Molecular analyses of rosette-forming glioneuronal tumor of the midbrain tegmentum: A report of two cases and a review of the FGFR1 status in unusual tumor locations
- Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
- Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan.
- Department of Pathology, Public Tomioka General Hospital, Tomioka, Japan.
- Department of Pathology, National Center for Child Health and Development, Tokyo, Japan.
Ichiyo Shibahara, Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
DOI:10.25259/SNI_55_2022Copyright: © 2022 Surgical Neurology International This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, transform, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.
How to cite this article: Hajime Handa1, Ichiyo Shibahara1, Yoshiko Nakano2, Madoka Inukai1, Sumito Sato1, Takuichiro Hide1, Junko Hirato3, Takako Yoshioka4, Koichi Ichimura2, Toshihiro Kumabe1. Molecular analyses of rosette-forming glioneuronal tumor of the midbrain tegmentum: A report of two cases and a review of the FGFR1 status in unusual tumor locations. 20-May-2022;13:213
How to cite this URL: Hajime Handa1, Ichiyo Shibahara1, Yoshiko Nakano2, Madoka Inukai1, Sumito Sato1, Takuichiro Hide1, Junko Hirato3, Takako Yoshioka4, Koichi Ichimura2, Toshihiro Kumabe1. Molecular analyses of rosette-forming glioneuronal tumor of the midbrain tegmentum: A report of two cases and a review of the FGFR1 status in unusual tumor locations. 20-May-2022;13:213. Available from: https://surgicalneurologyint.com/surgicalint-articles/11602/
Background: Rosette-forming glioneuronal tumor (RGNT) is a rare tumor that arises primarily in the posterior fossa, with molecular features of FGFR1 mutation. A previous study reported that brainstem RGNT accounts for only 2.7% cases; therefore, midbrain RGNT is infrequent.
Case Description: The authors encountered two cases of RGNT located in the midbrain tegmentum (Case 1: 23-year-old woman and Case 2: 18-year-old boy), both exhibiting similar cystic components with gadolinium-enhanced cyst walls on preoperative magnetic resonance imaging, surgically resected through the occipital transtentorial approach. Histological findings in both cases comprised two characteristic architectures of neurocytic and glial components, typical of RGNT. Molecular assessment revealed no FGFR1 mutation in the initial specimen, but revealed FGFR1 K656E mutation in the recurrent specimen in Case 1 and showed no FGFR1 mutation but showed TERT C228T mutation in Case 2. Neither case revealed IDH1/2, BRAF, H3F3A K27, H3F3A G34, or HIST1H3B K27 mutations. DNA methylation-based classification (molecularneuropathology.org) categorized both cases as RGNT, whose calibrated scores were 0.99 and 0.47 in Cases 1 and 2, respectively.
Conclusion: Midbrain tegmentum RGNTs exhibited typical histological features but varied FGFR1 statuses with TERT mutation. RGNT in rare locations may carry different molecular alterations than those in other common locations, such as the posterior fossa.
Keywords: FGFR1, Midbrain, Rosette-forming glioneuronal tumor, Tegmentum, TERT
Rosette-forming glioneuronal tumor (RGNT) is a rare tumor that arises primarily in the posterior fossa[
We encountered two cases of RGNT located in the midbrain tegmentum, both of which demonstrated a gadolinium-enhanced cyst wall and were radically resected using the occipital transtentorial approach. Molecular analyses of the rare midbrain tegmentum RGNT included FGFR1, TERT, IDH1, IDH2, H3F3A, HIST1H3B, BRAF, KIAA1549-BRAF fusion, and DNA methylation-based classifiers provided by MolecularNeuropathology.org.[
A 23-year-old woman presented with sensory disturbances in the left face and hand. Gadolinium-enhanced T1-weighted (GdT1WI) magnetic resonance imaging (MRI) revealed enhancement suggestive of a thin cystic wall without nodule formation on the right side of the midbrain tegmentum [
Gadolinium-enhanced T1-weighted magnetic resonance imaging (GdT1WI) of Cases 1 and 2. Case 1: Preoperative GdT1WI reveals an enhanced cystic tumor on the right side of the midbrain tegmentum (a). Postoperative magnetic resonance imaging indicates partial resection of the tumor (b). GdT1WI obtained 15 months after the initial surgery reveals tumor regression (c). After 30 months, follow-up GdT1WI reveals regrowth of the enhanced tumor (d). GdT1WI obtained immediately after the second surgery indicates gross total tumor resection (e). GdT1WI obtained 3 years after the second surgery reveals no recurrence (f). Case 2: Preoperative GdT1WI reveals an enhanced cystic tumor on the left side of the midbrain tegmentum (g). Postoperative GdT1WI indicates subtotal resection of the tumor (h). GdT1WI obtained 2 years after the second surgery reveals no recurrence (i).
An 18-year-old boy presented with a tremor in the right hand. GdT1WI MRI revealed a cystic tumor with thin-wall enhancement on the left side of the midbrain tegmentum [
Tumor specimens, DNA extraction, and pyrosequencing
Surgical tumor specimens of the initial and recurrent tissue samples of Case 1 and the initial tissue sample of Case 2 were subjected to the central pathological review by the Japan Children’s Cancer Group. Due to the tumor location in the midbrain, the tumor specimens were small. We were only able to obtain fresh frozen tissue from the recurrent tumor in Case 1, while paraffin-embedded specimens were available for the others. DNA from the frozen tumor tissue was extracted using a DNeasy Blood and Tissue Kit (Qiagen, Tokyo, Japan), and DNA from paraffin-embedded tumor tissue was extracted using a QIAamp DNA FFPE Tissue Kit (Qiagen, Tokyo, Japan). Hotspot mutations, including IDH1 R132, IDH2 R172, BRAF T599, BRAF V600, H3F3A K27, H3F3A G34, HIST1H3B K27, FGFR1 N546, FGFR1 K656, and C228T or C250T mutations in the promoter region of TERT (TERTp), were assessed through pyrosequencing[
Cases 1 [
Histological findings of Case 1. Hematoxylin and Eosin (HE) staining demonstrate coexistence of glial and neurocytic components (a). Higher magnification reveals the glial component (b) and neurocytic component (c). The glial component is GFAP positive (d) and the neurocytic component is synaptophysin positive (e). HE staining of the recurrent tissue does not reveal malignant changes (f). The black bar indicates 100 um.
The results of molecular analyses are summarized in [
FGFR1 mutation was assessed using the initial FFPE specimen, but neither N546 nor K656 mutations were detected [
Molecular analysis of Case 1 (a and b) and Case 2 (c and d). Sanger sequencing reveals FGFR1 K656E mutation (c.1966A>G, arrow) in the recurrent specimen (a), and the DNA methylation-based classification reveals flattened copy-number alterations corresponding to those of RGNT (b). Pyrosequencing reveals a mutation at the C228T of TERT promoter (c, red arrow) and the DNA methylation-based classification reveals flattened copy-number alterations corresponding to those of RGNT (d).
Molecular analyses using the initial FFPE specimen revealed no FGFR1 mutations but revealed TERTp C228T mutation [
We have reported two cases of histologically confirmed RGNT located in the midbrain tegmentum using molecular analyses. Brainstem RGNT has a prevalence of 2.7%,[
Diffuse midline gliomas or tectal gliomas can be differential diagnoses due to the midline, brainstem, or midbrain locations. A report of adult brainstem gliomas included nine lesions located in the midbrain tectum and two in the midbrain tegmentum. One case each exhibited H3K27M positivity on immunohistochemistry,[
The initial tumors in Cases 1 and 2 did not harbor FGFR1 mutations, in contrast to the findings of Sievers et al., all of whose RGNT cases carried FGFR1 hotspot mutations.[
We found a TERTp mutation in the RGNT cases. Duan et al. analyzed TERTp mutations in spinal RGNTs found no mutations.[
We have reported two cases of cystic tumor in the midbrain tegmentum, histologically diagnosed as RGNTs. Molecular analyses showed that both cases were negative for FGFR1 mutation in the initial tumor specimens, and one case presented with TERTp mutation. The present cases indicate that RGNT in uncommon tumor locations, including the midbrain tegmentum, may molecularly differ from RGNTs in other common tumor locations, and demonstrate the importance of molecular analyses for understanding the pathophysiology of RGNTs.
Institutional Review Board (IRB) permission obtained for the study.
This work was in part supported by JSPS KAKENHI Grant Number 20K16873 (YN).
There are no conflicts of interest.
The authors would like to thank central pathological and molecular review by Japan Children’s Cancer Group, and Enago (“ http://www.enago.jp ” www.enago.jp) for the English language review. We thank M. Kitahara and Y. Hibiya for their technical support.
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