The association between p21 and HRAS overexpression and grading, heterogeneity, and likelihood of prognosis and relapse in urothelial carcinoma of the bladder

Background: Along with clinical and histological parameters that may discriminate high from low grade urothelial carcinomas (UC) of the urinary bladder, some biomarkers havebeen recently introduced that may be useful for assessing tumor grade, heterogeneity, outcome and prognosis. We conducted this study to examine the association of theoverexpression of p21 and HRAS with urothelial carcinoma grading, heterogeneity, prognosis and relapse.Methods: This cross-sectional study was performed on 413 samples obtained from 413 patients with biopsy-proven UCs of bladder. Representative tumor regions were selectedfrom paraffin embedded blocks of patients’ samples and punched into the recipient tissue microarray (TMA) paraffin blocks. Immunohistochemical staining for p21 and HRAS wasdone and semi-quantitative and combined scoring system (called H score) was employed to score intensity and extent of staining by two pathologists separately.Results: Both P21 and HRAS expression differs significantly among high-grade and lowgrade UCs. P21 is expressed more in high grade and HRAS in low-grade UCs (p = 0.001,p = 0.001). Using the ROC curve analysis, p21 marker is proved to be able to predict highgrade pattern (AUC = 0.596, p=0.002) and HRAS can discriminate low-grade ones (AUC= 0.664, p=0.001). The best cutoff value for p21 and HRAS H score to differentiate high grade from low grade pattern is 92.5 and 85, yielding a sensitivity of 67.7% and 55.7% anda specificity of 44.7% and 76.8% respectively. Overexpression of this marker is not associated with tumor-related death. According to logistic regression analysis, of allbaseline variables, Overexpression of HRAS is associated with tumor-related death and non-papillary (p = 0.001) and heterogeneous (p = 0.001) patterns could effectively predicttumor recurrence. Conclusion: p21 and HRAS markers are valuable to discriminate high and low-grade pattern in UCs with acceptable sensitivity and specificity; Tumors with non-papillary and heterogeneous pattern of growth are more prone to relapse. HRAS overexpression is associated with poor prognosis

Keywords:

Urothelial carcinoma , Urinary Bladder Neoplasm , Prognosis , p21 , HRAS , grade , heterogeneity