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 [beta]-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 [beta]-tubulin isotype ([beta]III) 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 [beta]III-tubulin is not neuron-specific, an observation that calls for a cautious interpretation of [beta]III-positive phenotypes in the histopathologic evaluation of neoplastic lesions.2-4
Expectedly, Martinez-Diaz and colleagues demonstrated a robust, presumably widespread, [beta]III 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-Pind).1 These findings are consistent with our previously published observations, insofar as [beta]III 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" [beta]III immunoreactivity in 8 of 9 PXA specimens, which is detected both in "large pleomorphic" and "smaller spindle cells." The presence of [beta]III in subpopulations of presumed astroglial cells in this neoplasm is to be expected, given the wide range of [beta]III labeling indices in common low-grade (WHO grade II) diffuse astrocytomas.3 However, to ascertain differences in the extent of [beta]III 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 [beta]III 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 glialneuronal phenotypes. The detection of synaptophysin staining in 7 of 9 PXA cases is strongly indicative of neuronal differentiation. The ratio of [beta]III-positive/glial fibrillary acidic protein-negative to [beta]III-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^sub ind^ are not described. Moreover, it is unknown whether the [beta]III/glial fibrillary acidic protein-negative cells in PXAs are doubly immunoreactive for NF-P^sub ind^, neuronal nuclear antigen, or synaptophysin. The painstaking elucidation of phenotypic identity of the [beta]III-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 [beta]III isotype is conserved in the developing and postnatal human nervous system, an attribute that is recapitulated in embryonal- and adult-type neuronal/neuroblastic tumors.26 Furthermore, [beta]III-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 [beta]III isotype is differentially expressed in neuronal versus glial tumors. In the former, [beta]III expression is differentiation-dependent (ie, associated with neuronal morphologic differentiation and decreased cell proliferation).26 Conversely, in glial tumors (astrocytomas and oligodendrogliomas), [beta]III 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 [beta]III 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 [beta]III 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 [beta]III, in conjunction with other neuronal marker proteins, such as synaptophysin and/or neuronal nuclear antigen, may denote neuronal differentiation. Although [beta]III 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 [beta]III in PXA is associated either with astroglial phenotypes, neuronal phenotypes, or with maldeveloped neuroepithelial cells (in which case the anomalous [beta]III expression may be linked to dysgenesis rather than anaplasia). The localization of [beta]III 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 [beta]III in glioma tumorigenesis cannot be overlooked. Dynamic instability of microtubules can be influenced by selective upregulation of certain tubulin isotypes, including [beta]III. 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 [beta]III 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.
CHRISTOS D. KATSETOS, MD, PhD, MRCPath
JEAN-PIERRE DE CHADAREVIAN, MD, FRCPC
AGUSTIN LEGIDO, MD, PhD
Drexel University College of Medicine and
St Christopher's Hospital for Children
Philadelphia, PA 19134
ELIAS PERENTES, MD, DMSc
Preclinical Safety
Novartis AG
Basel, Switzerland
SVERRE J. MORK, MD, PhD
University of Bergen
Haukeland Hospital
Bergen, Norway
1. Martinez-Diaz H, Kleinschmidt-DeMasters BK, Powell SZ, Yachnis AT. Giant cell glioblastoma and pleomorphic xanthoastrocytoma show different immunohistochemical profiles for neuronal antigens and p53 but share reactivity for class III [beta]-tubulin. Arch Kithol Lab Med. 2003;127:1187-1191.
2. Katsetos CD, Herman MM, Mork SJ. Class III [beta]-tubulin in human development and cancer. Cell Motil Cytoskeleton. 2003;55:77-96.
3. Katsetos CD, Del Valle L, Geddes JF, et al. Aberrant localization of the neuronal class III [beta]-tubulin in astrocytomas: a marker for anaplastic potential. Arch Pathol Lab Med. 2001;125:613-624.
4. Katsetos CD, Del Valle L, Geddes JF, et al. Localization of the neuronal class III [beta]-tubulin in oligodendrogliomas: comparison with Ki-67 proliferative index and 1p/19q status. J Neuropathol Exp Neurol. 2002;61:307-320.
5. Giannini C, Scheithauer BW, Lopes MB, Hirose T, Kros JM, VandenBerg SR. Immunophenotype of pleomorphic xanthoastrocytoma. Am J Surg Pathol. 2002;26:479-485.
6. Kalsetos CD, Del Valle L, Legido A, de Chadarevian J-P, Perentes E, Mork SJ. On the neuronal/ neuroblastic nature of medulloblastomas: a tribute to Pio del Rio Hortega and Moises Polak. Acta Neuropathol (Berl). 2003;105:1-13.
7. Powell SZ, Yachnis AT, Rorke LB, Rojiani AM, Eskin TA. Divergent differentiation in pleomorphic xanthoastrocytoma: evidence for a neuronal element and possible relationship to ganglion cell tumors. Am J Surg Pathol. 1996;20:80-85.
8. Perry A, Giannini C, Scheithauer BW, et al. Composite pleomorphic xanthoastrocytoma and ganglioglioma: report of four cases and review of the literature. Am J Surg Pathol. 1997;21:763-771.
9. Lopes MBS, Altermatt HJ, Scheithauer BW, Shepherd CW, VandenBerg SR. Immunohistochemical characterization of subependymal giant cell astrocytomas. Acta Neuropathol (Berl). 1996;91:368-375.
10. Dennis K, Uittenbogaard M, Chiaramello A, Moody SA. Cloning and characterization of the 5'-flanking region of the rat neuron-specific class III [beta]-tubulin gene. Gene. 2002;294:269-277.
In Reply.-We appreciate the comments concerning our study1 comparing the immunohistochemical (IHC) profiles of giant cell glioblastomas (GCGBMs) and pleomorphic xanthoastrocytomas (PXAs), and we agree with virtually all of them. They focus on the interpretation of results from 1 IHC marker used in our study, class III [beta]-tubulin ([beta]III).
Studies by Katsetos and colleagues show the utility of [beta]III as an IHC marker for nonneoplastic and neoplastic cells of neuronal or neuroendocrine lineage (reviewed in Katsetos et al2). However, [beta]III subsequently proved to be less specific for neuronal differentiation when applied to high-grade gliomas.3,4 In a separate study, we also observed widespread [beta]III immunoreactivity in high-grade gliomas, including many conventional types of glioblastoma.5 We agree that immunoreactivity for [beta]III (when staining is used in isolation and not in conjunction with other neuronal markers, such as synaptophysin or neuronal nuclear antigen) is not indicative of neuronal differentiation in high-grade glial neoplasms. What had not been previously reported, to our knowledge, is whether [beta]III would also be found in the GCGBM, a rare subtype of glioblastoma.
Our recently published study in the ARCHIVES was not a specific investigation of [beta]III expression, but rather was a comparison of IHC profiles (using a panel of antibodies that recognize p53, glial, and neuronal antigens) between 2 rare types of glial tumors, the GCGBM and PXA. As we noted in the article, these 2 tumors have sufficiently overlapping clinicopathologic features, including occurrence in younger patients, gross circumscription, reticulin deposition, lymphocytic infiltrates, and tumor giant cells, to create a potential diagnostic conundrum. To address this possible confusion, we studied reasonable numbers of each tumor (9 each), obtained from the combined files of several large institutions, and found that GCGBM can be reliably distinguished from PXA based on results of an IHC panel rather than a single antibody in isolation. Indeed, we specifically cautioned that the 2 tumors share reactivity for [beta]III.
Applying this IHC panel has practical implications, since these 2 tumor types have differing prognoses and treatments (PXA, World Health Organization [WHO] grade II, vs GCGBM, WHO grade IV). While we did not study PXA with anaplastic features (WHO grade III), the diagnostic criteria for this tumor have not been well established, and some neuropathologists do not even recognize "anaplastic PXA" as a specific entity. Also, distinguishing between a grade III and grade IV tumor would have less significant therapeutic and prognostic implications for the individual patient than correctly categorizing a tumor as a grade II glioma (PXA) versus a grade IV glioma (GCGBM).
We hope our study will assist practicing pathologists, who see relatively few examples of these rare tumors, in making the correct diagnosis. At the very least, the difference in IHC profile may further dispel any notion that these 2 tumor types are the same biological entity, however many features they have in common.
B. K. KLEINSCHMIDT-DEMASTERS, MD
Department of Pathology
University of Colorado Health Science Center
Denver, CO 80262
ANTHONY T. YACHNIS, MD
Department of Pathology, Immunology and Laboratory Medicine
University of Florida College of Medicine
Gainesville, FL 32610-0275
1. Martinez-Diaz H, Kleinschmidt-DeMasters BK, Powell SZ, Yachnis AT. Giant cell glioblastoma and pleomorphic xanthoastrocytoma show different immunohistochemical profiles for neuronal antigens and p53 but share reactivity for class III [beta]-tubulin. Arch Pathol Lab Med 2003;127:1187-1191.
2. Katsetos CD, Herman MM, Mork SJ. Class III [beta]-tubulin in human development and cancer. Cell Motil Cytoskeleton. 2003;55:77-96.
3. Katsetos CD, Del Valle L, Geddes JF, et al. Aberrant localization of the neuronal class III [beta]-tubulin in astrocytomas: a marker for anaplastic potential. Arch Pathol Lab Med. 2001;125:613-624.
4. Katsetos CD, Dell Valle L, Geddes JF, et al. Localization of the neuronal class III [beta]-tubulin in oligodendrogliomas: comparison with Ki67 proliferative index and 1p/19q status. J Neuropathol Exp Neurol. 2002;61:307-332.
5. Yachnis AT. Class III [beta] tubulin immunoreactivity in gliomas. J Neuropathol Exp Neurol. 2001;60: 517.
Copyright College of American Pathologists Apr 2004
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