ROLE OF GEMISTOCYTES IN ASTROCYTOMA PROGRESSION

The presence of gemistocytes in low-grade astrocytomas is regarded as a sign of poor prognosis because the majority of gemistocytic astrocyt omas rapidly progress to anaplastic astrocytoma or glioblastoma. To el ucidate the role of gemistocytes in astrocytoma progression, we assess ed the fraction of neoplastic gemistocytes, bcl-2 expression, p53 muta tions, p53 immunoreactivity (PAb 1801), and proliferative activity (MI B-1) in 40 low-grade astrocytomas (World Health Organization (WHO) Gra de II) with histologically proven progression to anaplastic astrocytom a (WHO Grade III) or glioblastoma (WHO Grade IV). Astrocytoma progress ion took significantly less time in patients with a low-grade astrocyt oma containing more than 5% gemistocytes (35 months) than in those wit h lesions containing less than 5% gemistocytes (64 months; p = 0.038). All 11 astrocytomas with more than 5% gemistocytes contained a p53 mu tation, whereas the incidence of p53 mutations in astrocytomas with le ss than 5% gemistocytes was 61% (p = 0.017). In low-grade astrocytomas , the p53 labeling index (LI) of gemistocytes (7.4%) was significantly higher than in all tumor cells (3.2%, p = 0.0014). Gemistocytes showe d a significantly higher bcl-2 expression than all tumor cells, with a mean bcl-2 LI of 15.6% versus 2.7% in low-grade astrocytomas (p = 0.0 004), 20.9% versus 3.0% in anaplastic astrocytoma (p = 0.002), and 30. 2% versus 5.2% in glioblastomas (p = 0.0002). In contrast, gemistocyte s showed a significantly lower proliferating activity than the mean of all tumor cells, with a mean MIB-1 LI of 0.5% versus 2.6% in low-grad e astrocytomas, 1.5% versus 11.6% in anaplastic astrocytoma, and 1.7% versus 16.6% in glioblastomas (p < 0.0001). These data show that low-g rade astrocytomas with a significant fraction of gemistocytes progress more rapidly and typically carry a p53 mutation. The vast majority of gemistocytes are, however, in a nonproliferative state (G(0) phase of the cell cycle), which suggests terminal differentiation. Their accum ulation within astrocytomas may be due to bcl-2-mediated escape from a poptosis.