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Imaging, Diagnosis, Prognosis |
in Clear Cell Renal Cell CarcinomaAuthors' Affiliations: Departments of 1 Urology, 2 Pathology and Laboratory Medicine, and 3 Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
Requests for reprints: Arie S. Belldegrun, Department of Urology, David Geffen School of Medicine at UCLA, 66-118 CHS Los Angeles, CA 90095-1738. Phone: 310-206-1434; Fax: 310-206-5343; E-mail: abelldegrun{at}mednet.ucla.edu.
Purpose: Hypoxia-inducible factor-1
(HIF-1
) plays an important role in tumoral adaptation to hypoxic conditions by serving as a transcription factor for several crucial proteins, including vascular endothelial growth factor and carbonic anhydrase IX (CAIX). Here, we evaluated the significance of HIF-1
in renal cell carcinoma (RCC).
Experimental Design: Immunohistochemical analysis was done on a tissue microarray constructed from paraffin-embedded primary tumor specimens from 357 patients treated by nephrectomy for RCC. Nuclear expression was evaluated by a single pathologist who was blinded to outcome. The expression levels were associated with pathologic variables and survival.
Results: HIF-1
expression was greater in RCC than in benign tissue. Clear cell RCC showed the highest expression levels. In clear cell RCC, HIF-1
was significantly correlated with markers of apoptosis (p21, p53), the mammalian target of rapamycin pathway (pAkt, p27), CXCR3, and proteins of the vascular endothelial growth factor family. HIF-1
was correlated with CAIX and CAXII in localized, but not in metastatic RCC. HIF-1
expression predicted outcome in metastatic patients: patients with high HIF-1
expression (>35%) had significantly worse survival than patients with low expression (
35%); median survival, 13.5 versus 24.4 months, respectively (P = 0.005). Multivariate analysis retained HIF-1
and CAIX expression as the strongest independent prognostic factors for patients with metastatic clear cell RCC.
Conclusions: HIF-1
is an important independent prognostic factor for patients with metastatic clear cell RCC. Because HIF-1
and CAIX are independently and differentially regulated in metastatic clear cell RCC, both tumor markers can be complementary in predicting prognosis.
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