Cell Cycle Checkpoints p16 and p21—Strong Predictors of Clinicopathologic Outcomes in High-Grade Osteosarcoma

Abstract

Osteosarcoma is the most common primary malignant neoplasm of bone. Despite recent advances in the management of the disease, the overall survival of patients has failed to improve in the past 30 years due to the biological and genetic complexities of the disease and the lack of reliable prognostic and predictive markers to guide the treatments. Histologic tumor necrosis in response to chemotherapy has served as the most reliable predictor of disease outcome for years. Patients with a good histologic response (greater than 90% tumor necrosis) to chemotherapy had better disease outcomes compared with patients with a poor histologic response (less than 90% tumor necrosis). With the changes in the intensity of chemotherapeutic regimens, the prognostic value of histologic measurement of tumor necrosis has been questioned in recent studies. Purpose In this study, we used a series of immunohistochemical measurements of 2 cell cycle regulators, p16 and p21, to evaluate their prognostic value, separately and in combination, for the disease outcomes. Method A total of 101 patients with high-grade osteosarcoma were included in this study. Clinicopathologic data were collected, and immunohistochemistry for p16 and p21 was performed and interpreted by 3 independent pathologists. Statistical analysis was performed to assess the strength of each of these markers relative to disease outcome. Results Our results indicate that more than 90% expression (high) of p16 by immunohistochemistry on the initial biopsy has a strong predictive value for good histologic response to chemotherapy. The patients are also more likely to survive the past 5 years and less likely to develop metastasis than patients with less than 90% p16 (low) expression. The results for p21, on the other hand, show a unique pattern of relationship to the clinicopathologic outcomes of the disease. Patients with less than 1% (low) or more than 50% (high) expression of p21 by immunohistochemistry show a higher chance of metastasis, poor necrotic response to chemotherapy, and an overall decreased survival rate when compared with p21 expression between 1% and 50% (moderate). Our results also showed that the expression of p16 and combined p16 and p21 demonstrates a stronger predictive relationship to 5-year survival than tumor histologic necrosis and p21 alone. Discussion The results of this study, once proven to be reproducible by a larger number of patients, will be valuable in the initial assessment and risk stratification of the patients for treatment and possibly the clinical trials.