Definition/General
Introduction:
Ovarian glassy cell carcinoma is an extremely rare variant of ovarian adenocarcinoma characterized by cells with distinctive glassy, ground-glass cytoplasm
Represents less than 1% of all ovarian carcinomas
Originally described in cervical location but rarely occurs in ovary
Shows aggressive behavior with poor prognosis similar to cervical counterpart.
Origin:
Arises from ovarian surface epithelium or inclusion cysts with müllerian differentiation
May develop from endometrioid or mucinous adenocarcinoma through morphological transformation
Shows loss of typical glandular differentiation with acquisition of glassy cell features
HPV association not established in ovarian location (unlike cervical glassy cell carcinoma).
Classification:
WHO 2014/2020 classifies under rare variants of epithelial tumors
Previously considered as adenosquamous carcinoma variant
FIGO staging system applies (Stage I-IV)
Grading typically high-grade (Grade 3) due to poor differentiation
Distinguished from cervical glassy cell carcinoma by anatomical location and HPV negativity.
Epidemiology:
Extremely rare with fewer than 50 cases reported worldwide
Peak incidence in 4th-5th decades (mean age 45-55 years)
No clear association with BRCA mutations (unlike other ovarian carcinomas)
Indian population data limited due to rarity
Associated with nulliparity and infertility in some cases.
Clinical Features
Presentation:
Pelvic mass (90-95% cases) often large and rapidly growing
Abdominal distension and bloating (80% cases)
Pelvic pain (70-75% cases) - dull, aching
Early satiety and weight loss
Ascites in advanced cases (60-70%)
Constitutional symptoms (fatigue, anorexia) due to rapid tumor growth.
Symptoms:
Abdominal pain (70-80% cases) - constant, progressive
Abnormal vaginal bleeding (40-50% cases)
Urinary frequency or urgency
Bowel symptoms (constipation, obstruction)
Nausea and vomiting
Dyspnea if pleural involvement
Back pain in retroperitoneal extension.
Risk Factors:
Nulliparity or low parity
Infertility history
Advanced age (>40 years)
Endometriosis history (possible link)
No clear genetic predisposition identified
Hormonal factors (unopposed estrogen)
Obesity (possible association).
Screening:
CA-125 levels elevated in 80-85% cases (>35 U/mL)
HE4 may be elevated
CEA levels occasionally elevated
Transvaginal ultrasound shows complex solid mass
CT/MRI demonstrates heterogeneous enhancement
PET-CT shows high FDG uptake.
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Gross Description
Appearance:
Large, solid masses with smooth to lobulated surface
Gray-white to tan cut surface with glassy appearance
Areas of necrosis and hemorrhage common (70-80% cases)
Firm consistency with occasional cystic areas
Surface may show capsular rupture or adhesions.
Characteristics:
Smooth, glistening cut surface characteristic of glassy cell morphology
Homogeneous appearance with minimal cystic change
Necrosis present in 60-70% cases
Hemorrhage due to rapid growth
Calcifications rare
Mucin production minimal compared to mucinous tumors.
Size Location:
Mean size 10-15 cm at presentation (range 5-20 cm)
Unilateral involvement more common (70-80% cases)
May involve both ovaries in advanced cases
Surface involvement common with capsular rupture
Omental involvement in 50-60% cases.
Multifocality:
Usually unifocal within affected ovary
Bilateral involvement in 20-30% cases (less than serous carcinoma)
Peritoneal seeding occurs but less extensive than high-grade serous
Nodal metastases in 40-50% cases
Distant metastases to liver, lung in advanced stages.
Microscopic Description
Histological Features:
Sheets of large polygonal cells with characteristic ground-glass cytoplasm
Eosinophilic, granular cytoplasm with glassy appearance
Distinct cell borders with minimal cohesion
Large vesicular nuclei with prominent nucleoli
High mitotic rate (>15 per 10 HPF)
Extensive necrosis and inflammatory infiltrate.
Cellular Characteristics:
Large polygonal cells (20-30 μm diameter) with abundant cytoplasm
Ground-glass, eosinophilic cytoplasm (hallmark feature)
Well-defined cell membranes
Large, vesicular nuclei with irregular contours
Prominent nucleoli (1-3 per nucleus)
Nuclear pleomorphism moderate to marked
Multinucleated giant cells occasionally present.
Architectural Patterns:
Solid sheets of glassy cells predominant pattern
Lack of glandular differentiation
Minimal cohesion between cells
Infiltrative growth pattern into stroma
Vascular invasion frequently present
Lymphatic invasion common
Perineural invasion may be seen.
Grading Criteria:
Universally high-grade (Grade 3) by definition
High mitotic rate (>15 mitoses per 10 HPF)
Marked nuclear atypia (score 3)
Absence of tubule formation (score 3)
Poor differentiation with loss of glandular architecture
Ki-67 proliferation index typically >60%.
Immunohistochemistry
Positive Markers:
CK7 (90-95% positive)
PAX8 (70-80% positive)
EMA (85-90% positive)
CEA (60-70% positive)
p53 (aberrant expression in 60-70%)
Ki-67 (high proliferation index >60%)
CK19 (80-85% positive).
Negative Markers:
CK20 (typically negative)
p16 (negative - unlike cervical glassy cell carcinoma)
HPV (negative by ISH)
WT1 (usually negative)
ER/PR (negative in most cases)
TTF-1 (negative)
CDX2 (negative).
Diagnostic Utility:
CK7/PAX8 combination supports ovarian origin
p16 negativity distinguishes from cervical glassy cell carcinoma
HPV negativity confirms non-viral etiology
CK20/CDX2 negativity excludes gastrointestinal primary
TTF-1 negativity excludes lung primary
Ki-67 >60% confirms high-grade nature.
Molecular Subtypes:
Non-HPV associated subtype (unlike cervical counterpart)
p53 altered in majority of cases
Microsatellite stable in most cases
No specific molecular signature identified
BRCA1/2 wild-type in most cases
Homologous recombination proficient pattern.
Molecular/Genetic
Genetic Mutations:
TP53 mutations (60-70% cases) - most common alteration
KRAS mutations (30-40% cases)
PIK3CA mutations (20-30% cases)
ARID1A mutations (15-25% cases)
PTEN loss (20% cases)
No BRCA1/2 mutations in most reported cases.
Molecular Markers:
p53 protein overexpression or complete loss (60-70%)
Ki-67 proliferation index >60% (high-grade)
CA-125 elevated in 80-85% cases
CEA may be elevated (40-50%)
p16 negative (distinguishes from cervical type)
HPV negative by molecular testing.
Prognostic Significance:
p53 mutations associated with aggressive behavior
High Ki-67 indicates poor prognosis
Advanced stage at presentation (70-80% Stage III-IV)
Poor overall survival (5-year survival <30%)
Platinum resistance develops rapidly
No targeted therapy options currently available.
Therapeutic Targets:
Limited targeted options due to rarity
Platinum-based chemotherapy (carboplatin/paclitaxel) first-line
PI3K/AKT pathway inhibitors under investigation
Anti-angiogenic agents (bevacizumab) may be considered
Immunotherapy limited efficacy due to microsatellite stability
Clinical trials recommended due to poor prognosis.
Differential Diagnosis
Similar Entities:
Cervical glassy cell carcinoma (metastatic to ovary)
Clear cell carcinoma (clear cytoplasm vs
glassy)
Endometrioid carcinoma (squamous differentiation)
Undifferentiated carcinoma (lacks glassy cytoplasm)
Metastatic adenocarcinoma (GI, lung primaries)
Large cell carcinoma (different cytoplasmic features).
Distinguishing Features:
Ovarian glassy cell: p16 negative
Ovarian glassy cell: HPV negative
Cervical glassy cell: p16 positive
Cervical glassy cell: HPV positive
Clear cell carcinoma: clear, glycogen-rich cytoplasm
Endometrioid: glandular differentiation
Metastatic GI: CK20/CDX2 positive.
Diagnostic Challenges:
Distinguishing from metastatic cervical glassy cell carcinoma requires HPV/p16 testing
Frozen section diagnosis challenging due to rare entity
Small biopsy specimens may not show classic glassy features
Extensive necrosis may obscure diagnostic morphology
Lack of experience due to extreme rarity.
Rare Variants:
Glassy cell carcinoma with clear cell features
Mixed glassy cell and endometrioid carcinoma
Glassy cell carcinoma with squamous differentiation
Glassy cell carcinoma with sarcomatoid features
Poorly differentiated adenocarcinoma with focal glassy cell areas.
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
[Unilateral/Bilateral] salpingo-oophorectomy specimen, [right/left] ovary measuring [X x Y x Z] cm, with attached fallopian tube
Gross Description
Solid, [unilateral/bilateral] ovarian mass with gray-white, glassy cut surface, areas of necrosis and hemorrhage, [intact/ruptured] capsule
Diagnosis
Ovarian glassy cell carcinoma
Histological Features
Sheets of large polygonal cells with characteristic ground-glass, eosinophilic cytoplasm, large vesicular nuclei, prominent nucleoli, high mitotic rate
Immunohistochemistry
CK7: Positive, PAX8: Positive, p16: Negative, HPV ISH: Negative, CEA: [Positive/Negative], Ki-67: >60%
Molecular Studies
HPV DNA: Negative (excludes cervical primary), p53: [Pattern], recommend clinical correlation to exclude cervical primary
Staging (FIGO 2014)
Stage [I/II/III/IV] - [detailed staging criteria based on extent of disease]
Prognostic Factors
High-grade morphology, glassy cell variant, [unilateral/bilateral] involvement, [stage], [residual disease status]
Comments
Extremely rare variant of ovarian adenocarcinoma. Clinical correlation recommended to exclude metastatic cervical glassy cell carcinoma. Consider multidisciplinary team discussion for management.
Final Diagnosis
[Unilateral/Bilateral] ovarian glassy cell carcinoma, FIGO Stage [X], Grade 3