Acta Neuropathol (2010) 119:7–35 27 Fig. 8 GFAP immunoreactive cells in primary CNS neoplasms. a High magniﬁcation image of a subependymal giant cell astrocytoma (SEGA) immunohistochemically stained for GFAP. Note variable staining intensity within tumor cells, including some that show uniform cytoplasmic staining. b High magniﬁcation image of a high- grade glioma (glioblastoma, WHO grade IV) immunohistochemically stained for GFAP. Note the variable staining of tumor cells as well as the pronounced nuclear and cytological atypia. Scale bars a, b 10 lm astrocytes, glial precursors, or stem cells, are the subject of intense investigation [76]. In a manner consistent with the cancer stem cell hypothesis, there is considerable evidence that only minor populations of cells in primary gliomas are capable of forming a tumor, [76, 223]. The presence throughout adult brain of periventricular adult NSC that express the astrocyte marker GFAP (see above), raises interesting questions regarding the possible contribution of these cells to astrocytoma initiation. Astrocytic gliomas contain small numbers of cells that exhibit stem cell-like properties in that they self-renew, are multipotent and form neurospheres in vitro and constitutively produce the different types of cells found within the parent tumors [160]. Growth properties of glioma-derived neurospheres in vitro were found to be signiﬁcant predictors of tumor progression in vivo and of clinical outcome [118]. Nevertheless, the origins of gli- oma are not yet understood and could be heterogeneous. Fig. 9 Reactive astrogliosis in response to CNS tumors. a High magniﬁcation image of autopsy specimen from a man with widely inﬁltrating primary CNS lymphoma. Two color immunohistochem- istry for GFAP and the cell cycle marker Ki67, shows the cytoplasm of reactive astrocytes stained blue (arrows), with nuclei of inﬁltrating, malignant and highly proliferative lymphoid elements stained brown (arrowheads). Note that essentially none of the GFAP-immunoreac- tive astrocytes show Ki-67-immunoreactive nuclei and are thus not proliferative and exhibit only a moderate degree of reactive astrogl- iosis with cell hypertrophy and up regulation of GFAP, in spite of the presence of numerous inﬁltrating lymphoma cells. b High magniﬁ- cation image of a medulloblastoma immunohistochemically stained for GFAP and showing many processes of reactive astrocytes along one edge of the tumor (at right of ﬁgure). Scale bars a 15 lm, b 25 lm Astrocytic gliomas exhibit molecular heterogeneity, particularly as regards expression patterns of transcriptional regulators, tumor-suppressor proteins and kinase mutations, and molecular phenotyping of glioma is opening up the potential for molecularly targeted therapies [99]. Some properties of astroglioma appear related to astrocyte func- tions. For example, glutamate production by glioma may increase invasive growth properties [228]. Enhanced STAT3 signaling activity by astroglioma reduces inﬂam- mation and tumor-immune surveillance and increases cell proliferation [24] in a manner consistent with functions of STAT3 signaling in astrocytes [95]. 123