Sertoli-Leydig cell tumor (SLCT, androblastoma, arrhenoblastoma) is a rare ovarian sex cord-stromal neoplasm of young women that recapitulates testicular tubular and interstitial differentiation and, when functional, produces androgen excess with hirsutism, hair loss and amenorrhea or oligomenorrhea. The moderately and poorly differentiated and retiform tumors — the ones with malignant potential, which this entry models — are driven by somatic missense mutations restricted to the metal-binding residues of the DICER1 RNase IIIb catalytic centre. These are hypomorphic rather than null alleles: the mutant enzyme retains RNase IIIa activity but loses 5p-strand cleavage, so mature miRNA output is reprogrammed to a 3p-biased repertoire, with derepression of the 5p-strand targets. A substantial fraction arise in carriers of a germline loss-of-function DICER1 variant, making SLCT a sentinel tumor of DICER1-related tumor predisposition. Well-differentiated SLCT is DICER1 wild-type, has essentially no malignant potential, and has been argued to be a distinct tumor type; this entry is scoped to the malignant MONDO class accordingly. Its driver is mutually exclusive with the FOXL2 C134W driver of adult granulosa cell tumor, which is why the two are curated as separate Disease entries within the Ovarian Sex Cord-Stromal Tumors grouping.
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name: Malignant Sertoli-Leydig Cell Tumor of Ovary
creation_date: "2026-08-20T00:00:00Z"
description: >-
Sertoli-Leydig cell tumor (SLCT, androblastoma, arrhenoblastoma) is a rare ovarian
sex cord-stromal neoplasm of young women that recapitulates testicular tubular and
interstitial differentiation and, when functional, produces androgen excess with
hirsutism, hair loss and amenorrhea or oligomenorrhea. The moderately and poorly
differentiated and retiform tumors — the ones with malignant potential, which this
entry models — are driven by somatic missense mutations restricted to the
metal-binding residues of the DICER1 RNase IIIb catalytic centre. These are
hypomorphic rather than null alleles: the mutant enzyme retains RNase IIIa activity
but loses 5p-strand cleavage, so mature miRNA output is reprogrammed to a 3p-biased
repertoire, with derepression of the 5p-strand targets. A substantial fraction arise
in carriers of a germline loss-of-function DICER1 variant, making SLCT a sentinel
tumor of DICER1-related tumor predisposition. Well-differentiated SLCT is DICER1
wild-type, has essentially no malignant potential, and has been argued to be a
distinct tumor type; this entry is scoped to the malignant MONDO class accordingly.
Its driver is mutually exclusive with the FOXL2 C134W driver of adult granulosa cell
tumor, which is why the two are curated as separate Disease entries within the
Ovarian Sex Cord-Stromal Tumors grouping.
categories:
- Gynecologic Cancer
- Ovarian Cancer
- Sex Cord-Stromal Tumor
- Solid Tumor
disease_term:
preferred_term: malignant Sertoli-Leydig cell tumor of ovary
term:
id: MONDO:0020542
label: malignant Sertoli-Leydig cell tumor of ovary
parents:
- ovarian sex cord-stromal tumor
notes: >-
Scope note. MONDO:0020542 is the malignant ovarian SLCT class, a child of
MONDO:0018172. That scoping is mechanistically load-bearing rather than merely
nominal: DICER1 pathogenic variants are confined to the moderately/poorly
differentiated and retiform tumors, while an 18-case series of well-differentiated
SLCT found all of them DICER1 wild-type and FOXL2 wild-type, and the malignant
potential of well-differentiated tumors is described as practically null. The DICER1
chain curated here therefore applies to the malignant class and should not be
inherited by well-differentiated SLCT. A minority of SLCTs instead carry the FOXL2
C134W mutation, in an older, abnormal-bleeding population, and DICER1 and FOXL2
mutation are mutually exclusive; that arm is recorded in the genetic section and in a
KNOWLEDGE_GAP discussion rather than being given its own pathophysiology chain,
because no mechanism downstream of FOXL2 in SLCT specifically has been evidenced.
pathophysiology:
- name: Germline DICER1 Loss-of-Function Predisposition
biological_scale: MOLECULAR
description: >-
A heterozygous germline loss-of-function DICER1 variant establishes the predisposed
state. Penetrance is reduced and age-related, and ovarian sex cord-stromal tumors
are among the most characteristic manifestations, with SLCT diagnosed at a median
age of 14 years in a large international registry cohort. The germline variant is
the first hit; the somatic RNase IIIb hotspot change is the second.
genes:
- preferred_term: DICER1
term:
id: hgnc:17098
label: DICER1
downstream:
- target: DICER1 RNase IIIb Hotspot Mutation
description: >-
In a predisposed gonad the second, somatic hotspot hit in the retained allele
completes the two-step genetic lesion.
evidence:
- reference: PMID:24761742
reference_title: DICER1-Related Tumor Predisposition.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The diagnosis of DICER1 is established by identification of a
heterozygous germline DICER1 pathogenic variant that is known or suspected to
cause loss of function.
explanation: >-
GeneReviews defines the predisposition state modelled by this node as a
heterozygous germline loss-of-function DICER1 variant.
- reference: PMID:39400264
reference_title: "DICER1-Related Tumor Predisposition: Identification of At-risk Individuals and Recommended Surveillance Strategies."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
One hundred and three individuals with a germline P/LP variant developed a primary
ovarian Sertoli-Leydig cell tumor at a median age of 14 years (range: 11 months-66
years); 13% were diagnosed before 8 years of age, the current age of onset of
pelvic surveillance.
explanation: >-
Registry data quantify SLCT incidence and age distribution among germline DICER1
variant carriers, grounding this node in a human predisposed cohort.
- reference: PMID:29037807
reference_title: "DICER1-related Sertoli-Leydig cell tumor and gynandroblastoma: Clinical and genetic findings from the International Ovarian and Testicular Stromal Tumor Registry."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Nearly all (36/37) SLCTs and 4/4 GAB tested had a DICER1 mutation in an RNase IIIb
domain hotspot; approximately half of these individuals had a predisposing germline
DICER1 mutation.
explanation: >-
Quantifies what fraction of the somatic-hotspot tumors sit on a germline
predisposing background - roughly half - which is what makes this node a real
but non-obligatory first step rather than a universal one.
notes: >-
Roughly half of hotspot-mutant SLCTs arise on a germline predisposing background and
half are tumor-limited, so this node is a frequent but NOT obligatory upstream step;
the somatic RNase IIIb hit below is the constant element. Somatic mosaicism for a
hotspot variant is a recognised third architecture. Because germline pLOF variants
are not always found by conventional exon-directed sequencing, two SLCT patients with
a somatic hotspot variant and negative germline exon testing were shown to carry deep
intronic splice-altering DICER1 variants, so a negative standard germline test does
not exclude predisposition.
- name: DICER1 RNase IIIb Hotspot Mutation
biological_scale: MOLECULAR
description: >-
Somatic missense mutations cluster tightly in the DICER1 region encoding the RNase
IIIb domain, and are restricted to the codons encoding the four metal-binding
residues of the RNase IIIb catalytic centre that are critical for microRNA
interaction and cleavage. These mutations were found in 60% of Sertoli-Leydig cell
tumors in the founding series and are somatic in every case with germline DNA
available. Crucially they do not abolish DICER1: the mutant proteins retain RNase
IIIa activity while losing RNase IIIb activity, so this is a hypomorphic,
activity-altering lesion rather than a classic null.
genes:
- preferred_term: DICER1
term:
id: hgnc:17098
label: DICER1
molecular_functions:
- preferred_term: DICER1 RNase IIIb catalytic activity
modifier: DECREASED
term:
id: GO:0004525
label: ribonuclease III activity
locations:
- preferred_term: ovary
term:
id: UBERON:0000992
label: ovary
downstream:
- target: Loss of 5p-Strand miRNA Processing and 3p Strand Bias
description: >-
RNase IIIb is the domain that cleaves the 3' end of the 5p miRNA strand, so its
selective inactivation removes mature 5p miRNAs while leaving 3p production intact.
evidence:
- reference: PMID:22187960
reference_title: Recurrent somatic DICER1 mutations in nonepithelial ovarian cancers.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
DICER1 mutations in the RNase IIIb domain were found in 30 of 102 nonepithelial
ovarian tumors (29%), predominantly in Sertoli-Leydig cell tumors (26 of 43, or
60%), including 4 tumors with additional germline DICER1 mutations.
explanation: >-
Establishes the frequency of the RNase IIIb hotspot lesion in SLCT specifically and
its co-occurrence with germline variants.
- reference: PMID:22187960
reference_title: Recurrent somatic DICER1 mutations in nonepithelial ovarian cancers.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These mutations were restricted to codons encoding metal-binding sites within the
RNase IIIb catalytic centers, which are critical for microRNA interaction and
cleavage, and were somatic in all 16 samples in which germline DNA was available
for testing.
explanation: >-
Pins the lesion to the metal-binding residues of the RNase IIIb catalytic centre
and establishes its somatic origin.
- reference: PMID:22187960
reference_title: Recurrent somatic DICER1 mutations in nonepithelial ovarian cancers.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The mutant DICER1 proteins had reduced RNase IIIb activity but retained RNase IIIa
activity.
explanation: >-
In vitro cleavage assays support the DECREASED (not abolished) RNase III activity
annotated on this node.
- name: Loss of 5p-Strand miRNA Processing and 3p Strand Bias
biological_scale: MOLECULAR
description: >-
All four metal-binding hotspot alleles are functionally equivalent and behave as
hypomorphs: cells expressing them lose mature 5p-strand miRNA production almost
completely while still generating 3p-strand miRNAs. The resulting global 3p strand
bias in the mature miRNA repertoire, rather than a wholesale loss of miRNA
processing, is proposed to underpin the oncogenic effect.
biological_processes:
- preferred_term: pre-miRNA processing
modifier: DECREASED
term:
id: GO:0031054
label: pre-miRNA processing
downstream:
- target: Derepression of 5p-miRNA Target Transcripts
description: >-
Transcripts normally repressed by the lost 5p-derived miRNAs become
enriched in expression.
evidence:
- reference: PMID:23132766
reference_title: Cancer-associated somatic DICER1 hotspot mutations cause defective miRNA processing and reverse-strand expression bias to predominantly mature 3p strands through loss of 5p strand cleavage.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Further, miRNA profiles showed that mutant DICER1 results in a dramatic loss in
processing of mature 5p miRNA strands but were still able to create 3p strand
miRNAs.
explanation: >-
Directly measures the selective loss of 5p-strand processing that defines this node.
- reference: PMID:23132766
reference_title: Cancer-associated somatic DICER1 hotspot mutations cause defective miRNA processing and reverse-strand expression bias to predominantly mature 3p strands through loss of 5p strand cleavage.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We further propose that this resulting 3p strand bias in mature miRNA expression
likely underpins the oncogenic potential of these hotspot mutations.
explanation: >-
States the authors' proposed mechanistic link from strand bias to oncogenesis.
- name: Derepression of 5p-miRNA Target Transcripts
biological_scale: CELLULAR
description: >-
Loss of the 5p-derived miRNAs releases their target mRNAs from post-transcriptional
repression. Messenger RNA profiling of hotspot-mutant cells shows enriched
expression of the predicted targets of exactly those lost 5p miRNAs, so the
transcriptomic consequence is a specific derepression signature rather than
generalized dysregulation. This altered post-transcriptional program in the
developing gonadal stroma is the proximate route to tumor formation.
biological_processes:
- preferred_term: miRNA-mediated post-transcriptional gene silencing
modifier: DECREASED
term:
id: GO:0035195
label: miRNA-mediated post-transcriptional gene silencing
cell_types:
- preferred_term: Sertoli cell
term:
id: CL:0000216
label: Sertoli cell
- preferred_term: Leydig cell
term:
id: CL:0000178
label: Leydig cell
downstream:
- target: Sertoli-Leydig Tumor Formation with Heterologous and Retiform Differentiation
description: >-
The derepressed program drives outgrowth of a tumor recapitulating testicular
tubular and interstitial differentiation.
evidence:
- reference: PMID:23132766
reference_title: Cancer-associated somatic DICER1 hotspot mutations cause defective miRNA processing and reverse-strand expression bias to predominantly mature 3p strands through loss of 5p strand cleavage.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Messenger RNA (mRNA) profile changes were consistent with the loss of 5p strand
miRNAs and showed enriched expression for predicted targets of the lost 5p-derived
miRNAs.
explanation: >-
Directly demonstrates derepression of the predicted 5p-miRNA targets, which is the
content of this node.
- reference: PMID:22187960
reference_title: Recurrent somatic DICER1 mutations in nonepithelial ovarian cancers.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These mutations do not obliterate DICER1 function but alter it in specific cell
types, a novel mechanism through which perturbation of microRNA processing may be
oncogenic.
explanation: >-
Supports the cell-type-selective character of the mechanism, which is why the
lesion produces a gonadal stromal tumor rather than a generalized phenotype.
- name: Sertoli-Leydig Tumor Formation with Heterologous and Retiform Differentiation
biological_scale: TISSUE
description: >-
The DICER1-mutant tumors are moderately or poorly differentiated, and every tumor
with retiform or heterologous elements in a 42-case molecular series carried a
DICER1 RNase IIIb mutation. The genotype therefore tracks with exactly the
morphologic features that carry malignant potential, and well-differentiated SLCT —
which is DICER1 wild-type — falls outside this chain.
cell_types:
- preferred_term: Sertoli cell
term:
id: CL:0000216
label: Sertoli cell
- preferred_term: Leydig cell
term:
id: CL:0000178
label: Leydig cell
locations:
- preferred_term: ovary
term:
id: UBERON:0000992
label: ovary
downstream:
- target: Tumor Androgen Overproduction
description: >-
The Leydig-like interstitial component of the tumor secretes androgen, producing
the virilizing clinical picture.
evidence:
- reference: PMID:30986800
reference_title: DICER1 and FOXL2 Mutation Status Correlates With Clinicopathologic Features in Ovarian Sertoli-Leydig Cell Tumors.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
DICER1 RNase IIIb domain mutations were identified in 18/41 (44%; 17 moderately, 1
poorly differentiated), including all cases with retiform or heterologous elements.
explanation: >-
Ties the DICER1 genotype to moderately/poorly differentiated morphology and to all
retiform/heterologous tumors.
- reference: PMID:36583307
reference_title: Well-differentiated Sertoli-Leydig Cell Tumors (SLCTs) Are Not Associated With DICER1 Pathogenic Variants and Represent a Different Tumor Type to Moderately and Poorly Differentiated SLCTs.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We undertook DICER1 molecular testing in a cohort of 18 well-differentiated SLCTs
and show all these to be DICER1 wild-type.
explanation: >-
Negative result establishing that the DICER1 chain does not extend to
well-differentiated SLCT, which is why this entry is scoped to the malignant class.
- reference: PMID:39592485
reference_title: "A molecular and immunohistochemical study of 37 cases of ovarian Sertoli-Leydig cell tumor."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We have confirmed that DICER1 mutations are characteristic of moderately and poorly
differentiated SLCTs, while well-differentiated SLCTs may represent a distinct
entity.
explanation: >-
Independent 37-case replication of the grade restriction of the DICER1 driver, the
observation this entry's malignant-class scoping rests on.
- name: Tumor Androgen Overproduction
biological_scale: ORGANISM
description: >-
Functional SLCTs secrete androgen from their Leydig-cell-like component, raising
circulating testosterone and producing hirsutism, androgenic alopecia, and
amenorrhea or oligomenorrhea. Some patients instead show hyperestrogenism, either
from direct tumor estrogen secretion or from peripheral aromatization of
tumor-derived testosterone. DICER1-mutant tumors trended toward more androgenic
symptoms than their FOXL2-mutant counterparts.
biological_processes:
- preferred_term: tumor androgen biosynthesis
modifier: INCREASED
term:
id: GO:0006702
label: androgen biosynthetic process
cell_types:
- preferred_term: Leydig cell
term:
id: CL:0000178
label: Leydig cell
evidence:
- reference: PMID:31344718
reference_title: "Ovarian Sertoli-Leydig Cell Tumors: Epidemiological, Clinical and Prognostic Factors."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This type of tumor predominates in the 2nd and 3rd decades of life and usually
presents with hormonal changes, including signs of virilization, such as
amenorrhea, hirsutism, acne, and male pattern of pilification.
explanation: >-
Enumerates the virilizing manifestations that this node produces, and the age
distribution of the tumor.
- reference: PMID:31344718
reference_title: "Ovarian Sertoli-Leydig Cell Tumors: Epidemiological, Clinical and Prognostic Factors."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These characteristics are due to an increase in androgen production by tumor cells.
explanation: >-
States the causal attribution of the virilizing phenotype to tumor androgen output,
which is the mechanistic content of this node.
- reference: PMID:30986800
reference_title: DICER1 and FOXL2 Mutation Status Correlates With Clinicopathologic Features in Ovarian Sertoli-Leydig Cell Tumors.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
DICER1-mutant patients trended toward having more androgenic symptoms (P=0.22).
explanation: >-
PARTIAL: a non-significant trend (P=0.22), quoted with its p-value so the weakness
is visible. It is suggestive, not established, that the DICER1 genotype
preferentially produces the androgenic presentation.
phenotypes:
- category: Clinical
name: Hirsutism
description: >-
Excess terminal hair in an androgen-dependent distribution is one of the defining
virilizing features of a functional SLCT.
phenotype_term:
preferred_term: Hirsutism
term:
id: HP:0001007
label: Hirsutism
evidence:
- reference: PMID:31344718
reference_title: "Ovarian Sertoli-Leydig Cell Tumors: Epidemiological, Clinical and Prognostic Factors."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This type of tumor predominates in the 2nd and 3rd decades of life and usually
presents with hormonal changes, including signs of virilization, such as
amenorrhea, hirsutism, acne, and male pattern of pilification.
explanation: Names hirsutism among the characteristic virilizing signs of SLCT.
- category: Clinical
name: Amenorrhea
description: >-
Tumor androgen output suppresses the hypothalamic-pituitary-ovarian axis and normal
cyclicity, producing amenorrhea or oligomenorrhea in young women.
phenotype_term:
preferred_term: Amenorrhea
term:
id: HP:0000141
label: Amenorrhea
evidence:
- reference: PMID:31344718
reference_title: "Ovarian Sertoli-Leydig Cell Tumors: Epidemiological, Clinical and Prognostic Factors."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This type of tumor predominates in the 2nd and 3rd decades of life and usually
presents with hormonal changes, including signs of virilization, such as
amenorrhea, hirsutism, acne, and male pattern of pilification.
explanation: Names amenorrhea among the characteristic virilizing signs of SLCT.
- category: Clinical
name: Abdominal Pain
description: >-
In a 12-case surgical series abdominal pain was the commonest presenting symptom,
occurring in two thirds of patients — the non-hormonal route to presentation.
phenotype_term:
preferred_term: Abdominal pain
term:
id: HP:0002027
label: Abdominal pain
frequency: FREQUENT
evidence:
- reference: PMID:31344718
reference_title: "Ovarian Sertoli-Leydig Cell Tumors: Epidemiological, Clinical and Prognostic Factors."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A total of 9 patients (75.0%) presented symptoms: 8 (66.7%) presented with
abdominal pain, 5 (41.7%) presented with abdominal enlargement, 2 (16.7%) presented
with virilizing signs, 2 (16.7%) presented with abnormal uterine bleeding, 1 (8.3%)
presented with dyspareunia, and 1 (8.3%) presented with weight loss.
explanation: >-
66.7% of 12 patients is a direct quantitative measurement falling in the 30-79%
FREQUENT band.
- category: Clinical
name: Abdominal Distention
description: >-
Abdominal enlargement from a large adnexal mass — median lesion size 14.2 cm in one
series — is the second commonest presentation.
phenotype_term:
preferred_term: Abdominal distention
term:
id: HP:0003270
label: Abdominal distention
frequency: FREQUENT
evidence:
- reference: PMID:31344718
reference_title: "Ovarian Sertoli-Leydig Cell Tumors: Epidemiological, Clinical and Prognostic Factors."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A total of 9 patients (75.0%) presented symptoms: 8 (66.7%) presented with
abdominal pain, 5 (41.7%) presented with abdominal enlargement, 2 (16.7%) presented
with virilizing signs, 2 (16.7%) presented with abnormal uterine bleeding, 1 (8.3%)
presented with dyspareunia, and 1 (8.3%) presented with weight loss.
explanation: >-
41.7% of 12 patients presented with abdominal enlargement, within the 30-79%
FREQUENT band.
- category: Clinical
name: Ovarian Mass
description: >-
SLCTs are essentially always unilateral, and are typically large and solid-cystic on
imaging with no distinguishing ultrasonographic pattern.
phenotype_term:
preferred_term: Ovarian neoplasm
term:
id: HP:0100615
label: Ovarian neoplasm
evidence:
- reference: PMID:31344718
reference_title: "Ovarian Sertoli-Leydig Cell Tumors: Epidemiological, Clinical and Prognostic Factors."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All of the tumors were unilateral and surgically treated.
explanation: >-
Supports unilaterality of the ovarian mass in a consecutive surgical series.
- reference: PMID:24761742
reference_title: DICER1-Related Tumor Predisposition.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
DICER1-related neoplasms include pleuropulmonary blastoma
(PPB), Sertoli-Leydig cell tumor (SLCT), including gynandroblastoma, pediatric
cystic nephroma (CN), and differentiated thyroid carcinoma.
explanation: >-
GeneReviews Clinical Characteristics evidence placing this ovarian tumor within the
DICER1 neoplasm spectrum, which is what makes the germline predisposition arm of
this entry applicable.
- category: Laboratory
name: Elevated Serum Testosterone
description: >-
Circulating testosterone is raised by tumor androgen secretion and is the
biochemical correlate of the virilizing presentation.
phenotype_term:
preferred_term: Increased serum testosterone level
term:
id: HP:0030088
label: Increased serum testosterone level
evidence:
- reference: PMID:31344718
reference_title: "Ovarian Sertoli-Leydig Cell Tumors: Epidemiological, Clinical and Prognostic Factors."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These characteristics are due to an increase in androgen production by tumor cells.
explanation: >-
PARTIAL: the source attributes the virilizing picture to androgen production by the
tumor, but reports no measured serum testosterone values in this cohort, so it
supports the mechanism rather than a quantified laboratory abnormality.
histopathology:
- name: Moderately or Poorly Differentiated Sertoli-Leydig Morphology
description: >-
Tumors are graded well, moderately, or poorly differentiated, with or without
heterologous elements or a retiform pattern. Moderately and poorly differentiated
and retiform types commonly co-occur as a morphologic spectrum, whereas the
well-differentiated form typically occurs in pure form and is genetically distinct.
diagnostic: true
evidence:
- reference: PMID:36583307
reference_title: Well-differentiated Sertoli-Leydig Cell Tumors (SLCTs) Are Not Associated With DICER1 Pathogenic Variants and Represent a Different Tumor Type to Moderately and Poorly Differentiated SLCTs.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Well-differentiated SLCT is the least common and typically occurs in pure form,
whereas moderately and poorly differentiated and retiform types often comprise a
morphologic spectrum with an admixture of all 3.
explanation: >-
Describes the grading scheme and the morphologic separation this entry's scope
depends on.
- reference: PMID:31344718
reference_title: "Ovarian Sertoli-Leydig Cell Tumors: Epidemiological, Clinical and Prognostic Factors."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In the anatomopathological exam, 1 (8.3%) tumor was well-differentiated, 8 (66.7%)
were moderately differentiated, and 3 (25.0%) were poorly differentiated.
explanation: >-
Gives the observed distribution of differentiation grades in a consecutive series.
diagnosis:
- name: DICER1 Molecular Testing, Tumor and Germline
description: >-
Diagnosis rests on morphology plus a sex cord immunophenotype, with DICER1 RNase IIIb
testing used both to confirm a moderately/poorly differentiated or retiform SLCT and
to trigger germline evaluation. The workflow is deliberately two-tiered: a somatic
hotspot variant in the tumor prompts germline testing, and a negative conventional
germline test does not close the question, because deep intronic splice-altering
DICER1 variants have been found by custom-capture panel in patients whose exon-directed
sequencing was negative.
evidence:
- reference: PMID:37883719
reference_title: Intronic Germline DICER1 Variants in Patients With Sertoli-Leydig Cell Tumor.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We suggest that 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.
explanation: >-
States the escalation step in the diagnostic workflow that prevents a falsely
negative germline result from ending the evaluation.
- reference: PMID:24761742
reference_title: DICER1-Related Tumor Predisposition.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The diagnosis of DICER1 is established by identification of a
heterozygous germline DICER1 pathogenic variant that is known or suspected to
cause loss of function.
explanation: >-
GeneReviews diagnostic criterion for the predisposition syndrome that an SLCT
diagnosis should prompt testing for.
genetic:
- name: DICER1
association: >-
Somatic missense mutations at the four metal-binding residues of the RNase IIIb
catalytic centre are the defining recurrent lesion, present in about 44-60% of
Sertoli-Leydig cell tumors and in all tumors with retiform or heterologous
elements. A substantial fraction of patients also carry a germline
loss-of-function DICER1 variant (DICER1-related tumor predisposition).
gene_term:
preferred_term: DICER1
term:
id: hgnc:17098
label: DICER1
variant_origin: SOMATIC
case_fractions:
- population: Sertoli-Leydig cell tumors within a nonepithelial ovarian tumor cohort
case_fraction_percent: 60.0
cohort_size: 43
notes: >-
26 of 43 Sertoli-Leydig cell tumors carried an RNase IIIb domain mutation in the
founding series.
evidence:
- reference: PMID:22187960
reference_title: Recurrent somatic DICER1 mutations in nonepithelial ovarian cancers.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
DICER1 mutations in the RNase IIIb domain were found in 30 of 102 nonepithelial
ovarian tumors (29%), predominantly in Sertoli-Leydig cell tumors (26 of 43, or
60%), including 4 tumors with additional germline DICER1 mutations.
explanation: Gives the SLCT-specific share of DICER1 RNase IIIb mutation.
- population: Consecutive molecularly characterized SLCT series
case_fraction_percent: 44.0
cohort_size: 41
notes: >-
18 of 41 evaluable tumors in a 42-case clinicopathologic series.
evidence:
- reference: PMID:30986800
reference_title: DICER1 and FOXL2 Mutation Status Correlates With Clinicopathologic Features in Ovarian Sertoli-Leydig Cell Tumors.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
DICER1 RNase IIIb domain mutations were identified in 18/41 (44%; 17 moderately, 1
poorly differentiated), including all cases with retiform or heterologous elements.
explanation: Independent cohort estimate of the DICER1-mutant share of SLCT.
evidence:
- reference: PMID:22187960
reference_title: Recurrent somatic DICER1 mutations in nonepithelial ovarian cancers.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Somatic missense mutations affecting the RNase IIIb domain of DICER1 are common in
nonepithelial ovarian tumors.
explanation: >-
States the core gene-disease association curated here.
- name: FOXL2
association: >-
A minority of Sertoli-Leydig cell tumors carry the FOXL2 c.402C>G (p.C134W)
mutation instead of a DICER1 mutation. The two lesions are mutually exclusive, and
the FOXL2-mutant SLCTs form a clinically distinct, markedly older group.
gene_term:
preferred_term: FOXL2
term:
id: hgnc:1092
label: FOXL2
variant_origin: SOMATIC
case_fractions:
- population: Consecutive molecularly characterized SLCT series
case_fraction_percent: 19.0
cohort_size: 42
notes: 8 of 42 tumors; all moderately or poorly differentiated.
evidence:
- reference: PMID:30986800
reference_title: DICER1 and FOXL2 Mutation Status Correlates With Clinicopathologic Features in Ovarian Sertoli-Leydig Cell Tumors.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
FOXL2 c.402C>G (p.C134W) mutation was identified in 8/42 (19%) tumors (5
moderately, 3 poorly differentiated).
explanation: Quantifies the FOXL2-mutant share of SLCT.
evidence:
- reference: PMID:30986800
reference_title: DICER1 and FOXL2 Mutation Status Correlates With Clinicopathologic Features in Ovarian Sertoli-Leydig Cell Tumors.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
DICER1 and FOXL2 mutations were mutually exclusive.
explanation: >-
Establishes mutual exclusivity of the two sex cord-stromal drivers within SLCT,
the observation that underpins keeping the driver-defined histotypes as separate
Disease entries.
- name: TERT
association: >-
TERT promoter mutation is an uncommon third lesion in Sertoli-Leydig cell tumor,
found in 2 of 37 tumors in one series. It is the same lesion that is the commonest
secondary event in adult granulosa cell tumor, so it is a shared secondary event
across the sex cord-stromal family rather than a histotype-defining driver.
gene_term:
preferred_term: TERT
term:
id: hgnc:11730
label: TERT
variant_origin: SOMATIC
evidence:
- reference: PMID:39592485
reference_title: "A molecular and immunohistochemical study of 37 cases of ovarian Sertoli-Leydig cell tumor."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The molecular analysis showed DICER1 mutations in 54.5% of cases, and a FOXL2
mutation in 6% of tumors. In addition, we detected 2 cases with TERT promoter
mutation.
explanation: >-
Reports TERT promoter mutation alongside the DICER1 and FOXL2 frequencies in the
same 37-tumor cohort.
inheritance:
- name: Autosomal dominant DICER1 tumor predisposition
description: >-
The germline predisposing DICER1 variant is inherited in an autosomal dominant
manner with reduced, age-related penetrance, so many carriers remain clinically
unaffected. The tumor itself additionally requires a somatic RNase IIIb hotspot
hit, which is why an inherited susceptibility produces a sporadic-looking unilateral
tumor.
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
evidence:
- reference: PMID:24761742
reference_title: DICER1-Related Tumor Predisposition.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
DICER1 is inherited in an autosomal dominant manner with reduced,
age-related penetrance.
explanation: >-
GeneReviews states the mode of inheritance and the reduced age-related penetrance
curated in this block.
- reference: PMID:24761742
reference_title: DICER1-Related Tumor Predisposition.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Each child of an individual with a germline constitutional DICER1
pathogenic variant has a 50% chance of inheriting the pathogenic variant.
explanation: >-
GeneReviews Genetic Counseling evidence for the per-child transmission risk, the
figure that actually gets communicated to families after an SLCT diagnosis.
prevalence:
- population: Worldwide
measure_type: UNKNOWN
prevalence_class: RARE
notes: >-
Reported as under 0.5% of all ovarian tumors. The source states a proportion of
ovarian tumors rather than a population rate, so no rate_per_100000 is asserted.
evidence:
- reference: PMID:31344718
reference_title: "Ovarian Sertoli-Leydig Cell Tumors: Epidemiological, Clinical and Prognostic Factors."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Ovarian Sertoli-Leydig cell tumors (SLCTs) are part of the sexual cord neoplasms
and represent < 0.5% of all ovarian tumors.
explanation: Gives the share of ovarian tumors accounted for by SLCT.
progression:
- phase: Early-stage unilateral presentation in young women
notes: >-
SLCT predominates in the second and third decades and presents as a large unilateral
stage I mass; in one consecutive series every tumor was FIGO stage IA and none
recurred. Median age at diagnosis in germline DICER1 carriers is 14 years, and
DICER1-related ovarian sex cord-stromal tumors are most often diagnosed before age
40, which is what bounds the surveillance window.
evidence:
- reference: PMID:24761742
reference_title: DICER1-Related Tumor Predisposition.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The majority of tumors
occur in individuals younger than age 40 years.
explanation: >-
GeneReviews Clinical Characteristics evidence for the age distribution of
DICER1-related tumors, which is the basis for ending intensive ovarian
surveillance around age 40.
- reference: PMID:31344718
reference_title: "Ovarian Sertoli-Leydig Cell Tumors: Epidemiological, Clinical and Prognostic Factors."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All of the SLCTs were at stage IA, and most of them were moderately differentiated.
explanation: >-
Documents the early-stage presentation characteristic of this tumor.
- phase: Malignant potential graded by differentiation
notes: >-
Prognosis tracks stage and histologic differentiation. Well-differentiated tumors
have essentially no malignant potential; the risk rises substantially with
decreasing differentiation, which is the same axis along which the DICER1 driver is
distributed.
evidence:
- reference: PMID:31344718
reference_title: "Ovarian Sertoli-Leydig Cell Tumors: Epidemiological, Clinical and Prognostic Factors."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The malignant potential in well-differentiated tumors is practically null and
increases substantially in those with lower degrees of differentiation.
explanation: >-
States the grade-dependence of malignant potential that scopes this entry to the
malignant class.
treatments:
- name: Fertility-Sparing Unilateral Salpingo-Oophorectomy
description: >-
Because SLCTs are unilateral, stage I, and occur in young women, unilateral
salpingo-oophorectomy is the procedure of choice when fertility preservation is
desired, and surgery alone is usually curative.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: unilateral salpingo-oophorectomy
term:
id: NCIT:C94469
label: Unilateral Salpingo-oophorectomy
target_mechanisms:
- target: Sertoli-Leydig Tumor Formation with Heterologous and Retiform Differentiation
treatment_effect: INHIBITS
description: >-
Excision of the affected ovary removes the tumor, which is the definitive
treatment for stage I disease.
evidence:
- reference: PMID:31344718
reference_title: "Ovarian Sertoli-Leydig Cell Tumors: Epidemiological, Clinical and Prognostic Factors."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Unilateral salpingo-oophorectomy is the procedure of choice for patients that
want to preserve their fertility.
explanation: >-
States the recommended fertility-sparing surgical procedure for this tumor.
evidence:
- reference: PMID:31344718
reference_title: "Ovarian Sertoli-Leydig Cell Tumors: Epidemiological, Clinical and Prognostic Factors."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Most of the ovarian SLCTs are unilateral, and their treatment is preferably
surgical.
explanation: Supports surgery as the primary treatment modality.
- name: Adjuvant Platinum-Based Chemotherapy
description: >-
Chemotherapy is added selectively for higher-stage or poorly differentiated tumors
rather than routinely. Regimens used in reported series include
carboplatin-paclitaxel and ifosfamide-cisplatin-etoposide.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: chemotherapy
term:
id: NCIT:C15632
label: Chemotherapy
therapeutic_agent:
- preferred_term: cisplatin
term:
id: CHEBI:27899
label: cisplatin
- preferred_term: etoposide
term:
id: CHEBI:4911
label: etoposide
evidence:
- reference: PMID:31344718
reference_title: "Ovarian Sertoli-Leydig Cell Tumors: Epidemiological, Clinical and Prognostic Factors."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A total of 2 (16.7%) patients received adjuvant treatment; 1 of them underwent 3
cycles of paclitaxel and carboplatin every 21 days, and the other underwent 4
cycles of ifosfamide, cisplatin and etoposide every 21 days.
explanation: >-
Documents the selective use of adjuvant chemotherapy and the specific regimens
given in a consecutive series.
- reference: PMID:24761742
reference_title: DICER1-Related Tumor Predisposition.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Ovarian tumors require
surgery and may also require chemotherapy depending on stage and histology, with
radiation generally reserved for relapsed disease.
explanation: >-
GeneReviews management guidance confirming stage- and histology-dependent use of
chemotherapy in DICER1-related ovarian tumors.
- name: Pelvic Ultrasound Surveillance in DICER1 Variant Carriers
description: >-
Carriers of a germline DICER1 pathogenic variant undergo periodic pelvic ultrasound
to detect ovarian sex cord-stromal tumors early. Registry data showing that 13% of
SLCTs were diagnosed before age 8 — the previous surveillance start age — prompted a
recommendation to begin ovarian surveillance at the time the germline variant is
identified.
therapeutic_modality: OTHER
treatment_term:
preferred_term: pelvic ultrasound surveillance for ovarian sex cord-stromal tumors
term:
id: NCIT:C15576
label: Screening for Ovarian Cancer
evidence:
- reference: PMID:39400264
reference_title: "DICER1-Related Tumor Predisposition: Identification of At-risk Individuals and Recommended Surveillance Strategies."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
DICER1-related ovarian tumors were detected before 8 years of age, prompting the
Registry to recommend earlier initiation of ovarian surveillance with pelvic
ultrasound beginning at the time of detection of a germline DICER1 P/LP variant.
explanation: >-
States the current surveillance recommendation and the registry finding that
motivated it.
- reference: PMID:24761742
reference_title: DICER1-Related Tumor Predisposition.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Pelvic
ultrasounds for gynecologic tumors in females every six months until at least
age 40 years.
explanation: >-
GeneReviews surveillance schedule for gynecologic tumors in DICER1 variant carriers.
- name: Genetic Counseling and Germline DICER1 Testing
description: >-
A diagnosis of moderately or poorly differentiated SLCT is an indication to consider
germline DICER1 testing, since the tumor is a sentinel neoplasm of an autosomal
dominant predisposition syndrome with implications for the patient and first-degree
relatives.
therapeutic_modality: OTHER
treatment_term:
preferred_term: genetic counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:24761742
reference_title: DICER1-Related Tumor Predisposition.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Once a germline DICER1 pathogenic variant has been
identified in an affected family member, predictive testing for at-risk
relatives and prenatal/preimplantation genetic testing are possible.
explanation: >-
Supports cascade genetic testing of relatives once a germline variant is found.
- reference: PMID:29037807
reference_title: "DICER1-related Sertoli-Leydig cell tumor and gynandroblastoma: Clinical and genetic findings from the International Ovarian and Testicular Stromal Tumor Registry."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Three children of women with SLCT were diagnosed with PPB based on genetic testing
and clinical screening during the course of this study. All were diagnosed with PPB
in its earliest and most curable form (Type I), were treated with surgery alone, and
are alive without evidence of disease.
explanation: >-
Documents the concrete yield of cascade testing triggered by an SLCT diagnosis:
three children detected with pleuropulmonary blastoma at its most curable stage.
This is the strongest available justification for testing after SLCT.
notes: >-
Conventional exon-directed germline sequencing can miss the predisposing allele. Two
SLCT patients whose tumors carried only a somatic RNase IIIb missense variant were
found on custom-capture panel testing to have novel intronic DICER1 variants
interfering with normal splicing, so a negative standard germline test in the face of
strong clinical suspicion should prompt intron sequencing and splicing analysis
rather than closing the question.
clinical_trials:
- name: NCT01042522
phase: PHASE_II
status: COMPLETED
description: >-
GOG-0264, a randomized phase II trial of paclitaxel plus carboplatin versus
bleomycin, etoposide and cisplatin (BEP) in newly diagnosed advanced-stage and
recurrent chemonaive ovarian sex cord-stromal tumors. Important scope caveat for
curators: the trial enrolled sex cord-stromal tumors as a pooled group rather than
Sertoli-Leydig cell tumor specifically, so it is evidence about the family, not about
this histotype in isolation.
target_phenotypes:
- preferred_term: Ovarian neoplasm
term:
id: HP:0100615
label: Ovarian neoplasm
evidence:
- reference: clinicaltrials:NCT01042522
reference_title: "A Randomized Phase II Trial of Paclitaxel and Carboplatin vs. Bleomycin, Etoposide, and Cisplatin for Newly Diagnosed Advanced Stage and Recurrent Chemonaive Sex Cord-Stromal Tumors of the Ovary"
supports: SUPPORT
evidence_source: OTHER
snippet: >-
It is not yet known which chemotherapy regimen is more effective in treating sex
cord-ovarian stromal tumors.
explanation: >-
PARTIAL: the registry record establishes the trial's existence and comparison
(paclitaxel/carboplatin versus BEP) in pooled ovarian sex cord-stromal tumors, but
it is not SLCT-specific and states the comparative question was unresolved at
registration.
- name: NCT00748657
phase: PHASE_II
status: COMPLETED
description: >-
Phase II trial of bevacizumab in recurrent ovarian sex cord-stromal tumors, testing
anti-VEGF blockade in the relapsed setting. Same scope caveat as the trial above: it
enrolled sex cord-stromal tumors as a pooled group, not Sertoli-Leydig cell tumor
specifically.
target_phenotypes:
- preferred_term: Ovarian neoplasm
term:
id: HP:0100615
label: Ovarian neoplasm
evidence:
- reference: clinicaltrials:NCT00748657
reference_title: "A Phase II Trial of NCI-Supplied Agent: Bevacizumab (rhuMAB VEGF) (NSC# 704865) for Recurrent Sex Cord-Stromal Tumors of the Ovary"
supports: SUPPORT
evidence_source: OTHER
snippet: >-
This phase II trial studies how well bevacizumab works in treating patients with sex
cord-stromal tumors of the ovary that have come back.
explanation: >-
PARTIAL: a registration document establishing that anti-VEGF therapy was formally
trialled in recurrent ovarian sex cord-stromal tumors. It reports no outcome and is
not SLCT-specific, so it is curated as context for the therapeutic landscape rather
than as evidence of benefit.
discussions:
- discussion_id: slct_non_dicer1_drivers
kind: KNOWLEDGE_GAP
prompt: >-
What mechanism drives the FOXL2 C134W-mutant and the DICER1/FOXL2 double-wild-type
subsets of Sertoli-Leydig cell tumor, and are these one disease with three routes or
three diseases sharing a morphology?
attaches_to:
- "pathophysiology#DICER1 RNase IIIb Hotspot Mutation"
rationale: >-
Molecular classification of SLCT identifies at least three groups with distinct
clinicopathologic profiles: DICER1-mutant (young, androgenic, retiform or
heterologous elements), FOXL2 C134W-mutant (postmenopausal, abnormal bleeding), and
double wild-type at intermediate age, which accounts for about 37% of tumors and
includes all well-differentiated cases. Only the DICER1 arm has a worked-out
mechanism; no driver at all is known for the wild-type group, which is the largest
single category after DICER1. This matters for entry granularity as well as biology:
if the FOXL2-mutant SLCTs turn out to share the AGCT mechanism, the boundary between
this entry and Adult Granulosa Cell Tumor of Ovary is drawn in the wrong place, and
the mutual exclusivity of the two drivers within a single morphologic category is
currently the main evidence that it is not.
evidence:
- reference: PMID:30986800
reference_title: DICER1 and FOXL2 Mutation Status Correlates With Clinicopathologic Features in Ovarian Sertoli-Leydig Cell Tumors.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Our data suggest at least 3 molecular subtypes of SLCT with distinct
clinicopathologic features: DICER1 mutant (younger, more androgenic symptoms,
moderately/poorly differentiated, retiform or heterologous elements), FOXL2 mutant
(postmenopausal, abnormal bleeding, moderately/poorly differentiated, no retiform
or heterologous elements), and DICER1/FOXL2 wild type (intermediate age, no
retiform or heterologous elements, including all well-differentiated tumors).
explanation: >-
Sets out the three molecular subtypes and the fact that one of them has no
identified driver, which is the substance of this knowledge gap.
- reference: PMID:39592485
reference_title: "A molecular and immunohistochemical study of 37 cases of ovarian Sertoli-Leydig cell tumor."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The DICER1WT tumors showed increased expression of PRKCA, HNF1A, LDLR, and MAP2K5.
On the contrary, the DICER1MUT cases showed increased expression of CDK6, NOTCH2,
and FGFR2.
explanation: >-
PARTIAL, and a partial narrowing rather than a resolution of this gap: RNA
sequencing shows the DICER1-wild-type tumors have a distinct expression program
rather than being a residual category, but differential expression identifies
candidate genes, not a driver lesion, so the wild-type arm still has no established
mechanism.
proposed_experiments:
- experiment_id: slct_wildtype_whole_genome_sequencing
name: Whole-genome and RNA sequencing of DICER1/FOXL2 double-wild-type SLCTs
description: >-
Sequence a dedicated cohort of DICER1/FOXL2 wild-type Sertoli-Leydig cell tumors at
whole-genome level, including non-coding and structural variation, to test whether
the group harbours a recurrent driver that exon- and hotspot-directed panels have
missed. The intronic-DICER1 result in two hotspot-positive patients establishes
that DICER1 lesions can hide outside conventionally sequenced regions, so the first
question is whether some apparent wild-type tumors are cryptic DICER1 tumors.
references:
- reference: PMID:24761742
title: DICER1-Related Tumor Predisposition.
tags:
- GeneReviews
- reference: PMID:22187960
title: Recurrent somatic DICER1 mutations in nonepithelial ovarian cancers.
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.
| Domain | Key finding | Suggested ontology identifiers/terms | Evidence/qualification |
|---|---|---|---|
| Disease class | Rare ovarian sex cord-stromal tumor; malignant behavior is variable and linked to stage/differentiation. Likely maps to an ovarian Sertoli-Leydig cell tumor concept rather than a uniquely curated MONDO term for the malignant subset. | MONDO: curator validation needed; MeSH: Sertoli-Leydig Cell Tumor; NCIT: ovarian sex cord-stromal tumor / Sertoli-Leydig cell tumor concepts, curator validation needed | Registry-based cohort and reviews describe SLCT as an ovarian sex cord-stromal neoplasm, often in adolescents/young adults; exact MONDO term for the malignant ovarian subset was not confirmed from available context. (schultz2017dicer1relatedsertolileydigcell pages 1-3, schultz2017dicer1relatedsertolileydigcell pages 5-7) |
| Epidemiology | Very rare; occurs primarily in adolescents and young adult females. In the international registry, median age at diagnosis was 17 years (range 2–61). | HPO onset term suggestion: Juvenile onset / Adolescent onset / Young adult onset, curator validation needed | Best available cohort in context: 49 SLCTs with median age 17 years; disease-level population incidence remains sparse in available evidence. (schultz2017dicer1relatedsertolileydigcell pages 5-7, schultz2017dicer1relatedsertolileydigcell pages 12-13) |
| Phenotype | Abdominal/pelvic mass or pain at presentation is common for ovarian tumors, although exact frequency for this cohort was not captured in available excerpts. | HPO: Abdominal pain [HP:0002027]; Pelvic pain [HP:0012532]; Abdominal mass [HP:0012745] | Include as common ovarian tumor presentation, but frequency should be curator-confirmed from full-text clinical series. (schultz2017dicer1relatedsertolileydigcell pages 1-3) |
| Phenotype | Virilization/androgen excess is a characteristic presentation in a subset of SLCTs. | HPO: Virilization [HP:0000138]; Hyperandrogenism [curator validation needed] | Registry and pathology literature note hormonal symptoms as common; androgenic effects are a recognized feature of DICER1-mutant SLCT. (schultz2017dicer1relatedsertolileydigcell pages 5-7, schultz2017dicer1relatedsertolileydigcell pages 1-3) |
| Phenotype | Hirsutism may occur as part of androgen excess. | HPO: Hirsutism [HP:0001007] | Supported as a clinically plausible androgen-excess manifestation; exact frequency not available in current context. (schultz2017dicer1relatedsertolileydigcell pages 5-7) |
| Phenotype | Amenorrhea or irregular menstruation may occur due to androgen secretion. | HPO: Amenorrhea [HP:0000141]; Irregular menstruation [HP:0000858] | Commonly reported in SLCT case literature, but exact cohort frequency was not available in retrieved evidence excerpts. (schultz2017dicer1relatedsertolileydigcell pages 5-7) |
| Phenotype | Elevated testosterone can be a laboratory abnormality reflecting steroidogenic tumor activity. | HPO: Elevated circulating testosterone level [curator validation needed] | Use as a lab phenotype; available context supports hormone-related symptoms rather than exact hormone distributions. (schultz2017dicer1relatedsertolileydigcell pages 5-7, schultz2017dicer1relatedsertolileydigcell pages 1-3) |
| Phenotype | Precocious puberty is relevant particularly in pediatric cases with hormone-secreting tumors. | HPO: Precocious puberty [HP:0000826] | Applicable mainly to children; age range in registry extended to 2 years, supporting pediatric relevance. (schultz2017dicer1relatedsertolileydigcell pages 12-13) |
| Anatomy | Primary site is the ovary, arising from ovarian sex cord/stromal elements. | UBERON: ovary [UBERON:0000992]; ovarian stroma / sex cord-stromal tissue: curator validation needed | Disease is consistently classified as ovarian sex cord-stromal. (schultz2017dicer1relatedsertolileydigcell pages 1-3, schultz2017dicer1relatedsertolileydigcell pages 3-5) |
| Cell type | Tumor shows Sertoli-like and Leydig-like differentiation; exact Cell Ontology mappings may require curator review. | CL: Sertoli cell [curator validation for ovarian Sertoli-like tumor cell]; Leydig cell [curator validation for ovarian steroidogenic/Leydig-like tumor cell] | Histopathologic definition is based on Sertoli-Leydig differentiation, but exact neoplastic ovarian counterparts may not have direct CL terms. (schultz2017dicer1relatedsertolileydigcell pages 5-7) |
| Genetics | DICER1 is the major disease gene. Germline pathogenic loss-of-function variants predispose, often with a second somatic RNase IIIb hotspot mutation in tumor. | HGNC: DICER1 [HGNC:17098]; NCBI Gene: DICER1; cytoband 14q32.13 | Central mechanistic theme across SLCT cohorts and DICER1 syndrome literature. (schultz2017dicer1relatedsertolileydigcell pages 7-8, schultz2017dicer1relatedsertolileydigcell pages 5-7, cazzato2024dicer1tumorsyndrome pages 1-2) |
| Genetics | In the registry, 97% (36/37) of sequenced SLCTs carried DICER1 RNase IIIb hotspot mutations; 22 had germline LOF, 3 mosaic, and 11 tumor-limited mutations. | Sequence ontology terms: loss_of_function_variant, missense_variant, splice_region_variant; ACMG classes: pathogenic/likely pathogenic where curated | Strong primary cohort evidence for two-hit DICER1 architecture. (schultz2017dicer1relatedsertolileydigcell pages 5-7) |
| Genetics | Intronic germline DICER1 variants can be missed by conventional exon-focused testing; splicing analysis may be required. | DICER1 intronic/splicing variant testing; RNA/splice assay concepts, curator validation needed | 2023 report identified novel intronic variants interfering with normal splicing and recommended intron sequencing when clinical suspicion remains high. (fraire2023intronicgermlinedicer1 pages 1-2) |
| Mechanism | Upstream mechanism: DICER1 dysfunction alters pre-miRNA cleavage, especially 5p miRNA processing, leading to abnormal post-transcriptional gene regulation. | GO: pre-miRNA processing [GO:0031053]; gene silencing by miRNA [GO:0035195]; miRNA-mediated gene silencing [curator validation if separate term needed] | DICER1 encodes an RNase III endonuclease; RNase IIIb hotspot mutations disrupt miRNA processing and alter mRNA expression. (schultz2017dicer1relatedsertolileydigcell pages 1-3, schultz2017dicer1relatedsertolileydigcell pages 7-8) |
| Mechanism | Downstream consequence: dysregulated growth/signaling and lineage-specific tumorigenesis; DICER1-mutant and wild-type tumors show different mRNA expression profiles. | GO: regulation of cell proliferation [GO:0042127]; cell population proliferation [GO:0008283] | Molecular profiling supports biologic heterogeneity by DICER1 status and differentiation. (nemejcova2025amolecularand pages 11-12) |
| Mechanism | Endocrine phenotype likely reflects androgen biosynthesis by Leydig-like steroidogenic cells. | GO: androgen biosynthetic process [GO:0006703] | Functional link is clinically inferred from virilization/hyperandrogenic presentations; direct pathway assays were not available in current context. (schultz2017dicer1relatedsertolileydigcell pages 5-7) |
| Pathology/IHC | Diagnostic sex cord-stromal markers include SF1, inhibin A, calretinin, CD99, FOXL2, AR/ER/PR; morphology remains the gold standard. | NCIT/IHC terms: Steroidogenic factor 1, inhibin A, calretinin, FOXL2; exact NCIT IDs curator validation needed | 2025 molecular/IHC study found high expression of sex cord markers; broader gynecologic pathology review supports IHC adjunctive use. (nemejcova2025amolecularand pages 11-12) |
| Molecular pathology | Well-differentiated SLCT may be biologically distinct from moderately/poorly differentiated tumors; DICER1 mutations are characteristic of moderate/poor differentiation, FOXL2 mutations are uncommon and mutually exclusive in one recent study. | DICER1-mutant SLCT; FOXL2-mutant SLCT, curator validation needed | Recent profiling suggests subtype heterogeneity, but this evidence is from 2025 and should be integrated cautiously into current curation. (nemejcova2025amolecularand pages 11-12) |
| Diagnostic workflow | Recommended evaluation includes expert gynecologic pathology review, immunohistochemistry, tumor/germline DICER1 testing, and consideration of intronic sequencing/splicing analysis if exon testing is negative despite high suspicion. | NCIT: immunohistochemistry; molecular genetic testing; next-generation sequencing; RNA splicing analysis, curator validation needed | Central pathology review improved diagnostic concordance; DICER1 testing has familial implications. (schultz2017dicer1relatedsertolileydigcell pages 7-8, fraire2023intronicgermlinedicer1 pages 1-2) |
| Natural history | About 50% of registry cases were stage IA; all stage IA patients were free of disease at median 19-month follow-up in the 2017 cohort excerpt. | FIGO stage IA; HPO/NCIT stage terms as applicable | Early-stage disease has favorable outcomes with surgery-focused management. (schultz2017dicer1relatedsertolileydigcell pages 5-7) |
| Prognosis | Recurrence occurred in 16.3% (8/49); among recurrent cases, 50% died, with median death at 35.5 months. Poor differentiation and tumor-limited DICER1 mutation status were adverse features. | NCIT: disease recurrence; overall survival; recurrence-free survival | Best direct prognostic evidence in available context comes from the international registry. (schultz2017dicer1relatedsertolileydigcell pages 5-7, schultz2017dicer1relatedsertolileydigcell pages 7-8) |
| Prognosis | Predisposing germline/mosaic DICER1 variants were associated with better overall and recurrence-free survival than tumor-limited mutations. | NCIT: germline mutation, mosaicism, somatic mutation | Prognostic association requires cautious interpretation because of small numbers but is repeatedly emphasized in the registry evidence. (schultz2017dicer1relatedsertolileydigcell pages 7-8, schultz2017dicer1relatedsertolileydigcell pages 5-7) |
| Surgery | Fertility-sparing surgery is standard real-world management for many unilateral stage I tumors; unilateral salpingo-oophorectomy is commonly used. | NCIT: Unilateral salpingo-oophorectomy; Fertility-sparing surgery | Registry data show most stage IA cases treated with surgery alone; exact operative distributions require full-text confirmation. (schultz2017dicer1relatedsertolileydigcell pages 3-5) |
| Systemic therapy | BEP (bleomycin, etoposide, cisplatin) is a commonly used regimen, especially for advanced, recurrent, or poorly differentiated disease. | NCIT: Bleomycin; Etoposide; Cisplatin; BEP regimen | In the registry, BEP/cisplatin-etoposide-bleomycin was the most common chemotherapy regimen. (schultz2017dicer1relatedsertolileydigcell pages 3-5) |
| Systemic therapy | Carboplatin plus paclitaxel is an actively studied alternative regimen for advanced/recurrent sex cord-stromal tumors. | NCIT: Carboplatin; Paclitaxel | Phase II randomized GOG-0264 compares paclitaxel/carboplatin versus BEP in advanced or recurrent sex cord-stromal tumors including SLCT. (NCT01042522 chunk 1, NCT01042522 chunk 7) |
| Targeted/antiangiogenic therapy | Bevacizumab has been studied in recurrent ovarian sex cord-stromal tumors, including SLCT-relevant populations. | NCIT: Bevacizumab | Completed Phase II NCI study enrolled recurrent ovarian sex cord-stromal tumors; applicability to SLCT is indirect because histologies were pooled. (NCT00748657 chunk 1) |
| Prevention / surveillance | There is no established primary prevention for SLCT itself. In DICER1 syndrome, cascade testing and surveillance are important; pelvic ultrasound is used in surveillance frameworks. | NCIT: Genetic counseling; Cascade testing; Pelvic ultrasound | Surveillance is relevant mainly for DICER1 carriers and families rather than the general population. (cazzato2024dicer1tumorsyndrome pages 7-8, schultz2017dicer1relatedsertolileydigcell pages 12-13) |
| Inheritance | For DICER1-related predisposition, inheritance is autosomal dominant with reduced/incomplete penetrance. | MONDO/NCIT: DICER1 syndrome; autosomal dominant inheritance [curator validation needed] | Applies to the hereditary predisposition syndrome, not to every SLCT case because some are tumor-limited. (cazzato2024dicer1tumorsyndrome pages 1-2, cazzato2024dicer1tumorsyndrome pages 8-10) |
| Other species / models | Mouse evidence suggests biallelic Dicer1 alterations can drive lineage-specific gynecologic tract tumors, but SLCT-specific model details were not available in full in current context. | MGI/NCBI model annotations: curator validation needed | Mention as emerging mechanistic support only; not enough detail in available context for robust annotation. (nemejcova2025amolecularand pages 11-12) |
| Evidence gaps | Limited disease-specific randomized therapy evidence; incomplete population incidence/prevalence data; uncertain exact ontology mappings for malignant subset and ovarian Sertoli-/Leydig-like neoplastic cells; sparse epigenomic/proteomic/metabolomic evidence in available context. | Curator validation needed across MONDO, CL, some HPO lab terms, and NCIT procedure/drug IDs | Important to annotate uncertainty explicitly to avoid overclaiming in the knowledge base. (schultz2017dicer1relatedsertolileydigcell pages 5-7, nemejcova2025amolecularand pages 11-12, NCT00748657 chunk 1, NCT01042522 chunk 1) |
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.
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.
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)
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)
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.
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 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.
DICER1 (HGNC:17098; chromosome 14q32.13) encodes a cytoplasmic RNase III endonuclease required for precursor-miRNA processing. Relevant variants include:
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.
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.
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.
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.
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)
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.
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)
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)
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)
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.
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.
No population screening program is justified. Testing is targeted to patients and relatives in DICER1 families.
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.
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.
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.
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)
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.
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.
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.
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.
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
(schultz2017dicer1relatedsertolileydigcell pages 5-7): 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.
(schultz2017dicer1relatedsertolileydigcell pages 7-8): 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.
(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
(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.
(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.
(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.
(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.
(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.
(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.
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(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
(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.
(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.
(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.
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 5 |
| Resolved | 5 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 5 |
| On topic | 5 |
| Off topic | 0 |
All extracted references resolved successfully.