In general, the oligodendroglioma infrequently presents a problem to the diagnostic pathologist reviewing paraffinembedded sections of nonfrozen material. Its histologic appearance of round, regular cells exhibiting perinuclear water-clear cytoplasm is typical and easily recognizable. The additional features of punctate calcification, perineuronal, and perivascular satellitosis, and thin, wiry, branching vessels make the majority of these tumors easily classified. The present chapter will discuss the well-differentiated oligodendroglioma with an emphasis on problematic features and how to solve these problems. The most common problem involves the presence of GFAP-positive cells apart from interspersed reactive astrocytes, called gliofibrillary astrocytes and mini-gemistocytes, found in the majority of tumors that give rise to the diagnosis of mixed glioma. The percentage of these cellular elements that are required for the diagnosis of mixed glioma vary by pathologist (Bruner et al., 1997). The result is that the term ‘mixed glioma’ is a catch-all category that includes tumors spanning the histologic spectrum separating oligodendroglial tumors from astrocytic tumors. For instance, the histopathologic picture of gemistocytic astrocytoma may be part of an otherwise typical astrocytoma, but also of a glioma with classic oligodendroglial parts. We shall also discuss the recent molecular investigations, related to this phenomenon, that note a strong relationship between the diagnosis of oligodendroglioma and allelic losses of the short arm of chromosome 1 (1p) and the
long arm of 19 (19q) and offer the possibility of being an objective oligodendroglial marker.