Testicular Sex Cord-Stromal Neoplasm

MONDO:0003125 Pathograph 17 Show in embeddings browser sex cord-stromal tumor neoplasm of testis

Testicular sex cord-stromal tumors (SCSTs) are uncommon neoplasms (about 4-6% of testicular tumors in adults, but a larger fraction in children) that arise from the non-germ-cell, gonadal-stromal compartment of the testis rather than from germ cells. They derive from the Sertoli cells, Leydig cells, granulosa cells, and undifferentiated gonadal stroma. Leydig cell tumor is the most common subtype and frequently presents with hormone production (testosterone or, via aromatization, estrogen), producing gynecomastia in adults or isosexual precocious puberty in boys. Sertoli cell tumors include a sclerosing variant and a large-cell calcifying variant that is strongly associated with Carney complex (PRKAR1A) and Peutz-Jeghers syndrome (STK11). Recurrent activating mutations in CTNNB1 (Wnt/beta-catenin) and GNAS underlie a subset of Sertoli and Leydig cell tumors. The great majority are benign and cured by orchiectomy or testis-sparing surgery; a minority (roughly 10%) are malignant, and malignant SCSTs respond poorly to chemotherapy and radiotherapy.

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9
Pathophys.
6
Phenotypes
17
Pathograph
5
Genes
2
Medical Actions
5
Subtypes
2
References
🏷

Classifications

ICD-O Morphology
Sex Cord-Stromal Tumor
◆

Subtypes

5
Leydig Cell Tumor MONDO:0003124
GNAS hgnc:4392 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in GNAS (hgnc:4392). hgnc:4392 is a gene from the HUGO Gene Nomenclature Committee.
The most common testicular sex cord-stromal tumor, arising from steroidogenic Leydig cells of the testicular interstitium. Frequently hormonally active, producing testosterone and/or estrogen and presenting with gynecomastia in adults or precocious puberty in children. About 90% are benign. Recurrent activating mutations affect the cAMP/PKA pathway, including GNAS, and a subset harbor CTNNB1 (beta-catenin) mutations.
Sertoli Cell Tumor MONDO:0020808
CTNNB1 hgnc:2514 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in CTNNB1 (hgnc:2514). hgnc:2514 is a gene from the HUGO Gene Nomenclature Committee.
Arises from the supporting Sertoli cells of the seminiferous tubules. Includes a sclerosing variant. Recurrent CTNNB1 (Wnt/beta-catenin) activating mutations are characteristic of a subset, and GNAS mutations occur in some cases. Most are benign.
Large-Cell Calcifying Sertoli Cell Tumor
PRKAR1A hgnc:9388 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in PRKAR1A (hgnc:9388). hgnc:9388 is a gene from the HUGO Gene Nomenclature Committee. STK11 hgnc:11389 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in STK11 (hgnc:11389). hgnc:11389 is a gene from the HUGO Gene Nomenclature Committee.
A distinctive Sertoli cell tumor variant characterized by large eosinophilic cells and conspicuous intratumoral calcification, frequently bilateral and multifocal. It is strongly associated with Carney complex (germline PRKAR1A inactivation) and with Peutz-Jeghers syndrome (germline STK11 inactivation).
Show evidence (2 references)
PMID:38154678 SUPPORT Human Clinical
"Almost 40 % of patients with LCCSCTs will present in the context of the inherited tumor predisposition syndrome, the Carney complex."
Confirms the strong association between large cell calcifying Sertoli cell tumor and the Carney complex predisposition syndrome.
PMID:20301463 SUPPORT Human Clinical
"Large cell calcifying Sertoli cell tumors (LCCSCTs) are observed in one third of affected males within the first decade and in most adult males."
Carney complex GeneReviews documents that LCCSCTs occur in a large fraction of affected males, often in childhood, underscoring the syndromic predisposition.
Granulosa Cell Tumor (Adult and Juvenile) MONDO:0003395
FOXL2 hgnc:1092 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in FOXL2 (hgnc:1092). hgnc:1092 is a gene from the HUGO Gene Nomenclature Committee.
Granulosa cell tumors of the testis recapitulate ovarian granulosa cell tumors. The juvenile type is the most common congenital testicular tumor and is virtually always benign. The adult type is rare and can behave aggressively. Adult-type tumors may carry a FOXL2 mutation (e.g., C134W) as seen in ovarian counterparts.
Show evidence (1 reference)
PMID:37565864 SUPPORT Human Clinical
"A high-throughput sequencing of 520 cancer-related genes revealed FOXL2 C134W, CDKN2A E87Gfs*24, TP53 S183*, TERT c.-124C > T, and H3F3A K28R mutations in this case."
An adult testicular granulosa cell tumor carried the FOXL2 C134W mutation characteristic of adult-type granulosa cell tumors.
Malignant Sex Cord-Stromal Tumor
A minority (approximately 10%) of testicular sex cord-stromal tumors are malignant, most often malignant Leydig or Sertoli cell tumors. Malignancy is suggested by large size (>5 cm), infiltrative margins, vascular invasion, necrosis, cytologic atypia, and increased mitotic activity. Malignant SCSTs metastasize to retroperitoneal lymph nodes, lung, liver, and bone, and respond poorly to chemotherapy and radiotherapy.
Show evidence (1 reference)
PMID:40345119 SUPPORT Human Clinical
"Sex cord stromal cell tumours (SCSCT) are a rare subset of testicular tumours, the majority of which are benign but a small proportion can be malignant."
Establishes that most testicular sex cord-stromal tumors are benign, with only a small malignant subset, and that histopathological risk factors predict malignancy.
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Pathophysiology

9
Neoplastic Transformation of Gonadal Stromal Cells
Testicular sex cord-stromal tumors arise from clonal proliferation of the non-germ-cell gonadal stromal lineages of the testis: steroidogenic Leydig cells of the interstitium, supporting Sertoli cells of the seminiferous tubules, and granulosa-type cells. This distinguishes them from germ cell tumors, which arise from the germ cell lineage.
Leydig cell CL:0000178 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Leydig cell (CL:0000178). CL:0000178 is a cell type from the Cell Ontology. Sertoli cell CL:0000216 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sertoli cell (CL:0000216). CL:0000216 is a cell type from the Cell Ontology. granulosa cell CL:0000501 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves granulosa cell (CL:0000501). CL:0000501 is a cell type from the Cell Ontology.
testis UBERON:0000473 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in testis (UBERON:0000473). UBERON:0000473 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Wnt/Beta-Catenin Pathway Activation A subset of Sertoli and Leydig cell tumors are driven by CTNNB1 mutation.
cAMP/PKA Pathway Activation GNAS and PRKAR1A lesions activate cAMP/PKA signaling in tumor cells.
TGF-beta-Driven Sertoli-to-Granulosa Transdifferentiation In a subset of tumors, dysregulated TGF-beta signaling reprograms Sertoli cells toward a granulosa-like fate, contributing to granulosa-cell tumor formation.
Autonomous Gonadal Steroidogenesis Tumor cells secrete sex steroids independent of normal regulation.
Testicular Mass Clonal expansion of the gonadal stromal cells forms the intratesticular mass through which most of these tumors present.
Wnt/Beta-Catenin Pathway Activation
Recurrent activating (exon 3) mutations in CTNNB1 stabilize beta-catenin, leading to constitutive canonical Wnt signaling and nuclear beta-catenin accumulation in a subset of testicular Sertoli cell and Leydig cell tumors.
Sertoli cell CL:0000216 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sertoli cell (CL:0000216). CL:0000216 is a cell type from the Cell Ontology.
CTNNB1 hgnc:2514 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CTNNB1 (hgnc:2514). hgnc:2514 is a gene from the HUGO Gene Nomenclature Committee.
canonical Wnt signaling pathway GO:0060070 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased canonical Wnt signaling pathway (GO:0060070). GO:0060070 is a biological process from the Gene Ontology. ↑ INCREASED
beta-catenin transcription coactivator activity GO:0003713 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves beta-catenin transcription coactivator activity, annotated with transcription coactivator activity (GO:0003713), qualified as gain of function. GO:0003713 is a molecular function from the Gene Ontology. ⇑ GAIN OF FUNCTION
Show evidence (1 reference)
PMID:28204871 SUPPORT Human Clinical
"β-catenin mutation in SCT results in nuclear β-catenin and cyclin-D1 expressions on immunohistochemical analysis."
Exon 3 CTNNB1 (beta-catenin) mutation in testicular Sertoli cell tumors produces nuclear beta-catenin and cyclin D1 expression, the molecular hallmark of constitutive canonical Wnt pathway activation.
cAMP/PKA Pathway Activation
Activating GNAS mutations (constitutive Gs-alpha) and loss of the PKA regulatory subunit PRKAR1A (in Carney complex) both increase protein kinase A signaling, driving proliferation and steroidogenesis in Leydig and Sertoli cell tumors. PRKAR1A inactivation underlies large-cell calcifying Sertoli cell tumors in Carney complex.
Leydig cell CL:0000178 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Leydig cell (CL:0000178). CL:0000178 is a cell type from the Cell Ontology. Sertoli cell CL:0000216 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sertoli cell (CL:0000216). CL:0000216 is a cell type from the Cell Ontology.
GNAS hgnc:4392 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GNAS (hgnc:4392). hgnc:4392 is a gene from the HUGO Gene Nomenclature Committee. PRKAR1A hgnc:9388 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PRKAR1A (hgnc:9388). hgnc:9388 is a gene from the HUGO Gene Nomenclature Committee.
cAMP/PKA signal transduction GO:0141156 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cAMP/PKA signal transduction (GO:0141156). GO:0141156 is a biological process from the Gene Ontology. ↑ INCREASED
protein kinase A catalytic activity GO:0004691 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased protein kinase A catalytic activity, annotated with cAMP-dependent protein kinase activity (GO:0004691). GO:0004691 is a molecular function from the Gene Ontology. ↑ INCREASED
Downstream
Autonomous Gonadal Steroidogenesis Elevated cAMP/PKA signaling drives steroidogenic gene expression in Leydig cell tumors, promoting autonomous sex-steroid synthesis.
Show evidence (2 references)
PMID:38154678 SUPPORT Human Clinical
"PRKAR1A alterations were present in all cases and appear to be the major driver in LCCSCTs."
Targeted sequencing of large-cell calcifying Sertoli cell tumors identified PRKAR1A alterations as the major molecular driver, supporting dysregulated cAMP/PKA signaling as the central mechanism in this Sertoli cell tumor variant.
PMID:22016347 SUPPORT Human Clinical
"A heterozygous missense somatic gsp mutation (R201C) was found in tumoral tissue, whereas no mutation was found in the surrounding normal tissue or in leukocyte DNA."
A tumour-restricted activating GNAS (gsp) mutation in a Leydig cell tumour, the Leydig-cell route into this node alongside PRKAR1A loss in Sertoli cell tumours.
TGF-beta-Driven Sertoli-to-Granulosa Transdifferentiation
In a genetically engineered mouse model, sustained Sertoli cell-specific activation of the TGF-beta receptor TGFBR1 is sufficient to reprogram Sertoli cells toward a granulosa-like fate and to drive testicular granulosa cell tumor formation. This provides a mechanistic link between TGF-beta signaling dysregulation and the granulosa-cell phenotype of a subset of testicular sex cord-stromal tumors.
Sertoli cell CL:0000216 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sertoli cell (CL:0000216). CL:0000216 is a cell type from the Cell Ontology. granulosa cell CL:0000501 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves granulosa cell (CL:0000501). CL:0000501 is a cell type from the Cell Ontology.
transforming growth factor beta receptor signaling pathway GO:0007179 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased transforming growth factor beta receptor signaling pathway (GO:0007179). GO:0007179 is a biological process from the Gene Ontology. ↑ INCREASED
Show evidence (1 reference)
PMID:38067144 SUPPORT Model Organism
"overactivation of TGFBR1 in Sertoli cells would promote their transdifferentiation into granulosa-like cells and the formation of TGCTs."
A mouse model demonstrates that constitutive TGFBR1 activation in Sertoli cells drives their transdifferentiation into granulosa-like cells and testicular granulosa cell tumor formation, implicating TGF-beta signaling in SCST pathogenesis.
LKB1 Loss in Sertoli Cells
In boys with Peutz-Jeghers syndrome, the germline STK11 mutation is joined by loss of the second allele in Sertoli cells of the abnormal testicular cords, so those cells lack the LKB1 serine/threonine kinase. Loss of LKB1 reduces phosphorylation of its target AMPK, and AMPK no longer holds the CRTC transcriptional coactivators out of the nucleus.
Sertoli cell CL:0000216 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sertoli cell (CL:0000216). CL:0000216 is a cell type from the Cell Ontology.
STK11 hgnc:11389 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves STK11 (hgnc:11389). hgnc:11389 is a gene from the HUGO Gene Nomenclature Committee.
LKB1 serine/threonine kinase activity GO:0004674 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves LKB1 serine/threonine kinase activity, annotated with protein serine/threonine kinase activity (GO:0004674), qualified as loss of function. GO:0004674 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
Downstream
Sertoli Cell Aromatase Overexpression Without LKB1-dependent AMPK activity, CRTC coactivators accumulate in the nucleus and stimulate aromatase (CYP19A1) expression.
Show evidence (2 references)
PMID:24037887 SUPPORT Human Clinical
"Loss of heterozygosity of STK11, measured by the absence of LKB1 immunofluorescence, was observed in Sertoli cells of abnormal cords of testis samples from affected individuals."
Testicular biopsies from two boys with Peutz-Jeghers syndrome show loss of the second STK11 allele and absent LKB1 protein in Sertoli cells.
PMID:24037887 SUPPORT Human Clinical
"This was associated with loss of p21 expression and decreased phosphorylation of AMPK, known downstream targets of LKB1"
Reduced AMPK phosphorylation in the same Sertoli cells is the functional readout of lost LKB1 kinase activity.
Sertoli Cell Aromatase Overexpression
Sertoli cell tumors arising in Peutz-Jeghers syndrome and Carney complex, typically the large-cell calcifying type, overexpress aromatase and so convert androgen to estrogen within the testis. This is how prepubertal boys with these tumors develop gynecomastia and advanced bone age while their gonadotropins and testosterone stay prepubertal, and why aromatase inhibitors control those signs.
Sertoli cell CL:0000216 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sertoli cell (CL:0000216). CL:0000216 is a cell type from the Cell Ontology.
estrogen biosynthetic process GO:0006703 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased estrogen biosynthetic process (GO:0006703). GO:0006703 is a biological process from the Gene Ontology. ↑ INCREASED
aromatase activity GO:0070330 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased aromatase activity (GO:0070330). GO:0070330 is a molecular function from the Gene Ontology. ↑ INCREASED
Downstream
Estrogen-Mediated Clinical Manifestations Estrogen made by the tumor's aromatase drives breast growth and skeletal advancement; blocking aromatase reverses both.
Precocious Puberty with Sertoli Cell Tumor Estrogen from an aromatase-expressing large-cell calcifying Sertoli cell tumor advances skeletal maturation and can trigger central precocious puberty in boys.
Show evidence (1 reference)
PMID:16944977 SUPPORT Human Clinical
"Mean expression of aromatase and TGFbeta1 mRNAs in Tu was 6- and 2.3-fold higher than in ExTu, respectively (P<0.05)."
In a large-cell calcifying Sertoli cell tumor from a boy with bilateral gynecomastia, aromatase mRNA was six-fold higher in tumor nodules than in the adjacent normal-looking testis.
FOXL2 C134W Neomorphic Transcription Factor Activity
The recurrent somatic FOXL2 c.402C>G (p.C134W) variant of adult-type granulosa cell tumors, found also in the rare testicular adult granulosa cell tumor, changes what the FOXL2 transcription factor does rather than removing it. The mutant protein gains the ability to bind SMAD4 and, with SMAD2/3, occupies a hybrid DNA motif that wild-type FOXL2 does not bind, switching on genes for epithelial-to-mesenchymal transition, stemness and oncogenesis.
granulosa cell CL:0000501 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves granulosa cell (CL:0000501). CL:0000501 is a cell type from the Cell Ontology.
FOXL2 hgnc:1092 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FOXL2 (hgnc:1092). hgnc:1092 is a gene from the HUGO Gene Nomenclature Committee.
FOXL2 C134W DNA-binding transcription factor activity GO:0003700 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves FOXL2 C134W DNA-binding transcription factor activity, annotated with DNA-binding transcription factor activity (GO:0003700), qualified as gain of function. GO:0003700 is a molecular function from the Gene Ontology. ⇑ GAIN OF FUNCTION
Show evidence (4 references)
PMID:37565864 SUPPORT Human Clinical
"A high-throughput sequencing of 520 cancer-related genes revealed FOXL2 C134W, CDKN2A E87Gfs*24, TP53 S183*, TERT c.-124C > T, and H3F3A K28R mutations in this case."
The FOXL2 C134W variant is present in an adult granulosa cell tumor of the testis.
PMID:32641411 SUPPORT BACKGROUND Human Clinical
"is also found in the rare male version of GCTs and in some Sertoli-Leydig cell sex cord tumors"
The introduction of this mechanistic study states that the variant occurs in male granulosa cell tumors, placing the testicular tumor under the same driver.
PMID:32641411 SUPPORT INDIRECT In Vitro
"mutant FOXL2C134W acquires the ability to bind SMAD4, forming a FOXL2C134W/SMAD4/SMAD2/3 complex that binds a novel hybrid DNA motif AGHCAHAA, unique to the FOXL2C134W mutant."
Establishes the gained activity in granulosa cell lines; indirect for the testis because the work is on ovarian tumor biology.
+ 1 more reference
Autonomous Gonadal Steroidogenesis
Hormonally active Leydig cell tumors autonomously synthesize testosterone; peripheral and intratumoral aromatase converts androgens to estrogens. Excess sex steroids produce gynecomastia in adults and isosexual precocious puberty in prepubertal boys.
Leydig cell CL:0000178 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Leydig cell (CL:0000178). CL:0000178 is a cell type from the Cell Ontology.
androgen biosynthetic process GO:0006702 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased androgen biosynthetic process (GO:0006702). GO:0006702 is a biological process from the Gene Ontology. ↑ INCREASED estrogen biosynthetic process GO:0006703 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased estrogen biosynthetic process (GO:0006703). GO:0006703 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Estrogen-Mediated Clinical Manifestations Excess estrogen drives gynecomastia and feminization.
Show evidence (1 reference)
PMID:22016347 SUPPORT Human Clinical
"activating gsp mutation in Leydig cells may result in tumor development, leading to overexpression of the inhibin alpha subunit and hyperactivity of the testosterone biosynthetic pathway."
A somatic activating GNAS (gsp R201C) mutation in a Leydig cell tumor drove hyperactivity of the testosterone biosynthetic pathway, demonstrating autonomous tumoral steroidogenesis.
Estrogen-Mediated Clinical Manifestations
Tumor-derived estrogen excess produces gynecomastia and can suppress the hypothalamic-pituitary-gonadal axis, reducing spermatogenesis and fertility.
estrogen receptor signaling pathway GO:0030520 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased estrogen receptor signaling pathway (GO:0030520). GO:0030520 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Gynecomastia Tumor-derived estrogen stimulates male breast tissue growth; the gynecomastia regresses once the tumor is removed.
Show evidence (4 references)
PMID:9235082 SUPPORT Human Clinical
"The more frequent hormonal manifestations of these tumors are high plasmatic and urinary estrogen levels, low serum testosterone, low testosterone/estradiol index, and FSH or LH low levels as well."
Summarises the endocrine picture of Leydig cell tumors as estrogen excess with suppressed FSH and LH, the two arms of this node.
PMID:16671273 SUPPORT Human Clinical
"Endocrine function tests showed decreased gonadotropin concentrations, and reduction of testosterone/estradiol ratio."
A man with bilateral gynecomastia and a Leydig cell tumor had a lowered testosterone-to-estradiol ratio with suppressed gonadotropins.
PMID:16671273 SUPPORT Human Clinical
"After surgery, the gynecomastia has completely disappeared and hormonal alterations returned to normal."
Removing the tumor reversed both the gynecomastia and the hormonal changes, tying them to the tumor's output.
+ 1 more reference
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Testicular Sex Cord-Stromal Neoplasm Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

6
Breast 1
Gynecomastia HP:0000771 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gynecomastia (HP:0000771). HP:0000771 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22016347 SUPPORT Human Clinical
"In adult patients, gynecomastia, oligozoospermia, erectile dysfunction, and other signs of feminization can be present"
Adult Leydig cell tumors commonly present with gynecomastia and other signs of feminization due to tumoral sex steroid production.
Endocrine 2
Precocious Puberty HP:0000826 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Precocious puberty (HP:0000826). HP:0000826 is a phenotype from the Human Phenotype Ontology.
Precocious Puberty with Sertoli Cell Tumor HP:0008204 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Precocious puberty with Sertoli cell tumor (HP:0008204). HP:0008204 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301463 SUPPORT Human Clinical
"orchiectomy for boys with aggressive LCCSCT and gynecomastia to avoid premature epiphyseal fusion and induction of central precocious puberty"
The Carney complex GeneReviews documents that aromatase-expressing large cell calcifying Sertoli cell tumors in boys can induce gynecomastia and central precocious puberty, supporting the endocrine presentation of testicular Sertoli cell tumors.
Genitourinary 3
Testicular Mass HP:0032404 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Testicular mass (HP:0032404). HP:0032404 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38879834 SUPPORT Human Clinical
"The Testicular Juvenile Granulosa Cell Tumor (JGCT) is a rare testicular neoplasm that appears in the first months of life as a painless testicular mass."
Juvenile granulosa cell tumor, a testicular sex cord-stromal tumor, classically presents as a painless testicular mass.
Testicular Neoplasm HP:0010788 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Testicular neoplasm (HP:0010788). HP:0010788 is a phenotype from the Human Phenotype Ontology.
Decreased Fertility Decreased fertility in males HP:0012041 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased fertility in males (HP:0012041). HP:0012041 is a phenotype from the Human Phenotype Ontology.
🧬

Genetic Associations

5
CTNNB1 (Recurrent activating exon 3 mutations in CTNNB1 stabilize beta-catenin and drive canonical Wnt signaling in a subset of testicular Sertoli and Leydig cell tumors.)
Gene: CTNNB1 hgnc:2514 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CTNNB1 (hgnc:2514). hgnc:2514 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (1 reference)
PMID:28204871 SUPPORT Human Clinical
"mutation analyses of the β-catenin gene (exon 3; CTNNB1) were performed."
Exon 3 CTNNB1 mutation analysis in testicular sex cord-stromal tumors identified recurrent beta-catenin mutations in Sertoli cell tumors.
GNAS (Activating GNAS mutations producing a constitutively active Gs-alpha subunit and elevated cAMP/PKA signaling occur in a subset of Leydig and Sertoli cell tumors.)
Gene: GNAS hgnc:4392 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GNAS (hgnc:4392). hgnc:4392 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (1 reference)
PMID:22016347 SUPPORT Human Clinical
"A heterozygous missense somatic gsp mutation (R201C) was found in tumoral tissue, whereas no mutation was found in the surrounding normal tissue or in leukocyte DNA."
A somatic activating GNAS (gsp R201C) mutation was identified specifically in Leydig cell tumor tissue, implicating GNAS activation in tumorigenesis.
PRKAR1A (Germline inactivating PRKAR1A mutations cause Carney complex and predispose to large-cell calcifying Sertoli cell tumor through loss of PKA regulatory control.)
Gene: PRKAR1A hgnc:9388 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PRKAR1A (hgnc:9388). hgnc:9388 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: RISK_FACTOR variant_origin: GERMLINE_AND_SOMATIC
Show evidence (1 reference)
PMID:38619599 SUPPORT Human Clinical
"Such examples include Carney complex and large cell calcifying Sertoli cell tumor"
Carney complex, caused by germline PRKAR1A inactivation, is a well-established predisposition syndrome for large cell calcifying Sertoli cell tumor.
STK11 (Germline STK11 (LKB1) inactivation causes Peutz-Jeghers syndrome and predisposes to Sertoli cell tumors, including the large-cell calcifying variant.)
Gene: STK11 hgnc:11389 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is STK11 (hgnc:11389). hgnc:11389 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: RISK_FACTOR variant_origin: GERMLINE
Show evidence (1 reference)
PMID:38619599 SUPPORT Human Clinical
"Peutz-Jeghers syndrome and intratubular large cell hyalinizing Sertoli cell neoplasia"
Peutz-Jeghers syndrome, caused by germline STK11 inactivation, is associated with a distinctive intratubular large cell hyalinizing Sertoli cell neoplasia of the testis.
FOXL2 (Adult-type granulosa cell tumors of the testis can harbor the FOXL2 C134W mutation, the same recurrent somatic variant characteristic of ovarian adult granulosa cell tumors, reflecting a shared granulosa-lineage oncogenic driver.)
Gene: FOXL2 hgnc:1092 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FOXL2 (hgnc:1092). hgnc:1092 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (1 reference)
PMID:37565864 SUPPORT Human Clinical
"A high-throughput sequencing of 520 cancer-related genes revealed FOXL2 C134W, CDKN2A E87Gfs*24, TP53 S183*, TERT c.-124C > T, and H3F3A K28R mutations in this case."
Sequencing of an adult testicular granulosa cell tumor identified the FOXL2 C134W mutation, the hallmark driver of adult-type granulosa cell tumors.
💊

Medical Actions

2
Radical or Testis-Sparing Orchiectomy
Action: Surgical ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. NCIT:C15329
Platform: Surgery
Surgical removal of the tumor is the mainstay of treatment. Most sex cord-stromal tumors are benign and cured by radical inguinal orchiectomy or, for small benign lesions, testis-sparing (partial) orchiectomy.
Show evidence (1 reference)
PMID:20301463 SUPPORT Human Clinical
"orchiectomy for boys with aggressive LCCSCT and gynecomastia to avoid premature epiphyseal fusion and induction of central precocious puberty"
Orchiectomy is indicated for aggressive Sertoli cell tumors with endocrine manifestations, supporting surgery as the mainstay of management.
Retroperitoneal Lymph Node Dissection
Action: Surgical ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. NCIT:C15329
Platform: Surgery
Considered for malignant sex cord-stromal tumors with features predictive of metastasis, since these tumors respond poorly to chemotherapy and radiotherapy.
Show evidence (2 references)
PMID:12910519 SUPPORT Human Clinical
"RPLND remains an option to be performed immediately after orchiectomy, especially in patients who have tumors with malignant features and/or small-volume metastatic disease."
Retroperitoneal lymph node dissection is an option performed after orchiectomy for testicular sex cord-stromal tumors with malignant features or small-volume metastatic disease, directly supporting RPLND as a surgical management modality.
PMID:40345119 SUPPORT Human Clinical
"It has been demonstrated that certain histopathological risk factors can be useful in identifying those with malignant potential."
Histopathological risk factors identify sex cord-stromal tumors with malignant potential, guiding selection for patients who warrant more aggressive surgical management such as retroperitoneal lymph node dissection.
{ }

Source YAML

click to show 
name: Testicular Sex Cord-Stromal Neoplasm
creation_date: "2026-06-08T00:00:00Z"
description: >-
  Testicular sex cord-stromal tumors (SCSTs) are uncommon neoplasms (about 4-6% of
  testicular tumors in adults, but a larger fraction in children) that arise from the
  non-germ-cell, gonadal-stromal compartment of the testis rather than from germ cells.
  They derive from the Sertoli cells, Leydig cells, granulosa cells, and undifferentiated
  gonadal stroma. Leydig cell tumor is the most common subtype and frequently presents
  with hormone production (testosterone or, via aromatization, estrogen), producing
  gynecomastia in adults or isosexual precocious puberty in boys. Sertoli cell tumors
  include a sclerosing variant and a large-cell calcifying variant that is strongly
  associated with Carney complex (PRKAR1A) and Peutz-Jeghers syndrome (STK11). Recurrent
  activating mutations in CTNNB1 (Wnt/beta-catenin) and GNAS underlie a subset of Sertoli
  and Leydig cell tumors. The great majority are benign and cured by orchiectomy or
  testis-sparing surgery; a minority (roughly 10%) are malignant, and malignant SCSTs
  respond poorly to chemotherapy and radiotherapy.
classifications:
  icdo_morphology:
    classification_value: Sex Cord-Stromal Tumor
    notes: >-
      Bound to NCIT:C3794 (Sex Cord-Stromal Tumor). The value covers the
      testicular and ovarian sex cord-stromal neoplasms alike, and is
      behaviour-neutral - most testicular sex cord-stromal tumours are benign.
references:
- reference: PMID:20301463
  title: "Carney Complex."
  tags:
  - GeneReviews
- reference: PMID:36645400
  title: "News in the classification of WHO 2022 testicular tumours."
  found_in:
  - Testicular Sex Cord Stromal Tumor-deep-research-falcon.md
categories:
- Sex Cord-Stromal Neoplasm
- Solid Tumor
- Urologic Cancer
parents:
- sex cord-stromal tumor
- neoplasm of testis
disease_term:
  preferred_term: testicular sex cord-stromal neoplasm
  term:
    id: MONDO:0003125
    label: testicular sex cord-stromal neoplasm
has_subtypes:
- name: Leydig Cell Tumor
  display_name: Leydig Cell Tumor
  subtype_term:
    preferred_term: testicular Leydig cell tumor
    term:
      id: MONDO:0003124
      label: testicular Leydig cell tumor
  genes:
  - preferred_term: GNAS
    term:
      id: hgnc:4392
      label: GNAS
  description: >-
    The most common testicular sex cord-stromal tumor, arising from steroidogenic
    Leydig cells of the testicular interstitium. Frequently hormonally active,
    producing testosterone and/or estrogen and presenting with gynecomastia in adults
    or precocious puberty in children. About 90% are benign. Recurrent activating
    mutations affect the cAMP/PKA pathway, including GNAS, and a subset harbor CTNNB1
    (beta-catenin) mutations.
- name: Sertoli Cell Tumor
  display_name: Sertoli Cell Tumor
  subtype_term:
    preferred_term: testicular Sertoli cell tumor
    term:
      id: MONDO:0020808
      label: testicular sertoli cell tumor
  genes:
  - preferred_term: CTNNB1
    term:
      id: hgnc:2514
      label: CTNNB1
  description: >-
    Arises from the supporting Sertoli cells of the seminiferous tubules. Includes a
    sclerosing variant. Recurrent CTNNB1 (Wnt/beta-catenin) activating mutations are
    characteristic of a subset, and GNAS mutations occur in some cases. Most are benign.
- name: Large-Cell Calcifying Sertoli Cell Tumor
  display_name: Large-Cell Calcifying Sertoli Cell Tumor
  genes:
  - preferred_term: PRKAR1A
    term:
      id: hgnc:9388
      label: PRKAR1A
  - preferred_term: STK11
    term:
      id: hgnc:11389
      label: STK11
  description: >-
    A distinctive Sertoli cell tumor variant characterized by large eosinophilic cells
    and conspicuous intratumoral calcification, frequently bilateral and multifocal. It
    is strongly associated with Carney complex (germline PRKAR1A inactivation) and with
    Peutz-Jeghers syndrome (germline STK11 inactivation).
  evidence:
  - reference: PMID:38154678
    reference_title: "Molecular characterization of large cell calcifying sertoli cell tumors: A multi-institutional study of 6 benign and 2 malignant tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Almost 40 % of patients with
      LCCSCTs will present in the context of the inherited tumor predisposition
      syndrome, the Carney complex.
    explanation: >-
      Confirms the strong association between large cell calcifying Sertoli cell tumor
      and the Carney complex predisposition syndrome.
  - reference: PMID:20301463
    reference_title: "Carney Complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Large cell calcifying Sertoli cell tumors (LCCSCTs) are observed in one third of
      affected males within the first decade and in most adult males.
    explanation: >-
      Carney complex GeneReviews documents that LCCSCTs occur in a large fraction of
      affected males, often in childhood, underscoring the syndromic predisposition.
- name: Granulosa Cell Tumor
  display_name: Granulosa Cell Tumor (Adult and Juvenile)
  subtype_term:
    preferred_term: testicular granulosa cell tumor
    term:
      id: MONDO:0003395
      label: testicular granulosa cell tumor
  genes:
  - preferred_term: FOXL2
    term:
      id: hgnc:1092
      label: FOXL2
  description: >-
    Granulosa cell tumors of the testis recapitulate ovarian granulosa cell tumors. The
    juvenile type is the most common congenital testicular tumor and is virtually always
    benign. The adult type is rare and can behave aggressively. Adult-type tumors may
    carry a FOXL2 mutation (e.g., C134W) as seen in ovarian counterparts.
  evidence:
  - reference: PMID:37565864
    reference_title: "Adult granulosa cell tumor of the testis with malignant tendency: A case report with genetic analysis using high-throughput sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A high-throughput sequencing of 520 cancer-related genes revealed FOXL2 C134W,
      CDKN2A E87Gfs*24, TP53 S183*, TERT c.-124C > T, and H3F3A K28R mutations in this
      case.
    explanation: >-
      An adult testicular granulosa cell tumor carried the FOXL2 C134W mutation
      characteristic of adult-type granulosa cell tumors.
- name: Malignant Sex Cord-Stromal Tumor
  display_name: Malignant Sex Cord-Stromal Tumor
  description: >-
    A minority (approximately 10%) of testicular sex cord-stromal tumors are malignant,
    most often malignant Leydig or Sertoli cell tumors. Malignancy is suggested by large
    size (>5 cm), infiltrative margins, vascular invasion, necrosis, cytologic atypia,
    and increased mitotic activity. Malignant SCSTs metastasize to retroperitoneal lymph
    nodes, lung, liver, and bone, and respond poorly to chemotherapy and radiotherapy.
  evidence:
  - reference: PMID:40345119
    reference_title: "A Single Centre Review of the Management of Testicular Sex Cord-Stromal Cell Tumours."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sex cord stromal cell tumours (SCSCT) are a rare subset of testicular
      tumours, the majority of which are benign but a small proportion can be
      malignant.
    explanation: >-
      Establishes that most testicular sex cord-stromal tumors are benign, with only a
      small malignant subset, and that histopathological risk factors predict malignancy.
pathophysiology:
- name: Neoplastic Transformation of Gonadal Stromal Cells
  description: >-
    Testicular sex cord-stromal tumors arise from clonal proliferation of the
    non-germ-cell gonadal stromal lineages of the testis: steroidogenic Leydig cells of
    the interstitium, supporting Sertoli cells of the seminiferous tubules, and
    granulosa-type cells. This distinguishes them from germ cell tumors, which arise from
    the germ cell lineage.
  cell_types:
  - preferred_term: Leydig cell
    term:
      id: CL:0000178
      label: Leydig cell
  - preferred_term: Sertoli cell
    term:
      id: CL:0000216
      label: Sertoli cell
  - preferred_term: granulosa cell
    term:
      id: CL:0000501
      label: granulosa cell
  locations:
  - preferred_term: testis
    term:
      id: UBERON:0000473
      label: testis
  downstream:
  - target: Wnt/Beta-Catenin Pathway Activation
    description: A subset of Sertoli and Leydig cell tumors are driven by CTNNB1 mutation.
  - target: cAMP/PKA Pathway Activation
    description: GNAS and PRKAR1A lesions activate cAMP/PKA signaling in tumor cells.
  - target: TGF-beta-Driven Sertoli-to-Granulosa Transdifferentiation
    description: >-
      In a subset of tumors, dysregulated TGF-beta signaling reprograms Sertoli cells
      toward a granulosa-like fate, contributing to granulosa-cell tumor formation.
  - target: Autonomous Gonadal Steroidogenesis
    description: Tumor cells secrete sex steroids independent of normal regulation.
  - target: Testicular Mass
    description: >-
      Clonal expansion of the gonadal stromal cells forms the intratesticular
      mass through which most of these tumors present.
- name: Wnt/Beta-Catenin Pathway Activation
  description: >-
    Recurrent activating (exon 3) mutations in CTNNB1 stabilize beta-catenin, leading to
    constitutive canonical Wnt signaling and nuclear beta-catenin accumulation in a subset
    of testicular Sertoli cell and Leydig cell tumors.
  genes:
  - preferred_term: CTNNB1
    description: >-
      The gene whose exon 3 activating mutation stabilizes beta-catenin in this
      node.
    term:
      id: hgnc:2514
      label: CTNNB1
  molecular_functions:
  - preferred_term: beta-catenin transcription coactivator activity
    modifier: GAIN_OF_FUNCTION
    description: >-
      Exon 3 mutations remove the sites through which the destruction complex
      targets beta-catenin for degradation, so the stabilized protein enters the
      nucleus and co-activates TCF/LEF target genes such as cyclin D1 without an
      upstream Wnt signal. The qualitative modifier records that the activity
      has escaped regulation, not merely risen.
    term:
      id: GO:0003713
      label: transcription coactivator activity
  cell_types:
  - preferred_term: Sertoli cell
    term:
      id: CL:0000216
      label: Sertoli cell
  biological_processes:
  - preferred_term: canonical Wnt signaling pathway
    modifier: INCREASED
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
  evidence:
  - reference: PMID:28204871
    reference_title: "The role of beta-catenin mutation and SOX9 expression in sex cord-stromal tumours of the testis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      β-catenin mutation in SCT results in nuclear β-catenin
      and cyclin-D1 expressions on immunohistochemical analysis.
    explanation: >-
      Exon 3 CTNNB1 (beta-catenin) mutation in testicular Sertoli cell tumors produces
      nuclear beta-catenin and cyclin D1 expression, the molecular hallmark of
      constitutive canonical Wnt pathway activation.
- name: cAMP/PKA Pathway Activation
  description: >-
    Activating GNAS mutations (constitutive Gs-alpha) and loss of the PKA regulatory
    subunit PRKAR1A (in Carney complex) both increase protein kinase A signaling, driving
    proliferation and steroidogenesis in Leydig and Sertoli cell tumors. PRKAR1A
    inactivation underlies large-cell calcifying Sertoli cell tumors in Carney complex.
  notes: >-
    GNAS and PRKAR1A reach this node by different lesions, a gained Gs-alpha
    activity upstream of cAMP and a lost PKA regulatory subunit downstream of
    it, and the one molecular function true of both is the resulting
    catalytic activity of protein kinase A, which is what is bound. The Sertoli
    cell is included beside the Leydig cell because the PRKAR1A evidence on
    this node is from large-cell calcifying Sertoli cell tumors.
  genes:
  - preferred_term: GNAS
    description: >-
      Somatic activating (gsp, e.g. R201C) mutation in Leydig cell tumors,
      producing a constitutively active Gs-alpha subunit.
    term:
      id: hgnc:4392
      label: GNAS
  - preferred_term: PRKAR1A
    description: >-
      Germline (Carney complex) or somatic inactivation of the PKA type I-alpha
      regulatory subunit in large-cell calcifying Sertoli cell tumors.
    term:
      id: hgnc:9388
      label: PRKAR1A
  molecular_functions:
  - preferred_term: protein kinase A catalytic activity
    modifier: INCREASED
    description: >-
      Both lesions converge on unrestrained PKA catalytic activity: more cAMP
      from constitutive Gs-alpha, or less inhibition of the catalytic subunit
      when the regulatory subunit is lost.
    term:
      id: GO:0004691
      label: cAMP-dependent protein kinase activity
  cell_types:
  - preferred_term: Leydig cell
    term:
      id: CL:0000178
      label: Leydig cell
  - preferred_term: Sertoli cell
    term:
      id: CL:0000216
      label: Sertoli cell
  biological_processes:
  - preferred_term: cAMP/PKA signal transduction
    modifier: INCREASED
    term:
      id: GO:0141156
      label: cAMP/PKA signal transduction
  evidence:
  - reference: PMID:38154678
    reference_title: "Molecular characterization of large cell calcifying sertoli cell tumors: A multi-institutional study of 6 benign and 2 malignant tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PRKAR1A alterations were present in all cases and appear to
      be the major driver in LCCSCTs.
    explanation: >-
      Targeted sequencing of large-cell calcifying Sertoli cell tumors identified
      PRKAR1A alterations as the major molecular driver, supporting dysregulated
      cAMP/PKA signaling as the central mechanism in this Sertoli cell tumor variant.
  - reference: PMID:22016347
    reference_title: "A rare cause of hypertestosteronemia in a 68-year-old patient: a Leydig cell tumor due to a somatic GNAS (guanine nucleotide-binding protein, alpha-stimulating activity polypeptide 1)-activating mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A heterozygous missense somatic gsp mutation (R201C)
      was found in tumoral tissue, whereas no mutation was found in the surrounding
      normal tissue or in leukocyte DNA.
    explanation: >-
      A tumour-restricted activating GNAS (gsp) mutation in a Leydig cell tumour,
      the Leydig-cell route into this node alongside PRKAR1A loss in Sertoli
      cell tumours.
  downstream:
  - target: Autonomous Gonadal Steroidogenesis
    description: >-
      Elevated cAMP/PKA signaling drives steroidogenic gene expression in Leydig cell
      tumors, promoting autonomous sex-steroid synthesis.
- name: TGF-beta-Driven Sertoli-to-Granulosa Transdifferentiation
  description: >-
    In a genetically engineered mouse model, sustained Sertoli cell-specific activation
    of the TGF-beta receptor TGFBR1 is sufficient to reprogram Sertoli cells toward a
    granulosa-like fate and to drive testicular granulosa cell tumor formation. This
    provides a mechanistic link between TGF-beta signaling dysregulation and the
    granulosa-cell phenotype of a subset of testicular sex cord-stromal tumors.
  cell_types:
  - preferred_term: Sertoli cell
    term:
      id: CL:0000216
      label: Sertoli cell
  - preferred_term: granulosa cell
    term:
      id: CL:0000501
      label: granulosa cell
  biological_processes:
  - preferred_term: transforming growth factor beta receptor signaling pathway
    modifier: INCREASED
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
  evidence:
  - reference: PMID:38067144
    reference_title: "Sertoli Cell-Specific Activation of Transforming Growth Factor Beta Receptor 1 Leads to Testicular Granulosa Cell Tumor Formation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      overactivation of TGFBR1 in Sertoli cells would promote their transdifferentiation
      into granulosa-like cells and the formation of TGCTs.
    explanation: >-
      A mouse model demonstrates that constitutive TGFBR1 activation in Sertoli cells
      drives their transdifferentiation into granulosa-like cells and testicular
      granulosa cell tumor formation, implicating TGF-beta signaling in SCST pathogenesis.
- name: LKB1 Loss in Sertoli Cells
  biological_scale: MOLECULAR
  subtypes:
  - Large-Cell Calcifying Sertoli Cell Tumor
  description: >-
    In boys with Peutz-Jeghers syndrome, the germline STK11 mutation is joined
    by loss of the second allele in Sertoli cells of the abnormal testicular
    cords, so those cells lack the LKB1 serine/threonine kinase. Loss of LKB1
    reduces phosphorylation of its target AMPK, and AMPK no longer holds the
    CRTC transcriptional coactivators out of the nucleus.
  genes:
  - preferred_term: STK11
    description: >-
      Germline heterozygous in Peutz-Jeghers syndrome, with loss of
      heterozygosity in the affected Sertoli cells.
    term:
      id: hgnc:11389
      label: STK11
  molecular_functions:
  - preferred_term: LKB1 serine/threonine kinase activity
    modifier: LOSS_OF_FUNCTION
    description: >-
      LKB1 protein is absent from the affected Sertoli cells after loss of the
      second allele, so its kinase activity toward AMPK is lost rather than
      reduced.
    term:
      id: GO:0004674
      label: protein serine/threonine kinase activity
  cell_types:
  - preferred_term: Sertoli cell
    term:
      id: CL:0000216
      label: Sertoli cell
  evidence:
  - reference: PMID:24037887
    reference_title: "Overexpression of aromatase associated with loss of heterozygosity of the STK11 gene accounts for prepubertal gynecomastia in boys with Peutz-Jeghers syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Loss of heterozygosity of STK11, measured by the absence of LKB1
      immunofluorescence, was observed in Sertoli cells of abnormal cords of
      testis samples from affected individuals.
    explanation: >-
      Testicular biopsies from two boys with Peutz-Jeghers syndrome show loss of
      the second STK11 allele and absent LKB1 protein in Sertoli cells.
  - reference: PMID:24037887
    reference_title: "Overexpression of aromatase associated with loss of heterozygosity of the STK11 gene accounts for prepubertal gynecomastia in boys with Peutz-Jeghers syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This was associated with loss of p21 expression and decreased
      phosphorylation of AMPK, known downstream targets of LKB1
    explanation: >-
      Reduced AMPK phosphorylation in the same Sertoli cells is the functional
      readout of lost LKB1 kinase activity.
  downstream:
  - target: Sertoli Cell Aromatase Overexpression
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Without LKB1-dependent AMPK activity, CRTC coactivators accumulate in the
      nucleus and stimulate aromatase (CYP19A1) expression.
    evidence:
    - reference: PMID:24037887
      reference_title: "Overexpression of aromatase associated with loss of heterozygosity of the STK11 gene accounts for prepubertal gynecomastia in boys with Peutz-Jeghers syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Loss of heterozygosity of the STK11 gene leads to an increase in
        aromatase expression associated with an increase in CRTC nuclear
        localization
      explanation: >-
        States the step this edge asserts, from STK11 loss to aromatase
        overexpression, with CRTC nuclear localization as the intermediate.
- name: Sertoli Cell Aromatase Overexpression
  biological_scale: CELLULAR
  subtypes:
  - Large-Cell Calcifying Sertoli Cell Tumor
  description: >-
    Sertoli cell tumors arising in Peutz-Jeghers syndrome and Carney complex,
    typically the large-cell calcifying type, overexpress aromatase and so
    convert androgen to estrogen within the testis. This is how prepubertal
    boys with these tumors develop gynecomastia and advanced bone age while
    their gonadotropins and testosterone stay prepubertal, and why aromatase
    inhibitors control those signs.
  notes: >-
    The upstream edge from STK11 loss is sourced; a corresponding edge from
    PRKAR1A loss in Carney complex is not drawn, because the only source found
    for it (PMID:16944977) proposes it as a hypothesis for both syndromes
    rather than showing it.
  molecular_functions:
  - preferred_term: aromatase activity
    modifier: INCREASED
    term:
      id: GO:0070330
      label: aromatase activity
  biological_processes:
  - preferred_term: estrogen biosynthetic process
    modifier: INCREASED
    term:
      id: GO:0006703
      label: estrogen biosynthetic process
  cell_types:
  - preferred_term: Sertoli cell
    term:
      id: CL:0000216
      label: Sertoli cell
  evidence:
  - reference: PMID:16944977
    reference_title: "High TGFbeta1, estrogen receptor, and aromatase gene expression in a large cell calcifying sertoli cell tumor (LCCSCT): implications for the mechanism of oncogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mean expression of aromatase and TGFbeta1 mRNAs in Tu was 6- and 2.3-fold
      higher than in ExTu, respectively (P<0.05).
    explanation: >-
      In a large-cell calcifying Sertoli cell tumor from a boy with bilateral
      gynecomastia, aromatase mRNA was six-fold higher in tumor nodules than in
      the adjacent normal-looking testis.
  downstream:
  - target: Estrogen-Mediated Clinical Manifestations
    causal_link_type: DIRECT
    description: >-
      Estrogen made by the tumor's aromatase drives breast growth and skeletal
      advancement; blocking aromatase reverses both.
    evidence:
    - reference: PMID:30052520
      reference_title: "Prepubertal gynaecomastia in a boy with Peutz-Jeghers syndrome: managing the aromatase overexpression."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Gynaecomastia, although rarely related to testicular tumours, in boys
        with Peutz-Jeghers syndrome (PJS) usually occurs due to large-cell
        calcifying Sertoli cell tumour (LCCSCT).
      explanation: >-
        Attributes gynecomastia in boys with Peutz-Jeghers syndrome to the
        large-cell calcifying Sertoli cell tumor.
    - reference: PMID:30052520
      reference_title: "Prepubertal gynaecomastia in a boy with Peutz-Jeghers syndrome: managing the aromatase overexpression."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In the last follow-up, 2 years after the start of therapy, he experienced
        a less tense Tanner-B2 and a decrease in HV
      explanation: >-
        Breast development and height velocity fell on anastrozole, so the
        manifestations depend on aromatase activity; a therapeutic response is
        indirect support for the edge.
  - target: Precocious Puberty with Sertoli Cell Tumor
    description: >-
      Estrogen from an aromatase-expressing large-cell calcifying Sertoli cell
      tumor advances skeletal maturation and can trigger central precocious
      puberty in boys.
    evidence:
    - reference: PMID:20301463
      reference_title: "Carney Complex."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        orchiectomy for boys with aggressive LCCSCT and gynecomastia to avoid premature
        epiphyseal fusion and induction of central precocious puberty
      explanation: >-
        The Carney complex GeneReviews recommends orchiectomy in boys with
        aggressive LCCSCT and gynecomastia specifically to prevent central
        precocious puberty, a consequence of the tumor's estrogen.
- name: FOXL2 C134W Neomorphic Transcription Factor Activity
  biological_scale: MOLECULAR
  subtypes:
  - Granulosa Cell Tumor
  description: >-
    The recurrent somatic FOXL2 c.402C>G (p.C134W) variant of adult-type
    granulosa cell tumors, found also in the rare testicular adult granulosa
    cell tumor, changes what the FOXL2 transcription factor does rather than
    removing it. The mutant protein gains the ability to bind SMAD4 and, with
    SMAD2/3, occupies a hybrid DNA motif that wild-type FOXL2 does not bind,
    switching on genes for epithelial-to-mesenchymal transition, stemness and
    oncogenesis.
  notes: >-
    The mechanism was worked out in ovarian adult granulosa cell tumors and
    granulosa cell lines; for the testis there is the variant itself in
    sequenced tumors, so the node's testicular claim is that the same lesion is
    present. It is not placed on TGF-beta-Driven Sertoli-to-Granulosa
    Transdifferentiation, although both involve SMAD signalling: that node is
    TGFBR1 activation in Sertoli cells of a mouse model, a different lesion in
    a different starting cell, and none of the sources links the two. No
    downstream edge is drawn because this entry does not model granulosa cell
    proliferation as a separate node.
  genes:
  - preferred_term: FOXL2
    description: >-
      Somatic, typically monoallelic, p.C134W variant.
    term:
      id: hgnc:1092
      label: FOXL2
  molecular_functions:
  - preferred_term: FOXL2 C134W DNA-binding transcription factor activity
    modifier: GAIN_OF_FUNCTION
    description: >-
      Neomorphic: the mutant binds SMAD4 and a hybrid DNA motif unique to it,
      so the change is a new activity rather than more of the old one.
    term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
  cell_types:
  - preferred_term: granulosa cell
    term:
      id: CL:0000501
      label: granulosa cell
  evidence:
  - reference: PMID:37565864
    reference_title: "Adult granulosa cell tumor of the testis with malignant tendency: A case report with genetic analysis using high-throughput sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A high-throughput sequencing of 520 cancer-related genes revealed FOXL2 C134W,
      CDKN2A E87Gfs*24, TP53 S183*, TERT c.-124C > T, and H3F3A K28R mutations in this
      case.
    explanation: >-
      The FOXL2 C134W variant is present in an adult granulosa cell tumor of the
      testis.
  - reference: PMID:32641411
    reference_title: "Mutant FOXL2(C134W) Hijacks SMAD4 and SMAD2/3 to Drive Adult Granulosa Cell Tumors."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      is also found in the rare male version of GCTs and in some Sertoli-Leydig
      cell sex cord tumors
    explanation: >-
      The introduction of this mechanistic study states that the variant occurs
      in male granulosa cell tumors, placing the testicular tumor under the same
      driver.
  - reference: PMID:32641411
    reference_title: "Mutant FOXL2(C134W) Hijacks SMAD4 and SMAD2/3 to Drive Adult Granulosa Cell Tumors."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      mutant FOXL2C134W acquires the ability to bind SMAD4, forming a
      FOXL2C134W/SMAD4/SMAD2/3 complex that binds a novel hybrid DNA motif
      AGHCAHAA, unique to the FOXL2C134W mutant.
    explanation: >-
      Establishes the gained activity in granulosa cell lines; indirect for the
      testis because the work is on ovarian tumor biology.
  - reference: PMID:36409821
    reference_title: "The Oncogenic FOXL2 C134W Mutation Is a Key Driver of Granulosa Cell Tumors."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The genes dysregulated in mouse AGCTs exhibited the hallmarks of cancer and
      were consistent with a gain-of-function of the mutated allele affecting
      TGFβ signaling.
    explanation: >-
      A knock-in mouse carrying the variant develops ovarian adult granulosa
      cell tumors whose transcriptome reads as a gain of function of the mutant
      allele, supporting the modifier on this node.
- name: Autonomous Gonadal Steroidogenesis
  description: >-
    Hormonally active Leydig cell tumors autonomously synthesize testosterone; peripheral
    and intratumoral aromatase converts androgens to estrogens. Excess sex steroids produce
    gynecomastia in adults and isosexual precocious puberty in prepubertal boys.
  cell_types:
  - preferred_term: Leydig cell
    term:
      id: CL:0000178
      label: Leydig cell
  biological_processes:
  - preferred_term: androgen biosynthetic process
    modifier: INCREASED
    term:
      id: GO:0006702
      label: androgen biosynthetic process
  - preferred_term: estrogen biosynthetic process
    modifier: INCREASED
    term:
      id: GO:0006703
      label: estrogen biosynthetic process
  evidence:
  - reference: PMID:22016347
    reference_title: "A rare cause of hypertestosteronemia in a 68-year-old patient: a Leydig cell tumor due to a somatic GNAS (guanine nucleotide-binding protein, alpha-stimulating activity polypeptide 1)-activating mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      activating gsp mutation in Leydig cells may result in tumor development, leading
      to overexpression of the inhibin alpha subunit and hyperactivity of the
      testosterone biosynthetic pathway.
    explanation: >-
      A somatic activating GNAS (gsp R201C) mutation in a Leydig cell tumor drove
      hyperactivity of the testosterone biosynthetic pathway, demonstrating autonomous
      tumoral steroidogenesis.
  downstream:
  - target: Estrogen-Mediated Clinical Manifestations
    description: Excess estrogen drives gynecomastia and feminization.
- name: Estrogen-Mediated Clinical Manifestations
  description: >-
    Tumor-derived estrogen excess produces gynecomastia and can suppress the
    hypothalamic-pituitary-gonadal axis, reducing spermatogenesis and fertility.
  biological_processes:
  - preferred_term: estrogen receptor signaling pathway
    modifier: INCREASED
    term:
      id: GO:0030520
      label: estrogen receptor signaling pathway
  notes: >-
    No estrogen receptor gene is bound on this node. It is ligand excess from
    the tumor acting on structurally normal receptors in two remote target
    tissues, the breast and the hypothalamic-pituitary axis, and the node
    carries no cell type that would fix which receptor is meant. None of the
    sources cited in this entry names a receptor. PubMed searches run for this
    decision: Leydig cell tumor with gynecomastia and estrogen receptor in the
    title or abstract returned nothing; sex cord-stromal with testis and
    estrogen receptor returned one record (PMID:21974818), which reports GPER
    expression in tumor and normal testis and states that testicular estrogen
    signaling runs through estrogen receptor beta isoforms, measuring the
    tumor tissue rather than the tissues where this node's manifestations
    arise; Sertoli cell tumor with estrogen receptor returned five, of which
    the one human testis report (PMID:16944977) describes aromatase and
    estrogen receptor expression within a large-cell calcifying Sertoli cell
    tumor as a mechanism of tumor development, again the tumor rather than the
    target tissue; and gynecomastia in the title with estrogen receptor alpha
    or ESR1 returned two, of which PMID:21597315 found estrogen receptor beta
    expressed above alpha in stromal cells of pubertal gynecomastia tissue and
    both barely detectable in epithelial cells, so even the breast arm of this
    node does not reduce to ESR1. Records for Leydig cell tumor with
    gynecomastia and estradiol are case reports of estradiol-producing tumors;
    the abstracts of those cited as evidence here report estradiol excess,
    gynecomastia and low gonadotropins but name no receptor. The INCREASED
    modifier on the pathway term carries the ligand-excess consequence.
  evidence:
  - reference: PMID:9235082
    reference_title: "[Gynecomastia and Leydig cell tumor]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The more frequent hormonal manifestations of these tumors are high
      plasmatic and urinary estrogen levels, low serum testosterone, low
      testosterone/estradiol index, and FSH or LH low levels as well.
    explanation: >-
      Summarises the endocrine picture of Leydig cell tumors as estrogen excess
      with suppressed FSH and LH, the two arms of this node.
  - reference: PMID:16671273
    reference_title: "[An uncommon cause of gynecomastia: testicular Leydig cell tumor. Hormonal profile before and after orchiectomy]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Endocrine function tests showed decreased gonadotropin concentrations, and
      reduction of testosterone/estradiol ratio.
    explanation: >-
      A man with bilateral gynecomastia and a Leydig cell tumor had a lowered
      testosterone-to-estradiol ratio with suppressed gonadotropins.
  - reference: PMID:16671273
    reference_title: "[An uncommon cause of gynecomastia: testicular Leydig cell tumor. Hormonal profile before and after orchiectomy]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After surgery, the gynecomastia has completely disappeared and hormonal
      alterations returned to normal.
    explanation: >-
      Removing the tumor reversed both the gynecomastia and the hormonal
      changes, tying them to the tumor's output.
  - reference: PMID:29166332
    reference_title: "Testicular Estrogen-Secreting Leydig Cell Tumor in 18F-FDG PET/CT: An Incidental Detection in a Patient Treated by Chemotherapy for Hodgkin Lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The serum estradiol level was abnormally elevated reflecting the
      estrogen-secreting profile.
    explanation: >-
      A benign Leydig cell tumor presenting with bilateral gynecomastia secreted
      estradiol.
  downstream:
  - target: Gynecomastia
    causal_link_type: DIRECT
    description: >-
      Tumor-derived estrogen stimulates male breast tissue growth; the
      gynecomastia regresses once the tumor is removed.
    evidence:
    - reference: PMID:12628123
      reference_title: "[Gynecomastia secondary to Leydig cell tumor]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Two months after surgery, the gynecomastia diminished gradually and
        estrogen levels returned to normal.
      explanation: >-
        Gynecomastia and estrogen excess fell together after orchidectomy for a
        Leydig cell tumor, tying the breast growth to the tumor's estrogen.
phenotypes:
- name: Testicular Mass
  category: Neoplastic
  description: >-
    Painless unilateral testicular mass is the most common presentation of testicular
    sex cord-stromal tumors.
  phenotype_term:
    preferred_term: Testicular mass
    term:
      id: HP:0032404
      label: Testicular mass
  evidence:
  - reference: PMID:38879834
    reference_title: "Testicular juvenile granulosa cell tumor: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The Testicular Juvenile Granulosa Cell Tumor (JGCT) is a rare testicular
      neoplasm that appears in the first months of life as a painless testicular mass.
    explanation: >-
      Juvenile granulosa cell tumor, a testicular sex cord-stromal tumor, classically
      presents as a painless testicular mass.
- name: Testicular Neoplasm
  category: Neoplastic
  description: >-
    Sex cord-stromal tumors are non-germ-cell neoplasms of the testis.
  phenotype_term:
    preferred_term: Testicular neoplasm
    term:
      id: HP:0010788
      label: Testicular neoplasm
- name: Gynecomastia
  category: Endocrine
  description: >-
    Gynecomastia results from tumor-derived estrogen excess and is a common presenting
    feature of hormonally active Leydig cell tumors in adults.
  phenotype_term:
    preferred_term: Gynecomastia
    term:
      id: HP:0000771
      label: Gynecomastia
  evidence:
  - reference: PMID:22016347
    reference_title: "A rare cause of hypertestosteronemia in a 68-year-old patient: a Leydig cell tumor due to a somatic GNAS (guanine nucleotide-binding protein, alpha-stimulating activity polypeptide 1)-activating mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In adult patients, gynecomastia, oligozoospermia, erectile
      dysfunction, and other signs of feminization can be present
    explanation: >-
      Adult Leydig cell tumors commonly present with gynecomastia and other signs of
      feminization due to tumoral sex steroid production.
- name: Precocious Puberty
  category: Endocrine
  description: >-
    In prepubertal boys, androgen-secreting Leydig cell tumors cause isosexual precocious
    puberty.
  phenotype_term:
    preferred_term: Precocious puberty
    term:
      id: HP:0000826
      label: Precocious puberty
- name: Precocious Puberty with Sertoli Cell Tumor
  category: Endocrine
  description: >-
    Sertoli cell tumors, particularly the large-cell calcifying variant in Peutz-Jeghers
    syndrome and Carney complex, can present with precocious puberty.
  phenotype_term:
    preferred_term: Precocious puberty with Sertoli cell tumor
    term:
      id: HP:0008204
      label: Precocious puberty with Sertoli cell tumor
  evidence:
  - reference: PMID:20301463
    reference_title: "Carney Complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      orchiectomy for boys with aggressive LCCSCT and gynecomastia to avoid premature
      epiphyseal fusion and induction of central precocious puberty
    explanation: >-
      The Carney complex GeneReviews documents that aromatase-expressing large cell
      calcifying Sertoli cell tumors in boys can induce gynecomastia and central
      precocious puberty, supporting the endocrine presentation of testicular Sertoli
      cell tumors.
- name: Decreased Fertility
  category: Reproductive
  description: >-
    Hormonally active tumors suppressing the HPG axis and surgical management can reduce
    male fertility.
  phenotype_term:
    preferred_term: Decreased fertility in males
    term:
      id: HP:0012041
      label: Decreased fertility in males
genetic:
- name: CTNNB1
  association: >-
    Recurrent activating exon 3 mutations in CTNNB1 stabilize beta-catenin and drive
    canonical Wnt signaling in a subset of testicular Sertoli and Leydig cell tumors.
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: CTNNB1
    term:
      id: hgnc:2514
      label: CTNNB1
  evidence:
  - reference: PMID:28204871
    reference_title: "The role of beta-catenin mutation and SOX9 expression in sex cord-stromal tumours of the testis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mutation analyses of the β-catenin gene (exon 3;
      CTNNB1) were performed.
    explanation: >-
      Exon 3 CTNNB1 mutation analysis in testicular sex cord-stromal tumors identified
      recurrent beta-catenin mutations in Sertoli cell tumors.
- name: GNAS
  association: >-
    Activating GNAS mutations producing a constitutively active Gs-alpha subunit and
    elevated cAMP/PKA signaling occur in a subset of Leydig and Sertoli cell tumors.
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: GNAS
    term:
      id: hgnc:4392
      label: GNAS
  evidence:
  - reference: PMID:22016347
    reference_title: "A rare cause of hypertestosteronemia in a 68-year-old patient: a Leydig cell tumor due to a somatic GNAS (guanine nucleotide-binding protein, alpha-stimulating activity polypeptide 1)-activating mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A heterozygous missense somatic gsp mutation (R201C)
      was found in tumoral tissue, whereas no mutation was found in the surrounding
      normal tissue or in leukocyte DNA.
    explanation: >-
      A somatic activating GNAS (gsp R201C) mutation was identified specifically in
      Leydig cell tumor tissue, implicating GNAS activation in tumorigenesis.
- name: PRKAR1A
  association: >-
    Germline inactivating PRKAR1A mutations cause Carney complex and predispose to
    large-cell calcifying Sertoli cell tumor through loss of PKA regulatory control.
  relationship_type: RISK_FACTOR
  variant_origin: GERMLINE_AND_SOMATIC
  notes: >-
    RISK_FACTOR rather than CAUSATIVE for this entry: germline PRKAR1A
    inactivation (Carney complex) predisposes to one subtype, the large-cell
    calcifying Sertoli cell tumor, and is neither necessary nor sufficient for
    testicular sex cord-stromal neoplasia as a whole. Sporadic large-cell
    calcifying Sertoli cell tumors also carry PRKAR1A alterations, hence the
    combined variant origin.
  gene_term:
    preferred_term: PRKAR1A
    term:
      id: hgnc:9388
      label: PRKAR1A
  evidence:
  - reference: PMID:38619599
    reference_title: "Familial syndromes associated with testicular and paratesticular neoplasms: a comprehensive review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Such examples include Carney complex and large cell
      calcifying Sertoli cell tumor
    explanation: >-
      Carney complex, caused by germline PRKAR1A inactivation, is a well-established
      predisposition syndrome for large cell calcifying Sertoli cell tumor.
- name: STK11
  association: >-
    Germline STK11 (LKB1) inactivation causes Peutz-Jeghers syndrome and predisposes to
    Sertoli cell tumors, including the large-cell calcifying variant.
  relationship_type: RISK_FACTOR
  variant_origin: GERMLINE
  notes: >-
    RISK_FACTOR for the same reason as PRKAR1A: germline STK11 inactivation
    (Peutz-Jeghers syndrome) predisposes to Sertoli cell tumors in a minority
    of the entry's cases. The tumor-level event is loss of the second allele in
    Sertoli cells (see LKB1 Loss in Sertoli Cells).
  gene_term:
    preferred_term: STK11
    term:
      id: hgnc:11389
      label: STK11
  evidence:
  - reference: PMID:38619599
    reference_title: "Familial syndromes associated with testicular and paratesticular neoplasms: a comprehensive review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Peutz-Jeghers syndrome and intratubular large
      cell hyalinizing Sertoli cell neoplasia
    explanation: >-
      Peutz-Jeghers syndrome, caused by germline STK11 inactivation, is associated with
      a distinctive intratubular large cell hyalinizing Sertoli cell neoplasia of the
      testis.
- name: FOXL2
  association: >-
    Adult-type granulosa cell tumors of the testis can harbor the FOXL2 C134W mutation,
    the same recurrent somatic variant characteristic of ovarian adult granulosa cell
    tumors, reflecting a shared granulosa-lineage oncogenic driver.
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: FOXL2
    term:
      id: hgnc:1092
      label: FOXL2
  evidence:
  - reference: PMID:37565864
    reference_title: "Adult granulosa cell tumor of the testis with malignant tendency: A case report with genetic analysis using high-throughput sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A high-throughput sequencing of 520 cancer-related genes revealed FOXL2 C134W,
      CDKN2A E87Gfs*24, TP53 S183*, TERT c.-124C > T, and H3F3A K28R mutations in this
      case.
    explanation: >-
      Sequencing of an adult testicular granulosa cell tumor identified the FOXL2 C134W
      mutation, the hallmark driver of adult-type granulosa cell tumors.
treatments:
- name: Radical or Testis-Sparing Orchiectomy
  description: >-
    Surgical removal of the tumor is the mainstay of treatment. Most sex cord-stromal
    tumors are benign and cured by radical inguinal orchiectomy or, for small benign
    lesions, testis-sparing (partial) orchiectomy.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:20301463
    reference_title: "Carney Complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      orchiectomy for boys with aggressive LCCSCT and gynecomastia to avoid premature
      epiphyseal fusion and induction of central precocious puberty
    explanation: >-
      Orchiectomy is indicated for aggressive Sertoli cell tumors with endocrine
      manifestations, supporting surgery as the mainstay of management.
- name: Retroperitoneal Lymph Node Dissection
  description: >-
    Considered for malignant sex cord-stromal tumors with features predictive of
    metastasis, since these tumors respond poorly to chemotherapy and radiotherapy.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:12910519
    reference_title: "Does retroperitoneal lymph node dissection have a curative role for patients with sex cord-stromal testicular tumors?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RPLND remains an option to be performed
      immediately after orchiectomy, especially in patients who have tumors with
      malignant features and/or small-volume metastatic disease.
    explanation: >-
      Retroperitoneal lymph node dissection is an option performed after orchiectomy
      for testicular sex cord-stromal tumors with malignant features or small-volume
      metastatic disease, directly supporting RPLND as a surgical management modality.
  - reference: PMID:40345119
    reference_title: "A Single Centre Review of the Management of Testicular Sex Cord-Stromal Cell Tumours."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It has been demonstrated that certain histopathological risk factors
      can be useful in identifying those with malignant potential.
    explanation: >-
      Histopathological risk factors identify sex cord-stromal tumors with malignant
      potential, guiding selection for patients who warrant more aggressive surgical
      management such as retroperitoneal lymph node dissection.
📚

References & Deep Research

References

2
PMID:20301463
Carney Complex.
No top-level findings curated for this source.
PMID:36645400
News in the classification of WHO 2022 testicular tumours.
No top-level findings curated for this source.