Malignant Sertoli–Leydig Cell Tumor of the Ovary: Research Report

Executive summary

Ovarian Sertoli–Leydig cell tumor (SLCT) is a rare sex cord–stromal neoplasm composed of cells showing Sertoli-like and Leydig-like differentiation. “Malignant SLCT” is not a wholly separate molecular entity: malignant potential varies principally with FIGO stage, degree of differentiation, retiform or heterologous components, and recurrence. The disease disproportionately affects adolescents and young adults and may present with an adnexal mass, abdominal pain, or androgen excess/virilization.

The dominant contemporary finding is the close relationship between moderately and poorly differentiated SLCT and DICER1. In a centrally reviewed international registry cohort, 36/37 sequenced SLCTs had a DICER1 RNase IIIb hotspot mutation; germline loss-of-function, mosaic, and tumor-limited alterations were all observed. This supports expert pathology review, paired tumor–germline testing, genetic counseling, and DICER1-family surveillance as central elements of care. Early-stage disease usually has an excellent outcome after fertility-sparing surgery, whereas advanced stage, poor differentiation, and recurrence confer substantially greater mortality. Evidence for systemic therapy remains extrapolated from pooled ovarian sex cord–stromal tumor studies rather than SLCT-specific randomized trials. (schultz2017dicer1relatedsertolileydigcell pages 5-7, schultz2017dicer1relatedsertolileydigcell pages 7-8, NCT01042522 chunk 1)

The following table provides compact knowledge-base annotations; uncertain ontology mappings are deliberately marked for curator validation.

Table: This table summarizes high-value knowledge-base annotations for malignant ovarian Sertoli-Leydig cell tumor, including ontology suggestions, core genetic and mechanistic findings, and clinically relevant evidence with uncertainty flags for curator review.

1. Disease information

Definition and category

SLCT is an ovarian sex cord–stromal tumor with variable proportions of Sertoli-type tubules/cords and steroidogenic Leydig-like cells. Tumors are conventionally classified as well, moderately/intermediately, or poorly differentiated, with recognition of retiform patterns and heterologous elements. The “malignant” designation is most clinically meaningful for moderately or poorly differentiated, extraovarian, recurrent, or otherwise aggressive tumors rather than all histologically diagnosed SLCTs.

Category: rare malignant ovarian neoplasm; non-epithelial ovarian cancer; sex cord–stromal tumor; endocrine-active tumor in a subset.

Identifiers and synonyms

• Preferred name: ovarian Sertoli–Leydig cell tumor.
• Synonyms: Sertoli–Leydig tumor; Sertoli–Leydig cell tumour; androblastoma; arrhenoblastoma; ovarian androblastoma; mixed Sertoli–Leydig cell tumor. The older terms arrhenoblastoma and androblastoma should be retained as synonyms but not preferred labels.
• MONDO: a distinct, verified MONDO identifier specifically for the malignant ovarian subset was not established by the retrieved resources; map provisionally to the broader ovarian SLCT concept and validate against the current MONDO release.
• MeSH: Sertoli-Leydig Cell Tumor.
• ICD-10-CM: histology is not represented adequately by a unique code; malignant ovarian disease is generally site-coded under C56.-, with laterality-specific subcodes where used.
• ICD-11: use the malignant neoplasm of ovary site category with morphology captured separately in a cancer-registry/ICD-O field.
• ICD-O-3: morphology and behavior should be checked against the current WHO/IARC release rather than inferred from the site code.
• OMIM/Orphanet: DICER1 tumor-predisposition syndrome has disease-level entries, but SLCT itself is primarily represented in tumor/pathology ontologies rather than as a classic Mendelian disorder.

The evidence summarized here is aggregated disease-level evidence from registries, cohorts, reviews, pathology studies, and ClinicalTrials.gov—not individual EHR data. The principal human cohort enrolled 107 ovarian sex cord–stromal tumor participants and included 49 SLCTs with central pathology review. (schultz2017dicer1relatedsertolileydigcell pages 5-7, schultz2017dicer1relatedsertolileydigcell pages 1-3, schultz2017dicer1relatedsertolileydigcell pages 3-5)

2. Etiology, risk, and protective factors

Causal factors

The best-established causal mechanism is DICER1-driven tumorigenesis. DICER1 syndrome is an autosomal-dominant, incompletely penetrant cancer-predisposition disorder caused by germline DICER1 pathogenic variants at 14q32.13. In associated SLCT, tumorigenesis usually follows an unusual two-hit pattern: one allele carries a loss-of-function alteration and the other a somatic missense hotspot alteration in the RNase IIIb domain. Tumor-limited biallelic disease and mosaicism also occur. (schultz2017dicer1relatedsertolileydigcell pages 7-8, schultz2017dicer1relatedsertolileydigcell pages 5-7, cazzato2024dicer1tumorsyndrome pages 1-2)

In the international registry, DICER1 RNase IIIb hotspot mutations were found in 36/37 tumors (97%); among these cases, 22 patients had germline loss-of-function variants, three were mosaic, and 11 had tumor-limited alterations. This very high estimate reflects central pathology review and enrichment for correctly classified moderately/poorly differentiated tumors; lower frequencies in unselected series may partly reflect inclusion of well-differentiated or misclassified lesions. (schultz2017dicer1relatedsertolileydigcell pages 5-7, schultz2017dicer1relatedsertolileydigcell pages 7-8)

Genetic risk factors

• A germline pathogenic/likely pathogenic DICER1 loss-of-function variant is the principal inherited risk factor.
• Family history may include pleuropulmonary blastoma, thyroid nodular disease or carcinoma, cystic nephroma, renal tumors, nasal chondromesenchymal hamartoma, embryonal rhabdomyosarcoma, or ovarian SLCT.
• In the registry, 33% of SLCT/gynandroblastoma patients reported thyroid nodules and 11% thyroid carcinoma, although ascertainment and referral bias should be considered. (schultz2017dicer1relatedsertolileydigcell pages 5-7)
• Deep intronic splice-altering variants can escape routine exon-directed sequencing. A 2023 report described two patients in whom extended analysis identified novel intronic DICER1 variants after conventional testing was unrevealing. The authors’ abstract recommendation was: “when no DICER1 pLOF variants or large deletions are discovered in exonic regions despite strong clinical suspicion, intron sequencing and splicing analysis should be performed.” [Fraire et al., September 2023; DOI: https://doi.org/10.1200/PO.23.00189]. (fraire2023intronicgermlinedicer1 pages 1-2)

Environmental, lifestyle, infectious, and protective factors

No reproducible toxin, radiation, occupation, infection, smoking, alcohol, dietary, obesity, reproductive, or medication exposure has been established as an SLCT-specific cause. Risk factors for common epithelial ovarian cancer should not be transferred to SLCT without evidence. Likewise, no genetic protective allele, diet, lifestyle intervention, vaccine, or chemopreventive agent is known to prevent SLCT. No established gene–environment interaction has been demonstrated. These are genuine evidence gaps, not evidence of absence.

3. Phenotypes

Typical clinical manifestations

• Pelvic/abdominal mass, distension, or pain: mass-effect symptoms can be acute or subacute; torsion and rupture are uncommon but clinically important complications. Suggested HPO: Abdominal pain (HP:0002027), Pelvic pain (HP:0012532), Abdominal mass (HP:0012745).
• Androgen excess: elevated testosterone may cause hirsutism, acne, deepened voice, clitoromegaly, increased muscle mass, temporal hair recession, or other virilization. Suggested HPO: Virilization (HP:0000138), Hirsutism (HP:0001007), Abnormal circulating testosterone level—exact current HPO child term should be verified.
• Menstrual/reproductive abnormalities: oligomenorrhea, irregular menses, secondary amenorrhea, or anovulation. Suggested HPO: Amenorrhea (HP:0000141) and Irregular menstruation (HP:0000858).
• Pediatric endocrine manifestations: precocious puberty can occur in hormone-secreting tumors; HPO: Precocious puberty (HP:0000826).
• Laboratory abnormalities: testosterone and androstenedione may be elevated; AFP can rise when hepatocytic or other heterologous differentiation is present, but AFP is not a universal SLCT marker. Inhibin A/B and anti-Müllerian hormone can be informative in some sex cord–stromal tumors but lack SLCT-specific sensitivity sufficient for exclusion.

Hormonal symptoms were common in the international cohort, but the retrieved evidence did not provide reliable manifestation-specific percentages. Median diagnosis age was 17 years (range 2–61), illustrating pediatric through adult presentation but strong adolescent/young-adult concentration. (schultz2017dicer1relatedsertolileydigcell pages 5-7, schultz2017dicer1relatedsertolileydigcell pages 12-13)

Severity, progression, and quality of life

Severity is variable. Localized tumors may be cured surgically, and endocrine manifestations can improve after resection. Advanced or recurrent disease can cause pain, bowel or urinary compression, endocrine changes, infertility, treatment toxicity, and death. Virilizing changes such as hirsutism and menstrual dysfunction may improve, whereas voice deepening or clitoromegaly may be incompletely reversible. No validated SLCT-specific EQ-5D, SF-36, or PROMIS dataset was identified.

4. Genetic and molecular information

Principal gene and variant architecture

DICER1 (HGNC:17098; chromosome 14q32.13) encodes a cytoplasmic RNase III endonuclease required for precursor-miRNA processing. Relevant variants include:

1. Germline or mosaic first hits: nonsense, frameshift, canonical splice-site, exon-level or larger deletion, and less commonly pathogenic missense variants, generally causing loss of function.
2. Somatic second hits: recurrent missense substitutions in metal-binding residues of the RNase IIIb domain. These impair processing of the 5p miRNA arm rather than simply eliminating all DICER1 activity.
3. Tumor-limited biallelic alterations: both alterations can be detectable only in neoplastic tissue.
4. Deep intronic splice variants: the 2023 study reported c.1752+213A>G and c.1509+16A>G in the transcript used by the authors; nomenclature must be normalized to the clinically reported transcript before database ingestion. (schultz2017dicer1relatedsertolileydigcell pages 7-8, fraire2023intronicgermlinedicer1 pages 1-2)

Population allele frequencies are variant-specific. A pathogenic germline loss-of-function variant is expected to be rare in gnomAD; no single founder variant or carrier frequency explains most SLCTs. Each variant should therefore be annotated directly from ClinVar/gnomAD using genome build and transcript-specific nomenclature rather than assigning one disease-wide frequency.

Other genes and molecular classes

FOXL2 mutation is uncommon in authentic SLCT and helps distinguish SLCT from adult granulosa-cell tumor, in which FOXL2 p.Cys134Trp is characteristic. A recent 37-case molecular/IHC study found DICER1 mutations in 54.5%, FOXL2 mutations in 6%, two TERT-promoter-mutant tumors, and mutually exclusive DICER1 and FOXL2 alterations in that series. DICER1-mutant tumors overexpressed CDK6, NOTCH2, and FGFR2, whereas DICER1-wild-type tumors showed increased PRKCA, HNF1A, LDLR, and MAP2K5 expression. These findings are hypothesis-generating and do not yet define validated therapeutic biomarkers. [Němejcová et al.; DOI online in 2024, journal issue November 2025: https://doi.org/10.1007/s00428-024-03984-5]. (nemejcova2025amolecularand pages 11-12)

No reproducible modifier gene, constitutional chromosomal abnormality, founder effect, epigenetic signature, or prognostic methylation classifier is established. Comprehensive copy-number, proteomic, metabolomic, and lipidomic datasets remain sparse.

5. Environmental information

No infectious agent causes SLCT, and the disease is not transmissible or zoonotic. There is no evidence supporting HPV, other viruses, pelvic inflammatory disease, endocrine-disrupting chemicals, occupational exposures, diet, alcohol, or tobacco as disease-specific triggers. The environmental component of DICER1 penetrance is currently poorly understood.

6. Mechanism and pathophysiology

Causal chain

1. Predisposition/first hit: constitutional or mosaic DICER1 loss of function—or an initial tumor-limited event—reduces normal DICER1 dosage.
2. Lineage-specific second hit: an ovarian sex cord–stromal progenitor acquires an RNase IIIb hotspot missense alteration.
3. miRNA-processing bias: abnormal cleavage depletes mature 5p miRNAs and distorts post-transcriptional repression.
4. Transcriptomic dysregulation: altered gene-expression programs affect differentiation, proliferation, and survival in Sertoli-/Leydig-like lineages.
5. Tumor phenotype: sex cord differentiation produces tubular/cord-like morphology, while Leydig-like steroidogenesis can generate androgen excess and virilization.
6. Progression: poor differentiation, sarcomatous or heterologous components, rupture, extraovarian spread, and treatment-resistant subclones contribute to recurrence and mortality. (schultz2017dicer1relatedsertolileydigcell pages 1-3, schultz2017dicer1relatedsertolileydigcell pages 7-8, nemejcova2025amolecularand pages 11-12)

Suggested GO terms include pre-miRNA processing (GO:0031053), gene silencing by miRNA (GO:0035195), regulation of cell-population proliferation (GO:0042127), cell population proliferation (GO:0008283), and androgen biosynthetic process (GO:0006703). Suggested cellular annotations are ovarian stromal/sex-cord progenitor, Sertoli-like tumor cell, and steroidogenic Leydig-like tumor cell; exact CL identifiers require validation because these neoplastic ovarian analogues may not map cleanly to normal testicular cell terms.

Immune, metabolic, and multi-omic findings

The available evidence does not support a primary autoimmune or chronic-inflammatory pathogenesis. In the recent 37-case study, tumors were mismatch-repair proficient and HER2- and PD-L1-negative; CTLA4 staining occurred in 43%, but this is not a validated predictor of checkpoint-inhibitor benefit. Loss of PTEN expression occurred in 14%. No validated metabolomic or lipidomic signature exists. (nemejcova2025amolecularand pages 11-12)

7. Anatomical structures affected

The primary site is the ovary (UBERON:0000992), usually involving ovarian sex cord/stromal tissue. Tumors are generally unilateral at initial presentation; bilateral or metachronous contralateral tumors are uncommon but particularly relevant in germline DICER1 carriers. Three germline carriers in the registry developed metachronous SLCTs 5–14 years after the first diagnosis. (schultz2017dicer1relatedsertolileydigcell pages 7-8, schultz2017dicer1relatedsertolileydigcell pages 5-7)

Potential secondary sites include the contralateral ovary, peritoneum, omentum, pelvic/abdominal lymphatic regions, liver, and lung in advanced or recurrent disease. Subcellularly, the relevant compartment is primarily the cytoplasmic miRNA-processing machinery containing DICER1, with downstream effects on cytoplasmic mRNA regulation and nuclear transcriptional programs.

8. Temporal development and natural history

Onset is most often adolescent or young adult, but the observed range of 2–61 years precludes an absolute age boundary. Presentation may be acute with pain/torsion or insidious with progressive virilization, menstrual change, or abdominal enlargement. (schultz2017dicer1relatedsertolileydigcell pages 5-7)

Approximately half of the 49-case registry cohort had stage IA disease. Recurrence occurred in 8/49 (16.3%). Among recurrent cases, half died of disease, with a reported median of 35.5 months in the fatal recurrent group. All stage IA patients were disease-free at a median follow-up of 19 months, although that follow-up is too short to exclude late events. (schultz2017dicer1relatedsertolileydigcell pages 5-7)

A distinction is essential between recurrence and a metachronous new primary contralateral SLCT, the latter being possible years later in DICER1 carriers. Accordingly, surveillance should not cease solely because the initial tumor was stage IA. (schultz2017dicer1relatedsertolileydigcell pages 7-8)

9. Inheritance and population

Epidemiology

SLCT is very rare; robust population incidence and prevalence per 100,000 are not available from the retrieved evidence. It occurs only in patients with ovarian tissue and is concentrated in adolescents and young women. In pediatric/adolescent ovarian neoplasia, sex cord–stromal tumors constitute a minority, while SLCT is one of the important DICER1-associated entities. Registry estimates should not be treated as population incidence because of referral enrichment. (schultz2017dicer1relatedsertolileydigcell pages 1-3)

Inheritance

DICER1 predisposition is autosomal dominant with reduced, age-dependent, and tumor-specific penetrance and variable expressivity. The germline variant is inherited by offspring with a 50% probability, but an SLCT itself is not inherited. De novo variants, postzygotic mosaicism, and tumor-only mutations occur. Genetic anticipation is not established. Consanguinity is not a recognized risk factor. (cazzato2024dicer1tumorsyndrome pages 7-8, cazzato2024dicer1tumorsyndrome pages 1-2)

In the registry, predisposition-associated cases presented at a median age of 16 versus 21 years for tumor-limited cases; 82% of those with predisposing variants were diagnosed before 21. No consistent ethnic or geographic enrichment, founder effect, or population-specific sex ratio beyond the requirement for ovarian tissue has been demonstrated. (schultz2017dicer1relatedsertolileydigcell pages 5-7)

10. Diagnostics

Clinical and imaging evaluation

Evaluation should include history of tempo of virilization, menstrual development, abdominal symptoms, personal/family DICER1-spectrum tumors, and physical examination. Laboratory assessment commonly includes total and free testosterone, SHBG, androstenedione, DHEAS, 17-hydroxyprogesterone, β-hCG, AFP, LDH, and selected inhibin A/B or AMH measurements. Rapidly progressive virilization with high testosterone and relatively non-elevated DHEAS favors an ovarian rather than adrenal source, but no blood marker rules SLCT in or out.

Pelvic ultrasound is first-line, with MRI useful for characterization and surgical planning; CT chest/abdomen/pelvis is appropriate when malignancy or spread is suspected. Imaging is not histologically specific.

Histopathology and immunohistochemistry

Diagnosis requires resection or biopsy review by a gynecologic pathologist. Morphology may show Sertoli-cell tubules, cords, nests, primitive gonadal stroma, Leydig-cell clusters, retiform architecture, and heterologous mucinous, cartilaginous, skeletal-muscle, or sarcomatous elements. In the 49-case registry, 47% had heterologous elements and 22% sarcomatous features. (schultz2017dicer1relatedsertolileydigcell pages 5-7)

Useful positive markers include SF1, inhibin, calretinin, WT1, CD99, FOXL2, and androgen receptor, interpreted as a panel. Cytokeratin may highlight Sertoli-type epithelial differentiation. No individual marker is completely specific, and morphology remains the diagnostic foundation. (nemejcova2025amolecularand pages 11-12)

Important differentials include juvenile and adult granulosa-cell tumor, steroid-cell tumor, gynandroblastoma, endometrioid carcinoma with sex cord-like areas, carcinoid/neuroendocrine tumor, yolk-sac tumor, immature teratoma, and metastatic endocrine neoplasms. DICER1 RNase IIIb testing supports moderately/poorly differentiated SLCT, whereas FOXL2 p.Cys134Trp favors adult granulosa-cell tumor.

Genetic testing workflow

1. Test tumor tissue with an NGS panel that covers the DICER1 RNase IIIb domain and detects small variants, copy-number changes, and ideally both hits.
2. Perform germline DICER1 sequencing plus deletion/duplication analysis for every confirmed SLCT, preferably with genetic counseling.
3. If blood is negative but tumor findings or phenotype strongly suggest DICER1 syndrome, assess mosaicism using high-depth sequencing and consider another normal tissue.
4. If exon-focused testing is negative, consider whole-gene intronic sequencing and RNA/splicing analysis.
5. WES/WGS can be useful after targeted testing is unrevealing, but conventional WES may inadequately cover deep introns. CMA, karyotyping, FISH, mitochondrial sequencing, and repeat-expansion testing are not routine diagnostic tests. (schultz2017dicer1relatedsertolileydigcell pages 7-8, fraire2023intronicgermlinedicer1 pages 1-2)

No population screening program is justified. Testing is targeted to patients and relatives in DICER1 families.

11. Outcome and prognosis

Stage and histologic differentiation are the strongest established clinical variables. Poor differentiation and tumor-limited DICER1 mutations were adverse in the registry, whereas germline/mosaic predisposition-associated cases had better overall and recurrence-free survival. This molecular association may be confounded by age, stage, biology, and ascertainment and should not replace stage-based risk assessment. (schultz2017dicer1relatedsertolileydigcell pages 5-7, schultz2017dicer1relatedsertolileydigcell pages 7-8)

Five- and ten-year SLCT-specific survival estimates vary across small retrospective series and were not reliably extractable from the retrieved full texts. The most defensible quantitative findings are the registry’s 16.3% recurrence rate, universal disease-free status among stage IA cases at median 19 months, and 50% disease-specific mortality among the eight recurrent cases. (schultz2017dicer1relatedsertolileydigcell pages 5-7)

Adverse features include extraovarian stage, rupture, poor differentiation, retiform pattern, heterologous/sarcomatous elements, residual disease, and recurrence. Morbidity includes infertility or reduced ovarian reserve, virilization, surgical menopause after bilateral surgery, platinum-related neuropathy/nephrotoxicity/ototoxicity, etoposide-associated marrow toxicity and rare secondary leukemia, and bleomycin pulmonary toxicity.

12. Treatment and real-world implementation

Surgery

For a unilateral, apparently stage I tumor in a young patient, the preferred real-world approach is fertility-sparing unilateral salpingo-oophorectomy with careful surgical staging, preservation of the normal contralateral ovary and uterus, and avoidance of tumor rupture. Routine biopsy of a grossly normal contralateral ovary is generally avoided because it can impair fertility. Completion surgery is individualized rather than automatic.

In the registry, 82% of stage IA patients received surgery alone. This supports observation for completely resected stage IA well/moderately differentiated tumors after expert review. Poorly differentiated stage IA disease is more controversial and may receive adjuvant chemotherapy. (schultz2017dicer1relatedsertolileydigcell pages 3-5)

Suggested NCIT intervention concepts: unilateral salpingo-oophorectomy, fertility-sparing surgery, ovarian cancer staging surgery, tumor resection.

Chemotherapy

For advanced, ruptured, incompletely resected, poorly differentiated, or recurrent disease, BEP—bleomycin, etoposide, and cisplatin—is the most established regimen by precedent. It was the most frequent chemotherapy in the registry, used in 12 SLCT cases. Toxicity and fertility risks require age-appropriate counseling and baseline pulmonary, renal, auditory, and reproductive assessment. (schultz2017dicer1relatedsertolileydigcell pages 3-5)

GOG-0264/NCT01042522 randomized 63 patients with advanced or recurrent chemotherapy-naïve ovarian sex cord–stromal tumors between paclitaxel/carboplatin for six 21-day courses and BEP for four courses. The primary endpoint was progression-free survival, with overall survival, response, toxicity, inhibin biomarkers, and tissue collection as secondary/tertiary objectives. Because histologies were pooled, any result is indirect for SLCT. ClinicalTrials.gov URL: https://clinicaltrials.gov/study/NCT01042522. (NCT01042522 chunk 1, NCT01042522 chunk 7)

Suggested NCIT terms: BEP regimen; bleomycin; etoposide; cisplatin; carboplatin; paclitaxel.

Targeted therapy and immunotherapy

There is no FDA-approved DICER1-directed, gene, RNA, or cell therapy for SLCT. NCT00748657 was a completed phase II study of IV bevacizumab every 21 days in 36 patients with recurrent ovarian sex cord–stromal tumors, measuring RECIST response, progression-free survival, overall survival, and toxicity. Its relevance to SLCT is indirect because histologies were pooled. ClinicalTrials.gov URL: https://clinicaltrials.gov/study/NCT00748657. (NCT00748657 chunk 1)

The recent finding that tumors were MMR-proficient and PD-L1-negative provides little biomarker rationale for routine checkpoint inhibition. HER2 negativity likewise argues against unselected HER2 therapy. Transcriptomic FGFR2, CDK6, NOTCH2, or MAPK-pathway signals remain investigational. (nemejcova2025amolecularand pages 11-12)

Supportive care and personalization

Care should include fertility preservation counseling, reproductive endocrinology referral when time permits, management of endocrine manifestations, psychosocial support, pulmonary/renal/auditory monitoring during BEP, menopausal care after bilateral oophorectomy, and genetic counseling. Personalized management is currently based primarily on stage, differentiation, residual disease, age/fertility goals, and germline DICER1 status—not a validated pharmacogenomic algorithm.

13. Prevention and surveillance

There is no established primary prevention or vaccine. General-population ovarian screening is not indicated.

For confirmed DICER1 carriers, prevention is primarily secondary prevention through surveillance and cascade testing. Contemporary DICER1 frameworks include age-adapted chest imaging in childhood, thyroid examination/ultrasound, renal surveillance in younger children, and periodic pelvic ultrasound for gynecologic tumors. Exact intervals should follow the current DICER1/PPB Registry or genetics-clinic guideline because schedules evolve and depend on age and prior tumors. A 2024 review emphasized pelvic ultrasound, thyroid evaluation, family testing, and multidisciplinary genetic counseling. [Cazzato et al., July 2024; DOI: https://doi.org/10.3390/jmp5030019]. (cazzato2024dicer1tumorsyndrome pages 7-8, cazzato2024dicer1tumorsyndrome pages 8-10)

Testing an affected woman can benefit relatives: in the international registry, cascade screening following SLCT-associated DICER1 findings led to detection of pleuropulmonary blastoma in three children at an early, highly curable stage. (schultz2017dicer1relatedsertolileydigcell pages 12-13)

Tertiary prevention includes complete initial resection without rupture, risk-adapted chemotherapy, long-term clinical and pelvic surveillance, prompt evaluation of recurrent endocrine symptoms, and monitoring for metachronous contralateral disease.

14. Other species and natural disease

Sex cord–stromal tumors with Sertoli- and Leydig-cell differentiation occur naturally in veterinary species, including domestic animals, but the retrieved evidence did not establish a naturally occurring nonhuman syndrome that reliably models human ovarian DICER1-associated SLCT. These tumors are not infectious and have no zoonotic potential.

Relevant orthologues include mouse Dicer1 and corresponding vertebrate DICER1 orthologues. Exact NCBI Taxonomy, breed-ontology, and veterinary gene identifiers should be populated from live NCBI/OMIA/VBO records rather than inferred. Comparative pathology is potentially useful, but spontaneous animal SLCTs should not automatically be assumed to share the human DICER1 two-hit mechanism.

15. Model organisms and experimental systems

A 2023 genetically engineered mouse study reported that biallelic Dicer1 alterations in the gynecologic tract drove lineage-specific DICER1-syndrome-associated cancers, providing experimental support for the two-hit and lineage-context model. However, the retrieved material did not provide sufficient SLCT-specific details to quantify penetrance, latency, histologic fidelity, or treatment response. Thus, it should be annotated as mechanistic support rather than a fully validated therapeutic SLCT model. (nemejcova2025amolecularand pages 11-12)

Potential systems include conditional Dicer1 loss-of-function plus RNase IIIb hotspot knock-in mice, primary tumor cultures, patient-derived organoids, xenografts, and engineered ovarian stromal cells. Major limitations are the rarity of specimens, uncertain fidelity of normal ovarian Sertoli-/Leydig-like lineage assignment, and lack of broadly distributed, genomically authenticated SLCT cell lines. No robust disease-specific CRISPR dependency screen was identified.

Evidence hierarchy, recent developments, and limitations

Highest-value human clinical evidence: the International Ovarian and Testicular Stromal Tumor Registry cohort, with central pathology review, paired genetic analysis, and outcome tracking. Its key abstract-level conclusion is reflected by the finding that DICER1 RNase IIIb mutations occurred in 36/37 sequenced SLCTs and that germline or mosaic variants occurred in more than half. [Schultz et al., December 2017; DOI: https://doi.org/10.1016/j.ygyno.2017.09.034]. (schultz2017dicer1relatedsertolileydigcell pages 12-13, schultz2017dicer1relatedsertolileydigcell pages 10-12)

Important 2023–2024 development: conventional exon-focused germline testing can miss pathogenic intronic DICER1 variants, supporting extended intronic sequencing and functional splice analysis in strongly suggestive cases. [Fraire et al., September 2023; DOI: https://doi.org/10.1200/PO.23.00189]. (fraire2023intronicgermlinedicer1 pages 1-2)

Recent molecular development: a contemporary 37-case analysis supports molecular separation of well-differentiated, frequently DICER1-wild-type tumors from DICER1-characteristic moderately/poorly differentiated disease and provides initial RNA-expression and predictive-marker data. Its abstract states: “DICER1MUT and DICER1WT tumors showed different mRNA expression profiles.” [DOI registered 2024; journal publication November 2025: https://doi.org/10.1007/s00428-024-03984-5]. (nemejcova2025amolecularand pages 11-12)

Major limitations: rarity, referral bias, changing histopathologic classification, small retrospective cohorts, heterogeneous chemotherapy, short follow-up in some early-stage series, and pooling of SLCT with granulosa and other sex cord–stromal tumors in trials. Many requested domains—population incidence, quantitative quality of life, environmental risk, epigenomics, metabolomics, pharmacogenomics, and validated targeted therapies—lack disease-specific evidence. PMIDs were not present in the retrieved records and therefore are not fabricated here; DOI and ClinicalTrials.gov URLs are supplied for authoritative record linkage.

References

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3. (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

4. (schultz2017dicer1relatedsertolileydigcell pages 1-3): Kris Ann P. Schultz, Anne K. Harris, Michael Finch, Louis P. Dehner, Jubilee B. Brown, David M. Gershenson, Robert H. Young, Amanda Field, Weiying Yu, Joyce Turner, Nicholas G. Cost, Dominik T. Schneider, Douglas R. Stewart, A. Lindsay Frazier, Yoav Messinger, and D. Ashley Hill. Dicer1-related sertoli-leydig cell tumor and gynandroblastoma: clinical and genetic findings from the international ovarian and testicular stromal tumor registry. Gynecologic oncology, 147 3:521-527, Dec 2017. URL: https://doi.org/10.1016/j.ygyno.2017.09.034, doi:10.1016/j.ygyno.2017.09.034. This article has 151 citations and is from a domain leading peer-reviewed journal.

5. (schultz2017dicer1relatedsertolileydigcell pages 12-13): Kris Ann P. Schultz, Anne K. Harris, Michael Finch, Louis P. Dehner, Jubilee B. Brown, David M. Gershenson, Robert H. Young, Amanda Field, Weiying Yu, Joyce Turner, Nicholas G. Cost, Dominik T. Schneider, Douglas R. Stewart, A. Lindsay Frazier, Yoav Messinger, and D. Ashley Hill. Dicer1-related sertoli-leydig cell tumor and gynandroblastoma: clinical and genetic findings from the international ovarian and testicular stromal tumor registry. Gynecologic oncology, 147 3:521-527, Dec 2017. URL: https://doi.org/10.1016/j.ygyno.2017.09.034, doi:10.1016/j.ygyno.2017.09.034. This article has 151 citations and is from a domain leading peer-reviewed journal.

6. (schultz2017dicer1relatedsertolileydigcell pages 3-5): Kris Ann P. Schultz, Anne K. Harris, Michael Finch, Louis P. Dehner, Jubilee B. Brown, David M. Gershenson, Robert H. Young, Amanda Field, Weiying Yu, Joyce Turner, Nicholas G. Cost, Dominik T. Schneider, Douglas R. Stewart, A. Lindsay Frazier, Yoav Messinger, and D. Ashley Hill. Dicer1-related sertoli-leydig cell tumor and gynandroblastoma: clinical and genetic findings from the international ovarian and testicular stromal tumor registry. Gynecologic oncology, 147 3:521-527, Dec 2017. URL: https://doi.org/10.1016/j.ygyno.2017.09.034, doi:10.1016/j.ygyno.2017.09.034. This article has 151 citations and is from a domain leading peer-reviewed journal.

7. (cazzato2024dicer1tumorsyndrome pages 1-2): Gerardo Cazzato, Nadia Casatta, Carmelo Lupo, Giuseppe Ingravallo, and Domenico Ribatti. Dicer1 tumor syndrome: a retrospective review and future perspectives. Journal of Molecular Pathology, 5:264-275, Jul 2024. URL: https://doi.org/10.3390/jmp5030019, doi:10.3390/jmp5030019. This article has 6 citations.

8. (fraire2023intronicgermlinedicer1 pages 1-2): Claudette R. Fraire, Paige R. Mallinger, Jessica N. Hatton, Jung Kim, David S. Dickens, Peter A. Argenta, Samuel Milanovich, Taylor Hartshorne, David J. Carey, Jeremy S. Haley, Gretchen Urban, Jeon Lee, D. Ashley Hill, Douglas R. Stewart, Kris Ann P. Schultz, and Kenneth S. Chen. Intronic germline dicer1 variants in patients with sertoli-leydig cell tumor. JCO Precision Oncology, Sep 2023. URL: https://doi.org/10.1200/po.23.00189, doi:10.1200/po.23.00189. This article has 16 citations and is from a peer-reviewed journal.

9. (nemejcova2025amolecularand pages 11-12): Kristýna Němejcová, Nikola Hájková, Eva Krkavcová, Michaela Kendall Bártů, Romana Michálková, Adam Šafanda, Marián Švajdler, Tetiana Shatokhina, Jan Laco, Radoslav Matěj, Jitka Hausnerová, Jozef Škarda, Monika Náležinská, Tomáš Zima, and Pavel Dundr. A molecular and immunohistochemical study of 37 cases of ovarian sertoli–leydig cell tumor. Virchows Archiv, 487:127-140, Nov 2025. URL: https://doi.org/10.1007/s00428-024-03984-5, doi:10.1007/s00428-024-03984-5. This article has 16 citations and is from a peer-reviewed journal.

10. (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

11. (NCT00748657 chunk 1): Bevacizumab in Treating Patients With Recurrent Sex Cord-Stromal Tumors of the Ovary. National Cancer Institute (NCI). 2008. ClinicalTrials.gov Identifier: NCT00748657

12. (cazzato2024dicer1tumorsyndrome pages 7-8): Gerardo Cazzato, Nadia Casatta, Carmelo Lupo, Giuseppe Ingravallo, and Domenico Ribatti. Dicer1 tumor syndrome: a retrospective review and future perspectives. Journal of Molecular Pathology, 5:264-275, Jul 2024. URL: https://doi.org/10.3390/jmp5030019, doi:10.3390/jmp5030019. This article has 6 citations.

13. (cazzato2024dicer1tumorsyndrome pages 8-10): Gerardo Cazzato, Nadia Casatta, Carmelo Lupo, Giuseppe Ingravallo, and Domenico Ribatti. Dicer1 tumor syndrome: a retrospective review and future perspectives. Journal of Molecular Pathology, 5:264-275, Jul 2024. URL: https://doi.org/10.3390/jmp5030019, doi:10.3390/jmp5030019. This article has 6 citations.

14. (schultz2017dicer1relatedsertolileydigcell pages 10-12): Kris Ann P. Schultz, Anne K. Harris, Michael Finch, Louis P. Dehner, Jubilee B. Brown, David M. Gershenson, Robert H. Young, Amanda Field, Weiying Yu, Joyce Turner, Nicholas G. Cost, Dominik T. Schneider, Douglas R. Stewart, A. Lindsay Frazier, Yoav Messinger, and D. Ashley Hill. Dicer1-related sertoli-leydig cell tumor and gynandroblastoma: clinical and genetic findings from the international ovarian and testicular stromal tumor registry. Gynecologic oncology, 147 3:521-527, Dec 2017. URL: https://doi.org/10.1016/j.ygyno.2017.09.034, doi:10.1016/j.ygyno.2017.09.034. This article has 151 citations and is from a domain leading peer-reviewed journal.

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