Definition/General
Introduction:
Clear cell renal cell carcinoma (ccRCC) represents the most common primary renal malignancy
It constitutes 75-80% of all renal cell carcinomas
It arises from the proximal tubular epithelium
Fine needle aspiration cytology (FNAC) provides valuable diagnostic information.
Origin:
Originates from the epithelial cells of the proximal convoluted tubules
The tumor cells demonstrate clear cytoplasm due to abundant glycogen and lipids
The neoplastic transformation involves VHL gene inactivation
It results in loss of hypoxia-inducible factor regulation.
Classification:
Classified according to WHO 2016 classification of renal tumors
FNAC findings help distinguish from other RCC subtypes
Fuhrman grading system is used for nuclear grading
Grade 1 (well-differentiated)
Grade 2 (moderately differentiated)
Grade 3-4 (poorly differentiated).
Epidemiology:
Peak incidence in 6th-7th decades
Male to female ratio is 2:1
Associated with Von Hippel-Lindau syndrome
Risk factors include smoking
Obesity
Hypertension
Chronic kidney disease
Industrial exposure to chemicals
Indian population shows increasing incidence with urbanization.
Clinical Features
Presentation:
Abdominal mass (most common presentation)
Flank pain (40%)
Hematuria (60%)
Classical triad (mass, pain, hematuria) in only 10% cases
Weight loss
Fever
Fatigue
Paraneoplastic syndromes (hypercalcemia, polycythemia).
Symptoms:
Hematuria (gross or microscopic)
Flank pain (dull, aching)
Constitutional symptoms (fever, weight loss, night sweats)
Paraneoplastic symptoms (hypercalcemia, hypertension, polycythemia)
Varicocele (left-sided)
Lower extremity edema
Bone pain (metastatic disease).
Risk Factors:
Smoking (2-fold increased risk)
Von Hippel-Lindau syndrome
Chronic kidney disease
Long-term dialysis
Acquired cystic kidney disease
Tuberous sclerosis
Family history
Chemical exposure (cadmium, organic solvents)
Obesity
Hypertension.
Screening:
High-risk individuals screening with imaging
VHL syndrome patients: annual screening
Acquired cystic kidney disease: periodic imaging
CT or MRI for suspicious masses
Ultrasound for initial evaluation.
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Gross Description
Appearance:
Well-circumscribed mass with golden-yellow cut surface
Areas of hemorrhage and necrosis common
Cystic changes may be present
Size ranges from 2-20 cm
Capsule may be present but often incomplete.
Characteristics:
Golden-yellow to orange cut surface due to lipid content
Areas of necrosis appear gray-white
Hemorrhagic areas appear dark red
Cystic degeneration in larger tumors
Clear demarcation from normal kidney parenchyma.
Size Location:
Variable size (1-30 cm, average 6-7 cm)
Can occur in any part of kidney
Upper pole slightly more common
May extend into renal vein or IVC
Bilateral involvement in 2-4% cases
Multifocal tumors possible.
Microscopic Description
Immunohistochemistry
Positive Markers:
RCC marker (CD10, Vimentin)
PAX8 (renal origin)
Carbonic anhydrase IX (CA IX) strongly positive
EMA (epithelial membrane antigen)
Kidney-specific cadherin (Ksp-cadherin)
CD117 (c-kit)
AMACR (focally positive).
Negative Markers:
CK7 (usually negative)
CK20 (negative)
p63 (negative)
TTF-1 (negative)
PSA (negative)
Chromogranin (negative)
Synaptophysin (negative)
These markers help exclude other primary sites.
Diagnostic Utility:
Essential for confirming renal origin
PAX8 positive supports renal primary
CA IX strong positivity characteristic of ccRCC
Helps distinguish from other RCC subtypes
Useful in metastatic workup
VHL protein loss in most cases.
Molecular/Genetic
Genetic Mutations:
VHL gene inactivation (90% cases)
3p chromosome loss (98% cases)
PBRM1 mutations (40%)
SETD2 mutations (15%)
BAP1 mutations (15%)
KDM5C mutations (7%)
PIK3CA mutations (5%).
Prognostic Significance:
BAP1 loss indicates poor prognosis
PBRM1 mutations associate with better immunotherapy response
High-grade nuclear features predict aggressive behavior
Sarcomatoid differentiation indicates poor outcome
Tumor size and stage remain important prognostic factors.
Therapeutic Targets:
VEGF pathway inhibitors (sunitinib, pazopanib, axitinib)
mTOR inhibitors (temsirolimus, everolimus)
Immune checkpoint inhibitors (nivolumab, pembrolizumab)
HIF-2α inhibitors (belzutifan)
Combination therapies increasingly used.
Differential Diagnosis
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
FNAC from [kidney mass/renal lesion], [location], performed under [guidance method]
Specimen Adequacy
[Adequate/Inadequate] for cytological interpretation
Cytological Findings
Cellular smears showing [cellularity] with [architectural pattern]. Cells show [cytoplasmic features] and [nuclear characteristics]
Background
Background shows [hemorrhage/necrosis/inflammatory elements]
Cytological Diagnosis
[Diagnostic category] - [specific diagnosis if possible]
Nuclear Grade
Nuclear grade: [Fuhrman grade] (if assessable)
Recommendations
[Histopathological correlation/Immunocytochemistry/Clinical correlation] recommended
Note
Final diagnosis requires histopathological correlation and clinical-radiological findings