova2024anextensiveimmunohistochemical pages 1-2)
• Salkeni et al., Journal of Immunotherapy and Precision Oncology, published November 2024, DOI: https://doi.org/10.36401/JIPO-23-40. (salkeni2024advancedgranulosacell pages 2-3, salkeni2024advancedgranulosacell pages 1-2)
• Landmark FOXL2 discovery literature is indexed under PMID 19516027; additional FOXL2–AGCT literature indexed in the retrieved disease-target resource includes PMIDs 19956657, 20693978, 21293260, and 21623383. (OpenTargets Search: adult granulosa cell tumor of ovary)

References

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11. (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.

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22. (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.

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