Clinico-prognostic value of D-type cyclins and p27 in laryngeal cancer patients : a review

Despite recent improvements in surgical and radiation therapy, failures still occur in patients with laryngeal squamous cell carcinomas, which may have a very different clinical outcome even when their clinical and histopathological characteristics are similar. The apparent inadequacy of "traditional" prognostic factors in predicting the clinical evolution of laryngeal squamous cell carcinomas has led to attempts to develop additional markers capable of distinguishing patients with a good prognosis from those who are more likely to relapse. A number of studies have demonstrated a relationship between tumourigenesis and alterations in the expression of cyclins, cyclin-dependent kinases and cyclin-dependent kinase inhibitors, but the data regarding laryngeal squamous cell carcinomas are somewhat conflicting. Herein a review is made of the published literature concerning the clinico-prognostic role of cyclin D1, D3 and p27, and personal data are described concerning laryngeal squamous cell carcinoma patients who underwent surgical resection at the ENT Department of the University of Milan. The results of our multivariate analyses demonstrated that cyclin D1, p27 and cyclin D3 overexpression are statistically significant predictors of disease-free survival (p = 0.0238, p = 0.0001 and p = 0.0217, respectively); the statistical correlation with overall survival was significant in the case of p27 (p = 0.0009) and cyclin D3 (p = 0.0189), and borderline in the case of cyclin D1 (p = 0.0622). In relation to cyclin D1/p27 coexpression, the patients with a cyclin D1-/p27+ phenotype showed the best prognosis, those with a cyclin D1/p27+ or cyclin D1-/p27- phenotype, an intermediate prognosis, and those with a cyclin D1+/p27- phenotype, the poorest prognosis (p = 0.0001 and p = 0.0001 for trend for disease-free survival; p = 0.0015 and p = 0.0008 for trend for overall survival). In the case of cyclin D1/cyclin D3 coexpression, the patients with cyclin D1+/cyclin D3+ tumours had the poorest overall survival, those with cyclin D1/cyclin D3+or cyclin D1+/cyclin D3- tumours showed intermediate course, and those with cyclin D1 /cyclin D3- tumours had the most favourable outcome (p = 0.0002). The findings of this review indicate that both types of cyclin D and p27 are involved in the genesis of laryngeal squamous cell carcinomas, and that immunohistochemical evaluations of biopsy samples may provide useful additional markers capable of identifying subgroups of patients with a poor prognosis who can be treated by means of more aggressive surgery, adjuvant radiotherapy and chemotherapy, as well as those requiring a closer and more prolonged follow-up. Finally, preliminary results suggest that the administration of new molecular therapies that exert their antitumoural activities by functionally subverting the pathways regulated by D-type cyclins and their cyclin-dependent kinase counterparts may represent a further therapeutic modality for patients with refractory head and neck squamous cell carcinomas