Definition/General
Introduction:
Renal cell carcinoma (RCC) is the most common primary malignancy of the kidney in adults, representing 90-95% of renal malignancies
It encompasses several distinct histologic subtypes with different genetic alterations and prognoses.
Origin:
Arises from renal tubular epithelium
Different subtypes originate from different segments of nephron: clear cell from proximal tubule, papillary from distal tubule, chromophobe from collecting duct.
Classification:
WHO Classification includes clear cell RCC (75%), papillary RCC (10-15%), chromophobe RCC (5%), collecting duct carcinoma (<1%), and unclassified RCC (4-6%).
Epidemiology:
Peak incidence 50-70 years
Male predominance (2:1)
Higher incidence in Western countries
Associated with smoking, obesity, hypertension, and genetic syndromes (VHL, hereditary papillary RCC).
Clinical Features
Presentation:
Classic triad (hematuria, flank pain, palpable mass) in <10% of patients
Often asymptomatic and detected incidentally
Paraneoplastic syndromes in 30% (hypercalcemia, erythrocytosis, hypertension).
Symptoms:
Gross or microscopic hematuria (50-60%)
Flank pain (35-40%)
Weight loss
Fatigue
Fever
Bone pain (metastases)
Varicocele (left-sided tumors).
Risk Factors:
Smoking (strongest modifiable risk factor)
Obesity
Hypertension
Chronic kidney disease
Von Hippel-Lindau syndrome
Acquired cystic kidney disease
Occupational exposures.
Screening:
No routine screening for general population
CT/MRI for diagnosis and staging
Genetic counseling for familial syndromes
Surveillance for high-risk individuals.
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Gross Description
Appearance:
Well-circumscribed mass with pseudocapsule
Clear cell: Golden-yellow color due to lipid content
Papillary: Gray-white, often multifocal
Chromophobe: Tan-brown, well-demarcated.
Characteristics:
Size ranges from small (<4 cm) to large (>10 cm)
Areas of necrosis and hemorrhage common
Cystic changes possible
Extension beyond kidney in advanced cases.
Size Location:
Can arise anywhere in kidney
Upper and lower poles equally affected
May extend into renal vein (especially clear cell)
Multifocal disease in hereditary syndromes.
Multifocality:
Usually solitary
Multifocal in hereditary syndromes (VHL, hereditary papillary RCC)
Bilateral disease possible in genetic syndromes.
Microscopic Description
Histological Features:
Varies by subtype
Clear cell: Cells with clear cytoplasm, rich vasculature
Papillary: Papillary/tubulopapillary architecture
Chromophobe: Voluminous cytoplasm with perinuclear clearing.
Cellular Characteristics:
Clear cell: Large cells with optically clear cytoplasm, distinct cell borders
Papillary: Smaller cells with eosinophilic cytoplasm
Chromophobe: Large cells with plant-like cytoplasm.
Architectural Patterns:
Clear cell: Solid, alveolar, cystic patterns
Papillary: True papillae with fibrovascular cores
Chromophobe: Solid nests and sheets.
Grading Criteria:
ISUP/WHO 2016 grading: Grade 1-4 based on nucleolar prominence
Clear cell and papillary: nucleolar size
Chromophobe: difficult to grade, usually low-grade.
Immunohistochemistry
Positive Markers:
Clear cell: CA-IX positive (95%), CD10 positive
Papillary: CK7 positive, AMACR positive
Chromophobe: CK7 positive, CD117 positive
All types: PAX8 positive.
Negative Markers:
Clear cell: CK7 negative (usually), AMACR negative
Papillary: CA-IX negative
Chromophobe: CD10 negative, AMACR negative
All: TTF-1 negative.
Diagnostic Utility:
Panel approach useful for subtyping
PAX8 confirms renal origin
CA-IX distinguishes clear cell from other subtypes
CK7/CD117 pattern helpful for chromophobe.
Molecular Subtypes:
Clear cell: VHL pathway alterations
Papillary: Type 1 (MET mutations), Type 2 (CDKN2A loss)
Chromophobe: Mitochondrial DNA mutations.
Molecular/Genetic
Genetic Mutations:
Clear cell: VHL mutations (80%), PBRM1 (40%), SETD2 (15%), BAP1 (10%)
Papillary: MET mutations (Type 1), CDKN2A deletions (Type 2)
Chromophobe: Complex karyotype.
Molecular Markers:
Clear cell: 3p deletion (VHL locus)
Papillary: Trisomy 7, 17
Chromophobe: Loss of multiple chromosomes (1, 2, 6, 10, 13, 17, 21).
Prognostic Significance:
Clear cell: BAP1 loss worse prognosis
Papillary: Type 2 worse than Type 1
Chromophobe: Generally good prognosis
Stage most important factor.
Therapeutic Targets:
VEGF inhibitors (sunitinib, pazopanib)
mTOR inhibitors (everolimus)
Immune checkpoint inhibitors (nivolumab, pembrolizumab)
Combination therapies.
Differential Diagnosis
Similar Entities:
Oncocytoma
Angiomyolipoma
Metastatic clear cell carcinoma
Urothelial carcinoma
Adrenal cortical carcinoma
Metastatic adenocarcinoma.
Distinguishing Features:
RCC: PAX8+, renal location
Oncocytoma: CD117+, central scar
Angiomyolipoma: Melanoma markers+, fat component
Urothelial: GATA3+, CK20+.
Diagnostic Challenges:
Clear cell RCC vs metastatic clear cell carcinoma
Chromophobe RCC vs oncocytoma
Papillary RCC vs urothelial carcinoma with glandular features.
Rare Variants:
Collecting duct carcinoma
Renal medullary carcinoma
Mucinous tubular and spindle cell carcinoma
MiT family translocation carcinomas
Unclassified RCC.
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
Nephrectomy specimen, [kidney] kidney, measuring [size] cm
Tumor Size
Tumor measures [X] x [Y] x [Z] cm
Histologic Subtype
[Clear cell/Papillary Type 1/Papillary Type 2/Chromophobe] renal cell carcinoma
Histologic Grade
ISUP/WHO Grade [1/2/3/4]
Extent of Invasion
Tumor [confined to kidney/extends beyond kidney] (pT[X])
Margins
Surgical margins: [negative/positive], closest margin [distance] cm
Lymph Nodes
[X] of [Y] lymph nodes involved (pN[X])
Lymphovascular Invasion
Lymphovascular invasion: [Present/Absent]
Renal Vein Invasion
Renal vein invasion: [Present/Absent]
Background Kidney
Background kidney shows [normal/chronic changes/specific pathology]
Immunohistochemistry
[Markers performed and results if done for subtyping]
TNM Staging
pT[X]N[X]M[X], Stage [I/II/III/IV]
Final Diagnosis
Final diagnosis: [Subtype] renal cell carcinoma, ISUP Grade [X], pT[X]N[X]M[X], Stage [X]