Definition/General
Introduction:
Fallopian tube clear cell carcinoma is a rare primary malignancy accounting for 5-10% of all fallopian tube carcinomas
It is characterized by clear cells with hobnail morphology and tubulocystic architecture
The tumor shows aggressive biological behavior similar to ovarian clear cell carcinoma
It has distinct molecular features including frequent ARID1A mutations and is typically resistant to conventional chemotherapy.
Origin:
Originates from the epithelial lining of the fallopian tube with clear cell differentiation
May arise from tubal endometriosis or areas of clear cell metaplasia
The tumor shows glycogen accumulation in clear cells
ARID1A mutations are frequent and lead to loss of chromatin remodeling function
Most commonly affects the ampullary and isthmic portions of the fallopian tube
Associated with endometriosis in some cases.
Classification:
WHO classification recognizes clear cell adenocarcinoma as a distinct histological subtype
Architectural patterns include tubulocystic, solid, and papillary
Grade is typically considered high due to clear cell morphology
FIGO staging follows the same system as ovarian carcinoma
Molecular classification based on ARID1A status and PIK3CA mutations
No established grading system as most are considered high-grade.
Epidemiology:
Peak incidence in 6th-7th decades (median age 60-65 years)
Less association with BRCA mutations compared to serous carcinoma
Association with endometriosis in 20-30% of cases
Resistance to platinum-based chemotherapy
Worse prognosis compared to endometrioid carcinoma but similar to high-grade serous
More common in Asian populations compared to Western populations.
Clinical Features
Presentation:
Pelvic pain (50-60% of cases) due to tubal distension
Abnormal vaginal bleeding (postmenopausal or irregular)
Palpable adnexal mass (40-50% of cases)
Abdominal distension and bloating
Ascites in advanced cases
Constitutional symptoms (weight loss, fatigue)
Thrombembolic events may occur due to tumor-associated hypercoagulability.
Symptoms:
Postmenopausal bleeding or menstrual irregularities
Pelvic pressure and discomfort
Abdominal pain and cramping
Early satiety due to mass effect
Urinary frequency from pelvic mass
Bowel symptoms (constipation, bloating)
Hypercalcemia may occur (paraneoplastic syndrome)
Thrombosis due to hypercoagulable state.
Risk Factors:
Endometriosis (20-30% of cases have associated endometriosis)
Nulliparity and infertility
Late menopause and early menarche
Asian ethnicity (higher incidence)
Family history of ovarian cancer (weaker association than serous)
Personal history of breast cancer
Hormone replacement therapy (controversial association).
Screening:
No specific screening guidelines due to rarity
Annual pelvic examination for high-risk women
Transvaginal ultrasound may detect masses
CA-125 may be elevated but not specific
Genetic counseling for patients with strong family history
Endometriosis surveillance in women with known endometriosis.
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Gross Description
Appearance:
Solid and cystic masses with smooth, lobulated surface
Tan to gray-white cut surface with clear, watery fluid in cystic areas
Firm consistency in solid areas
Hemorrhage and necrosis may be present
Calcifications are uncommon
Well-demarcated borders in some cases
Extension through tubal wall in advanced cases.
Characteristics:
Multinodular appearance with solid and cystic components
Clear fluid exuding from cystic spaces
Smooth, glistening cut surface in areas with clear cells
Firm, fleshy consistency in solid areas
Minimal surface ulceration compared to serous carcinoma
Yellow areas corresponding to lipid-rich clear cells.
Size Location:
Size ranges from small nodules to large masses (up to 20 cm)
Ampullary portion most commonly affected (60-70%)
Isthmic involvement more common than in serous carcinoma
Unilateral involvement in majority of cases
Bilateral disease in 15-25% of cases
Associated endometriotic cysts may be present.
Multifocality:
Multifocal disease less common than serous carcinoma (10-20%)
Associated endometriosis may be present in tube or ovary
Synchronous ovarian clear cell carcinoma in some cases
Concurrent endometrial carcinoma occasionally present
Atypical endometriosis may be found adjacent to tumor.
Microscopic Description
Histological Features:
Clear cells with abundant clear, glycogen-rich cytoplasm and distinct cell membranes
Hobnail cells with enlarged nuclei protruding into glandular lumens
Tubulocystic architecture with round to oval glands and cysts
Solid areas with sheets of clear cells
Papillary pattern with fibrovascular cores
Hyalinized stroma with minimal inflammatory infiltrate.
Cellular Characteristics:
Large polygonal cells with voluminous clear cytoplasm
Distinct cell membranes creating honeycomb appearance
Enlarged nuclei with irregular contours and prominent nucleoli
Hobnail morphology with nuclei protruding into luminal spaces
Eosinophilic cells admixed with clear cells
Multinucleated giant cells may be present.
Architectural Patterns:
Tubulocystic pattern (most common) with round glands and cystic spaces
Solid pattern with sheets and nests of clear cells
Papillary pattern with complex branching and fibrovascular cores
Mixed patterns commonly present in same tumor
Single cell infiltration into stroma
Oxyphilic variant with eosinophilic rather than clear cytoplasm.
Grading Criteria:
Clear cell carcinoma is typically considered high-grade by definition
Nuclear grade assessment based on nuclear size, pleomorphism, and nucleolar prominence
Architectural complexity with loss of glandular organization
Mitotic activity usually moderate to high
Necrosis indicates aggressive behavior
Solid growth pattern associated with worse prognosis.
Immunohistochemistry
Positive Markers:
PAX8 (nuclear, positive in >90% of cases)
Napsin A (cytoplasmic, positive in 80-90% of clear cell carcinomas)
CK7 (cytoplasmic, diffusely positive)
CA125 (cytoplasmic/luminal, positive)
HNF1β (nuclear, highly characteristic of clear cell carcinomas)
EMA (cytoplasmic/luminal, positive)
p53 (wild-type pattern in most cases)
ER (nuclear, negative to weakly positive).
Negative Markers:
WT1 (negative, helps distinguish from serous carcinoma)
CK20 (negative, excludes gastrointestinal origin)
TTF-1 (negative, excludes lung metastasis)
CDX2 (negative, excludes intestinal differentiation)
PR (usually negative)
p40/p63 (negative, excludes squamous differentiation)
RCC marker (negative, helps exclude renal cell carcinoma metastasis).
Diagnostic Utility:
Napsin A positivity is highly characteristic of clear cell carcinoma
HNF1β expression is specific for clear cell differentiation
PAX8 positivity supports müllerian origin
WT1 negativity helps exclude serous carcinoma
ARID1A loss by immunohistochemistry correlates with mutations
p53 wild-type pattern distinguishes from high-grade serous carcinoma.
Molecular Subtypes:
ARID1A-deficient subtype (loss of ARID1A expression, 50-70% of cases)
PIK3CA-mutated subtype (PI3K pathway activation)
PTEN-deficient subtype (loss of PTEN expression)
Endometriosis-associated subtype (arising from endometriotic cysts)
De novo subtype (without associated endometriosis)
Hepatocyte nuclear factor-1β positive subtype (HNF1β overexpression).
Molecular/Genetic
Genetic Mutations:
ARID1A mutations (50-70% of cases, chromatin remodeling gene)
PIK3CA mutations (40-50% of cases, PI3K pathway activation)
PTEN mutations (20-30% of cases, tumor suppressor loss)
KRAS mutations (15-25% of cases)
TP53 mutations (rare, <10% of clear cell carcinomas)
PPP2R1A mutations (specific to clear cell carcinomas, 5-10%)
TERT promoter mutations (subset of cases).
Molecular Markers:
ARID1A loss by immunohistochemistry (correlates with mutations)
PI3K pathway activation (pAKT, pmTOR expression)
HNF1β overexpression (transcription factor characteristic of clear cell)
p53 wild-type pattern (unlike high-grade serous carcinoma)
PTEN loss (correlates with mutations)
High Ki-67 index in aggressive tumors
PD-L1 expression (variable, potential immunotherapy target).
Prognostic Significance:
Stage at diagnosis is most important prognostic factor
ARID1A status may predict response to certain therapies
PIK3CA mutations associated with better prognosis in some studies
Solid growth pattern associated with worse outcomes
Age at diagnosis influences survival
Residual disease after surgery is crucial prognostic factor
Chemotherapy resistance associated with poor outcomes.
Therapeutic Targets:
PI3K/AKT/mTOR pathway (mTOR inhibitors, PI3K inhibitors for PIK3CA-mutated tumors)
ARID1A deficiency (synthetic lethality with EZH2 inhibitors)
DNA damage response (PARP inhibitors in homologous recombination deficient tumors)
Anti-angiogenic agents (bevacizumab)
Immunotherapy (PD-1/PD-L1 inhibitors for select cases)
HNF1β-dependent pathways (novel therapeutic targets under investigation).
Differential Diagnosis
Similar Entities:
Metastatic renal cell carcinoma (clear cell morphology)
Primary ovarian clear cell carcinoma
Yolk sac tumor (clear cell areas)
Secretory carcinoma (clear cell features)
Metastatic clear cell carcinoma from other sites
Glycogen-rich carcinoma (other subtypes with clear cell change)
Decidualized stromal cells (pregnancy-related changes).
Distinguishing Features:
Tubal vs renal clear cell: PAX8+/Napsin A+ vs RCC marker+/CD10+
Primary tubal vs ovarian: Tubal mucosal origin, normal ovaries, clinical presentation
Clear cell vs yolk sac tumor: Age (adult vs pediatric), AFP negative vs positive
Clear cell vs secretory: HNF1β positive vs negative, different morphology
Primary vs metastatic: Clinical correlation and immunohistochemistry panel.
Diagnostic Challenges:
Determining primary site when both tube and ovary involved
Small biopsy interpretation may be limited by sampling
Distinguishing from renal cell carcinoma metastasis requires careful immunohistochemistry
Mixed histological patterns within tumor
Association with endometriosis may complicate interpretation
Rare occurrence may lead to unfamiliarity.
Rare Variants:
Oxyphilic variant (eosinophilic rather than clear cytoplasm)
Signet ring variant (signet ring cell morphology)
Adenofibroma with clear cell carcinoma (malignant transformation in adenofibroma)
Mixed clear cell and endometrioid carcinoma
Clear cell carcinoma with neuroendocrine differentiation
Adenosquamous carcinoma with clear cell features.
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, fallopian tube measuring [size] cm
Diagnosis
Clear cell adenocarcinoma of fallopian tube
Classification
Clear cell adenocarcinoma with [predominant architectural pattern]
Histological Features
Shows clear cells with hobnail morphology, [tubulocystic/solid/papillary] architecture
Associated Findings
Endometriosis: [present/absent], Location: [specify if present]
Invasion and Extent
Size: [X] cm, Invasion: [through tubal wall], Serosal involvement: [present/absent]
Lymphovascular Invasion
Lymphovascular invasion: [present/absent]
Special Studies
Napsin A: positive, HNF1β: positive, PAX8: positive
WT1: negative, ER: [negative/weakly positive]
ARID1A: [retained/lost]
Molecular Features
p53: wild-type pattern, ARID1A status: [retained/lost expression]
FIGO Staging
FIGO Stage: [IA/IB/IC/II/III/IV] - [staging description]
Prognostic Factors
Clear cell histology (chemotherapy resistant), Stage: [I/II/III/IV], ARID1A: [retained/lost]
Final Diagnosis
Primary fallopian tube clear cell adenocarcinoma, FIGO Stage [IA/IB/IC/II/III/IV]