Definition/General
Introduction:
Ovarian clear cell carcinoma is an aggressive epithelial tumor characterized by clear cells
It accounts for 5-10% of all ovarian cancers
It arises from ovarian endometriosis in 60-70% of cases
It demonstrates distinctive histological patterns and molecular features.
Origin:
Originates from ovarian endometriosis in majority of cases
May arise from ovarian surface epithelium with clear cell differentiation
The neoplastic transformation involves PIK3CA and ARID1A mutations
It progresses through atypical endometriosis-carcinoma sequence
Strong association with endometriosis.
Classification:
Classified as Type I ovarian carcinoma (low-grade, stable genome)
Binary grading (low-grade vs high-grade) preferred over traditional grading
Associated with endometriosis and endometrioid carcinoma
Distinctive molecular profile compared to serous carcinoma.
Epidemiology:
Peak incidence in 5th-6th decades
Higher incidence in Asian populations (10-15% vs 5% in Western)
Strong association with endometriosis (60-70%)
Poorest prognosis among epithelial ovarian cancers
Chemotherapy-resistant characteristics.
Clinical Features
Presentation:
Pelvic mass (most common)
Abdominal pain (chronic or acute)
History of endometriosis in 60-70%
CA-125 elevation variable (less than serous)
Hypercalcemia (paraneoplastic, 10-15%).
Symptoms:
Pelvic or abdominal pain (70% cases)
Hypercalcemia symptoms (confusion, fatigue, kidney stones)
Thromboembolism (increased risk)
Abdominal distension
Urinary symptoms (mass effect).
Risk Factors:
Endometriosis (strongest risk factor, 60-70% association)
Asian ethnicity
Age 40-60 years
Nulliparity
Lynch syndrome (rare association)
Unopposed estrogen exposure.
Screening:
No specific screening available
CA-125 less reliable than in serous carcinoma
CA 19-9 may be elevated
Imaging shows complex solid-cystic mass
Hypercalcemia workup may reveal tumor.
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Gross Description
Appearance:
Solid and cystic mass with smooth external surface
Yellow-tan cut surface with cystic areas
Chocolate-colored cysts (endometriotic component)
Soft to firm consistency
Necrosis common.
Characteristics:
Yellow to tan solid areas (lipid-rich clear cells)
Cystic components with hemorrhagic fluid
Smooth, lobulated contours
Calcifications uncommon
Associated endometriotic cysts.
Size Location:
Variable size (5-25 cm, average 12 cm)
Unilateral in 80-85% cases
Right ovary more commonly affected
Bilateral involvement in 15-20%
Large size at presentation common.
Multifocality:
Usually confined to ovary at presentation
Synchronous endometrioid carcinoma possible
Peritoneal implants less common than serous
Deep infiltrating endometriosis may be present.
Microscopic Description
Histological Features:
Clear cells with abundant glycogen-rich cytoplasm
Hobnail pattern (cells protruding into lumina)
Tubular and papillary architecture
Hyalinized stroma
Psammoma bodies uncommon.
Cellular Characteristics:
Large cells with clear cytoplasm (glycogen-rich)
Hobnail cells with protruding nuclei
Prominent nucleoli
Moderate nuclear pleomorphism
Mitotic activity variable.
Architectural Patterns:
Tubulocystic pattern (most common)
Papillary pattern
Solid pattern
Hobnail pattern
Mixed patterns common
Hyalinized fibrous stroma.
Grading Criteria:
Binary grading system preferred: Low-grade (bland cytology, low mitotic rate)
High-grade (marked atypia, high mitotic rate)
Traditional grading less reproducible
Architectural pattern less important than cytology.
Immunohistochemistry
Positive Markers:
HNF1β (90-95%, highly specific)
Napsin A (90%)
PAX8 (85-90%)
CK7 (100%)
CA-125 (variable)
EMA (positive)
Hepatocyte nuclear factor 1β.
Negative Markers:
WT1 (negative)
p53 (wild-type pattern)
ER/PR (negative or weak)
CK20 (negative)
CDX2 (negative)
Inhibin (negative).
Diagnostic Utility:
HNF1β positivity highly specific for clear cell carcinoma
Napsin A supports clear cell differentiation
WT1 negativity helps distinguish from serous carcinoma
p53 wild-type pattern typical
Hormone receptor negativity distinguishes from endometrioid.
Molecular Subtypes:
PIK3CA-mutated (majority)
ARID1A-mutated (endometriosis-associated)
PTEN-mutated subtype
MET-amplified subtype.
Molecular/Genetic
Genetic Mutations:
PIK3CA mutations (50-60%)
ARID1A mutations (50%)
PTEN mutations (20%)
KRAS mutations (10%)
TP53 mutations (rare, <5%)
MET amplification (10-15%).
Molecular Markers:
PIK3CA overexpression
ARID1A loss of expression
PTEN loss
p53 wild-type pattern
HNF1β overexpression
mTOR pathway activation.
Prognostic Significance:
Stage at presentation most important
PIK3CA mutations may indicate PI3K pathway dependence
ARID1A loss associated with endometriosis
Chemotherapy resistance characteristic
Poor response to platinum.
Therapeutic Targets:
PI3K/mTOR inhibitors (PIK3CA mutations)
Anti-angiogenic agents
Immune checkpoint inhibitors (limited efficacy)
MET inhibitors (MET-amplified cases)
Hyperthermia combination therapy.
Differential Diagnosis
Similar Entities:
Endometrioid carcinoma with clear cells
Serous carcinoma with clear cells
Metastatic renal cell carcinoma
Yolk sac tumor (young patients)
Steroid cell tumor.
Distinguishing Features:
Clear cell: HNF1β+, napsin A+, WT1-
Endometrioid: ER/PR+, squamous elements
Serous: WT1+, p53 mutated
Renal: CD10+, RCC marker+
Yolk sac: AFP+, young age
Steroid cell: inhibin+, calretinin+.
Diagnostic Challenges:
Distinguishing from endometrioid with clear cell change
Identifying associated endometriosis
Mixed tumors with multiple patterns
Metastases vs primary
Frozen section limitations.
Rare Variants:
Clear cell carcinoma with spindle cells
Clear cell carcinoma with oxyphilic features
Clear cell adenofibroma with malignant transformation.
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
[laterality] salpingo-oophorectomy, measuring [size] cm
Diagnosis
Clear cell carcinoma with [tubulocystic/papillary/solid] pattern
Classification and Grade
Clear cell carcinoma, [low-grade/high-grade]
Histological Features
Shows clear cells with hobnail pattern and tubulocystic architecture
Size and Extent
Tumor size: [X] cm, [unilateral/bilateral], FIGO Stage: [stage]
Lymphovascular Invasion
Lymphovascular invasion: [present/absent]
Lymph Node Status
Pelvic lymph nodes: [X] negative out of [X] examined
Special Studies
IHC: HNF1β (+), Napsin A (+), PAX8 (+), WT1 (-), p53 (wild-type pattern)
Molecular: PIK3CA/ARID1A testing [result] if performed
Endometriosis: [present/absent]; Hypercalcemia: [present/absent]
Prognostic Factors
Grade: [low/high]; Stage: [FIGO stage]; Associated endometriosis: [present/absent]
Final Diagnosis
Ovarian clear cell carcinoma, [low/high-grade], Stage [X], arising in association with endometriosis