Giant Cell Glioblastoma and Pleomorphic Xanthoastrocytoma Open Access

To the Editor.—We read with interest the article by Martinez-Diaz et al,1 “Giant Cell Glioblastoma and Pleomorphic Xanthoastrocytoma Show Different Immunohistochemical Profiles for Neuronal Antigens and p53 but Share Reactivity for Class III β-Tubulin.” Although we agree for the most part with the authors' observations and conclusions, we would like to use this opportunity to offer our perspective with regard to the interpretation of the immunohistochemical localization of the class III β-tubulin isotype (βIII) in these 2 fundamentally distinct neuroepithelial tumors.

Our group has previously shown that under certain conditions of neoplasia, the expression of the so-called neuronal βIII-tubulin is not neuron-specific, an observation that calls for a cautious interpretation of βIII-positive phenotypes in the histopathologic evaluation of neoplastic lesions.2–4 

Expectedly, Martinez-Diaz and colleagues demonstrated a robust, presumably widespread, βIII immunoreactivity in giant cell glioblastoma, which is accompanied by a paucity of staining for other mature neuronal markers, such as synaptophysin, neuronal nuclear antigen, and a phosphorylation-independent epitope of neurofilament protein (NF-P_ind).1 These findings are consistent with our previously published observations, insofar as βIII is widely expressed in glioblastoma multiforme.3 

According to the World Health Organization (WHO) classification, pleomorphic xanthoastrocytoma (PXA) is a grade II glioma. In keeping with previous reports,5 the authors described “strong” βIII immunoreactivity in 8 of 9 PXA specimens, which is detected both in “large pleomorphic” and “smaller spindle cells.” The presence of βIII in subpopulations of presumed astroglial cells in this neoplasm is to be expected, given the wide range of βIII labeling indices in common low-grade (WHO grade II) diffuse astrocytomas.3 However, to ascertain differences in the extent of βIII immunoreactivity in giant cell glioblastoma versus PXA, it would be necessary to undertake semiquantitative studies and determine any statistically significant differences in the labeling indices between these 2 tumor types. Also, such differences should be sought in a larger series of cases comprising primary, recurrent, and aggressive PXA. Although the authors provide p53 labeling indices, it is unclear whether a statistically significant relationship exists between βIII and p53 labeling indices in giant cell glioblastoma, as compared to PXA.

The lack of an obvious ganglionic component in most PXAs does not negate the presence of mixed glial-neuronal phenotypes. The detection of synaptophysin staining in 7 of 9 PXA cases is strongly indicative of neuronal differentiation. The ratio of βIII-positive/glial fibrillary acidic protein–negative to βIII-positive/glial fibrillary acidic protein–positive (ie, presumed glial phenotype) is not reported. Also, the morphologic features of cells expressing synaptophysin and/or NF-P_ind are not described. Moreover, it is unknown whether the βIII/glial fibrillary acidic protein–negative cells in PXAs are doubly immunoreactive for NF-P_ind, neuronal nuclear antigen, or synaptophysin. The painstaking elucidation of phenotypic identity of the βIII-positive tumor cell(s) in PXA is critical, because expression of this protein has a diametrically different significance in the context of growth and differentiation of neuronal versus glial tumors.2 

Studies conducted in our laboratory during the past decade have shown that the neuronal specificity of the βIII isotype is conserved in the developing and postnatal human nervous system, an attribute that is recapitulated in embryonal- and adult-type neuronal/neuroblastic tumors.2,6 Furthermore, βIII-tubulin is also expressed, albeit only transiently, in somatic embryonic cells, including putative bipotential neuronal/glial progenitors and/or glial restricted precursor cells in the germinal matrix of the telencephalic subventricular zones.2 

The βIII isotype is differentially expressed in neuronal versus glial tumors. In the former, βIII expression is differentiation-dependent (ie, associated with neuronal morphologic differentiation and decreased cell proliferation).2,6 Conversely, in glial tumors (astrocytomas and oligodendrogliomas), βIII expression is aberrant and is increased according to an ascending gradient of histologic malignancy, as corroborated by a coordinate expression of markers of cell proliferation.2–4 The detection of βIII in neoplastic glial phenotypes may signify dedifferentiation associated with either (a) cellular deregulation in the context of genetic instability and anaplastic change or (b) incomplete/faulty cellular differentiation in the context of dysontogenesis.2,3 

It follows then that the lack of βIII lineage specificity in tumorigenesis is a confounding factor in the interpretation of immunoreactivity in mixed neuronal-glial tumors (gangliogliomas) or other neoplasms with ambiguous glioneuronal differentiation. Pleomorphic xanthoastrocytomas may be part of a nosologic spectrum of developmental neoplasms, overlapping with gangliogliomas and desmoplastic gangliogliomas.7,8 In this context, the detection of βIII, in conjunction with other neuronal marker proteins, such as synaptophysin and/or neuronal nuclear antigen, may denote neuronal differentiation. Although βIII and neurofilament protein are expressed by neoplastic astrocytes, to our knowledge, synaptophysin and neuronal nuclear antigen are not.3 It remains to be further elucidated whether βIII in PXA is associated either with astroglial phenotypes, neuronal phenotypes, or with maldeveloped neuroepithelial cells (in which case the anomalous βIII expression may be linked to dysgenesis rather than anaplasia). The localization of βIII in the phenotypically ambiguous giant/ballooned cells of subependymal giant cell astrocytomas of tuberous sclerosis is a case in point.9 

Despite its lack of phenotypic specificity, the biological import of βIII in glioma tumorigenesis cannot be overlooked. Dynamic instability of microtubules can be influenced by selective upregulation of certain tubulin isotypes, including βIII. The latter may contribute to the emergence of tumor cell resistance to microtubule acting compounds, including Taxol/paclitaxel (reviewed in Katsetos et al2). Doubtless, the characterization of the promoter region of the βIII gene10 and the identification of gene-associated regulatory elements10 are likely to provide critical insights into potential mechanisms of altered regulation of this cytoskeletal protein in neuronal versus glial tumors.