Percutaneous biopsy of renal masses appears to be safe and it carries minimal risk of tumor spread. Urologists should consider increasing the indications for renal biopsy of small renal masses that appear to be renal cell carcinoma, especially in elderly and unfit patients. With more experience and followup preoperative biopsy has the potential to decrease unnecessary treatment since up to a third of small renal masses are now reported to be benign at surgery. Percutaneous biopsy may also allow a better selection of renal tumors for active surveillance and minimally invasive ablative therapies. Finally, there is potential for stratifying initial therapy for metastatic renal cell carcinoma by histological subtype and in the future molecular characteristics.

Individuals who inherit one faulty von Hippel-Lindau gene (VHL) allele are predisposed to VHL disease, which is characterized by the development of cerebellar, spinal, and retinal hemangioblastoma, pheochromocytoma, and clear-cell renal cell carcinoma (CC-RCC) (29). The tumor develops upon the somatic loss of the remaining wild-type VHL allele in a susceptible cell. Importantly, biallelic loss of VHL is associated with the vast majority of sporadic CC-RCCs, establishing VHL as a critical suppressor of renal oncogenesis (29). CC-RCC is resistant to conventional radiation and chemotherapies, and approximately one-quarter of renal cancer patients present with advanced disease, including locally invasive or metastatic CC-RCC (12). Unfortunately, one-third of patients who undergo surgical removal of localized tumors have recurrence of the disease, and the median survival for patients harboring metastatic CC-RCC is 13 months (12). Moreover, the principal cause of morbidity and death of VHL patients is CC-RCC (29). Despite the need to better understand the aggressive nature of CC-RCC, the molecular pathways governing its malignant phenotype remain unresolved.The most well-characterized function of VHL is as a substrate-recognition component of the SCF (Skp1/Cdc53/F-box protein)-like E3 ubiquitin ligase complex called ECV (elongins/Cul2/VHL) that selectively ubiquitylates oxygen-dependent prolyl-hydroxylated ␣ subunits of hypoxia-inducible factor

The loss of functional von Hippel-Lindau (VHL) tumor suppressor gene is associated with the development of clear-cell renal cell carcinoma (CC-RCC). Recently, VHL was shown to promote the transcription of E-cadherin, an adhesion molecule whose expression is inversely correlated with the aggressive phenotype of numerous epithelial cancers. Here, we performed immunohistochemistry on CC-RCC tissue microarrays to determine the prognostic value of E-cadherin and VHL with respect to Fuhrman grade and clinical prognosis. Low Fuhrman grade and good prognosis associated with positive VHL and E-cadherin immunoreactivity, whereas poor prognosis and high-grade tumors associated with a lack of E-cadherin and lower frequency of VHL staining. A significant portion of CC-RCC with positive VHL immunostaining correlated with nuclear localization of C-terminally cleaved E-cadherin. DNA sequencing revealed in a majority of nuclear E-cadherin-positive CC-RCC, subtle point mutations, deletions and insertions in VHL. Furthermore, nuclear E-cadherin was not observed in chromophobe or papillary RCC, as well as matched normal kidney tissue. In addition, nuclear E-cadherin localization was recapitulated in CC-RCC xenografts devoid of functional VHL or reconstituted with synthetic mutant VHL grown in SCID mice. These findings provide the first evidence of aberrant nuclear localization of E-cadherin in CC-RCC harboring VHL mutations, and suggest potential prognostic value of VHL and E-cadherin in CC-RCC. [4][5][6][7] Currently, a prediction of patient survival is based on traditional clinical parameters, including tumor size and Fuhrman nuclear grade. 8 However, the emerging understanding of the molecular pathways implicated in CC-RCC genesis and progression is providing previously unappreciated markers, which may serve as additional or better prognostic indicators of CC-RCC.The principal cause of sporadic CC-RCC and familial von Hippel-Lindau (VHL) disease-associated CC-RCC is the inactivating mutations of VHL. Although VHL patients also develop tumors in other organs including the central nervous system, retina and the adrenal gland, CC-RCC remains to be the leading cause of morbidity and death for VHL patients. 9 The most well-established function of VHL is its role in the oxygen-dependent negative regulation of hypoxia-inducible factor (HIF). VHL is a substrate-conferring component of an E3 ubiquitin ligase ECV (elongins/Cul2/VHL) that polyubiquitylates the catalytic a-subunit of HIF that has undergone hydroxylation on conserved prolyl residues within the oxygen-dependent degradation (ODD) domain. Prolyl hydroxylation is mediated by a class of prolyl hydroxylases (PHD1-3) in an oxygen-dependent manner. Thus, under hypoxia or in the absence of a functional VHL, HIFa becomes stabilized and binds to its common and constitutively expressed b-subunit, forming an active HIF transcription factor capable of transactivating numerous hypoxia-inducible genes such as vascular endothelial growth factor (VEGF),

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