Markers of cell-proliferation as prognostic factors in differentiated thyroid-cancer

Age is the most accepted prognostic factor in differentiated thyroid cancer. Other parameters, such as tumor size, grading, extrathyroidal extension, have also been associated with the prognosis of these tumors. Since the identification of reliable prognostic factors is essential to avoid unnecessary aggressive treatment for a disease, such as thyroid carcinoma, which only rarely is fatal, we studied two indices of cell proliferation in patients with differentiated thyroid cancer, in relation to their outcome. We studied two groups of patients with differentiated thyroid cancer, selected in a way to have one group (33 patients) with a good outcome and one (16 patients) with a fatal outcome, after a follow-up of at least 5 years. By immunohistochemistry the primary tumors of all patients were analyzed for the expression of the proliferating cell nuclear antigen (PCNA)/cyclin. In 38 (77.5%) of them also the nuclear DNA content and the percentages of S-phases were analyzed by flow cytometric analysis. At diagnosis the two groups of patients differed significantly with regard to age and extrathyroidal extension, but not for tumor size and grading. A significant difference (p=0.02) was found in the positivity of PCNA/cyclin expression between the fatal outcome group (66.6%) and the surviving patients (27%), and in the percentage of cells in the S-phase, 16.4+/-7.7% in the fatal outcome group patients and 6.0+/-2.6% in the surviving patients (p=0.0001). No difference was found in the nuclear DNA content of the two groups. A positive correlation was found between PCNA expression and S-phase (r(s)=0.55; p<0.001). A positive correlation was found between age and both the percentage of S-phase cells (r(s)=0.48; p<0.002) and PCNA expression (r(s)=0.36; p<0.009). In a multivariate analysis (Cox model) age and S-phase had independent prognostic significance (regression coefficient: 3.85 and 1.70, respectively), while PCNA was not an independent variable (0.98). Our results indicate that differentiated thyroid tumors with fatal outcome are characterized by two parameters of active cell proliferation (S-phase cell fraction and PCNA expression), which can be used as useful prognostic factors.