Definition/General

Introduction:
-Ovarian sex cord-stromal tumors (SCST) represent a diverse group of ovarian neoplasms derived from sex cord and stromal elements
-They constitute 5-8% of all ovarian tumors
-These tumors arise from the supporting structures of the developing gonad
-They often produce hormonal effects due to steroid hormone synthesis.
Origin:
-Originate from the sex cord cells and stromal cells of the developing gonad
-Sex cord cells include granulosa cells and Sertoli cells
-Stromal cells include theca cells, Leydig cells, and fibroblasts
-These components can form pure or mixed tumors
-The tumors retain the capacity for hormone production.
Classification:
-Classified into pure forms and mixed forms
-Pure forms include granulosa cell tumor, thecoma, fibroma, and Sertoli-Leydig cell tumor
-Mixed forms include granulosa-theca cell tumor
-Classification based on WHO 2020 guidelines
-Grading follows histological criteria for specific subtypes.
Epidemiology:
-Peak incidence varies by subtype
-Granulosa cell tumors peak in 5th-6th decades
-Thecomas in postmenopausal women
-Fibromas in 4th-5th decades
-Sertoli-Leydig tumors in young women
-Indian population shows similar distribution with slight earlier age at presentation.

Clinical Features

Presentation:
-Pelvic mass (most common presentation)
-Hormonal effects due to estrogen or androgen production
-Abdominal distension and pain
-Meigs syndrome (ascites and pleural effusion)
-Feminizing effects (granulosa cell tumors)
-Virilizing effects (Sertoli-Leydig tumors)
-Postmenopausal bleeding in elderly patients.
Symptoms:
-Abdominal pain and distension
-Abnormal uterine bleeding (estrogen-producing tumors)
-Hirsutism and virilization (androgen-producing tumors)
-Early satiety
-Urinary frequency
-Breast tenderness (estrogen effects)
-Voice changes (androgen effects)
-Weight gain or loss.
Risk Factors:
-No specific known risk factors
-Genetic syndromes (rare association)
-Family history (uncommon)
-Age-related occurrence
-Hormonal factors may play a role
-Previous ovarian pathology
-BRCA mutations (minimal association).
Screening:
-No specific screening protocols
-Pelvic examination in symptomatic patients
-Transvaginal ultrasound for evaluation of pelvic masses
-Serum tumor markers (inhibin A and B)
-Hormonal assessment (estradiol, testosterone)
-CA-125 may be elevated but non-specific.

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Gross Description

Appearance:
-Variable size ranging from 2-30 cm in diameter
-Unilateral in majority of cases (80-90%)
-Solid, cystic, or mixed cut surface appearance
-Yellow coloration common due to lipid content
-Surface may be smooth or lobulated
-Hemorrhage and necrosis may be present in malignant cases.
Characteristics:
-Granulosa cell tumors: Gray-yellow, solid-cystic, hemorrhagic areas
-Thecomas: Yellow, solid, lobulated surface
-Fibromas: White-gray, solid, firm consistency
-Sertoli-Leydig tumors: Yellow-brown, solid areas with cysts
-Cut surface shows variegated appearance in mixed tumors.
Size Location:
-Size varies widely from microscopic to >30 cm
-Unilateral involvement in 85-95% cases
-Bilateral occurrence more common in granulosa cell tumors (5-10%)
-Right ovary slightly more commonly affected
-Large tumors may cause ovarian torsion.
Multifocality:
-Multifocal involvement within same ovary possible
-Bilateral disease varies by subtype
-Granulosa cell tumors: 5-10% bilateral
-Thecomas and fibromas: rarely bilateral
-Sertoli-Leydig tumors: usually unilateral
-Peritoneal implants possible in malignant cases.

Microscopic Description

Histological Features:
-Granulosa cell tumors: Small uniform cells with coffee-bean nuclei, Call-Exner bodies
-Thecomas: Spindle cells with abundant eosinophilic cytoplasm, lipid vacuoles
-Fibromas: Mature fibrous tissue with spindle cells
-Sertoli-Leydig tumors: Tubular structures (Sertoli cells) and polygonal cells (Leydig cells)
-Mixed patterns common.
Cellular Characteristics:
-Cell morphology varies by subtype
-Granulosa cells: Round to oval nuclei, scant cytoplasm, nuclear grooves
-Theca cells: Oval nuclei, abundant eosinophilic cytoplasm
-Sertoli cells: Elongated nuclei, clear to eosinophilic cytoplasm
-Leydig cells: Polygonal shape, abundant eosinophilic cytoplasm
-Mitotic activity varies with grade.
Architectural Patterns:
-Granulosa cell pattern: Diffuse, trabecular, insular, follicular patterns
-Theca cell pattern: Fascicular arrangement of spindle cells
-Fibroma pattern: Intersecting fascicles of mature fibrous tissue
-Sertoli pattern: Tubular and solid arrangements
-Mixed patterns with transition between components.
Grading Criteria:
-Granulosa cell tumors: Grade based on nuclear atypia, mitotic activity, necrosis
-Adult type: Usually low grade
-Juvenile type: May show higher grade features
-Sertoli-Leydig tumors: Well, moderately, or poorly differentiated
-Thecomas and fibromas: Generally benign with rare malignant transformation.

Immunohistochemistry

Positive Markers:
-Inhibin-A (positive in most SCST)
-Calretinin (positive in granulosa and Sertoli cells)
-SF-1 (steroidogenic factor-1)
-FOXL2 (granulosa cell tumors, especially adult type)
-CD99 (Sertoli-Leydig tumors)
-Vimentin (stromal components)
-Smooth muscle actin (theca cells, variable).
Negative Markers:
-Cytokeratins (usually negative, may be focally positive)
-EMA (epithelial membrane antigen)
-CD45 (leukocyte common antigen)
-Chromogranin and synaptophysin (neuroendocrine markers)
-Melanoma markers (S-100, HMB-45)
-CD117 (except some Sertoli-Leydig tumors).
Diagnostic Utility:
-Inhibin-A and calretinin help distinguish from epithelial ovarian tumors
-FOXL2 specific for adult granulosa cell tumors
-SF-1 confirms sex cord-stromal differentiation
-CD99 useful for Sertoli-Leydig tumor diagnosis
-Panel approach recommended for accurate subclassification
-Helps distinguish from metastatic tumors.
Molecular Subtypes:
-FOXL2 mutation (C134W) in adult granulosa cell tumors (95%)
-DICER1 mutations in Sertoli-Leydig tumors (60%)
-Juvenile granulosa cell tumors: Usually FOXL2 wild-type
-Molecular testing aids in classification
-Prognostic implications of genetic alterations under investigation.

Molecular/Genetic

Genetic Mutations:
-FOXL2 C134W mutation (adult granulosa cell tumors, 95%)
-DICER1 mutations (Sertoli-Leydig tumors, 60%)
-TP53 mutations (rare, associated with malignant behavior)
-CTNNB1 mutations (rare in fibromas)
-AKT pathway alterations (subset of cases)
-PIK3CA mutations (occasional).
Molecular Markers:
-FOXL2 expression (adult granulosa cell tumors)
-DICER1 expression (Sertoli-Leydig tumors)
-Cyclin D1 (variable expression)
-p53 expression (usually wild-type pattern)
-Ki-67 proliferation index (varies with grade)
-Hormone receptors (ER, PR variable).
Prognostic Significance:
-FOXL2 mutation associated with better prognosis in granulosa cell tumors
-DICER1 mutations correlate with younger age in Sertoli-Leydig tumors
-Tumor stage most important prognostic factor
-Histological grade influences outcome
-Molecular profiling may guide targeted therapy in future.
Therapeutic Targets:
-Hormone therapy (anti-estrogens for estrogen-producing tumors)
-Targeted therapy based on molecular alterations under investigation
-mTOR pathway inhibitors (potential target)
-PI3K/AKT pathway inhibitors
-CDK4/6 inhibitors (under study)
-Immunotherapy limited role currently.

Differential Diagnosis

Similar Entities:
-Epithelial ovarian tumors (especially clear cell carcinoma)
-Metastatic tumors (especially from breast, gastrointestinal tract)
-Krukenberg tumor (signet ring cell metastases)
-Lymphoma (especially in young patients)
-Germ cell tumors (dysgerminoma, yolk sac tumor)
-Mesenchymal tumors (leiomyoma, sarcoma).
Distinguishing Features:
-SCST: Inhibin-A and calretinin positive
-SCST: Cytokeratin negative or focal
-SCST: Hormonal effects common
-Epithelial tumors: Cytokeratin strongly positive
-Epithelial tumors: Inhibin-A negative
-Metastases: Clinical history and organ-specific markers
-Lymphoma: CD45 positive
-Germ cell: Age and specific markers.
Diagnostic Challenges:
-Distinguishing malignant from benign sex cord-stromal tumors
-Subclassification of mixed tumors
-Metastatic disease mimicking primary ovarian SCST
-Juvenile granulosa cell tumor vs other entities in young patients
-Poorly differentiated tumors may lose typical features
-Immunohistochemistry panel essential for accurate diagnosis.
Rare Variants:
-Sclerosing stromal tumor (young women, characteristic morphology)
-Steroid cell tumor (lipoid cell tumor)
-Unclassified sex cord-stromal tumor
-Mixed germ cell-sex cord-stromal tumor
-Ovarian tumor of probable Wolffian origin
-Small cell carcinoma, hypercalcemic type (differential in young patients).

Sample Pathology Report

Template Format

Sample Pathology Report

Complete Report: This is an example of how the final pathology report should be structured for this condition.

Specimen Information

Ovarian specimen measuring [size] cm, [unilateral/bilateral]

Diagnosis

Ovarian sex cord-stromal tumor, [specific subtype]

Classification

WHO 2020: [specific subtype], [grade if applicable]

Histological Features

Shows [specific morphological pattern] consistent with [subtype]

Size and Extent

Size: [X] cm, [confined/extends beyond ovary]

Surface and Capsule

Surface involvement: [present/absent], capsular breach: [present/absent]

Special Studies

IHC: Inhibin-A [+/-], Calretinin [+/-], FOXL2 [+/-]

Molecular: [test performed]: [result]

[other study]: [result]

Staging

FIGO Stage: [stage], TNM: [classification]

Prognostic Factors

Stage: [stage], Grade: [grade], Size: [size], Bilaterality: [yes/no]

Final Diagnosis

Ovarian sex cord-stromal tumor, [complete subtype and grade]