Definition/General

Introduction:
-Granulosa cell tumor is the most common sex cord-stromal tumor of the ovary
-It accounts for 2-5% of all ovarian tumors
-It arises from the granulosa cells of the ovarian follicle
-It demonstrates estrogen secretion and may cause hormonal manifestations.
Origin:
-Originates from the granulosa cells that line the ovarian follicles
-These cells are responsible for estrogen production in normal ovarian function
-The tumor retains the ability to produce hormones, particularly estrogen
-This leads to characteristic clinical manifestations related to hyperestrogenism.
Classification:
-Classified into adult type (95%) and juvenile type (5%)
-Adult type occurs in postmenopausal women (average age 50-55 years)
-Juvenile type occurs in children and young adults (average age 13 years)
-Both types are low-grade malignancies with potential for late recurrence.
Epidemiology:
-Peak incidence in postmenopausal women (5th-6th decade)
-Juvenile type affects children and adolescents
-Bilateral involvement in 2-5% of adult cases
-Bilateral involvement in 10% of juvenile cases
-Indian population shows similar age distribution patterns.

Clinical Features

Presentation:
-Estrogenic effects (postmenopausal bleeding, endometrial hyperplasia)
-Abdominal distension and mass effect
-Precocious puberty (juvenile type)
-Menstrual irregularities
-Virilization (rare, if testosterone production)
-Ascites in advanced cases.
Symptoms:
-Abnormal uterine bleeding (80-90% cases)
-Abdominal pain and fullness
-Postmenopausal bleeding (most common)
-Breast tenderness
-Weight gain
-Vaginal discharge
-Isosexual precocity (juvenile type).
Risk Factors:
-Age (postmenopausal women for adult type)
-Family history of ovarian cancer
-No established risk factors for most cases
-Genetic predisposition (rare)
-Environmental factors (unclear association)
-Previous ovarian disorders.
Screening:
-Pelvic examination and transvaginal ultrasound
-Inhibin B levels (tumor marker)
-Anti-Müllerian hormone (AMH) levels
-CA-125 (may be elevated)
-Hormonal assessment (estrogen levels)
-Regular gynecological follow-up.

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Gross Description

Appearance:
-Smooth, lobulated mass with intact capsule
-Yellow to tan-gray cut surface
-Solid and cystic areas
-Size ranges from 5-20 cm (average 12 cm)
-Hemorrhage and necrosis may be present.
Characteristics:
-Unilateral in 95% of adult cases
-Encapsulated appearance
-Cut surface shows solid yellow areas with cystic spaces
-Hemorrhagic areas common
-Necrosis in larger tumors
-Friable consistency.
Size Location:
-Variable size (2-30 cm diameter)
-Average size 10-15 cm
-Usually unilateral involvement
-No specific ovarian location preference
-Larger tumors may show surface irregularities
-Capsular breach in advanced cases.
Multifocality:
-Usually unifocal within the affected ovary
-Bilateral disease in 2-5% (adult type)
-Bilateral disease in 10% (juvenile type)
-Multifocal growth pattern rare
-Capsular involvement indicates advanced disease.

Microscopic Description

Histological Features:
-Uniform cells with coffee-bean nuclei (nuclear grooves)
-Call-Exner bodies (pathognomonic when present)
-Solid, trabecular, and follicular growth patterns
-Luteinized cells may be present
-Thecal cell component variable.
Cellular Characteristics:
-Medium-sized cells with pale to eosinophilic cytoplasm
-Oval nuclei with longitudinal grooves (coffee-bean appearance)
-Prominent nucleoli
-Low to moderate mitotic activity
-Luteinization may be prominent.
Architectural Patterns:
-Microfollicular pattern (most common)
-Macrofollicular pattern
-Trabecular pattern
-Insular pattern
-Solid pattern
-Call-Exner bodies (eosinophilic material in follicular spaces)
-Diffuse pattern (juvenile type).
Grading Criteria:
-Adult type: Well-differentiated (microfollicular pattern)
-Moderately differentiated (mixed patterns)
-Poorly differentiated (solid pattern)
-Juvenile type: More pleomorphic cells
-Higher mitotic activity
-Follicular pattern less common.

Immunohistochemistry

Positive Markers:
-Inhibin-alpha (95-100%)
-Calretinin (90-95%)
-CD99 (80-90%)
-Vimentin
-SF-1 (steroidogenic factor-1)
-FOXL2 (adult type)
-Estrogen receptor (variable)
-Progesterone receptor (variable).
Negative Markers:
-Cytokeratin (usually negative)
-EMA (usually negative)
-WT1 (negative)
-S-100 (negative)
-Alpha-fetoprotein (negative)
-HCG (negative)
-Chromogranin (negative)
-Synaptophysin (negative).
Diagnostic Utility:
-Essential for differential diagnosis from epithelial tumors
-Inhibin and calretinin confirm sex cord-stromal origin
-Distinguish from small cell carcinoma
-Distinguish from carcinoid tumors
-FOXL2 mutation (adult type diagnostic marker).
Molecular Subtypes:
-Adult type: FOXL2 C134W mutation (95%)
-Juvenile type: FOXL2 wild-type
-AKT pathway activation
-DICER1 mutations (some juvenile cases)
-GNAS mutations (rare)
-PIK3CA mutations (rare).

Molecular/Genetic

Genetic Mutations:
-FOXL2 C134W mutation (95% adult type)
-Wild-type FOXL2 (juvenile type)
-DICER1 mutations (juvenile type)
-AKT1 mutations
-PIK3CA mutations
-GNAS mutations
-Chromosomal instability (advanced cases).
Molecular Markers:
-FOXL2 protein expression (adult type)
-Inhibin-alpha overexpression
-AMH overexpression
-Estrogen receptor variable expression
-Progesterone receptor expression
-Steroidogenic enzymes (aromatase, 17β-HSD).
Prognostic Significance:
-FOXL2 mutation indicates adult type with better prognosis
-Wild-type FOXL2 (juvenile type) may have different behavior
-Stage at presentation most important prognostic factor
-Tumor size >10 cm associated with higher recurrence
-DNA ploidy may predict behavior.
Therapeutic Targets:
-Hormonal therapy: Anti-estrogens (tamoxifen)
-Aromatase inhibitors (anastrozole, letrozole)
-GnRH agonists (leuprolide)
-mTOR inhibitors (experimental)
-Anti-angiogenic agents (bevacizumab)
-CDK4/6 inhibitors (experimental).

Differential Diagnosis

Similar Entities:
-Thecoma (spindle cells, no Call-Exner bodies)
-Fibroma (spindle cells, inhibin negative)
-Sertoli-Leydig cell tumor (different histology, testosterone production)
-Small cell carcinoma (hypercalcemic type)
-Carcinoid tumor (neuroendocrine markers positive).
Distinguishing Features:
-Granulosa cell tumor: Coffee-bean nuclei
-Call-Exner bodies
-Inhibin positive
-Thecoma: Spindle cells
-Dense collagen
-No Call-Exner bodies
-Fibroma: Dense fibrous stroma
-Inhibin negative
-Sertoli-Leydig: Tubular pattern
-Testosterone effects
-Small cell carcinoma: High-grade features
-Hypercalcemia.
Diagnostic Challenges:
-Distinguishing adult from juvenile type
-Differentiating from poorly differentiated epithelial tumors
-Mixed sex cord-stromal tumors
-Distinguishing recurrence from new primary tumor
-Immunohistochemistry essential for accurate diagnosis.
Rare Variants:
-Sarcomatoid granulosa cell tumor (spindle cell areas)
-Cystic granulosa cell tumor (predominantly cystic)
-Luteinized granulosa cell tumor (prominent luteinization)
-Granulosa cell tumor with heterologous elements
-Bilateral granulosa cell tumor.

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 mass, [side], measuring [X x Y x Z] cm, weighing [X] grams

Diagnosis

Granulosa Cell Tumor, [Adult/Juvenile] Type

Classification

WHO Classification: Sex Cord-Stromal Tumor, Granulosa Cell Tumor

Histological Features

Shows [growth pattern] with characteristic coffee-bean nuclei and [presence/absence] of Call-Exner bodies

Size and Extent

Tumor size: [X] cm, [unilateral/bilateral], capsule [intact/breached]

Hormonal Effects

Associated with [estrogenic/androgenic/no] hormonal effects

Special Studies

IHC: Inhibin-alpha [positive/negative], Calretinin [positive/negative], FOXL2 [positive/negative]

Molecular: FOXL2 C134W mutation [detected/not detected]

Hormone levels: [specify results]

Prognostic Factors

Stage: [I/II/III/IV], Size: [10 cm], Type: [Adult/Juvenile], Capsular involvement: [yes/no]

Final Diagnosis

Ovarian Granulosa Cell Tumor, [Adult/Juvenile] Type, [Stage], [Side]