Definition/General
Introduction:
Ovarian small cell carcinoma is an extremely rare and highly aggressive malignant neoplasm
Constitutes less than 1% of all ovarian cancers
Occurs predominantly in young women (mean age 23 years)
Associated with hypercalcemia in 60% of cases
Also known as small cell carcinoma of hypercalcemic type
Has extremely poor prognosis.
Origin:
Arises from ovarian surface epithelium or inclusion cysts
Shows neuroendocrine differentiation in some cases
May arise from primitive germ cells (controversial)
The histogenesis remains poorly understood
Some cases may represent undifferentiated carcinoma with small cell morphology.
Classification:
WHO 2020 classifies as small cell carcinoma, hypercalcemic type
Separate from small cell carcinoma, pulmonary type
Distinguished from neuroendocrine carcinoma
Classified under surface epithelial tumors
All cases are considered high-grade by definition.
Epidemiology:
Median age 23 years (range 14-40 years)
More than 50% occur in women <30 years
Rare in postmenopausal women
No known racial predilection
No established risk factors
May be associated with family history of cancer in some cases.
Clinical Features
Presentation:
Most patients present with rapidly enlarging pelvic mass
Hypercalcemia in 60% of cases (parathyroid hormone-related protein)
Advanced stage disease common at presentation (Stage III-IV in 70%)
Acute abdominal pain due to rapid growth
Abdominal distension and ascites
Symptoms related to hypercalcemia.
Symptoms:
Hypercalcemic symptoms: fatigue, confusion, kidney stones, bone pain
Abdominal pain (80-90% cases)
Pelvic mass (95% cases)
Nausea and vomiting (hypercalcemia-related)
Polyuria and polydipsia
Weight loss (30-40%)
Constipation (hypercalcemia-related).
Risk Factors:
Young age (most important factor)
No established environmental factors
No hormonal associations
No genetic syndromes identified
Family history of cancer in some cases
Not associated with BRCA mutations.
Screening:
No screening available due to rarity
Serum calcium levels important for diagnosis
Parathyroid hormone-related protein (PTHrP) elevated
Pelvic ultrasound shows solid mass
CA-125 may be elevated (non-specific)
CT/MRI for staging.
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Gross Description
Appearance:
Large, solid mass with smooth or bosselated surface
Cut surface shows gray-white to tan color
Fleshy, soft consistency
Areas of necrosis and hemorrhage common due to rapid growth
May show cystic degeneration
Surface may be intact or ruptured.
Characteristics:
Size ranges from 8-30 cm (median 15-20 cm)
Soft to firm consistency
Cut surface shows homogeneous tan-gray appearance
Extensive necrosis in rapidly growing tumors
Hemorrhagic areas common
May contain small cystic spaces.
Size Location:
Most tumors are large at presentation (>10 cm in 90% cases)
Usually unilateral (90% cases)
Bilateral involvement rare (10%)
Can involve entire ovarian parenchyma
May show surface involvement with rupture
Capsular invasion common.
Multifocality:
Unilateral involvement in 90% of cases
Peritoneal implants common due to surface rupture
Omental involvement frequent
Ascites present in 60-70%
Lymph node metastases to pelvic and para-aortic nodes
Distant metastases to liver, lung, and bone.
Microscopic Description
Histological Features:
Tumor composed of small, uniform cells with high nuclear-cytoplasmic ratio
Cells arranged in sheets, nests, or follicle-like patterns
Follicle-like spaces containing eosinophilic material (characteristic feature)
High mitotic activity with numerous atypical mitoses
Extensive necrosis and hemorrhage.
Cellular Characteristics:
Small cells with scant cytoplasm
Round to oval nuclei with fine chromatin
Small, inconspicuous nucleoli
High nuclear-cytoplasmic ratio
Frequent mitotic figures (>20/10 HPF)
Apoptotic bodies common
Nuclear molding may be present.
Architectural Patterns:
Solid sheets of small cells most common pattern
Follicle-like spaces filled with eosinophilic fluid (pathognomonic)
Insular pattern with cell nests
Diffuse growth pattern
Pseudorosette formation occasionally seen
Single file pattern rare.
Grading Criteria:
All cases are high-grade by definition
Grading criteria include high mitotic rate (>20/10 HPF)
Marked nuclear pleomorphism
Presence of necrosis
High Ki-67 proliferation index (>50%)
Architectural disorganization.
Immunohistochemistry
Positive Markers:
Inhibin-α positive (90-95% cases) - most characteristic marker
Calretinin positive (80-90%)
WT1 positive (70-80%)
Vimentin positive (90-95%)
EMA positive (variable, 40-60%)
Chromogranin positive (30-40% cases)
Synaptophysin positive (20-30% cases).
Negative Markers:
Cytokeratins negative or weakly positive
CK7 negative (helps distinguish from epithelial tumors)
CK20 negative
PAX8 negative
TTF-1 negative (excludes pulmonary small cell carcinoma)
LCA negative (excludes lymphoma)
Desmin negative.
Diagnostic Utility:
Inhibin-α is the most important marker (highly sensitive and specific)
Combined inhibin + calretinin confirms diagnosis
Negative cytokeratins help exclude epithelial carcinomas
Negative TTF-1 excludes pulmonary small cell carcinoma
Panel: Inhibin, Calretinin, CK7, TTF-1, Chromogranin.
Molecular Subtypes:
Most cases are sporadic
No specific molecular subtypes identified
p53 mutations uncommon
FOXL2 mutations absent (unlike granulosa cell tumors)
SMARCA4 loss reported in some cases.
Molecular/Genetic
Genetic Mutations:
SMARCA4 (BRG1) mutations in 40-50% of cases
SMARCB1 mutations rare
TP53 mutations uncommon (<20%)
PIK3CA mutations rare
No recurrent driver mutations identified
Complex karyotype with multiple chromosomal aberrations.
Molecular Markers:
Loss of SMARCA4 expression by immunohistochemistry
High Ki-67 proliferation index (>50%)
p53 wild-type pattern in most cases
PTHrP overexpression (responsible for hypercalcemia)
No microsatellite instability.
Prognostic Significance:
Extremely poor prognosis regardless of stage
5-year survival <10% for all stages
Median survival 1-2 years
Young age may be associated with slightly better outcome
Stage I disease has better prognosis but still guarded
Hypercalcemia indicates poor prognosis.
Therapeutic Targets:
Limited targeted therapy options
SMARCA4-deficient tumors: PARP inhibitors under investigation
Platinum-based chemotherapy (carboplatin + paclitaxel)
Etoposide + cisplatin (small cell lung cancer regimen)
High-dose chemotherapy with stem cell rescue (investigational)
Immunotherapy under investigation.
Differential Diagnosis
Similar Entities:
Adult granulosa cell tumor
Juvenile granulosa cell tumor
Metastatic small cell carcinoma (lung)
Primitive neuroectodermal tumor (PNET)
Lymphoma (small cell type)
Endometrial stromal sarcoma
Poorly differentiated adenocarcinoma.
Distinguishing Features:
Adult granulosa cell: Call-Exner bodies, older age, FOXL2 mutations
Juvenile granulosa cell: younger age but different morphology, luteinized cells
Lung primary: TTF-1 positive, inhibin negative
PNET: CD99 positive, inhibin negative
Lymphoma: LCA positive, inhibin negative
Endometrial stromal: CD10 positive, different morphology.
Diagnostic Challenges:
Distinguishing from juvenile granulosa cell tumor (overlapping age group)
Excluding metastatic small cell carcinoma from lung
Recognizing follicle-like spaces as characteristic feature
Differentiating from other small round cell tumors
Confirming primary ovarian origin.
Rare Variants:
Small cell carcinoma with rhabdoid features
Small cell carcinoma with squamous differentiation
Small cell carcinoma arising in mature teratoma
Mixed small cell carcinoma with other histologic types
Small cell carcinoma without hypercalcemia.
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
Right/Left salpingo-oophorectomy specimen measuring [X x Y x Z] cm, weighing [X] grams
Gross Description
Ovary enlarged by solid mass measuring [X] cm. Cut surface shows gray-white, fleshy appearance with areas of necrosis and hemorrhage. Surface is [intact/ruptured]
Diagnosis
Small Cell Carcinoma, Hypercalcemic Type
Microscopic Description
Tumor composed of sheets of small cells with high nuclear-cytoplasmic ratio. Characteristic follicle-like spaces containing eosinophilic material present. High mitotic activity (>20/10 HPF) with extensive necrosis
Immunohistochemistry
Inhibin-α: Positive\nCalretinin: Positive\nCK7: Negative\nTTF-1: Negative\nChromogranin: [Positive/Negative]\nKi-67: >50%
Staging Information
Tumor size: [X] cm\nLaterality: [Unilateral/Bilateral]\nSurface involvement: [Present/Absent]\nCapsular rupture: [Present/Absent]\nFIGO Stage: [Stage]
Clinical Note
Small cell carcinoma of hypercalcemic type is an extremely aggressive tumor with poor prognosis. Recommend correlation with serum calcium and PTHrP levels. Imaging to exclude metastatic disease from lung primary recommended
Final Diagnosis
Ovarian Small Cell Carcinoma, Hypercalcemic Type, FIGO Stage [X]