Prognostic Markers in Chondrosarcoma: Evaluation of Cell Proliferation and of Regulators of the Cell Cycle

Purpose. The prognosis, treatment principles and prediction of clinical outcome of patients with chondrosarcoma currently rest on histologic grading which is somewhat ambiguous due to difficulty in pathologic interpretation of this neoplasm. Immunohistochemistry, flow cytometry and oncogene/tumor suppressor gene expression have been examined as alternative indices to predict the biologic behavior of these tumors. Because of partial successes obtained with flow cytometry and because of the improvement in predicting recurrence offered by examining the S-phase fraction, we undertook the current study to determine if expression of specific regulators of the cell cycle would act as prognostic indicators for these patients. Subjects/methods. We examined archival pathologic specimens from 39 patients with at least 2 years' clinical follow-up for the presence of p53, Rb, src and MIB-1 by immunohistochemistry and correlated this with clinical histories and incidence of recurrence. Results. While Rb, p53 and src gene products were identified to a variable extent in these specimens, there was no prognostic significance to their expression. In contrast, MIB-1, an epitope expressed only during semiconservative replication and an accepted marker of cell proliferation, served as a significant prognostic indicator. MIB-1 staining was present in 14.5% of tumor cells in all specimens (range 0–59%). When MIB-1 staining was examined with respect to disease recurrence, there was a statistically significant association between staining and histologic grade (p < 0.05) as well as event-free survival (p < 0.02). Comparing survival curves stratified by MIB-1 expression, there was a significant decrease in event-free survival associated with increasing MIB-1 indices (p < 0.003). Covariates that were associated with event-free survival include histologic grade (p = 0.025) and stage (Musculoskeletal Tumor Society) (p = 0.014). There was no statistical association with patient age (p = 0.15), tumor size (p = 0.47), tumor histology (p = 0.62) or anatomic location (p = 0.316). Discussion. These results indicate that determination of the proliferation index by MIB-1 immunostaining may serve as a useful adjunct to current histopathologic classification. Patients with a high proliferation index may benefit from established adjuvant therapies or experimental approaches including immunotherapy or biologic modulation.