Clear Cell Renal Cell Carcinoma
Clear cell renal cell carcinoma is a morphologically heterogeneous group of malignant tumors made up of cells with clear or eosinophilic cytoplasm and characteristic vessel formation.
Clear cell renal cell carcinoma is the most common malignancy among renal cell neoplasms, representing roughly 70% of all renal cell tumors.
It occurs in patients around 60–70 years of age.
Its male/female ratio is 2:1.
There is no site predilection.
Partial or radical nephrectomy is the standard treatment in clinically localized diseases. In metastatic cases, targeted therapies against angiogenesis and mammalian target of rapamycin (mTOR) pathway are extensively used either in patients previously treated by nephrectomy or without cytoreductive nephrectomy. Immunotherapy has recently shown promising clinical response.
The behavior mainly depends on TNM, however, at the same stage, clear cell renal cell carcinoma appears to be more aggressive than papillary and chromophobe renal cell carcinoma. Clear cell renal cell carcinomas most commonly metastasizes hematogenously to the lung. Lymphatic metastases are less frequent and can occur in hilar, aortic, and caval lymph nodes. Unusual metastatic sites may be observed.
PAX-8 is a nuclear transcription factor expressed in virtually all clear cell renal cell carcinomas and therefore useful in metastasis and in particular differential diagnosis among primary tumors. Carbonic anhydrase IX (CAIX) stained 75–100% of clear cell renal cell carcinomas as a membranous box-shaped distribution. Cytokeratin 7 is usually negative, and if present, it is almost limited to the cystic areas. Clear cell renal cell carcinoma also expresses other epithelial markers. CD10, a proximal tubule marker, is positive in clear cell renal cell carcinoma in a membranous distribution. Vimentin is positive in clear cell renal cell carcinoma, more intensely in high grade areas.
Clear cell renal cell carcinoma shows a highly specific deletion of chromosome 3p, which is considered one of the primary events in the development of this tumor. Mutation of the Von Hippel-Lindau (VHL) gene (3p25) occurs exclusively in this type of renal tumor, both in sporadic and hereditary forms. Genomic sequencing studies have demonstrated that the 3p locus harbors additional suppressor genes, such as SETD2, PBRM1, and BAP1.
Chromosome 14q allelic loss and loss of 9p have been associated with poor prognosis in clear cell renal cell carcinoma.
Several differential diagnoses should be considered. Among the low nucleolar grade tumors, the main differential diagnosis is with clear cell papillary renal cell carcinoma, in which different immunohistochemical expression of CAIX (box-shaped versus cup-shaped) and CK7 (negative versus positive) is useful. CK7 is often used to distinguish clear cell renal cell carcinomas from the chromophobe renal cell carcinomas almost made up of cells with flocculent clear cell cytoplasm, the latter demonstrating diffuse staining for CK7. Among the high nucleolar grade tumors, the main differential diagnosis are with MiT family translocation renal cell carcinomas and epithelioid angiomyolipoma/epithelioid PEComa, in which cathepsin K and melanogenic immunohistochemical markers are diagnostic.
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