The B7 family of co-regulatory ligands is implicated again in the pathogenesis of renal cell carcinoma progression

Previous reports from the group at Mayo Clinic have demonstrated that B7-H1 expression by renal cell carcinoma (RCC) is a marker of poor prognosis in both localized and metastatic RCC.

This marker represents one of a family of proteins that are co-regulatory ligands that function to inhibit T-cell mediated immunity. In this investigation, the authors examine another member of the B7 family, B7-H4, and it's relationship to prognosis in RCC. Of note, B7-H4 expression is normally relegated to lymphoid cells, although aberrant expression has been reported in human malignancies, but never correlated significantly with prognosis in these studies

The authors examined B7-H4 expression in 259 patients with RCC. Of these, 153 (59.1%) demonstrated positive expression (median level of staining 20%, range 5-90%) of B7-H4. Expression of B7-H4 was significantly associated with the presence of constitutional symptoms, coagulative necrosis in the tumor, increased tumor size, increased stage, and increased grade. Patients that had positive B7-H4 expression in their tumors were 3 times more likely to die from RCC (RR 3.05, p=0.002). The overall and cancer specific 3 year survival for patients with B7-H4 positive tumors was 66.1% and 71.2%, respectively, versus 84.5% and 90.5%, respectively, for those without positive staining. In a subset analysis of 215 patients with localized RCC, those that expressed B7-H4 were 3 times more likely to have disease progression (RR 2.99, p=0.006). The 3 year progression free survival was 74.1% for B7-H4 positive tumors, versus 91.2% for those that were B7-H4 negative.

The authors then evaluated the interrelationship between B7-H1 and B7-H4 expression in their study cohort. As shown in the table below, patients that had both B7-H1 and B7-H4 positive tumors had a significantly worse 3 year cancer specific survival (CSS) and were more than 4 times more likely to die of RCC (RR 4.49, p<0.001). This feature remained an independent variable for prognosis even after adjusting for the SSIGN score in multivariate analysis.

B7 Status CSS (3yr) H1-, H4- 94% H1-, H4+ 92.3% H1+, H4- 86.6% H1+, H4+ 60.9% p<0.001

Finally, the authors noted that 211 patients in their study cohort also demonstrated B7-H4 expression in the tumor vasculature (81.5%) as compared to only 6.5% noted in normal renal parenchyma. They hypothesize that B7-H4 expression by the tumor vasculature may play some as yet unrecognized role in the pathogenesis of RCC neovascularity.

The B7 family of immunoregulatory proteins appears to play an important role in the pathogenesis of RCC progression and metastasis. Further studies to identify therapies that target this pathway may improve the prognosis of patients that present with locally advanced or metastatic disease.

Am J Surg Pathol 2006;30:866-70

Written by Christopher G. Wood MD - UroToday

This article is republished with kind permission from our friends at UroToday. UroToday's vision is to create a quality, global online publication providing accurate and timely education that is clinically relevant in the practice of Urology. Copyright 2006 UroToday. All rights reserved.