p21, p27, cyclin D₁, and p53 in rectal cancer: immunohistology with prognostic significance?

Abstract.

Background and aims: This study examined the prognostic value of the cyclin-dependent kinase inhibitors p21^Waf1/Cip1 and p27^Kip1, and the cell cycle regulating proteins cyclin D₁ and p53 after curative surgery for rectal cancer. Patients and methods: Formalin-fixed, paraffin-embedded tissue samples of 160 rectal carcinomas resected curatively within a 5-year period were used. Immunohistochemical analysis used 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 studied for correlation with clinical and histopathological data of the prospective tumor registry including recurrence and patient survival. Results: Of the 160 rectal carcinomas 36% were p21^Waf1/Cip1 positive, 44% p27^Kip1 positive, 48% cyclin D₁ positive, and 39% p53 positive. The p21^Waf1/Cip1 staining pattern was correlated with p27^Kip1 and p53 expression and with UICC stage and lymph node status. p53 status was not correlated to any clinical or histopathological variable. p27^Kip1 expression was associated with tumor size and cyclin D₁ expression. Tumor progression caused by local and distant recurrence occurred in 20%. p21^Waf1/Cip1, p27^Kip1, and p53 were strong predictors of recurrence. p21^Waf1/Cip1 and p53 but not p27^Kip1 were independently correlated with disease-free survival. UICC stage was independently related to both recurrence and survival. The best prognosis was in 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 D₁ had no independent relationship to prognosis. Clinically, UICC stage was a strong predictor of prognosis after curative surgery for rectal cancer.