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From the Departments of Pathology,*
Biostatistics and
Epidemiology,
Human
Genetics,
and
Surgery,§
Memorial Sloan-Kettering Cancer
Center, New York, New York
Genetic alterations of cell cycle regulators are thought to
represent uncommon and possible secondary events in sarcomas
characterized by recurrent chromosomal 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 regulatory
proteins. A homogeneous cohort of 49 patients with localized
SS, restricted to the extremity and with available long-term
follow-up information, was selected from our files. We focused
our study on molecules involved in the G1 checkpoint and G1-S
transition, including cyclins D1 and E,
p21WAF1, p27Kip1, mdm2,
p53, and Ki67. A cutoff point of 10% immunoreactive tumor cell
nuclei was selected to define a positive phenotype for any given
marker, except for Ki67. High Ki67 proliferative index was
considered when 
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 modeled 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 histological
type distribution was 35 monophasic and 14 biphasic SS. The median
follow-up for survivors was 53 months, with a 5-year
disease-specific survival of 63% and a metastatic disease-free
survival of 40%. The positive phenotypes identified for the different
markers studied were as follows: cyclin D1, 59%; cyclin
E, 29%; p21, 51%; p27, 69%; mdm2,
59%; p53, 16%; and Ki67, 59%. We observed that
positive p53, cyclin E, and high Ki67 proliferative
index were correlated with survival, but only Ki67 and p53 were
independent variables for prognostication. The present study suggests
that alterations 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 high Ki67 proliferative index, in identifying a
subset of SS patients with increased risk of tumor
relapse.
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