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Spinal glioneuronal tumors: location matters!—Reply
Spinal glioneuronal tumors: location matters!—reply Marco Gessi MD, Torsten Pietsch PII: DOI: Reference:
S0046-8177(16)30028-4 doi: 10.1016/j.humpath.2016.02.031 YHUPA 3865
To appear in:
Human Pathology
Received date: Accepted date:
4 February 2016 18 February 2016
Please cite this article as: Gessi Marco, Pietsch Torsten, Spinal glioneuronal tumors: location matters!—reply, Human Pathology (2016), doi: 10.1016/j.humpath.2016.02.031
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Spinal Glioneuronal Tumors: Location Matters!—Reply
RI PT
Dear Editor, We have read with interest the commentary “Spinal glioneuronal tumors: location matters!” by K. Gupta. In the last few years, significant steps have been taken toward deciphering the
SC
molecular biology of glioneuronal tumors of the central nervous system, and in particular of gangliogliomas. BRAFV600E mutation, identified in about 30%-60% of cases, represents to date the
NU
most common molecular alteration found in gangliogliomas [1,2]. Various studies have further
MA
showed that the BRAFV600E mutation rate differs according to the tumor localization. While these mutations appear particularly frequent in gangliogliomas arising in the brain stem and the posterior fossa [2], they seem rare in spinal ganglioglioma, as demonstrated in our study [3]. Interestingly,
PT ED
along with typical BRAFV600-mutated cases the analysis of a series of gangliogliomas of the posterior fossa and brain stem revealed a group of glioneuronal tumors with histologic and molecular similarities to pilocytic astrocytomas [2]. These tumors, characterized by homogenous
CE
neuroradiological and molecular features with the presence of KIAA1549-BRAF fusions and by the
AC
presence of a focal clustered dysplastic ganglion cell component have been termed pilocytic astrocytoma with ganglionic differentiation. In two cases of our series of spinal gangliogliomas [3], we found evidence of extra copies of KIAA1549 and BRAF genes suggestive of KIAA1549-BRAF fusion, and in other two cases we demonstrated presence of BRAFV600E mutation. Histologically, we did not find significant differences between cases with fusion and mutation, in particular regarding the number and pattern of distribution of ganglionic cells. We would prefer to term them according to the current World Health Organization classification as ganglioglioma because the presence of dysplastic ganglionic cells in pilocytic astrocytomas is not widely accepted in the neuropathology community. Neuroradiological information was lacking for most cases in our study and cannot contribute in the classification of this series.
ACCEPTED MANUSCRIPT H3F3AK27M mutations are actually considered the genetic hallmark of midline high-grade gliomas and diffuse intrinsic pontine gliomas (DIPG) [4]. These mutations were found also in
RI PT
thalamic and spinal high-grade gliomas [5]. Besides high-grade gliomas, H3F3AK27M mutations have also been identified in glioneuronal tumors [6]. In this line, we identified two cases of anaplastic gangliogliomas affecting the spinal cord carrying this mutation [3]. We carefully
SC
considered other differential diagnoses, but the histology of these tumors, in particular the extent of dysplastic ganglion cell component as well as the cytological and immunohistochemical features,
NU
qualified the tumors for the diagnosis of anaplastic ganglioglioma rather than a diffusely infiltrating
MA
high-grade glioma.
According the available data, the type of genetic alterations found so far in anaplastic gangliogliomas (ie, CDKN2A deletion in supratentorial anaplastic gangliogliomas and H3F3AK27M
PT ED
mutation in spinal cases) seems to vary according to the localization of the tumor, as in diffuse anaplastic astrocytomas and glioblastomas. In this view, analysis of the H3F3AK27M status in brain stem and in hemispheric pediatric anaplastic gangliogliomas could be of particular interest. From a
CE
clinical point of view, anaplastic gangliogliomas in the spinal cord usually show an aggressive
AC
clinical behavior. Unfortunately, we cannot provide detailed follow-up information for these cases reported in our study [3]. However, it cannot be excluded that patients with these tumors, as observed in patients with supratentorial anaplastic gangliogliomas, may show a more favorable prognosis than patients affected by diffuse anaplastic astrocytoma and glioblastomas of the spinal cord.
Marco Gessi MD Torsten Pietsch [AU: Degree?] Institute of Neuropathology, University of Bonn Medical Center, D-53105 Bonn, Germany E-mail: [email protected]
ACCEPTED MANUSCRIPT References [1] Schindler G, Capper D, Meyer J, et al. Analysis of BRAF V600E mutation in 1,320 nervous
RI PT
system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 2011;121:397–405. [2] Gupta K, Orisme W, Harreld JH, et al. Posterior fossa and spinal gangliogliomas form two
SC
distinct clinicopathologic and molecular subgroups. Acta Neuropathol Commun 2014;2:18-25. [3] Gessi M, Dörner E, Dreschmann V, et al. Intramedullary gangliogliomas: histopathological and
NU
molecular features of 25 cases. HUM PATHOL 2016;49:107-13.
MA
[4] Fontebasso AM, Bechet D, Jabado N. Molecular biomarkers in pediatric glial tumors: a needed wind of change. Curr Opin Oncol 2013;25:665-73.
[5] Gessi M, Gielen GH, Dreschmann V, Waha A, Pietsch T. High frequency of H3F3A (K27M)
PT ED
mutations characterizes pediatric and adult high-grade gliomas of the spinal cord. Acta Neuropathol 2015;130:435-7.
[6] Nguyen AT, Colin C, Nanni-Metellus I, et al. Evidence for BRAF V600E and H3F3A K27M
AC
2015;41:403-8.
CE
double mutations in paediatric glial and glioneuronal tumours. Neuropathol Appl Neurobiol
S0046-8177(16)30028-4 doi: 10.1016/j.humpath.2016.02.031 YHUPA 3865
To appear in:
Human Pathology
Received date: Accepted date:
4 February 2016 18 February 2016
Please cite this article as: Gessi Marco, Pietsch Torsten, Spinal glioneuronal tumors: location matters!—reply, Human Pathology (2016), doi: 10.1016/j.humpath.2016.02.031
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Spinal Glioneuronal Tumors: Location Matters!—Reply
RI PT
Dear Editor, We have read with interest the commentary “Spinal glioneuronal tumors: location matters!” by K. Gupta. In the last few years, significant steps have been taken toward deciphering the
SC
molecular biology of glioneuronal tumors of the central nervous system, and in particular of gangliogliomas. BRAFV600E mutation, identified in about 30%-60% of cases, represents to date the
NU
most common molecular alteration found in gangliogliomas [1,2]. Various studies have further
MA
showed that the BRAFV600E mutation rate differs according to the tumor localization. While these mutations appear particularly frequent in gangliogliomas arising in the brain stem and the posterior fossa [2], they seem rare in spinal ganglioglioma, as demonstrated in our study [3]. Interestingly,
PT ED
along with typical BRAFV600-mutated cases the analysis of a series of gangliogliomas of the posterior fossa and brain stem revealed a group of glioneuronal tumors with histologic and molecular similarities to pilocytic astrocytomas [2]. These tumors, characterized by homogenous
CE
neuroradiological and molecular features with the presence of KIAA1549-BRAF fusions and by the
AC
presence of a focal clustered dysplastic ganglion cell component have been termed pilocytic astrocytoma with ganglionic differentiation. In two cases of our series of spinal gangliogliomas [3], we found evidence of extra copies of KIAA1549 and BRAF genes suggestive of KIAA1549-BRAF fusion, and in other two cases we demonstrated presence of BRAFV600E mutation. Histologically, we did not find significant differences between cases with fusion and mutation, in particular regarding the number and pattern of distribution of ganglionic cells. We would prefer to term them according to the current World Health Organization classification as ganglioglioma because the presence of dysplastic ganglionic cells in pilocytic astrocytomas is not widely accepted in the neuropathology community. Neuroradiological information was lacking for most cases in our study and cannot contribute in the classification of this series.
ACCEPTED MANUSCRIPT H3F3AK27M mutations are actually considered the genetic hallmark of midline high-grade gliomas and diffuse intrinsic pontine gliomas (DIPG) [4]. These mutations were found also in
RI PT
thalamic and spinal high-grade gliomas [5]. Besides high-grade gliomas, H3F3AK27M mutations have also been identified in glioneuronal tumors [6]. In this line, we identified two cases of anaplastic gangliogliomas affecting the spinal cord carrying this mutation [3]. We carefully
SC
considered other differential diagnoses, but the histology of these tumors, in particular the extent of dysplastic ganglion cell component as well as the cytological and immunohistochemical features,
NU
qualified the tumors for the diagnosis of anaplastic ganglioglioma rather than a diffusely infiltrating
MA
high-grade glioma.
According the available data, the type of genetic alterations found so far in anaplastic gangliogliomas (ie, CDKN2A deletion in supratentorial anaplastic gangliogliomas and H3F3AK27M
PT ED
mutation in spinal cases) seems to vary according to the localization of the tumor, as in diffuse anaplastic astrocytomas and glioblastomas. In this view, analysis of the H3F3AK27M status in brain stem and in hemispheric pediatric anaplastic gangliogliomas could be of particular interest. From a
CE
clinical point of view, anaplastic gangliogliomas in the spinal cord usually show an aggressive
AC
clinical behavior. Unfortunately, we cannot provide detailed follow-up information for these cases reported in our study [3]. However, it cannot be excluded that patients with these tumors, as observed in patients with supratentorial anaplastic gangliogliomas, may show a more favorable prognosis than patients affected by diffuse anaplastic astrocytoma and glioblastomas of the spinal cord.
Marco Gessi MD Torsten Pietsch [AU: Degree?] Institute of Neuropathology, University of Bonn Medical Center, D-53105 Bonn, Germany E-mail: [email protected]
ACCEPTED MANUSCRIPT References [1] Schindler G, Capper D, Meyer J, et al. Analysis of BRAF V600E mutation in 1,320 nervous
RI PT
system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 2011;121:397–405. [2] Gupta K, Orisme W, Harreld JH, et al. Posterior fossa and spinal gangliogliomas form two
SC
distinct clinicopathologic and molecular subgroups. Acta Neuropathol Commun 2014;2:18-25. [3] Gessi M, Dörner E, Dreschmann V, et al. Intramedullary gangliogliomas: histopathological and
NU
molecular features of 25 cases. HUM PATHOL 2016;49:107-13.
MA
[4] Fontebasso AM, Bechet D, Jabado N. Molecular biomarkers in pediatric glial tumors: a needed wind of change. Curr Opin Oncol 2013;25:665-73.
[5] Gessi M, Gielen GH, Dreschmann V, Waha A, Pietsch T. High frequency of H3F3A (K27M)
PT ED
mutations characterizes pediatric and adult high-grade gliomas of the spinal cord. Acta Neuropathol 2015;130:435-7.
[6] Nguyen AT, Colin C, Nanni-Metellus I, et al. Evidence for BRAF V600E and H3F3A K27M
AC
2015;41:403-8.
CE
double mutations in paediatric glial and glioneuronal tumours. Neuropathol Appl Neurobiol