Alterations of cell cycle regulators in localized synovial sarcoma - A multifactorial study with prognostic implications

Genetic alterations of cell cycle regulators are thought to represent uncom mon and possible secondary events in sarcomas characterized by recurrent ch romosomal translocations, The present study investigates this hypothesis on synovial sarcoma (SS), assessing the frequency of expression and possible clinical implications of detecting alterations in critical cell cycle regul atory proteins. A homogeneous cohort of 49 patients with localized SS, restricted to the ex tremity and with available longterm follow-up information, was selected fro m our files. We focused our study on molecules involved in the G1 checkpoin t and G1-S transition, including cyclins D1 and E, p21(WAF1), p27(Kip1), md m2, p53, and Ki67, A cutoff point of 10% immunoreactive tumor cell nuclei w as selected to define a positive phenotype for any given marker, except for Ki67, High Ki67 proliferative index was considered when greater than or eq ual to 20% tumor cells displayed nuclear immunoreactivity, Biphasic SS were analyzed, taking into account separately the expression of these proteins in the spindle and glandular components. Disease specific survival was mode led using the Kaplan-Meier method with log rank test and Cox regression. The cohort of patients analyzed included 23 females and 26 males, and the h istological type distribution was 35 monophasic and 14 biphasic SS. The med ian follow-up for survivors was 53 months, with a 5-year disease-specific s urvival of 63% and a metastatic disease-free survival of 40%. The positive phenotypes identified for the different markers studied were as follows: cy clin D1, 59%; cyclin E, 29%; p21, 51%; p27, 69%; mdm2, 59%; p53, 16%; and K i67, 59%. We observed that positive p53, cyclin E, and high Ki67 proliferat ive index were correlated with survival, but only Ki67 and p53 mere indepen dent variables for prognostication. The present study suggests that alterat ions of cell cycle regulators are more common events in SS than originally thought. p53 overexpression could be of use as a marker together with a hig h Ki67 proliferative index, in identifying a subset of SS patients with inc reased risk of tumor relapse.