The glioneuronal tumor with neuropil-like islands (GTNI) is an uncommon histopathological entity composed of diffuse astrocytic or oligoastrocytic elements interspersed with sharply delimited, micronodular loci of neuronal differentiation. Despite its initial description over 10 years ago [10], the lineage classification of GTNI remains speculative. The clinical features of GTNI, its infiltrative growth characteristics, typically dominating astroglial components, and frequent p53 expression, are all consistent with a fundamental linkage to the diffuse astrocytic tumor group. Supporting this notion are reports documenting, by comparative genomic hybridization, an astrocytoma-like profile of 7q21.1-qter gain and 9p21-pter loss in one case [8] and the absence of oligodendroglioma-associated 1p/19q deletions in a series assessed by polymerase chain reaction-based loss of heterozygosity analysis [3].
Point mutations in the isocitrate dehydrogenase enzymes, IDH1 and IDH2, are found in the majority of WHO grade II and III diffuse gliomas—both astrocytic and oligodendroglial—as well as secondary glioblastomas (GBM), but they are almost entirely absent from primary GBM [7, 9, 11]. As such, they appear to represent a defining early genomic lesion in the pathogenesis of diffuse glioma variants exhibiting step-wise malignant evolution. Glioma-associated IDH mutations invariably involve active site arginine residues—R132 and R172 for IDH1 and IDH2, respectively—and, while their precise pathogenic mechanism remains unclear, they appear to promote the generation of the cancer-predisposing toxic metabolite, R(-)-2-hydroxyglutarate [6].
Anzeige
We assembled 12 cases of GTNI (Table 1) seen at the Memorial Hospital Department of Pathology, along with pertinent clinical information from the patients’ medical records. To evaluate whether IDH1 and IDH2 mutations were present in our sample set, we performed custom genotyping assays on the Sequenom platform [1, 2] and/or employed validated immunohistochemical staining (IHC) for the most common IDH mutation, IDH1 R132H [5]. We found that every tumor in our sample set (12/12) exhibited evidence of the IDH1 R132H mutation by either one or both of our assay methods (Fig. 1a–d), and concordant results were achieved for all cases screened by both Sequenom® and IHC (Table 1). Both glial and neuronal components exhibited immuno-expression of mutant IDH1 in all examined cases (Fig. 1d).
Table 1
Cases included in GTNI study cohort listed with patient age at first diagnosis, sex, histopathological grade (Grade), Sequenom® genotyping result (Sequenom) and IHC for IDH1 R132H (R132H IHC)
Case
Age
Sex
Grade
Sequenom
R132H IHC
1
70
M
LG
R132H
NA
2a
40
M
HG: MVP/NEC
R132H
NA
3a
57
M
LG
R132H
NA
4a
56
M
HG
R132H
NA
5a
40
M
LG
R132H
+
6a
38
M
LG
R132H
+
7a
47
M
LG
R132H
+
8
43
F
LG
R132H
NA
9
40
M
HG
NA
+
10a
41
M
LG
R132H
+
11
53
F
HG
NA
+
12
29
F
HG
R132H
+
M male, F female, LG low-grade, HG high-grade, MVP microvascular proliferation, NEC necrosis, R132H IDH1 R132H mutation
aCases included in a previous study of 1p/19q co-deletion in GTNI [3]
×
The primary significance of our findings lies in strengthening the pathogenic link between GTNIs and the diffuse glioma tumor group. Studies to date indicate that within primary brain tumors, IDH mutations are largely restricted to diffuse gliomas evolving via step-wise malignant evolution (i.e., diffuse astrocytomas, oligodendrogliomas, and oligoastrocytomas). Combined with the frequent p53 immunoreactivity and general absence of 1p/19q chromosomal co-deletions previously documented in this setting, a high incidence of IDH1 mutations would fundamentally ally GTNIs with the diffuse astrocytoma and 1p/19q-intact oligoastrocytoma group. Indeed, the 100% incidence of IDH mutation in our sample set is even higher than that documented in diffuse astrocytoma so far (~80%) [7, 11]. As an aside, recent work has also identified IDH mutation as a prevalent feature of oligodendrogliomas with neurocytic differentiation [4], further emphasizing that focally prominent neuronal morphology falls well within the histopathological spectrum of diffuse gliomas in general. The invariable presence of the specific IDH1 R132H mutation in our GTNIs may represent an artifact of small sample number, but, nevertheless, it is striking. Whether other IDH1 or IDH2 mutational variants exist in GTNI and whether a genotypic restriction to IDH1 R132H alone would have any functional significance remain unclear.
Acknowledgments
We would like to thank Miriam Fayad for her assistance with immunohistochemical staining and Laetitia Borsu for assistance with Sequenom assays. The MSKCC Sequenom facility was supported by the Anbinder Fund.
Open Access
This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
Anzeige
Open AccessThis is an open access article distributed under the terms of the Creative Commons Attribution Noncommercial License (https://creativecommons.org/licenses/by-nc/2.0), which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
Mit e.Med Neurologie & Psychiatrie erhalten Sie Zugang zu CME-Fortbildungen der Fachgebiete, den Premium-Inhalten der dazugehörigen Fachzeitschriften, inklusive einer gedruckten Zeitschrift Ihrer Wahl.
Mit e.Med Neurologie erhalten Sie Zugang zu CME-Fortbildungen des Fachgebietes, den Premium-Inhalten der neurologischen Fachzeitschriften, inklusive einer gedruckten Neurologie-Zeitschrift Ihrer Wahl.
Wenn unter einer medikamentösen Hochdrucktherapie der diastolische Blutdruck in den Keller geht, steigt das Risiko für schwere kardiovaskuläre Ereignisse: Darauf deutet eine Sekundäranalyse der SPRINT-Studie hin.
Ist die Tau-Last noch gering, scheint der Vorteil von Lecanemab besonders groß zu sein. Und beginnen Erkrankte verzögert mit der Behandlung, erreichen sie nicht mehr die kognitive Leistung wie bei einem früheren Start. Darauf deuten neue Analysen der Phase-3-Studie Clarity AD.
Neue arznei- und zellbasierte Ansätze, Frühdiagnose mit Bewegungssensoren, Rückenmarkstimulation gegen Gehblockaden – in der Parkinsonforschung tut sich einiges. Auf dem Deutschen Parkinsonkongress ging es auch viel um technische Innovationen.
Wenn Demenzkranke aufgrund von Symptomen wie Agitation oder Aggressivität mit Antipsychotika behandelt werden, sind damit offenbar noch mehr Risiken verbunden als bislang angenommen.
Update Neurologie
Bestellen Sie unseren Fach-Newsletterund bleiben Sie gut informiert.