Prognostic impact of the coincident expression of interacting cell cycle regulators demonstrated in malignant fibrous histiocytoma

Functional interaction of cell cycle regulating proteins is involved in regulation of tumor growth and apoptosis and may be of importance in neoangiogenesis and sensitivity to chemotherapeutic drugs and radiation. This review examines the significance of the expression of cell cycle regulators (CCR) of the two pathways p53 (p53, MDM2, waf-1) and pRb-cyclin D (pRb, p16) in predicting course and outcome of patients with malignant fibrous histiocytoma (MFH) and also analyzes the statistical relationship between CCR and tumor proliferation. The results of immunoreactivity for the above markers and the proliferation-associated antigen Ki67 obtained on a large MFH sample are summarized. The expression of these proteins was quantified with respect to the percentage of immunolabeled tumor cells (index). Specimens with high indices for p53 (> 20), MDM2 (> 33), p16 (> 0) and EGFR (>- 30) and low waf-1 index (< 20) had a significantly higher Ki67 index than tumors that did not meet the criteria. Based on the results, 3 clinical outcome groups were defined. Prognostic Index Group I: patients with a low MDM2 index coincident with a high waf-1 index and patients with a combined pRb and p16 immunonegativity had a good prognosis. Prognostic Index Group II: patients with pRb immunonegativity with simultaneous p16 expression and patients with a high EGFR index had an intermediate prognosis. Prognostic Index Group III: patients characterized by either a high p53 index or combined high MDM2 and pRb positivity had a bad prognosis. When necroses (>- 10%) were present, the survival rate was lower, irrespective of the Prognostic Index Group. Therefore, any MFH patients showing necroses were assigned to the next higher Prognostic Index Group. A prognostic index based on the expression of CCR and EGFR plus the extent of necroses can be used in addition to grading as an independent predictor of survival in MFH patients. It is proposed that future studies on the prognostic and biological roles of cell cycle regulators in soft tissue tumors and other tumor types should consider the coincident presence of cell cycle regulator abberations, since these proteins exert their diverse functions by mutual interactions.