Definition/General
Introduction:
Renal Cell Carcinoma (RCC) is the most common kidney malignancy in adults (85-90%)
FNAC shows malignant epithelial cells with clear or eosinophilic cytoplasm
It demonstrates nuclear pleomorphism with prominent nucleoli
Subtypes include clear cell, papillary, and chromophobe RCC.
Origin:
Arises from renal tubular epithelium
Most commonly from proximal tubular cells
Results from genetic alterations affecting cell growth pathways
VHL gene inactivation in clear cell type
Hereditary syndromes account for 5-8% cases.
Classification:
WHO classification: Clear cell RCC (75-80%)
Papillary RCC (10-15%): Type 1 and Type 2
Chromophobe RCC (5%)
Collecting duct carcinoma (<1%)
Unclassified RCC (4-6%)
Translocation-associated RCC (rare)
Fuhrman nuclear grading (1-4).
Epidemiology:
Peak incidence in 6th-7th decades
Male predominance (M:F = 2:1)
Most common urologic cancer after prostate and bladder
Incidental detection increasing (50-60% cases)
Risk factors: smoking, obesity, hypertension
Hereditary RCC: younger age, bilateral, multifocal.
Clinical Features
Presentation:
Classical triad (flank pain, hematuria, palpable mass) in <10% cases
Incidental detection most common (50-60%)
Gross hematuria (40-50% cases)
Flank pain (40% cases)
Palpable mass (25% cases)
Paraneoplastic syndromes (20% cases).
Symptoms:
Hematuria (gross or microscopic)
Flank or abdominal pain
Weight loss and fatigue
Fever (paraneoplastic)
Hypertension (renin secretion)
Varicocele (left-sided, vena cava involvement)
Bone pain (metastatic disease).
Risk Factors:
Cigarette smoking (strongest modifiable risk)
Obesity (BMI >30)
Hypertension and antihypertensive medications
Chronic kidney disease
Occupational exposure (asbestos, cadmium)
Hereditary syndromes: VHL, hereditary papillary RCC
End-stage renal disease.
Screening:
No routine screening for general population
High-risk patients: hereditary syndromes
Imaging: ultrasound, CT, MRI
Contrast-enhanced CT gold standard
MRI for indeterminate lesions
PET-CT for staging
Tumor markers: none specific for RCC.
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Gross Description
Appearance:
FNAC yields cellular aspirate with epithelial clusters
Clear cytoplasm (clear cell type) or eosinophilic cytoplasm (papillary/chromophobe)
Nuclear pleomorphism with prominent nucleoli
Hemorrhagic background common
May show necrotic debris.
Characteristics:
Moderate to highly cellular aspirate
Cohesive cell clusters and single cells
Abundant cytoplasm (clear, eosinophilic, or granular)
Eccentric nuclei with irregular contours
Prominent nucleoli (grade-dependent)
Mitotic figures variable.
Size Location:
Variable size: 2-20 cm diameter
Any location within kidney
Upper pole slightly more common
Unilateral in sporadic cases
Bilateral in hereditary cases
Multifocal in 5-10% cases.
Multifocality:
Unifocal in 90% sporadic cases
Multifocal/bilateral in hereditary syndromes
Contralateral involvement (5% synchronous, 2% metachronous)
Satellite nodules around main tumor
Extracapsular extension in advanced cases.
Microscopic Description
Histological Features:
Malignant epithelial cells in clusters and sheets
Nuclear enlargement with pleomorphism
Prominent nucleoli (eosinophilic)
Abundant cytoplasm (clear, eosinophilic, or granular)
Cell borders distinct
Mitotic activity correlates with grade.
Cellular Characteristics:
Large polygonal cells with abundant cytoplasm
Clear cytoplasm (glycogen/lipid-rich) in clear cell type
Eosinophilic cytoplasm (mitochondria-rich) in oncocytic types
Nuclear enlargement with irregular contours
Nucleoli: small (grade 1) to prominent (grade 4)
Binucleated cells common.
Architectural Patterns:
Solid pattern (sheets and clusters)
Acinar pattern (glandular structures)
Papillary pattern (papillary RCC)
Trabecular pattern (cords of cells)
Cystic pattern (cystic RCC)
Sarcomatoid pattern (high-grade transformation).
Grading Criteria:
Fuhrman nuclear grading (most widely used)
Grade 1: small nuclei, inconspicuous nucleoli
Grade 2: larger nuclei, visible nucleoli at 400x
Grade 3: prominent nucleoli at 100x
Grade 4: bizarre nuclei, prominent nucleoli
WHO/ISUP grading (newer system).
Immunohistochemistry
Positive Markers:
RCC marker (CD10, positive in 85%)
Vimentin (positive, unlike most carcinomas)
PAX8 (renal lineage marker)
Carbonic anhydrase IX (clear cell RCC, 95%)
CD117 (chromophobe RCC)
CK7 (papillary RCC, chromophobe RCC).
Negative Markers:
CK20 (negative, excludes urothelial)
PSA (negative, excludes prostate)
TTF-1 (negative, excludes lung)
CDX2 (negative, excludes GI)
WT-1 (negative, excludes Wilms tumor)
Inhibin (negative, excludes adrenal).
Diagnostic Utility:
Essential for confirming renal origin
CD10+/Vimentin+ pattern characteristic
PAX8 confirms renal lineage
Subtype determination: CAIX (clear cell), CK7 (papillary/chromophobe), CD117 (chromophobe)
Excludes metastases from other sites.
Molecular Subtypes:
Clear cell RCC: VHL mutations (80%)
Papillary RCC: MET mutations (Type 1), CDKN2A loss (Type 2)
Chromophobe RCC: multiple chromosome losses
Collecting duct: TP53 mutations
Translocation RCC: specific fusions.
Molecular/Genetic
Genetic Mutations:
VHL mutations (clear cell RCC, 80%)
PBRM1 mutations (clear cell, 40%)
SETD2 mutations (clear cell, 15%)
MET mutations (papillary Type 1)
CDKN2A loss (papillary Type 2)
TP53 mutations (collecting duct, sarcomatoid).
Molecular Markers:
HIF pathway activation (VHL loss)
mTOR pathway (TSC1/TSC2)
PI3K/AKT pathway
Chromatin remodeling (PBRM1, SETD2)
DNA repair defects
Angiogenesis factors: VEGF overexpression.
Prognostic Significance:
Nuclear grade most important prognostic factor
Stage (TNM classification)
Histologic subtype: clear cell (intermediate), papillary Type 1 (good), Type 2 (poor), chromophobe (good), collecting duct (poor)
Sarcomatoid features (poor prognosis)
Molecular markers: PBRM1 loss (better immunotherapy response).
Therapeutic Targets:
VEGF inhibitors (sunitinib, pazopanib, axitinib)
mTOR inhibitors (temsirolimus, everolimus)
Immunotherapy (nivolumab, ipilimumab, pembrolizumab)
Tyrosine kinase inhibitors
HIF-2α inhibitors (belzutifan)
Combination therapies.
Differential Diagnosis
Similar Entities:
Oncocytoma (benign renal tumor)
Urothelial carcinoma (renal pelvis)
Metastatic carcinoma (lung, breast, colon)
Adrenal cortical carcinoma
Angiomyolipoma (epithelioid variant)
Chromophobe RCC vs oncocytoma.
Distinguishing Features:
RCC: CD10+, vimentin+, PAX8+
Oncocytoma: CD117 weak, CK7 negative, benign cytology
Urothelial carcinoma: CK20+, uroplakin+
Metastases: site-specific markers positive
Adrenal: inhibin+, melan-A+
AML: melanoma markers+.
Diagnostic Challenges:
Distinguishing chromophobe RCC from oncocytoma
Well-differentiated RCC from benign tubules
Cystic RCC from benign cysts
Metastatic clear cell tumors from primary RCC
Sarcomatoid RCC from primary sarcoma
Small biopsy interpretation challenges.
Rare Variants:
Sarcomatoid RCC (any subtype, 5%)
Rhabdoid RCC
Clear cell tubulopapillary RCC
Acquired cystic disease RCC
Multilocular cystic RCC
Mucinous tubular and spindle cell carcinoma
Translocation carcinomas.
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.
Clinical Information
Patient with [clinical presentation], imaging shows [renal mass characteristics]
Specimen Adequacy
Adequate for evaluation with [cellularity description]
Cytomorphological Features
Shows [epithelial cells] with [cytoplasm type] and [nuclear features]
Nuclear Grading
Nuclear grade: [1-4] based on [nucleolar prominence, pleomorphism]
Immunocytochemistry
Renal markers (CD10, PAX8): [positive/negative]
Subtype markers: [results]
Exclusion markers: [negative results]
Differential Diagnosis
Differential includes [oncocytoma, metastases, other renal tumors]
Final Cytological Diagnosis
Malignant: Renal Cell Carcinoma, [subtype if determinable], [grade]
Recommendations
Recommend [surgical consultation, staging studies, histopathological confirmation]