Differential Expression of the Transferrin Receptor in Renal Cell Neoplasms: A Novel Marker of Aggressive Behavior
Nick M Shillingford, Shaolei Lu, Shamlal Mangray, Rosemarie Tavares, Murray B Resnick, Evgeny Yakirevich. Warren Alpert Medical School of Brown University and Rhode Island Hospital, Providence, RI
Background: The transferrin receptor (TfR, CD71) is a cell surface glycoprotein related to cell growth and iron-requiring processes, including DNA synthesis, electron transport, and cell proliferation. Overexpression of TfR has been described in various malignancies including carcinomas of the lung, breast, colon, pancreas, and bladder, however its expression in tumors arising in the kidney has not been examined. The goal of this study was to evaluate the expression pattern and prognostic significance of TfR in different histologic subtypes of renal cell neoplasms (RCNs).
Design: Paraffin embedded microarray specimens from 205 consecutive patients with RCNs were analyzed for TfR expression by IHC. A mouse anti-TfR monoclonal Ab (Clone H68.4, 1:500) from Invitrogen was used as the primary Ab. Cases were stratified into 143 clear cell renal cell carcinomas (CRCC), 8 CRCC with sarcomatoid features (SCRCC), 19 papillary RCC type 1 (PRCC1), 6 papillary RCC type 2 (PRCC2) 15 chromophobe RCC (CHRCC), and 14 oncocytomas (OC). The immunoreactivity was assessed based on a combined score of the extent and intensity on a scale of 0-3+.
Results: Strong predominantly cytoplasmic TfR expression was present in the distal convoluted tubules of the normal kidney, whereas proximal convoluted tubules and glomeruli were negative. In the RCNs the staining pattern was both membranous and cytoplasmic. TfR expression was found in all SCRCC, in the majority of PRCC2 (83%), in 59% of CRCC, 53% PRCC1, 47% CHRCC, and 36% of OC (P=0.002). Within the SCRCC group the vast majority of positive cases demonstrated strong immunoreactivity (2+ and 3+). None of the OCs showed strong expression. Strong TfR expression was higher in PRCC2 as compared to PRCC1. TfR overexpression was strongly associated with tumors of high nuclear grade (Fuhrman grade 3 and 4, P=0.006) and advanced stage (stage 3 and 4, P=0.05). Univariate survival analysis revealed a significant direct correlation between TfR overexpression and poor overall survival in the CRCC group (P=0.03).