Clear cell renal cell carcinoma is the most common type of renal cell carcinoma.
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Epidemiology
The average age of onset of sporadic clear cell renal carcinoma is 61 years. In cases associated with von Hippel-Lindau disease, the average age of onset is 37 years 1.
Clinical presentation
Patients with the clear cell subtype of renal cell carcinoma are more likely to present with symptomatic disease and metastatic disease than with other types of renal cell carcinoma 5.
Pathology
Clear cell renal cell carcinoma represents around 75-80% of cases of renal cell carcinoma and arises from the epithelium of the proximal tubule 1. Clear cell carcinoma is sporadic in over 95% of cases; in the 5% of familial cases, most are seen in von Hippel-Lindau disease 1.
Genetics
Common to both sporadic and familial forms is the loss of sequences on the short arm of chromosome 3 in 98% of tumors, usually by deletion or unbalanced translocation resulting in loss of 3p12 to 3p26. The second allele often shows somatic mutation or epigenetic inactivation through hypermethylation. Interestingly, this region contains the sequence for the von Hippel-Lindau (VHL) gene, which is a tumor suppressor gene that normally results in increased expression of proteins of the ubiquitin ligase complex 1. The ubiquitin ligase complex normally identifies and tags proteins for destruction. Of particular relevance to clear cell carcinoma is ubiquitin mediated degradation of hypoxia inducible factor 1 (HIF-1), which is a pro-angiogenic factor normally expressed in hypoxic environments. As such, the loss of the VHL allele results in increased levels of HIF-1 and the resulting increase in pro-angiogenic factors such as VEGF, PDGF, TGF-α and TGF-β, leading to cellular dysplasia and, ultimately, neoplasia.
Macroscopic appearance
Tumors have a yellowish, golden appearance on sectioning due to the high lipid content 5.
Microscopic appearance
Microscopically, the tumor is characterized by 2:
large cells with a uniform appearance
abundant clear cytoplasm rich in glycogen and lipid
high vascularity
Radiographic appearance
CT
Clear cell carcinoma, compared to other forms of renal cell carcinoma, is said to have 3,5:
an exophytic appearance
a greater degree of enhancement on the corticomedullary and nephrographic phases on multiphasic CT (compared to papillary cell carcinoma)
a more heterogeneous appearance (due to multiple areas of internal necrosis, cystic change or hemorrhage)
MRI
MRI offers similar accuracy to CT in detecting clear cell renal cell carcinoma 3.
T1: heterogeneous appearance (due to multiple areas of internal necrosis, cystic change or hemorrhage)
T2: hyperintense 4
in and out of phase: frequently contains microscopic fat resulting in focal or diffuse non-curvilinear signal loss in the opposed phase (in 60% 7); this must not be mistaken for macroscopic fat frequently found in angiomyolipomas 6
Treatment and prognosis
Clear cell renal carcinoma has a worse prognosis than papillary and chromophobe types but not as bad as rare and aggressive forms such as medullary and collecting duct renal cell carcinoma. The 5-year survival rate for patients with clear cell renal cell carcinoma is 50-70%, but it decreases to 10% when metastatic 9.
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