2020 Volume 7 Issue 4 Pages 205-210
A 6-year-old female was incidentally found to have a brain tumor. Magnetic resonance imaging (MRI) demonstrated a gadolinium-enhanced mass in the left parietal lobe. We performed gross total resection with the assistance of fluorescent guidance by 5-aminolevulinic acid (5-ALA). A histological examination of the tumor specimen showed well-differentiated astroblastic features with focal anaplasia. Fluorescence in situ hybridization (FISH) revealed meningioma 1 (MN1) gene alteration and supported our diagnosis. She received local radiotherapy and oral temozolomide followed by maintenance temozolomide chemotherapy, and the tumor was well controlled without any neurological deficit for 27 months. Our case is considered to be valuable since it describes a patient who is diagnosed to have a well-differentiated astroblastoma with both focal anaplastic features and MN1 gene rearrangement. A larger study is warranted to establish evidence supporting the diagnosis and treatment of astroblastoma with molecular characteristic features. MN1 alteration will be a diagnostic marker for astroblastoma in the future.
Astroblastoma usually occurs in bimodal distribution, with a peak between the ages of 5- to 10-years old and another between the ages of 21- to 30-years old. It shows a female predominance and is thought to arise from astroblastic cells.1) The most recent WHO classification of brain tumors classified this tumor as “other glioma” and did not establish a WHO grade because of the absence of sufficient clinicopathological data.2) Recent literature has suggested a new molecular characteristic feature of meningioma 1 (MN1) gene rearrangement.3) However, the clinical course of astroblastoma with MN1 alteration has been unclear, and evidence supporting the appropriate treatment has been insufficient.
We encountered a patient with well-differentiated astroblastoma showing focal anaplastic features with meningioma 1 gene alteration. We herein report this rare case and discuss the pathogenesis and prognosis.
A 6-year-old girl complained of a painful head bruise and was examined at the closest hospital. A neurological examination revealed no deficit. Computed tomography (CT) showed an iso-density mass lesion with a calcified node on the left parietal lobe (Fig. 1A). She had a history of varicella and exanthema subitum. She was admitted to our department for treatment.
Magnetic resonance imaging (MRI) demonstrated a lobulated lesion with a small cystic component that showed iso-intensity on T1- and T2-weighted imaging and heterogeneous enhancement (Figs. 1B–1E). The enhanced lesion showed a high uptake on L-[methyl-11C] methionine (MET)-positron emission tomography (PET)/CT (Fig. 1F). Left parietal osteoplastic craniotomy was performed. On dissection of the cerebral cortex, the tumor was gray and well-circumscribed, and gross total resection was performed under fluorescent guidance with 5-aminolevulinic acid (5-ALA). On day 10 postoperatively, she was discharged from the hospital without neurological deficit.
After the histological diagnosis was obtained, concomitant chemoradiation therapy was performed, including extended local irradiation (54 Gy/30 Fr) and oral temozolomide (75 mg/m2). After 10 cycles of maintenance therapy using temozolomide, she was free from recurrence at 27 months after the initial treatment.
Pathological findingsThe tumor tissue showed relative homogeneity and several characteristic morphological findings. The main part showed high cellularity with perivascular hyalinization, a pseudopapillary pattern, and astroblastic pseudorosette with low nuclear mitosis (2/10 high-power fields [HPFs]) (Fig. 2A). There were no microvascular proliferations or necrosis. The immunohistochemical findings revealed oligodendrocyte transcription factor 2 (Olig2) positivity, multi-focal positivity for glial fibrillary acidic protein (GFAP), and dot-like positivity for epithelial membrane antigen (EMA) (Figs. 2B–2D). Cytokeratin markers, such as AE1/AE3, MNF116, and CAM5.2, were negative. Podoplanin, Vimentin, S-100 protein, ATRX, CD99, transthyretin, and CD56 were positive, while IDH1 R132H, p53, BRAF V600E, and L1CAM were negative. The Ki-67 labeling index was 6.2%. The other area was composed of epithelial-like cells with large and irregular nuclei (Fig. 2E). Tumor cells were also seen along the Virchow-Robin spaces. This part of the tumor showed a Ki-67 labeling index of 13.6% (Fig. 2F). Based on the presence of perivascular hyalinization and an astroblastic pseudorosette without high-mitosis nuclei, this main component of the tumor was identified as well-differentiated astroblastoma. However, this tumor specimen had marked nuclear anaplasia and a focally high mitotic rate. We also analyzed the MN1 gene alteration using break-apart fluorescence in situ hybridization (FISH), as described previously.3) The FISH analysis revealed MN1 rearrangement, characterized with two to three fused red/green signals and one to three isolated red or green signals in each tumor cell in well-differentiated lesions (Fig. 3). These multiple fused red/green signals suggested the gains of the MN1 locus and the separated red and green signals were considered to have a disrupting effect on the MN1 locus.3)
Based on these findings, we finally diagnosed the patient with well-differentiated astroblastoma showing focal anaplastic features with MN1 alteration.
Astroblastoma was not given a tumor grade in the 2016 WHO classification of CNS tumor and is sorted into high- (anaplastic) and low-grade lesions (well-differentiated) histologically.2) High-grade lesions show high cellularity, anaplastic nuclear features, high mitotic rates, vascular proliferation, and necrosis with psedopalisading, while low-grade lesions show the uniform perivascular arrangement of pseudorosettes, low-to-moderate numbers of mitotic figures, minimal cellular atypia, minimal-to-no vascular endothelial proliferation, and predominant sclerosis of the vascular walls. In addition, the WHO guideline suggested the cut-off for the Ki-67 labeling index of high grade astroblastoma be set at over 10%.2)
Thus far, our case could not be defined as high grade or not, because the pathological findings showed well differentiated astroblastic features with focal anaplasia. Two major studies have mentioned the origin of astroblastoma. One suggested the theory of dedifferentiation from mature astroglial cells, and the other proposed that astroblastic cells are intermediate cells between astrocytes and ependymal cells.4,5) Since our patient was diagnosed incidentally based on CT findings, we carefully investigated the pathological findings to determine the manner of malignant transformation or dedifferentiation of the astroblastic cells to an anaplastic pattern.
Table 1 shows the literature review of the 20 astroblastoma cases with MN1 rearrangement and survival information.3,6–10) Almost all patients had lesions in the cerebrum, with one patients showing a lesion in the spinal cord and another showing a lesion in the brainstem.7,8) As in our case, Shin et al.8) reported a patient with brainstem astroblastoma with focal anaplasia. The radiological findings of astroblastoma with MN1 translocation showed the tumors to be well-demarcated, lobular or nodular, and located superficially in the cerebral hemisphere. Occasionally, a tumor had calcified foci or cystic components. All patients underwent removal and survived, and eight cases remain alive with stable disease despite histological malignancy. Our case was able to be resected totally under fluorescent guidance with 5-ALA. At surgery, the tumor margin and residual specimen included cyst wall were clearly identified on fluorescence excitation. Other recent studies have described similar cases of fluorescence-guided surgery for astroblastoma.11) Although the standard adjuvant procedure for high-grade astroblastoma has not been confirmed, Mallick et al.12) advocated maximal surgical resection followed by adjuvant temozolomide and local radiotherapy and described a case treated according to their recommendation, as the case had potential malignant transformation or dedifferentiation of the astroblastic cells to an anaplastic pattern. Another previously reported case of focal anaplasia underwent near total resection and was administered combined chemotherapy with daily carboplatin plus weekly vincristine and radiotherapy (54 Gy/30 Fr).8) Astroblastoma with MN1 rearrangement seems to have a longer survival clinical course than anaplastic pleomorphic xanthoastrocytoma or IDH-wild-type glioblastoma. Lheman et al.9) reported in their genomic analysis of histologically diagnosed astroblastoma that MN1-rearranged cases showed a significantly better survival than BRAF-V600E mutant astroblastomas.
| Reference | Cases | Age(years)/sex | Symptom | Location | Grade | Radiology | Treatment | Prognosis |
| Wood, et al.6 | 1 | 10/F | NA | Left parietal | High | NA | Resection, radiation, chemotherapy (TMZ) | AWSD (2 yrs and 8 mos) |
| 2 | 31/F | NA | Left parietal | High | NA | Resection, radiation, chemotherapy (TMZ) | AWSD (1 yr) | |
| Yamada, et al.7 | 1 | 20/F | Weakness, hypesthesia | Spinal cord (T1-2) | Low | Contrast-enhancing intramedullary spinal cord lesion | Biopsy, radiation (52Gy), chemotherapy (TMZ and BEV) | NED (1 yr) |
| Hirose, et al.3 | 1 | 6/F | Generated convulsion | Left frontal | Low | Well-demarcated, contrast-enhancing lesion with calcified foci | GTR | NED (3 yrs and 3 mos) |
| 2 | 6/F | Headache | Occipital | Low | Well-demarcated, contrast-enhancing solid lesion | GTR | NED (6 yrs and 4 mos) | |
| 3 | 18/F | Headache, nausea | Right frontal | Low | Well-demarcated, contrast enhancing solid cystic lesion | GTR | NED (6 mos) | |
| 4 | 24/F | Weakness, seizures | Left frontal | High | Well-demarcated, contrast enhancing lesion | GTR, radiation (50Gy) | NED (5 yrs) | |
| 5 | 37/F | Headache, vomiting | Left occipital | High | Ill-defined, contrast enhancing lesion | GTR, radiation, chemotherapy | NED (2 yrs) | |
| Shin, et al.8 | 1 | 11/M | Headache, dizziness, photophobia, gait disturbances | Brainstem | unclear | Exophytic, solid, cystic contrast enhancing lesion | NTR, radiation (54Gy), chemotherapy (carboplatin and vincristine) | NA |
| Lehman, et al.9 | 1 | 16/F | NA | Left parieto-occipital | High | NA | Resection | AWSD (11 yrs and 6 mos) |
| 2 | 33/F | NA | Left temporal | High | NA | Resection | NED (10 yrs) | |
| 3 | 12/F | NA | Right fronto-parietal | Low | NA | Resection | AWSD (12 yrs and 3 mos) | |
| 4 | 9/F | NA | Right fronto-parietal | High | NA | Resection | NED (5 yrs and 8 mos) | |
| 5 | 18/F | NA | Left parietal | Low | NA | GTR, radiation at recurrence | AWSD (18 yrs and 11 mos) | |
| 6 | 8/M | NA | Left temporal | Low | NA | Resection | NED (12 yrs) | |
| 7 | 4/F | NA | Left parieto-occipital | High | NA | Resection | NED (10 yrs and 11 mos) | |
| Mhatre, et al.10 | 1 | 16/F | Headache, vomiting | Fronto-parietal | Low | Lobulated, heterogeneous enhancing lesion | Resection, radiation | AWSD (5 yrs) |
| 2 | 27/F | Headache, seizures | Frontal | High | Multilobulated, contrast enhancing solid cystic lesion | Resection, radiation | AWSD (6 yrs and 4 mos) | |
| 3 | 10/F | Weakness, decreased sensation | Parietal | High | Lobulated, heterogeneous enhancing lesion with blooming | Resection, radiation | AWSD (7 yrs) | |
| Present case | 1 | 6/F | None | Left parietal | unclear | Lobulated, heterogeneous enhancing solid cystic lesion | GTR, radiation (54Gy), chemotherapy (TMZ) | NED (2 yrs and 3 mos) |
AWSD: alive with stable disease, BEV: bevacizumab, F: female, GTR: gross total resection, M: male, mo: month, NA: not available, NED: no evidence of disease, NTR: near total resection, TMZ: temozolomide, yr: year.
A recent molecular analysis revealed a new classification of primitive neuroectodermal tumors of central nervous system (CNS-PNETs).13) CNS-PNETs have been classified into four new entities: “CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2),” “CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC),” “CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1),” and “CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR).” Among these new entities, CNS HGNET-MN1, which is characterized by MN1 gene rearrangements on DNA methylation profiling, has frequently shown astroblastic features, such as pseudopapillary patterns and dense pericellular hyalinization. The authors found that nearly 40% of tumors histologically diagnosed as astroblastoma belong to this category. MN1 rearrangements along with alterations of the X chromosome have also been reported as features of astroblasitma.3) The histopathological findings of astroblastoma are similar to those of ependymoma, which typically have rosette-forming tumor cells. Olig2 positivity is a useful diagnostic marker, since ependymoma generally does not express that molecule.14) In addition, RELA fusion on a FISH analysis or immunohistochemistry for p65/RELA and/or LICAM is also useful for making a diagnosis of ependymoma.9) Other studies have described cases in which MN1 rearrangement detected by a FISH analysis was useful for diagnosing astroblastoma and differentiating from ependymoma.3) Astroblastoma histology is not specific for CNS-HGNET-MN1. Wood et al.6) reported a case of astroblastoma diagnosed histologically without MN1 alteration showing genetic features of either anaplastic pleomorphic xanthoastrocytoma (BRAF p.V600E mutation, CDKN2A/B homozygous deletion and TERT promoter mutation) or IDH-wild-type glioblastoma (trisomy 7, monosomy 10, CDK4 amplification and TP53, NRAS, and TERT promoter mutations). Lucas et al.15) proposed that astroblastomas with MN1 fusions represent “true” astroblastomas and recommended the terminology “astroblastoma, MN1 fusion-positive.”
Our present report was limited by the short follow-up duration. The diagnosis and evaluation of malignancy for astroblastoma are made histologically, while no molecular diagnosis was made at this time; therefore, further molecular-based and larger-scale cases studies will be needed to determine whether or not MN1 alteration is a suitable diagnostic marker for astroblastoma.
We reported a case of well-differentiated astroblastoma with focal anaplastic features and MN1 alteration that was treated with gross total resection (GTR) and chemoradiotherapy. A larger-scale study is warranted to establish evidence supporting the diagnosis and treatment of astroblastoma with molecular characteristic features.
The authors declare there are no conflicts of interest.
