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

BACKGROUND AND AIMS: This study examined the prognostic value of the cyclin-dependent kinase inhibitors p21(Waf1/Cip1) and p27Kip1, 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), p27Kip1 (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% p27Kip1 positive, 48% cyclin D1 positive, and 39% p53 positive. The p21(Waf1/Cip1) staining pattern was correlated with p27Kip1 and p53 expression and with UICC stage and lymph node status. p53 status was not correlated to any clinical or histopathological variable. p27Kip1 expression was associated with tumor size and cyclin D1 expression. Tumor progression caused by local and distant recurrence occurred in 20%. p21(Waf1/Cip1), p27Kip1, and p53 were strong predictors of recurrence. p21(Waf1/Cip1) and p53 but not p27Kip1 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 p27Kip1 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.