p21, p27, Cyclin D1 und p53 beim Rektumkarzinom: Immunhistologie mit prognostischer Relevanz?

Abstract

Background: The aim of this study was to determine the prognostic value of the cyclindependent kinase inhibitors, p21 ^Waf1/CiP1 and p27^Kip1, and the cell cycle regulating proteins cyclin D1 and p53 after curative surgery for rectal cancer. Methods: Formalin-fixed, paraffin- embedded tissue samples of 160 rectal carcinomas resected curatively within a 5-year period were used. Immunohistochemical analysis was performed using monoclonal antibodies: p21^Waf1/Cip1 (clone SX118), p27^Kip1 (clone SX53G8), cyclin D1 (clone DCS-6) and p53 (DO-1). Positive nuclear protein expression was assessed at the 10% level. Results of immunohistochemistry were correlated with clinical and histopathologic data of the prospective tumor registry, including recurrence and patient survival. Statistics included univariate and multivariate analysis (p < 0.05 statistically significant), and survival was calculated using the Kaplan-Meier method. Results: Of the 160 rectal carcinomas, 36% (57/160) were p21^Waf1/Cip1-positive, 44% (70/160) were p27^Kip1-positive, 48% (76/160) were cyclin D1-positive, and 39% (63/160) were p53-positive. p21^Waf1/Cip1 staining pattern correlated with p27^Kp1 and p53 expression (p < 0.05). p21^Waf1/Cip1 was also associated with UICC stage and lymph node status (p < 0.05). p53 status was not correlated with any clinical or histopathologic variable (p < 0.05). p27^Kip1 expression was associated with tumor size and cyclin D1 expression (p < 0.05). Tumor progression caused by local and distant recurrence occurred in 20% (n = 32). p21^Waf1/Cip1 ,p27^Kip1 and P53 were strong predictors of recurrence, both in univariate and multivariate analysis. Furthermore, p21^Waf1/Cip1 and p53 but not p27^Kip1 were independently correlated with disease-free survival. Clinically, UICC stage was independently related to both recurrence and survival. Best prognosis was related to p21^Waf1/Cip1-positive and p53-negative rectal carcinomas. Conclusions: Reflecting tumor biology by immunohistochemical assessment of cell cycle regulators, p21^Waf1/Cip1 and p53 were independently predictive of prognosis in rectal cancer, and p27^Kip1 was independently related to recurrence. However, cyclin Di had no independent relationship to prognosis. Clinically, UICC stage was a strong predictor of both recurrence and survival after curative surgery for rectal cancer.