e15129 Background: The type II transmembrane protein 4F2hc (CD98hc, SLC3A2) has been shown to be essential in embryogenesis as well as in adolescence during cell proliferation, while in quiescent somatic cells 4F2 is not expressed. Overexpression of 4F2hc in somatic cells leads to malignant transformation. We were interested whether 4F2hc expression predicts malignant behavior of RCC. Methods: We analyzed 270 paraffin-embedded RCC tissue samples [219 from clear cell RCC (ccRCC) and 51 samples from papillary RCC (pRCC)] from a well characterized tissue bank of the Department of Clinical Patholgy, Medical University of Vienna. Tumors were classified according to recommendations of the WHO Classification 2004 and staged according to the TNM-System (Journal of Roentgenology, 2008), and graded according to Fuhrman et al (American Journal of Surgical Pathology, 1982). 4F2hc, cytocreatin 7 (CK7), CD10 as well as aquaporin-1 were detected via immunohistochemistry and semiquantitatively analyzed. By statistically analyses the Tukey test and students t- test was used and immunohistochemical scoring results, tumor type, grading and staging in carcinomas were compared. Results: We found that 4F2hc is highly expressed in papillary, as well as clear cell RCC, while no 4F2hc expression was found in benign oncocytomas. We found that 4F2 expression is mainly found in the more aggressive type II pRCC, whereby the less aggressive type I hardly showed any positive staining (type II 83.34%, type I 4.76% 4F2hc positive, p < 0.00001; n = 51). In ccRCC, we found a direct correlation between 4F2 expression and differentiation, whereby semiquantitative analysis showed the highest stain in less differentiated tumors. (grade 1: 31%, grade 2: 21%, grade 3: 67%, grade 4 - 96% 4F2hc positive, p<0.0003) Conclusions: We conclude that 4F2 expression reflects the more malignant phenotype in RCC and therefore represents a potential novel prognostic and diagnostic biomarker in renal cell cancer.