Histologic Description of Clear Cell Renal Cell Carcinoma
Clear cell renal cell carcinoma (ccRCC) is characterized microscopically by tumor cells with clear cytoplasm due to accumulation of glycogen and lipids, arranged in nests or tubules surrounded by a rich vascular network. 1
Macroscopic Features
- The cut surface of ccRCC tumors appears golden yellow with frequent hemorrhagic, necrotic, and cystic areas. 1
Microscopic Characteristics
Cellular Morphology
The hallmark "clear" appearance of the cytoplasm results from intracellular accumulation of glycogen and lipids, which are dissolved during routine histological processing, leaving empty spaces that create the characteristic clear appearance. 1
Tumor cells are distributed in tubular and solid areas with a very prominent capillary stroma, reflecting the highly vascularized nature of these tumors. 1
A variable proportion of tumor cells with granular eosinophilic cytoplasm can be observed, and in some cases, these eosinophilic cells may constitute the entire tumor mass. 1
Architectural Patterns
Cells are arranged in nests or tubules surrounded by an extensive network of thin-walled blood vessels. 1
The multilocular cystic variant, composed entirely of numerous cysts lined by clear cells, represents a low-aggressivity variant of ccRCC. 1
Nuclear Grading
- The Fuhrman grading system is the most widely used, defining four nuclear grades (1-4) based on increasing nuclear size, irregularity, and nucleolar prominence, with demonstrated prognostic value. 1
Molecular and Genetic Features
ccRCC is associated with VHL gene mutations and chromosomal abnormalities at 3p25-26 in 34-56% of sporadic cases. 1
VHL inactivation leads to constitutive activation of hypoxia-inducible factors (HIFs), resulting in a pseudo-hypoxic phenotype that drives the metabolic reprogramming characteristic of these tumors. 2, 3
Important Diagnostic Considerations
Clear cells are not unique to ccRCC and can be observed in papillary RCC, chromophobe RCC, and MiT family translocation RCC, requiring careful evaluation of cytological features, growth pattern, immunophenotype, and genetic alterations for proper diagnosis. 1
Eosinophilic areas within ccRCC are associated with higher grade and more aggressive tumors, displaying higher proliferative drive, lower differentiation, and exclusive TP53 mutations. 2
Sarcomatoid differentiation can occur in any RCC type and is no longer considered a separate entity but rather represents tumor progression, with enrichment in TP53 and CDKN2A mutations. 1