- Email: [email protected]
Intraventricular Epithelioid Glioblastoma: A Case Report
Accepted Manuscript Intraventricular epithelioid glioblastoma: A case report Naoki Nitta, Suzuko Moritani, Tadateru Fukami, Yayoi Yoshimura, Hisao Hirai, Kazuhiko Nozaki PII:
S1878-8750(18)30243-2
DOI:
10.1016/j.wneu.2018.01.200
Reference:
WNEU 7398
To appear in:
World Neurosurgery
Received Date: 24 October 2017 Revised Date:
29 January 2018
Accepted Date: 30 January 2018
Please cite this article as: Nitta N, Moritani S, Fukami T, Yoshimura Y, Hirai H, Nozaki K, Intraventricular epithelioid glioblastoma: A case report, World Neurosurgery (2018), doi: 10.1016/j.wneu.2018.01.200. 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 1 Nitta
Intraventricular epithelioid glioblastoma: A case report Naoki Nitta,1,3 Suzuko Moritani,2 Tadateru Fukami,1 Yayoi Yoshimura,1 Hisao Hirai,4 and
1
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Kazuhiko Nozaki1
Department of Neurosurgery, Shiga University of Medical Science, Seta-Tsukinowa-Cho, Otsu,
Shiga 520-2192, Japan
Department of Clinical Laboratory Medicine and Division of Diagnostic Pathology, Shiga
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2
3
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University of Medical Science, Seta-Tsukinowa-Cho, Otsu, Shiga 520-2192, Japan National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders,
Urushiyama 886, Aoi-ku, Shizuoka 420-8688, Japan
Department of Neurosurgery, Koto Memorial Hospital, Hiramatsu-Cho 2-1, Higashiomi, Shiga
527-0134, Japan
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Corresponding Author: Naoki Nitta, Department of Neurosurgery, Shiga University of Medical
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Science, Seta-Tsukinowa-Cho, Otsu, Shiga 520-2192, Japan
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e-mail: [email protected] Tel: +81-77-548-2259, Fax: +81-77-548-2531
Highest academic degree: Naoki Nitta,1,3 PhD; Suzuko Moritani,2 PhD; Tadateru Fukami,1 PhD; Yayoi Yoshimura,1 PhD; Hisao Hirai,4 PhD; and Kazuhiko Nozaki1 PhD
1
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Key words: epithelioid glioblastoma; intraventricular; lateral ventricle; malignant transformation Abbreviations and Acronyms
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CT: computed tomography; GFAP: glial fibrillary acidic protein; IDH: isocitrate dehydrogenase; MRI: magnetic resonance imaging; PXA: pleomorphic xanthoastrocytoma; SVZ: subventricular
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zone; WHO: World Health Organization
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Abstract
Background: Epithelioid glioblastoma, a high-grade, diffuse astrocytic tumor variant, comprises closely packed epithelioid cells and rhabdoid cells. This rare tumor usually develops in the
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cerebral cortex and diencephalon; however, in one woman, it was located intraventricularly.
Case description: A 47-year-old woman was referred to our hospital because the patient had a
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right intraventricular mass that had rapidly increased in size. Upon discovery of the tumor three
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years earlier by the referring hospital, the mass was small, calcified and attached to the periventricular parenchyma; until 1 year before, it grew slowly, as observed in periodic, magnetic resonance imaging scans. Forty days before the referral, the patient had a headache, nausea, marked growth and intratumoral hemorrhage, visible in a computed tomography scan of the head. The tumor was partially removed via a superior parietal lobule corticotomy. Histopathological examination confirmed an IDH-wildtype epithelioid glioblastoma with a BRAF V600E mutation, 2
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but it could no longer detect the original slow-growing lesion. Although this slow-growing mass was no longer detectable, we assume that a low-grade glioma transformed into an aggressively
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malignant epithelioid glioblastoma.
Conclusions: We present the first case of an intraventricular epithelioid glioblastoma that may
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have arisen from a low-grade glioma with calcification. Therefore, we recommend including this
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tumor variant in the differential diagnosis of lateral ventricle tumors.
Introduction
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Running title: Intraventricular epithelioid glioblastoma
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Epithelioid glioblastoma is a high-grade, diffuse astrocytic tumor variant characterized by a dominant population of closely packed epithelioid cells, some rhabdoid cells, and necrosis;
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it afflicts children and young adults.1 Epithelioid glioblastomas have a poor prognosis, with a median survival of 6.3 months in adults and 5.6 months in children.1 Most epithelioid glioblastomas usually arise de novo and are located in the cerebral cortex and diencephalon. However, in several cases, low-grade astrocytomas have been identified as a pre-existing or coexisting lesion with an epithelioid glioblastoma.1
3
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We report the first description of an intraventricular epithelioid glioblastoma, into
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which slow-growing, low grade glioma may have transformed.
Case details
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A 47-year-old woman was referred to our department due to a rapidly growing, right intraventricular mass. Three years before being referred to us, the mass had been found
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incidentally on computed tomography (CT) of the head (Figure 1A). The mass was initially small, 16 mm in the major axis, and attached to the periventricular parenchyma of the posterolateral wall of the right lateral ventricle with focal calcification (Figure 1A–C); it had
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grown slowly, as shown on follow-up magnetic resonance imaging (MRI) (Figure 1D–F). Forty days before the referral, the woman had headache and nausea. A CT scan of the head showed
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marked growth of the tumor with intratumoral hemorrhage and calcification (Figure 1G and H). Ten days before the referral, she was admitted to the referring hospital because of headache and
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loss of appetite; she had developed dysphagia, hoarseness and shallow breathing with bilateral oculomotor palsy and left facial palsy. Upon transfer to our hospital, the patient underwent postcontrast T1-weighted imaging of the brain that showed a heterogeneously-enhanced mass in the right lateral ventricle and dissemination around the upper and lower cranial nerves, brain stem, cerebellar hemispheres, and spinal cord (Figure 2A–E). During the night of transfer, she
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developed respiratory insufficiency with tachypnea and shallow breathing; on the next day, she underwent partial removal of the tumor via a superior parietal lobule corticotomy (Figure 2F).
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During recovery, she was placed on a ventilator in the intensive care unit. She underwent a tracheotomy on day 2 after the operation and regained consciousness on day 4. However, on day
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7, her systolic blood pressure fell to 60 mm Hg and she was pronounced brain-dead. She died on
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day 33.
Histopathological examination revealed a tumor comprising a fairly uniform population of epithelioid cells with large nuclei and abundant eosinophilic cytoplasm (Figure 3A
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and B). The nuclei had prominent nucleoli and tended to be located eccentrically. The tumor cells were arranged in loosely cohesive sheets with zonal-type necrosis. Palisading-type necrosis was not found (Figure 3A). The immunohistochemical analysis was positive for GFAP in a small
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number of tumor cells (Figure 3C), and negative for the IDH1 mutation. The VE antibody
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recognizing V600E-mutant BRAF was positive in most of the tumor cells (Figure 3D). The Ki-67 labeling index was 50%–60%, showing markedly elevated proliferative activity (Figure 3E). Since a slow-growing lesion was transformed into a rapidly and progressively growing epithelioid glioblastoma, we infer that an IDH-wildtype low grade glioma was transformed into an epithelioid glioblastoma.
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Discussion Here, we present the first case of an intraventricular epithelioid glioblastoma.
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In 1956, Rubinstein first described epithelial-like elements as “closely packed tumor cells arranged in solid trabeculae and club-like formations,” 1 and in 1982, Kepes et al. reported
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five cases of supratentorial gliosarcomas with epithelial structures that he called
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“pseudoglandular elements.” 2 Now, epithelioid glioblastomas are considered to be a high-grade diffuse astrocytic tumor variant corresponding histologically to WHO grade IV in the 2016 WHO classification scheme.3 Epithelioid glioblastomas usually develop in the cerebral cortex and are most often found in the temporal and frontal lobes, and diencephalon;3 they rarely
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develop in the cerebellum, and none have been found in the spinal cord and ventricles.3 To our knowledge, this is the first case of an intraventricular epithelioid glioblastoma.
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Here, we report a slow-growing lesion that was transformed into a rapidly growing
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epithelioid glioblastoma. The etiology and cell origin of epithelioid glioblastoma is unknown. In several cases, a low-grade astrocytoma has been identified as pre-existing or coexisting with an epithelioid tumor.4-11 Pre-existing lesions had been described before the diagnosis of epithelioid glioblastoma in 4 cases: a pre-existing calcified lesion on CT,7 a low-grade astrocytoma,4 a mixed oligoastrocytoma,6 and a pleomorphic xanthoastrocytoma9 (Table 1). Coexisting low-grade astrocytomas have also been reported in 4 cases (Table 2).5, 8 10, 11 The presence of 6
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these pre-existing and coexisting low-grade tumors suggest that a malignant transformation may develop into a secondary epithelioid glioblastoma in some cases and in our case too.
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In the present case, the epithelioid glioblastoma tested negative for IDH mutations and positive for BRAF V600E. All epithelioid glioblastoma cases with pre-existing and coexisting
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lesions but one tested also negative for IDH mutations and positive for the BRAF V600E
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mutation (Table 1, 2).6, 7, 8, 10, 11 These cases suggest that malignant transformation to epithelioid glioblastoma may occur in IDH-wild type, low-grade gliomas with a BRAF mutation. Although a malignant transformation usually occurs in an IDH1-mutant glioma, Leu et al. reported that 6 of 35 cases of IDH1-wildtype, low-grade gliomas underwent malignant transformation.12
gliomas.13,
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IDH-wildtype BRAF mutated gliomas have been reported to be transformed into malignant In one case of an IDH-wildtype epithelioid glioblastoma with a coexisting
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astrocytoma, an array comparative genomic hybridization performed separately for each
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histologically distinct component demonstrated a homozygous deletion in LSAMP, a heterozygous deletion in ODZ3, and a heterozygous deletion in LRP1B in epithelioid tumor cells (Table 2).8 They also reported that the heterozygous BRAF V600E mutation was found both in epithelioid tumor cells and the astrocytoma cells. These findings suggest that other mutations combined with a BRAF V600E mutation may cause transformation of an IDH-wildtype low-grade glioma into an epithelioid glioblastoma. 7
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In the present case, CT showed calcification in the original and secondarily growing lesion. In one reported case of a pre-existing lesion and two out of three cases of coexisting
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lesions, CT showed calcification (Table 1, 2).7, 10, 11 Broniscer et al. reported a case of epithelioid glioblastoma in which CT at 3 years before diagnosis showed an abnormal area with heavy
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calcification and CT at the time of diagnosis of epithelioid glioblastoma showed the same
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calcification within the tumor.7 Taken together, these findings suggest that secondary epithelioid glioblastomas might accompany calcification.
In the present case, the tumor appeared to have originally protruded from the subventricular zone (SVZ) in the posterolateral periventricular parenchyma (Figure 1A–D). The
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SVZ is one of the neurogenic niches in the adult mammalian brain within which there is a subpopulation of astrocytes that have features of self-renewal and multipotentiality as found in
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stem cells: germinal regions such as SVZ have been proposed to be a source of gliomas.15, 16 We
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speculate that one of the glioma stem cells arising from neural stem cells in the SVZ transformed into an epithelioid glioblastoma after a BRAF V600E mutation event.
Conclusion
We have presented the first case of intraventricular epithelioid glioblastoma developing from an earlier IDH1-wildtype, low-grade tumor with calcification in SVZ; this earlier lesion 8
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may have been transformed into the epithelioid glioblastoma. Intraventricular epithelioid
lesion with calcification develops into a rapidly growing tumor.
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There has been no previous presentation of the present case.
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glioblastoma should be considered in the differential diagnosis, especially when a slow-growing
Conflicts of Interest: none
Acknowledgement
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We thank professor Takanori Hirose, Pathology for Regional Communication, Kobe University, for his valuable advice on pathological diagnosis of the present case.
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This research was not supported by any specific grant from funding agencies in the public,
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commercial, or not-for-profit sectors.
Color figure: figure 3
References
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1) Ellison DW, Kleinschmidt-DeMasters BK, Park SH. Epithelioid glioblastoma. In: Louis DN,
Nervous System. 4th ed. Geneva: WHO Press; 2016:50-51.
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Ohgaki H, Wiestler OD, Cavenee WK, eds. WHO Classification of Tumors of the Central
2) RUBINSTEIN LJ. The development of contiguous sarcomatous and gliomatous tissue in
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intracranial tumours. Pathol Bacteriol. 1956;71:441-459.
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3) Kepes JJ, Fulling KH, Garcia JH. The clinical significance of "adenoid" formations of neoplastic astrocytes, imitating metastatic carcinoma, in gliosarcomas. A review of five cases. Clin Neuropathol. 1982;1:139-150.
4) Pimentel J, Silva R, Pimentel T. Primary malignant rhabdoid tumors of the central nervous considerations
about
two
cases
of
adulthood
presentation.
J
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system:
Neurooncol. 2003;61:121-126.
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5) Nagai S, Kurimoto M, Ishizawa S, Hayashi N, Hamada H, Kamiyama H, Endo S. A rare
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astrocytic tumor with rhabdoid features. Brain Tumor Pathol. 2009;26:19-24. 6) Kleinschmidt-DeMasters BK, Aisner DL, Birks DK, Foreman NK. Epithelioid GBMs show a high percentage of BRAF V600E mutation. Am J Surg Pathol. 2013;37:685-698. 7) Broniscer A, Tatevossian RG, Sabin ND, Klimo P Jr, Dalton J, Lee R, Gajjar A, Ellison DW. Clinical, radiological, histological and molecular characteristics of paediatric epithelioid glioblastoma. Neuropathol Appl Neurobiol. 2014;40:327-336. 10
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8) Nobusawa S, Hirato J, Kurihara H, Ogawa A, Okura N, Nagaishi M, Ikota H, Yokoo H, Nakazato
Y.
Intratumoral
heterogeneity
of
genomic
imbalance
in
a
case
of
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epithelioid glioblastoma with BRAF V600E mutation. Brain Pathol. 2014;24:239-246.
9) Tanaka S, Nakada M, Nobusawa S, Suzuki SO, Sabit H, Miyashita K, Hayashi Y.
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Epithelioid glioblastoma arising from pleomorphic xanthoastrocytoma with the BRAF
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V600E mutation. Brain Tumor Pathol. 2014;31:172-176.
10) Funata N, Nobusawa S, Yamada R, Shinoura N. A case of osteoclast-like giant cell-rich epithelioid glioblastoma
with
V600E
mutation.
Brain
Tumor
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Pathol. 2016;33:57-62.
BRAF
11) Kuroda J, Nobusawa S, Nakamura H, Yokoo H, Ueda R, Makino K, Yano S, Kuratsu J. A case of an epithelioid glioblastoma with the BRAF V600E mutation colocalized with BRAF
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intact low-grade diffuse astrocytoma. Neuropathology. 2016;36:181-186.
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12) Leu S, von Felten S, Frank S, Boulay JL, Mariani L: IDH mutation is associated with higher risk of malignant transformation in low-grade glioma. J Neurooncol. 2016;127:363-372. 13) Kanamori M,
Suzuki
H,
Takei
H,
Sonoda
Y,
Uenohara
H,
Tominaga
T.
Malignant transformation of diffuse astrocytoma to glioblastoma associated with newly developed BRAF V600E mutation. Brain Tumor Pathol. 2016;33:50-56.
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14) Suzuki Y, Takahashi-Fujigasaki J, Akasaki Y, Matsushima S, Mori R, Karagiozov K, Joki T, Ikeuchi S, Ikegami M, Manome Y, Murayama Y. BRAF V600E-mutated diffuse glioma in
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an adult patient: a case report and review. Brain Tumor Pathol. 2016;33:40-49.
15) Sanai N, Tramontin AD, Quiñones-Hinojosa A, Barbaro NM, Gupta N, Kunwar S, Lawton
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MT, McDermott MW, Parsa AT, Manuel-García Verdugo J, Berger MS, Alvarez-Buylla A:
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Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature. 2004;427:740-744.
16) Sanai N, Alvarez-Buylla A, Berger MS. Neural stem cells and the origin of gliomas. N Engl J
Figure legends
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Med. 2005;353:811-822.
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Figure 1. First and follow-up images
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Axial computed tomography (CT) of the head (A), axial T1-weighted image (B), axial T2-weighted image (C), and axial fluid-attenuated inversion recovery image (D) at three years before the referral showing a tumor with calcification in the subventricular zone under the posterior wall of the right lateral ventricle. Follow-up axial fluid-attenuated inversion recovery image at 6 months (E) and 18 months (F) after the first imaging showing a slowly growing tumor. CT images at 40 days before transfer showing progressive growth of the tumor with enlarged 12
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calcification and intratumoral hemorrhage (G, H). Figure 2. Pre- and postoperative images
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Preoperative axial (A), sagittal (B) and coronal (C) postcontrast T1-weighted images showing a heterogeneously enhancing tumor in the right lateral ventricle. Preoperative axial enlarged
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postcontrast T1-weighted images (D, E) showing dissemination around the optic, oculomotor
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and trigeminal nerves and the brainstem. Postoperative CT image (F) showing a partially removed tumor.
Figure 3. Histopathological features of the tumor
Hematoxylin and eosin staining of the tumor (A, B) showing zonal-type necrosis (A) and a fairly
(B).
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uniform population of epithelioid cells with large nuclei and abundant eosinophilic cytoplasm Immunohistochemistry for GFAP (C)
showing a sparse
GFAP-positive area.
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Immunohistochemistry for Ki-67 (D) showing elevated mitotic activity of the tumor.
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Immunohistochemistry for BRAF V600E mutation (E) showing BRAF V600E-mutant cells. (A) x 40. (B–E) x 400.
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Pathology and Image Data on Epithelioid Glioblastoma with Pre-existing Lesion Histology of
IDH mutation, BRAF V600E
Differences between pre-existing
pre-existing lesion
mutation
lesion and EGB
Images of pre-existing lesion
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Reference
Images at diagnosis of EGB
T1WIC+: Slightly enhanced mass
T1WIC+: Heterogeneous
without significant edema or mass
areas and marked contrast
effect
enhancement
Pre-existing lesion: Low Ki-67 LI Pimentel et al., 20034
Low grade astrocytoma
NM
Kleinschmidt-DeMasters EGB: IDH1 (+); BRAF (-)
et al., 20136
Present case
PXA
Not examined
NM
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20149
EGB: IDH1 (-); BRAF (+)
T1WIC+: Well demarcated
NM enhanced mass
CT: Heavily calcified in the posterior left thalamus MRI: An abnormal area in the
CT: The same calcifications
posterior thalamus, isointense on
as within the EGB
T1WI and hypointense on T2WI
PXA: IDH, NM; BRAF (+)
Pre-existing lesion: Ki-67 LI, ˂ 1%
T1WIC+: Enhanced solid mass
T1WIC+: Enhanced mass
EGB: IDH, NM; BRAF (+)
EGB: Ki-67 LI, 40%
with a large cyst
with intratumoral hemorrhage
CT: A calcified mass attached to
CT: Enlarged mass and
the wall of the atrium of right
calcification with intratumoral
lateral ventricle
hemorrhage
T1WI: Heterogeneous mass with
T1WIC+: Heterogeneously
calcification
enhanced mass
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Tanaka et al.,
Not examined
Pre-existing lesion: Not examined
EGB: IDH1 (-); BRAF (+)
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Broniscer et al., 20147
NM
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Mixed oligoastrocytoma
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EGB: High Ki-67 LI
EGB: Ki-67 LI, 50% to 60%
CT, computed tomography; EGB, epithelioid glioblastoma; LI, labeling index; MRI, magnetic resonance imaging; NM, not mentioned; PXA, pleomorphic xanthoastrocytoma; T1WI, T1 weighted image; T1WIC+, post contrast T1WI
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Pathology and Image Data on Epithelioid Glioblastoma with Coexistent Lesion Histology of coexisting
Markers (IDH mutation, BRAF
Differences between EGB and
lesion
V600E mutation)
coexisting lesion
Images before EGB diagnosis
EGB: GFAP weak; Ki-67 LI, 28.7% Nagai et al., NM
Coexisting lesion: GFAP distinctly
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expressed, Ki-67 LI, 4%
NM
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Diffuse astrocytoma 20095
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Reference
Images at EGB diagnosis
CT: Circumscribed hyperdense tumor containing a low-density area with perifocal edema T1WIC+: Entirely enhanced tumor
EGB: Homozygous deletion in
LSAMP; heterozygous deletion in
T1WI: Subcortical hemorrhage,
T1WIC+: Heterogeneously
ODZ3; heterozygous deletion in
enlargement of the hematoma at 2
enhanced mass with
LRP1B
months before diagnosis of EGB,
hemorrhagic components and
Coexisting lesion: Negative for all
without clear evidence of a tumor
prominent surrounding edema
EGB: IDH1/2 (-); BRAF (+) Nobusawa et al.,
Diffusely infiltrated, less Coexisting lesion: IDH1/2 (-);
20148
atypical astrocytoma cells
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BRAF (+)
mentioned above
Low-grade,
EGB: IDH1 (-); BRAF (+)
oligoastrocytoma-like
Coexisting lesion: IDH (-); BRAF
areas
(+)
Coexisting lesion: OLIG2 (+); Ki-67
CT: Solid and cystic lesions NM with calcification
LI, 4%
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201610
EGB: OLIG2 (-); Ki-67 LI, 20%
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Funata et al.,
CT: Massive lesion of
EGB: IDH1 (-); BRAF (+) Kuroda et al.,
Low-grade diffusely
201611
infiltrated astrocytoma
heterogeneous density with EGB: Ki-67 LI, 40% to 80%
Coexisting lesion: IDH1 (-); BRAF (-)
NM
obvious calcified component
Coexisting lesion: Ki-67 LI, ˂ 1% T1WIC+: Enhanced as well as circumscribed
CT, computed tomography; EGB, epithelioid glioblastoma; LI, labeling index; MRI, magnetic resonance imaging; NM, not mentioned;
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PXA, pleomorphic xanthoastrocytoma; T1WI, T1 weighted image; T1WIC+, post contrast T1WI
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Highlights
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Intraventricular epithelioid glioblastoma has not been previously reported. A slow-growing intraventricular lesion can develop into an epithelioid glioblastoma. BRAF mutation in IDH-wild type glioma can induce an epithelioid glioblastoma.
S1878-8750(18)30243-2
DOI:
10.1016/j.wneu.2018.01.200
Reference:
WNEU 7398
To appear in:
World Neurosurgery
Received Date: 24 October 2017 Revised Date:
29 January 2018
Accepted Date: 30 January 2018
Please cite this article as: Nitta N, Moritani S, Fukami T, Yoshimura Y, Hirai H, Nozaki K, Intraventricular epithelioid glioblastoma: A case report, World Neurosurgery (2018), doi: 10.1016/j.wneu.2018.01.200. 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 1 Nitta
Intraventricular epithelioid glioblastoma: A case report Naoki Nitta,1,3 Suzuko Moritani,2 Tadateru Fukami,1 Yayoi Yoshimura,1 Hisao Hirai,4 and
1
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Kazuhiko Nozaki1
Department of Neurosurgery, Shiga University of Medical Science, Seta-Tsukinowa-Cho, Otsu,
Shiga 520-2192, Japan
Department of Clinical Laboratory Medicine and Division of Diagnostic Pathology, Shiga
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2
3
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University of Medical Science, Seta-Tsukinowa-Cho, Otsu, Shiga 520-2192, Japan National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders,
Urushiyama 886, Aoi-ku, Shizuoka 420-8688, Japan
Department of Neurosurgery, Koto Memorial Hospital, Hiramatsu-Cho 2-1, Higashiomi, Shiga
527-0134, Japan
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4
Corresponding Author: Naoki Nitta, Department of Neurosurgery, Shiga University of Medical
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Science, Seta-Tsukinowa-Cho, Otsu, Shiga 520-2192, Japan
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e-mail: [email protected] Tel: +81-77-548-2259, Fax: +81-77-548-2531
Highest academic degree: Naoki Nitta,1,3 PhD; Suzuko Moritani,2 PhD; Tadateru Fukami,1 PhD; Yayoi Yoshimura,1 PhD; Hisao Hirai,4 PhD; and Kazuhiko Nozaki1 PhD
1
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Key words: epithelioid glioblastoma; intraventricular; lateral ventricle; malignant transformation Abbreviations and Acronyms
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CT: computed tomography; GFAP: glial fibrillary acidic protein; IDH: isocitrate dehydrogenase; MRI: magnetic resonance imaging; PXA: pleomorphic xanthoastrocytoma; SVZ: subventricular
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zone; WHO: World Health Organization
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Abstract
Background: Epithelioid glioblastoma, a high-grade, diffuse astrocytic tumor variant, comprises closely packed epithelioid cells and rhabdoid cells. This rare tumor usually develops in the
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cerebral cortex and diencephalon; however, in one woman, it was located intraventricularly.
Case description: A 47-year-old woman was referred to our hospital because the patient had a
EP
right intraventricular mass that had rapidly increased in size. Upon discovery of the tumor three
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years earlier by the referring hospital, the mass was small, calcified and attached to the periventricular parenchyma; until 1 year before, it grew slowly, as observed in periodic, magnetic resonance imaging scans. Forty days before the referral, the patient had a headache, nausea, marked growth and intratumoral hemorrhage, visible in a computed tomography scan of the head. The tumor was partially removed via a superior parietal lobule corticotomy. Histopathological examination confirmed an IDH-wildtype epithelioid glioblastoma with a BRAF V600E mutation, 2
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but it could no longer detect the original slow-growing lesion. Although this slow-growing mass was no longer detectable, we assume that a low-grade glioma transformed into an aggressively
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malignant epithelioid glioblastoma.
Conclusions: We present the first case of an intraventricular epithelioid glioblastoma that may
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have arisen from a low-grade glioma with calcification. Therefore, we recommend including this
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tumor variant in the differential diagnosis of lateral ventricle tumors.
Introduction
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Running title: Intraventricular epithelioid glioblastoma
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Epithelioid glioblastoma is a high-grade, diffuse astrocytic tumor variant characterized by a dominant population of closely packed epithelioid cells, some rhabdoid cells, and necrosis;
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it afflicts children and young adults.1 Epithelioid glioblastomas have a poor prognosis, with a median survival of 6.3 months in adults and 5.6 months in children.1 Most epithelioid glioblastomas usually arise de novo and are located in the cerebral cortex and diencephalon. However, in several cases, low-grade astrocytomas have been identified as a pre-existing or coexisting lesion with an epithelioid glioblastoma.1
3
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We report the first description of an intraventricular epithelioid glioblastoma, into
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which slow-growing, low grade glioma may have transformed.
Case details
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A 47-year-old woman was referred to our department due to a rapidly growing, right intraventricular mass. Three years before being referred to us, the mass had been found
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incidentally on computed tomography (CT) of the head (Figure 1A). The mass was initially small, 16 mm in the major axis, and attached to the periventricular parenchyma of the posterolateral wall of the right lateral ventricle with focal calcification (Figure 1A–C); it had
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grown slowly, as shown on follow-up magnetic resonance imaging (MRI) (Figure 1D–F). Forty days before the referral, the woman had headache and nausea. A CT scan of the head showed
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marked growth of the tumor with intratumoral hemorrhage and calcification (Figure 1G and H). Ten days before the referral, she was admitted to the referring hospital because of headache and
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loss of appetite; she had developed dysphagia, hoarseness and shallow breathing with bilateral oculomotor palsy and left facial palsy. Upon transfer to our hospital, the patient underwent postcontrast T1-weighted imaging of the brain that showed a heterogeneously-enhanced mass in the right lateral ventricle and dissemination around the upper and lower cranial nerves, brain stem, cerebellar hemispheres, and spinal cord (Figure 2A–E). During the night of transfer, she
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developed respiratory insufficiency with tachypnea and shallow breathing; on the next day, she underwent partial removal of the tumor via a superior parietal lobule corticotomy (Figure 2F).
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During recovery, she was placed on a ventilator in the intensive care unit. She underwent a tracheotomy on day 2 after the operation and regained consciousness on day 4. However, on day
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7, her systolic blood pressure fell to 60 mm Hg and she was pronounced brain-dead. She died on
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day 33.
Histopathological examination revealed a tumor comprising a fairly uniform population of epithelioid cells with large nuclei and abundant eosinophilic cytoplasm (Figure 3A
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and B). The nuclei had prominent nucleoli and tended to be located eccentrically. The tumor cells were arranged in loosely cohesive sheets with zonal-type necrosis. Palisading-type necrosis was not found (Figure 3A). The immunohistochemical analysis was positive for GFAP in a small
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number of tumor cells (Figure 3C), and negative for the IDH1 mutation. The VE antibody
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recognizing V600E-mutant BRAF was positive in most of the tumor cells (Figure 3D). The Ki-67 labeling index was 50%–60%, showing markedly elevated proliferative activity (Figure 3E). Since a slow-growing lesion was transformed into a rapidly and progressively growing epithelioid glioblastoma, we infer that an IDH-wildtype low grade glioma was transformed into an epithelioid glioblastoma.
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Discussion Here, we present the first case of an intraventricular epithelioid glioblastoma.
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In 1956, Rubinstein first described epithelial-like elements as “closely packed tumor cells arranged in solid trabeculae and club-like formations,” 1 and in 1982, Kepes et al. reported
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five cases of supratentorial gliosarcomas with epithelial structures that he called
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“pseudoglandular elements.” 2 Now, epithelioid glioblastomas are considered to be a high-grade diffuse astrocytic tumor variant corresponding histologically to WHO grade IV in the 2016 WHO classification scheme.3 Epithelioid glioblastomas usually develop in the cerebral cortex and are most often found in the temporal and frontal lobes, and diencephalon;3 they rarely
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develop in the cerebellum, and none have been found in the spinal cord and ventricles.3 To our knowledge, this is the first case of an intraventricular epithelioid glioblastoma.
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Here, we report a slow-growing lesion that was transformed into a rapidly growing
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epithelioid glioblastoma. The etiology and cell origin of epithelioid glioblastoma is unknown. In several cases, a low-grade astrocytoma has been identified as pre-existing or coexisting with an epithelioid tumor.4-11 Pre-existing lesions had been described before the diagnosis of epithelioid glioblastoma in 4 cases: a pre-existing calcified lesion on CT,7 a low-grade astrocytoma,4 a mixed oligoastrocytoma,6 and a pleomorphic xanthoastrocytoma9 (Table 1). Coexisting low-grade astrocytomas have also been reported in 4 cases (Table 2).5, 8 10, 11 The presence of 6
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these pre-existing and coexisting low-grade tumors suggest that a malignant transformation may develop into a secondary epithelioid glioblastoma in some cases and in our case too.
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In the present case, the epithelioid glioblastoma tested negative for IDH mutations and positive for BRAF V600E. All epithelioid glioblastoma cases with pre-existing and coexisting
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lesions but one tested also negative for IDH mutations and positive for the BRAF V600E
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mutation (Table 1, 2).6, 7, 8, 10, 11 These cases suggest that malignant transformation to epithelioid glioblastoma may occur in IDH-wild type, low-grade gliomas with a BRAF mutation. Although a malignant transformation usually occurs in an IDH1-mutant glioma, Leu et al. reported that 6 of 35 cases of IDH1-wildtype, low-grade gliomas underwent malignant transformation.12
gliomas.13,
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IDH-wildtype BRAF mutated gliomas have been reported to be transformed into malignant In one case of an IDH-wildtype epithelioid glioblastoma with a coexisting
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astrocytoma, an array comparative genomic hybridization performed separately for each
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histologically distinct component demonstrated a homozygous deletion in LSAMP, a heterozygous deletion in ODZ3, and a heterozygous deletion in LRP1B in epithelioid tumor cells (Table 2).8 They also reported that the heterozygous BRAF V600E mutation was found both in epithelioid tumor cells and the astrocytoma cells. These findings suggest that other mutations combined with a BRAF V600E mutation may cause transformation of an IDH-wildtype low-grade glioma into an epithelioid glioblastoma. 7
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In the present case, CT showed calcification in the original and secondarily growing lesion. In one reported case of a pre-existing lesion and two out of three cases of coexisting
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lesions, CT showed calcification (Table 1, 2).7, 10, 11 Broniscer et al. reported a case of epithelioid glioblastoma in which CT at 3 years before diagnosis showed an abnormal area with heavy
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calcification and CT at the time of diagnosis of epithelioid glioblastoma showed the same
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calcification within the tumor.7 Taken together, these findings suggest that secondary epithelioid glioblastomas might accompany calcification.
In the present case, the tumor appeared to have originally protruded from the subventricular zone (SVZ) in the posterolateral periventricular parenchyma (Figure 1A–D). The
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SVZ is one of the neurogenic niches in the adult mammalian brain within which there is a subpopulation of astrocytes that have features of self-renewal and multipotentiality as found in
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stem cells: germinal regions such as SVZ have been proposed to be a source of gliomas.15, 16 We
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speculate that one of the glioma stem cells arising from neural stem cells in the SVZ transformed into an epithelioid glioblastoma after a BRAF V600E mutation event.
Conclusion
We have presented the first case of intraventricular epithelioid glioblastoma developing from an earlier IDH1-wildtype, low-grade tumor with calcification in SVZ; this earlier lesion 8
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may have been transformed into the epithelioid glioblastoma. Intraventricular epithelioid
lesion with calcification develops into a rapidly growing tumor.
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There has been no previous presentation of the present case.
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glioblastoma should be considered in the differential diagnosis, especially when a slow-growing
Conflicts of Interest: none
Acknowledgement
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We thank professor Takanori Hirose, Pathology for Regional Communication, Kobe University, for his valuable advice on pathological diagnosis of the present case.
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This research was not supported by any specific grant from funding agencies in the public,
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commercial, or not-for-profit sectors.
Color figure: figure 3
References
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1) Ellison DW, Kleinschmidt-DeMasters BK, Park SH. Epithelioid glioblastoma. In: Louis DN,
Nervous System. 4th ed. Geneva: WHO Press; 2016:50-51.
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Ohgaki H, Wiestler OD, Cavenee WK, eds. WHO Classification of Tumors of the Central
2) RUBINSTEIN LJ. The development of contiguous sarcomatous and gliomatous tissue in
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intracranial tumours. Pathol Bacteriol. 1956;71:441-459.
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3) Kepes JJ, Fulling KH, Garcia JH. The clinical significance of "adenoid" formations of neoplastic astrocytes, imitating metastatic carcinoma, in gliosarcomas. A review of five cases. Clin Neuropathol. 1982;1:139-150.
4) Pimentel J, Silva R, Pimentel T. Primary malignant rhabdoid tumors of the central nervous considerations
about
two
cases
of
adulthood
presentation.
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system:
Neurooncol. 2003;61:121-126.
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5) Nagai S, Kurimoto M, Ishizawa S, Hayashi N, Hamada H, Kamiyama H, Endo S. A rare
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astrocytic tumor with rhabdoid features. Brain Tumor Pathol. 2009;26:19-24. 6) Kleinschmidt-DeMasters BK, Aisner DL, Birks DK, Foreman NK. Epithelioid GBMs show a high percentage of BRAF V600E mutation. Am J Surg Pathol. 2013;37:685-698. 7) Broniscer A, Tatevossian RG, Sabin ND, Klimo P Jr, Dalton J, Lee R, Gajjar A, Ellison DW. Clinical, radiological, histological and molecular characteristics of paediatric epithelioid glioblastoma. Neuropathol Appl Neurobiol. 2014;40:327-336. 10
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8) Nobusawa S, Hirato J, Kurihara H, Ogawa A, Okura N, Nagaishi M, Ikota H, Yokoo H, Nakazato
Y.
Intratumoral
heterogeneity
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epithelioid glioblastoma with BRAF V600E mutation. Brain Pathol. 2014;24:239-246.
9) Tanaka S, Nakada M, Nobusawa S, Suzuki SO, Sabit H, Miyashita K, Hayashi Y.
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Epithelioid glioblastoma arising from pleomorphic xanthoastrocytoma with the BRAF
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V600E mutation. Brain Tumor Pathol. 2014;31:172-176.
10) Funata N, Nobusawa S, Yamada R, Shinoura N. A case of osteoclast-like giant cell-rich epithelioid glioblastoma
with
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mutation.
Brain
Tumor
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Pathol. 2016;33:57-62.
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11) Kuroda J, Nobusawa S, Nakamura H, Yokoo H, Ueda R, Makino K, Yano S, Kuratsu J. A case of an epithelioid glioblastoma with the BRAF V600E mutation colocalized with BRAF
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intact low-grade diffuse astrocytoma. Neuropathology. 2016;36:181-186.
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12) Leu S, von Felten S, Frank S, Boulay JL, Mariani L: IDH mutation is associated with higher risk of malignant transformation in low-grade glioma. J Neurooncol. 2016;127:363-372. 13) Kanamori M,
Suzuki
H,
Takei
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Sonoda
Y,
Uenohara
H,
Tominaga
T.
Malignant transformation of diffuse astrocytoma to glioblastoma associated with newly developed BRAF V600E mutation. Brain Tumor Pathol. 2016;33:50-56.
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14) Suzuki Y, Takahashi-Fujigasaki J, Akasaki Y, Matsushima S, Mori R, Karagiozov K, Joki T, Ikeuchi S, Ikegami M, Manome Y, Murayama Y. BRAF V600E-mutated diffuse glioma in
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an adult patient: a case report and review. Brain Tumor Pathol. 2016;33:40-49.
15) Sanai N, Tramontin AD, Quiñones-Hinojosa A, Barbaro NM, Gupta N, Kunwar S, Lawton
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MT, McDermott MW, Parsa AT, Manuel-García Verdugo J, Berger MS, Alvarez-Buylla A:
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Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature. 2004;427:740-744.
16) Sanai N, Alvarez-Buylla A, Berger MS. Neural stem cells and the origin of gliomas. N Engl J
Figure legends
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Med. 2005;353:811-822.
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Figure 1. First and follow-up images
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Axial computed tomography (CT) of the head (A), axial T1-weighted image (B), axial T2-weighted image (C), and axial fluid-attenuated inversion recovery image (D) at three years before the referral showing a tumor with calcification in the subventricular zone under the posterior wall of the right lateral ventricle. Follow-up axial fluid-attenuated inversion recovery image at 6 months (E) and 18 months (F) after the first imaging showing a slowly growing tumor. CT images at 40 days before transfer showing progressive growth of the tumor with enlarged 12
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calcification and intratumoral hemorrhage (G, H). Figure 2. Pre- and postoperative images
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Preoperative axial (A), sagittal (B) and coronal (C) postcontrast T1-weighted images showing a heterogeneously enhancing tumor in the right lateral ventricle. Preoperative axial enlarged
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postcontrast T1-weighted images (D, E) showing dissemination around the optic, oculomotor
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and trigeminal nerves and the brainstem. Postoperative CT image (F) showing a partially removed tumor.
Figure 3. Histopathological features of the tumor
Hematoxylin and eosin staining of the tumor (A, B) showing zonal-type necrosis (A) and a fairly
(B).
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uniform population of epithelioid cells with large nuclei and abundant eosinophilic cytoplasm Immunohistochemistry for GFAP (C)
showing a sparse
GFAP-positive area.
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Immunohistochemistry for Ki-67 (D) showing elevated mitotic activity of the tumor.
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Immunohistochemistry for BRAF V600E mutation (E) showing BRAF V600E-mutant cells. (A) x 40. (B–E) x 400.
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Pathology and Image Data on Epithelioid Glioblastoma with Pre-existing Lesion Histology of
IDH mutation, BRAF V600E
Differences between pre-existing
pre-existing lesion
mutation
lesion and EGB
Images of pre-existing lesion
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Reference
Images at diagnosis of EGB
T1WIC+: Slightly enhanced mass
T1WIC+: Heterogeneous
without significant edema or mass
areas and marked contrast
effect
enhancement
Pre-existing lesion: Low Ki-67 LI Pimentel et al., 20034
Low grade astrocytoma
NM
Kleinschmidt-DeMasters EGB: IDH1 (+); BRAF (-)
et al., 20136
Present case
PXA
Not examined
NM
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EGB: IDH1 (-); BRAF (+)
T1WIC+: Well demarcated
NM enhanced mass
CT: Heavily calcified in the posterior left thalamus MRI: An abnormal area in the
CT: The same calcifications
posterior thalamus, isointense on
as within the EGB
T1WI and hypointense on T2WI
PXA: IDH, NM; BRAF (+)
Pre-existing lesion: Ki-67 LI, ˂ 1%
T1WIC+: Enhanced solid mass
T1WIC+: Enhanced mass
EGB: IDH, NM; BRAF (+)
EGB: Ki-67 LI, 40%
with a large cyst
with intratumoral hemorrhage
CT: A calcified mass attached to
CT: Enlarged mass and
the wall of the atrium of right
calcification with intratumoral
lateral ventricle
hemorrhage
T1WI: Heterogeneous mass with
T1WIC+: Heterogeneously
calcification
enhanced mass
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Tanaka et al.,
Not examined
Pre-existing lesion: Not examined
EGB: IDH1 (-); BRAF (+)
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Broniscer et al., 20147
NM
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Mixed oligoastrocytoma
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EGB: High Ki-67 LI
EGB: Ki-67 LI, 50% to 60%
CT, computed tomography; EGB, epithelioid glioblastoma; LI, labeling index; MRI, magnetic resonance imaging; NM, not mentioned; PXA, pleomorphic xanthoastrocytoma; T1WI, T1 weighted image; T1WIC+, post contrast T1WI
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Pathology and Image Data on Epithelioid Glioblastoma with Coexistent Lesion Histology of coexisting
Markers (IDH mutation, BRAF
Differences between EGB and
lesion
V600E mutation)
coexisting lesion
Images before EGB diagnosis
EGB: GFAP weak; Ki-67 LI, 28.7% Nagai et al., NM
Coexisting lesion: GFAP distinctly
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expressed, Ki-67 LI, 4%
NM
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Diffuse astrocytoma 20095
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Reference
Images at EGB diagnosis
CT: Circumscribed hyperdense tumor containing a low-density area with perifocal edema T1WIC+: Entirely enhanced tumor
EGB: Homozygous deletion in
LSAMP; heterozygous deletion in
T1WI: Subcortical hemorrhage,
T1WIC+: Heterogeneously
ODZ3; heterozygous deletion in
enlargement of the hematoma at 2
enhanced mass with
LRP1B
months before diagnosis of EGB,
hemorrhagic components and
Coexisting lesion: Negative for all
without clear evidence of a tumor
prominent surrounding edema
EGB: IDH1/2 (-); BRAF (+) Nobusawa et al.,
Diffusely infiltrated, less Coexisting lesion: IDH1/2 (-);
20148
atypical astrocytoma cells
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BRAF (+)
mentioned above
Low-grade,
EGB: IDH1 (-); BRAF (+)
oligoastrocytoma-like
Coexisting lesion: IDH (-); BRAF
areas
(+)
Coexisting lesion: OLIG2 (+); Ki-67
CT: Solid and cystic lesions NM with calcification
LI, 4%
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EGB: OLIG2 (-); Ki-67 LI, 20%
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Funata et al.,
CT: Massive lesion of
EGB: IDH1 (-); BRAF (+) Kuroda et al.,
Low-grade diffusely
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infiltrated astrocytoma
heterogeneous density with EGB: Ki-67 LI, 40% to 80%
Coexisting lesion: IDH1 (-); BRAF (-)
NM
obvious calcified component
Coexisting lesion: Ki-67 LI, ˂ 1% T1WIC+: Enhanced as well as circumscribed
CT, computed tomography; EGB, epithelioid glioblastoma; LI, labeling index; MRI, magnetic resonance imaging; NM, not mentioned;
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PXA, pleomorphic xanthoastrocytoma; T1WI, T1 weighted image; T1WIC+, post contrast T1WI
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Highlights
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Intraventricular epithelioid glioblastoma has not been previously reported. A slow-growing intraventricular lesion can develop into an epithelioid glioblastoma. BRAF mutation in IDH-wild type glioma can induce an epithelioid glioblastoma.