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1
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Mallick S, Benson R, Venkatesulu B, Melgandi W, Rath GK. Systematic Review and Individual Patient Data Analysis of Uncommon Variants of Glioblastoma: An Analysis of 196 Cases. Neurol India 2022; 70:2086-2092. [PMID: 36352613 DOI: 10.4103/0028-3886.359222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
OBJECTIVES Different variant of GBM has been reported viz. Epithelioid Glioblastoma (GBM-E), Rhabdoid GBM (GBM-R), Small cell GBM (GBM-SC), Giant cell GBM (GBM-GC), GBM with neuro ectodermal differentiation (GBM-PNET) with unknown behavior. MATERIALS We conducted a systematic review and individual patient data analysis of these rare GBM variants. We searched PubMed, google search, and Cochrane library for eligible studies till July 1st 2016 published in English language and collected data regarding age, sex, subtype and treatment received, Progression Free Survival (PFS), Overall Survival (OS). Statistical Package for social sciences (SPSS) v16 software was used for all statistical analysis. RESULTS We retrieved data of 196 patients with rare GBM subtypes. Among these GBM-GC is commonest (51%), followed by GBM-R (19%), GBM-PNET (13%), GBM-SC (9%) and GBM-E (8%). Median age at diagnosis was 38, 40, 43.5, 69.5 and 18 years, respectively. Male: female ratio was 2:1 for GBM-E, and 1:3 for GBM-SC. Maximal safe resection followed by adjuvant local radiation was used for most of the patients. However, 6 patients with GBM-PNET, 3 each of GBM-E, GBM-SC received adjuvant craniospinal radiation. Out of 88 patients who received chemotherapy, 64 received Temozolomide alone or combination chemotherapy containing Temozolomide. Median PFS and OS for the entire cohort were 9 and 16 months. In univariate analysis, patient with a Gross Total Resection had significantly better PFS and OS compared to those with a Sub Total Resection [23 vs. 13 months (p-0.01)]. Median OS for GBM PNET, GBM-GC, GBM-SC, GBM-R and GBM-E were 32, 18.3, 11, 12 and 7.7 months, respectively (P = 0.001). Interestingly, 31.3%, 37.8% of patients with GBM-E, GBM-R had CSF dissemination. CONCLUSION Overall cohort of rarer GBM variant has equivalent survival compared to GBM not otherwise specified. However, epithelioid and Rhabdoid GBM has worst survival and one third shows CSF dissemination.
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Affiliation(s)
- Supriya Mallick
- Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India
| | - Rony Benson
- Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India
| | | | - Wineeta Melgandi
- Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India
| | - Goura K Rath
- Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India
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Natsumeda M, Kanemaru Y, Kawaguchi Y, Umezu H, Kakita A, Fujii Y. Less-invasive diagnosis of disseminated epithelioid glioblastoma harboring BRAF V600E mutation by cerebrospinal fluid analysis-A case report. Clin Case Rep 2021; 9:e04551. [PMID: 34295500 PMCID: PMC8283864 DOI: 10.1002/ccr3.4551] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 05/31/2021] [Accepted: 06/13/2021] [Indexed: 11/11/2022] Open
Abstract
Spinal dissemination in epithelioid glioblastoma can be diagnosed by cerebrospinal fluid cytology and liquid biopsy to detect BRAF V600E mutation.
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Affiliation(s)
- Manabu Natsumeda
- Department of NeurosurgeryBrain Research InstituteNiigata UniversityNiigataJapan
| | - Yu Kanemaru
- Department of NeurosurgeryBrain Research InstituteNiigata UniversityNiigataJapan
| | - Yukie Kawaguchi
- Division of PathologyNiigata University Medical & Dental HospitalNiigataJapan
| | - Hajime Umezu
- Division of PathologyNiigata University Medical & Dental HospitalNiigataJapan
| | - Akiyoshi Kakita
- Department of PathologyBrain Research InstituteNiigata UniversityNiigataJapan
| | - Yukihiko Fujii
- Department of NeurosurgeryBrain Research InstituteNiigata UniversityNiigataJapan
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3
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Primary and metastatic glioblastoma of the spine in the pediatric population: a systematic review. Childs Nerv Syst 2021; 37:1849-1858. [PMID: 33675391 DOI: 10.1007/s00381-021-05098-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 02/18/2021] [Indexed: 01/15/2023]
Abstract
Pediatric glioblastoma multiforme (GBM) involving the spine is an aggressive tumor with a poor quality of life for patients. Despite this, there is only a limited number of reports describing the outcomes of pediatric spinal GBMs, both as primary spinal GBMs and metastases from an intracranial tumor. Here, we performed an individual patient meta-analysis to characterize factors affecting prognosis of pediatric spinal GBM. MEDLINE, Embase, and the Cochrane databases were searched for published studies on GBMs involving the spine in pediatric patients (age ≤ 21 years old). Factors associated with the survival were assessed with multi-factor ANOVAs, Cox hazard regression, and Kaplan-Meier analyses. We extracted data on 61 patients with spinal GBM from 40 studies that met inclusion criteria. Median survival was significantly longer in the primary spinal GBM compared that those with metastatic GBM (11 vs 3 months, p < 0.001). However, median survival of metastatic GBM patients was 10 months following diagnosis of their primary brain tumor, which was not different from that of primary spinal GBM patients (p = 0.457). Among primary spinal GBM patients, chemotherapy (hazard ratio (HR) = 0.255 [0.106-0.615], p = 0.013) and extent of resection (HR = 0.582 [0.374-0.905], p = 0.016) conferred a significant survival benefit. Younger age (less than 14 years) was associated with longer survival in patients treated with chemotherapy than those who did not undergo chemotherapy (β = - 1.12, 95% CI [- 2.20, - 0.03], p < 0.05). In conclusion, survival after presentation of metastases from intracranial GBM is poor in the pediatric population. In patients with metastatic GBM, chemotherapy may have provided the most benefit in young patients, and its efficacy might have an association with extent of surgical resection.
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4
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Meredith DM. Advances in Diagnostic Immunohistochemistry for Primary Tumors of the Central Nervous System. Adv Anat Pathol 2020; 27:206-219. [PMID: 30720470 DOI: 10.1097/pap.0000000000000225] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
As genomic characterization becomes increasingly necessary for accurate diagnosis of tumors of the central nervous system, identification of rapidly assessible biomarkers is equally important to avoid excessive cost and delay in initiation of therapy. This article reviews novel immunohistochemical markers that may be used to determine mutation status, activation of signaling pathways, druggable targets, and cell lineage in many diverse tumor types. In particular, recently added entities to the 2016 WHO classification of central nervous system tumors will be addressed, including IDH-mutant gliomas, diffuse midline glioma, epithelioid glioblastoma, angiocentric glioma, RELA-rearranged ependymoma, embryonal tumors (medulloblastoma, atypical teratoid/rhabdoid tumor, pineoblastoma, embryonal tumor with multilayered rosettes, and other genetically defined high-grade neuroepithelial tumors), and meningiomas associated with germline alterations.
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Kohno D, Inoue A, Fukushima M, Aki T, Matsumoto S, Suehiro S, Nishikawa M, Ozaki S, Shigekawa S, Watanabe H, Kitazawa R, Kunieda T. Epithelioid glioblastoma presenting as multicentric glioma: A case report and review of the literature. Surg Neurol Int 2020; 11:8. [PMID: 31966927 PMCID: PMC6969379 DOI: 10.25259/sni_544_2019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2019] [Accepted: 12/31/2019] [Indexed: 02/04/2023] Open
Abstract
Background: Epithelioid glioblastoma is a rare aggressive variant of glioblastoma multiforme (GBM), which was formally recognized by the World Health Organization classification of the central nervous system in 2016. Clinically, epithelioid GBMs are characterized by aggressive features, such as metastases and cerebrospinal fluid dissemination, and an extremely poor prognosis. A rare case of epithelioid GBM that was discovered as a multicentric glioma with different histopathology is reported. Case Description: A 78-year-old man was admitted to our hospital with mild motor weakness of the right leg. Neuroimaging showed small masses in the left frontal and parietal lobes on magnetic resonance imaging. The abnormal lesion had been increasing rapidly for 3 weeks, and a new lesion appeared in the frontal lobe. 11C-methionine positron emission tomography (PET) showed abnormal uptake corresponding to the lesion. To reach a definitive diagnosis, surgical excision of the right frontal mass lesion was performed. Histological findings showed diffuse astrocytoma. Only radiotherapy was planned, but the left frontal and parietal tumors progressed further within a short period. Therefore, it was thought that these tumors were GBM, and a biopsy of the left parietal tumor was performed. The histological diagnosis was epithelioid GBM. Immunohistochemistry showed that most tumor cells were negatively stained for p53 and isocitrate dehydrogenase 1. BRAF V600E mutations were not identified, but TERT promoter mutations were identified. Immediately after surgery, the patient was given chemotherapy using temozolomide, extended local radiotherapy and then bevacizumab. After 6 months, he showed no signs of recurrence. Conclusion: Epithelioid GBM is one of the rarest morphologic subtypes of GBM and has a strongly infiltrative and aggressive nature. Therefore, careful identification of preoperative imaging studies and detailed evaluation of genetic studies are necessary to select the appropriate treatment for epithelioid GBM.
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Affiliation(s)
- Daisuke Kohno
- Department of Neurosurgery, Ehime University School of Medicine
| | - Akihiro Inoue
- Department of Neurosurgery, Ehime University School of Medicine
| | - Mana Fukushima
- Division of Diagnostic Pathology, Ehime University Hospital, Shitsukawa, Toon, Ehime, Japan
| | - Tomoharu Aki
- Department of Neurosurgery, Ehime University School of Medicine
| | | | - Satoshi Suehiro
- Department of Neurosurgery, Ehime University School of Medicine
| | | | - Saya Ozaki
- Department of Neurosurgery, Ehime University School of Medicine
| | - Seiji Shigekawa
- Department of Neurosurgery, Ehime University School of Medicine
| | | | - Riko Kitazawa
- Division of Diagnostic Pathology, Ehime University Hospital, Shitsukawa, Toon, Ehime, Japan
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Lu VM, George ND, Brown DA, Akinduro OO, Raghunathan A, Jentoft M, Quinones-Hinojosa A, Chaichana KL. Confirming Diagnosis and Effective Treatment for Rare Epithelioid Glioblastoma Variant: An Integrated Survival Analysis of the Literature. World Neurosurg 2019; 131:243-251.e2. [PMID: 31404694 DOI: 10.1016/j.wneu.2019.08.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 07/31/2019] [Accepted: 08/01/2019] [Indexed: 11/27/2022]
Abstract
BACKGROUND Epithelioid glioblastoma (eGBM) is a very rare histologic variant of glioblastoma that has not been studied in isolation and, therefore, its optimal management has been largely assumed, but not confirmed. The aim of this study was to analyze all reported cases describing the presentation and clinical features to better understand the clinical significance of this histologic diagnosis. METHODS A comprehensive literature search was conducted from 2005 to April 2019 identifying cases of eGBM that satisfied selection criteria for analysis. Survival was investigated using Kaplan-Meier estimations, and then univariate and multivariate logistic regression analyses for primary end point overall survival (OS) and second end point progression-free survival (PFS). RESULTS A total cohort of 59 eGBM cases from 28 articles were included for final analysis. Median age of patients at diagnosis was 30 years, with 29 (46%) female patients. When reported, 100% (37/37) cases were IDH1-wild-type and 63% (19/30) were positive for the BRAF V600E mutation by immunohistochemistry. Median OS and PFS were estimated to be 11.0 months (95% confidence interval, 6.5-13.0) and 7.0 months (95% confidence interval, 3.0-10.0), respectively. Surgical extent of resection, radiation therapy, and chemotherapy all predicted superior OS and PFS on multivariate analysis (P < 0.05). No biomarkers prognosticated survival. CONCLUSIONS These findings indicate that the histologic diagnosis of eGBM does not deviate from the clinical course of the broader glioblastoma diagnosis, despite being a unique histologic identity. These results argue against the temptation to deviate from the traditional management paradigm of surgery, radiation, and chemotherapy for glioblastoma based on this histology alone.
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Affiliation(s)
- Victor M Lu
- Department of Neurosurgery, Mayo Clinic, Rochester, Minnesota, USA.
| | - Naveen D George
- Magdalen College, University of Oxford, Oxford, United Kingdom
| | - Desmond A Brown
- Department of Neurosurgery, Mayo Clinic, Rochester, Minnesota, USA
| | | | | | - Mark Jentoft
- Department of Pathology, Mayo Clinic, Jacksonville, Florida, USA
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Kanemaru Y, Natsumeda M, Okada M, Saito R, Kobayashi D, Eda T, Watanabe J, Saito S, Tsukamoto Y, Oishi M, Saito H, Nagahashi M, Sasaki T, Hashizume R, Aoyama H, Wakai T, Kakita A, Fujii Y. Dramatic response of BRAF V600E-mutant epithelioid glioblastoma to combination therapy with BRAF and MEK inhibitor: establishment and xenograft of a cell line to predict clinical efficacy. Acta Neuropathol Commun 2019; 7:119. [PMID: 31345255 PMCID: PMC6659204 DOI: 10.1186/s40478-019-0774-7] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2019] [Accepted: 07/18/2019] [Indexed: 11/14/2022] Open
Abstract
Epithelioid glioblastoma is a rare aggressive variant of glioblastoma (GBM) characterized by a dismal prognosis of about 6 months and frequent leptomeningeal dissemination. A recent study has revealed that 50% of epithelioid GBMs harbor three genetic alterations - BRAF V600E mutation, TERT promoter mutations, and homozygous deletions of CDKN2A/2B. Emerging evidence support the effectiveness of targeted therapies for brain tumors with BRAF V600E mutation. Here we describe a dramatic radiographical response to combined therapy with BRAF and MEK inhibitors in a patient with epithelioid GBM harboring BRAF V600E mutation, characterized by thick spinal dissemination. From relapsed tumor procured at autopsy, we established a cell line retaining the BRAF V600E mutation, TERT promoter mutation and CDKN2A/2B loss. Intracranial implantation of these cells into mice resulted in tumors closely resembling the original, characterized by epithelioid tumor cells and dissemination, and invasion into the perivascular spaces. We then confirmed the efficacy of treatment with BRAF and MEK inhibitor both in vitro and in vivo. Epithelioid GBM with BRAF V600E mutation can be considered a good treatment indication for precision medicine, and this patient-derived cell line should be useful for prediction of the tumor response and clarification of its biological characteristics.
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Affiliation(s)
- Yu Kanemaru
- From the Departments of Neurosurgery, Niigata University, 1-757 Asahimachidori, Chuo-ku, Niigata, Japan
| | - Manabu Natsumeda
- From the Departments of Neurosurgery, Niigata University, 1-757 Asahimachidori, Chuo-ku, Niigata, Japan.
| | - Masayasu Okada
- From the Departments of Neurosurgery, Niigata University, 1-757 Asahimachidori, Chuo-ku, Niigata, Japan
| | - Rie Saito
- Pathology, Brain Research Institute, Niigata University, Niigata, Japan
| | - Daiki Kobayashi
- From the Departments of Neurosurgery, Niigata University, 1-757 Asahimachidori, Chuo-ku, Niigata, Japan
| | - Takeyoshi Eda
- From the Departments of Neurosurgery, Niigata University, 1-757 Asahimachidori, Chuo-ku, Niigata, Japan
| | - Jun Watanabe
- From the Departments of Neurosurgery, Niigata University, 1-757 Asahimachidori, Chuo-ku, Niigata, Japan
| | - Shoji Saito
- From the Departments of Neurosurgery, Niigata University, 1-757 Asahimachidori, Chuo-ku, Niigata, Japan
| | - Yoshihiro Tsukamoto
- From the Departments of Neurosurgery, Niigata University, 1-757 Asahimachidori, Chuo-ku, Niigata, Japan
| | - Makoto Oishi
- From the Departments of Neurosurgery, Niigata University, 1-757 Asahimachidori, Chuo-ku, Niigata, Japan
| | - Hirotake Saito
- Department of Radiology and Radiation Oncology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Masayuki Nagahashi
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Takahiro Sasaki
- Department of Neurosurgery, Northwestern University, Chicago, IL, USA
| | - Rintaro Hashizume
- Department of Neurosurgery, Northwestern University, Chicago, IL, USA
| | - Hidefumi Aoyama
- Department of Radiology and Radiation Oncology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Toshifumi Wakai
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Akiyoshi Kakita
- Pathology, Brain Research Institute, Niigata University, Niigata, Japan
| | - Yukihiko Fujii
- From the Departments of Neurosurgery, Niigata University, 1-757 Asahimachidori, Chuo-ku, Niigata, Japan
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9
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Miyahara M, Nobusawa S, Inoue M, Okamoto K, Mochizuki M, Hara T. Glioblastoma with Rhabdoid Features: Report of Two Young Adult Cases and Review of the Literature. World Neurosurg 2016; 86:515.e1-9. [DOI: 10.1016/j.wneu.2015.10.065] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Revised: 10/12/2015] [Accepted: 10/13/2015] [Indexed: 11/26/2022]
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Sugimoto K, Ideguchi M, Kimura T, Kajiwara K, Imoto H, Sadahiro H, Ishii A, Kawano H, Ikeda E, Suzuki M. Epithelioid/rhabdoid glioblastoma: a highly aggressive subtype of glioblastoma. Brain Tumor Pathol 2015; 33:137-46. [DOI: 10.1007/s10014-015-0243-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Accepted: 11/29/2015] [Indexed: 11/28/2022]
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11
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Alexandrescu S, Korshunov A, Lai SH, Dabiri S, Patil S, Li R, Shih CS, Bonnin JM, Baker JA, Du E, Scharnhorst DW, Samuel D, Ellison DW, Perry A. Epithelioid Glioblastomas and Anaplastic Epithelioid Pleomorphic Xanthoastrocytomas--Same Entity or First Cousins? Brain Pathol 2015; 26:215-23. [PMID: 26238627 DOI: 10.1111/bpa.12295] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Accepted: 07/27/2015] [Indexed: 02/03/2023] Open
Abstract
Epithelioid glioblastoma (eGBM) and pleomorphic xanthoastrocytoma (PXA) with anaplastically transformed foci (ePXA) show overlapping features. Eleven eGBMs and 5 ePXAs were reviewed and studied immunohistochemically. Fluorescence in situ hybridization for EGFR amplification, PTEN deletion and ODZ3 deletion was also performed, with Ilumina 450 methylome analysis obtained in five cases. The average age for eGBM was 30.9 (range 2-79) years, including five pediatric cases and a M : F ratio of 4.5. The ePXA patients had a M : F ratio of 4 and averaged 21.2 (range 10-38) years in age, including two pediatric cases. Six eGBMs and two ePXAs recurred (median recurrence interval of 12 and 3.3 months, respectively). All tumors were composed of solid sheets of loosely cohesive, "melanoma-like" cells with only limited infiltration. ePXAs showed lower grade foci with classic features of PXA. Both tumor types showed focal expression of epithelial and glial markers, retained INI1 and BRG1 expression, occasional CD34 positivity, and lack of mutant IDH1 (R132H) immunoreactivity. BRAF V600E mutation was present in four eGBMs and four ePXAs. ODZ3 deletion was detected in seven eGBMs and two ePXAs. EGFR amplification was absent. Methylome analysis showed that one ePXA and one eGBM clustered with PXAs, one eGBM clustered with low-grade gliomas, and two eGBMs clustered with pediatric-type glioblastomas. Common histologic, immunohistochemical, molecular and clinical features found in eGBM and ePXA suggest that they are closely related or the same entity. If the latter is true, the nomenclature and WHO grading remains to be resolved.
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Affiliation(s)
| | - Andrey Korshunov
- Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Siang Hui Lai
- Department of Pathology, Singapore General Hospital, Singapore
| | - Salma Dabiri
- Department of Pathology, Good Samaritan Hospital, San Jose, CA
| | - Sushama Patil
- Department of Pathology, Apollo Specialty Hospital, Chennai, India
| | - Rong Li
- Department of Pathology, Children's Hospital of Alabama, Birmingham, AL
| | - Chie-Schin Shih
- Department of Pediatrics, Indiana University, Indianapolis, IN
| | - Jose M Bonnin
- Department of Pathology, Indiana University, Indianapolis, IN
| | - Jonathan A Baker
- Department of Pathology, Texas Health Presbyterian Hospital, Dallas, TX
| | - Emma Du
- Department of Pathology, Scripps Clinic, La Jolla, CA
| | | | - David Samuel
- Department of Pediatric Oncology, Children's Hospital Central California, Madera, CA
| | - David W Ellison
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN
| | - Arie Perry
- Department of Pathology, University of California, San Francisco, CA
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12
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Detection of a Distinctive Genomic Signature in Rhabdoid Glioblastoma, A Rare Disease Entity Identified by Whole Exome Sequencing and Whole Transcriptome Sequencing. Transl Oncol 2015; 8:279-87. [PMID: 26310374 PMCID: PMC4562980 DOI: 10.1016/j.tranon.2015.05.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Revised: 05/10/2015] [Accepted: 05/20/2015] [Indexed: 12/23/2022] Open
Abstract
We analyzed the genome of a rhabdoid glioblastoma (R-GBM) tumor, a very rare variant of GBM. A surgical specimen of R-GBM from a 20-year-old woman was analyzed using whole exome sequencing (WES), whole transcriptome sequencing (WTS), single nucleotide polymorphism array, and array comparative genomic hybridization. The status of gene expression in R-GBM tissue was compared with that of normal brain tissue and conventional GBM tumor tissue. We identified 23 somatic non-synonymous small nucleotide variants with WES. We identified the BRAF V600E mutation and possible functional changes in the mutated genes, ISL1 and NDRG2. Copy number alteration analysis revealed gains of chromosomes 3, 7, and 9. We found loss of heterozygosity and focal homozygous deletion on 9q21, which includes CDKN2A and CDKN2B. In addition, WTS revealed that CDK6, MET, EZH2, EGFR, and NOTCH1, which are located on chromosomes 7 and 9, were over-expressed, whereas CDKN2A/2B were minimally expressed. Fusion gene analysis showed 14 candidate genes that may be functionally involved in R-GBM, including TWIST2, and UPK3BL. The BRAF V600E mutation, CDKN2A/2B deletion, and EGFR/MET copy number gain were observed. These simultaneous alterations are very rarely found in GBM. Moreover, the NDRG2 mutation was first identified in this study as it has never been reported in GBM. We observed a unique genomic signature in R-GBM compared to conventional GBM, which may provide insight regarding R-GBM as a distinct disease entity among the larger group of GBMs.
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13
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Gelal MF, Rezanko TA, Sarp AF, Dirilenoğlu F, Güvenç G, Ölmezoğlu A. Magnetic Resonance Imaging Features of Rhabdoid Glioblastomas. Clin Neuroradiol 2014; 26:329-40. [PMID: 25516148 DOI: 10.1007/s00062-014-0366-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2014] [Accepted: 11/21/2014] [Indexed: 11/30/2022]
Abstract
PURPOSE Rhabdoid glioblastoma (rGB) is a recently described, highly aggressive brain tumor, in which glioblastoma (GB) is associated with a rhabdoid component. So far only 21 cases have been reported and its imaging findings have not been studied in detail. In this paper, we present 11 additional cases and aim to depict detailed magnetic resonance imaging (MRI) features of this tumor in comparison with the previous cases of rGBs and our cohort of typical GBs. METHODS Retrospective evaluation of the glass slides of 249 GB patients disclosed 14 cases with rhabdoid morphology. Eleven of these cases with available MRI were included in the study. Immunohistochemistry was also performed. MRI and clinicopathologic findings were compared with those of previous rGBs and typical GBs. RESULTS (1) rGB is usually a large, well-delineated solid tumor with extensive necrosis, heterogeneous contrast enhancement, occasional hemorrhage, and cysts, (2) rGB may present at an older age than previously reported, but still in younger individuals compared with typical GB patients, (3) tumor dissemination in the form of leptomeningeal seeding and more rarely extracranial metastases is a feature of rGBs, although leptomeningeal seeding may not be as high as previously reported, (4) prognosis is poor in rGBs. CONCLUSIONS rGB is a new entity which has not yet appeared in the WHO classification of central nervous system (CNS) tumors. Understanding its clinical and imaging features may help to distinguish it from other tumors of CNS.
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Affiliation(s)
- M F Gelal
- Department of Radiology, İzmir Katip Celebi University Atatürk Training and Research Hospital, İzmir, Turkey.
| | - T A Rezanko
- Department of Pathology, İzmir Katip Celebi University Atatürk Training and Research Hospital, İzmir, Turkey
| | - A F Sarp
- Department of Radiology, İzmir Katip Celebi University Atatürk Training and Research Hospital, İzmir, Turkey
| | - F Dirilenoğlu
- Department of Pathology, İzmir Katip Celebi University Atatürk Training and Research Hospital, İzmir, Turkey
| | - G Güvenç
- Department of Neurosurgery, İzmir Katip Celebi University Atatürk Training and Research Hospital, İzmir, Turkey
| | - A Ölmezoğlu
- Department of Radiation Oncology, İzmir Katip Celebi University Atatürk Training and Research Hospital, İzmir, Turkey
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14
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Broniscer A, Tatevossian RG, Sabin ND, Klimo P, Dalton J, Lee R, Gajjar A, Ellison DW. Clinical, radiological, histological and molecular characteristics of paediatric epithelioid glioblastoma. Neuropathol Appl Neurobiol 2014; 40:327-36. [PMID: 24127995 DOI: 10.1111/nan.12093] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Accepted: 10/08/2013] [Indexed: 11/29/2022]
Abstract
AIMS A few case series in adults have described the characteristics of epithelioid glioblastoma (e-GB), one of the rarest variants of this cancer. We evaluated clinical, radiological, histological and molecular characteristics in the largest series to date of paediatric e-GB. METHODS Review of clinical characteristics and therapy, imaging studies and histology was performed in patients younger than 22 years with e-GB seen at our institution over 15 years. Sequencing of hotspot mutations and fluorescence in situ hybridization of relevant genes were undertaken. RESULTS Median age at diagnosis of six patients was 7.6 years. Tumours originated in the cerebral cortex (n = 2) or diencephalon (n = 4). Three patients presented with acute, massive haemorrhage and three had leptomeningeal dissemination at diagnosis. Paediatric e-GB had the typical histological characteristics seen in adult tumours. Universal immunoreactivity for INI1 and lack of diverse protein expression were seen in all cases. One tumour had a chromosome 22q loss. Three tumours (50%) harboured a BRAF: p.V600E. One thalamic tumour had an H3F3A p.K27M. All patients received radiation therapy with (n = 3) or without chemotherapy (n = 3). All patients experienced tumour progression with a median survival of 169 days. One patient with nonmetastatic disease had early leptomeningeal progression. Two patients had symptomatic tumour spread outside the central nervous system (CNS) through a ventriculoperitoneal shunt. One additional patient had widespread metastases outside the CNS identified at autopsy. CONCLUSIONS Paediatric e-GBs are rare cancers with an aggressive behaviour that share histological and genetic characteristics with their adult counterparts. BRAF inhibition is a potential treatment for these tumours.
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Affiliation(s)
- A Broniscer
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA; Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA
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Byeon SJ, Cho HJ, Baek HW, Park CK, Choi SH, Kim SH, Kim HK, Park SH. Rhabdoid glioblastoma is distinguishable from classical glioblastoma by cytogenetics and molecular genetics. Hum Pathol 2014; 45:611-20. [DOI: 10.1016/j.humpath.2013.08.024] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2013] [Revised: 07/31/2013] [Accepted: 08/02/2013] [Indexed: 02/09/2023]
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16
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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 epithelioid glioblastoma with BRAF V600E mutation. Brain Pathol 2014; 24:239-46. [PMID: 24354918 DOI: 10.1111/bpa.12114] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Accepted: 12/10/2013] [Indexed: 02/01/2023] Open
Abstract
Epithelioid glioblastoma is among the rarest variants of glioblastoma and is not formally recognized in the World Health Organization classification; it is composed of monotonous, discohesive sheets of small, round cells with eccentric nuclei and eosinophilic cytoplasm devoid of cytoplasmic stellate processes, showing the retention of nuclear staining of INI-1 protein. Here, we report a case involving a 22-year-old man with a right occipital lobe tumor, which comprised mainly epithelioid tumor cells with a small area of diffusely infiltrating less atypical astrocytoma cells showing a lower cell density. Array comparative genomic hybridization separately performed for each histologically distinct component demonstrated eight shared copy number alterations (CNAs) and three CNAs observed only in epithelioid cells; one of the latter was a homozygous deletion of a tumor suppressor gene, LSAMP, at 3q13.31. BRAF V600E mutation was observed both in epithelioid tumor cells and in diffusely infiltrating less atypical astrocytoma cells. Our findings suggest that the regional loss of LSAMP led to the aggressive nature of epithelioid cells in the present case of epithelioid glioblastoma.
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Affiliation(s)
- Sumihito Nobusawa
- Department of Human Pathology, Gunma University Graduate School of Medicine, Maebashi, Japan
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Rhabdoid glioblastoma: a recently recognized subtype of glioblastoma. Acta Neurochir (Wien) 2013; 155:1443-8; discussion 1448. [PMID: 23812963 DOI: 10.1007/s00701-013-1793-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2013] [Accepted: 06/04/2013] [Indexed: 10/26/2022]
Abstract
BACKGROUND Rhabdoid glioblastoma is a rare type of recently described malignant brain tumor. It is characterized by a glioblastoma associated with rhabdoid components. METHODS Here we report two cases of rhabdoid glioblastoma and a brief literature review. The first patient was a 19-year-old boy who initially presented with a foul-smelling odor and progressive right-side weakness. The second case was a 29-year-old male patient who presented only with a severe headache. RESULTS Both of these patients were young, and the disease progression was quick despite optimal treatment. CONCLUSION The diagnosis of rhabdoid glioblastoma was confirmed after microscopic and immunohistochemical findings.
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18
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Babu R, Hatef J, McLendon RE, Cummings TJ, Sampson JH, Friedman AH, Adamson C. Clinicopathological characteristics and treatment of rhabdoid glioblastoma. J Neurosurg 2013; 119:412-9. [DOI: 10.3171/2013.3.jns121773] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Object
Rhabdoid glioblastoma (GB) is an exceedingly rare tumor in which some of the tumor cells possess rhabdoid features such as eccentric nuclei, abundant eosinophilic cytoplasm, and pseudopapillary formations. These tumors are exceptionally aggressive, and leptomeningeal dissemination is common. In the 9 previously reported cases, the longest survival was only 9 months, with a median survival of 17.8 weeks. The authors report the clinicopathological characteristics of 4 cases of rhabdoid GB and demonstrate the utility of intensive temozolomide and adjuvant therapy in these tumors. The authors also review the literature to provide the most comprehensive understanding of these rare tumors to date.
Methods
A retrospective review was performed of patients treated for GB at the Duke University Medical Center between 2004 and 2012. One of two experienced neuropathologists identified 4 cases as being rhabdoid GBs. Immunohistochemistry and fluorescence in situ hybridization analyses were performed in all cases. Kaplan-Meier analysis was used to assess overall survival, with the log-rank test being used to evaluate differences between survival curves. An extensive review of the literature was also performed.
Results
The median age of patients with rhabdoid GB was 30 years. Clinical presentation varied with location, with headache being a presenting symptom in 90% of patients. All lesions were supratentorial, and 45.5% of the cases involved the temporal lobe. Leptomeningeal dissemination occurred in 63.6% of patients, with 1 patient having extracranial metastasis to the scalp and lungs. Fluorescence in situ hybridization revealed epidermal growth factor receptor gain or amplification in all study cases. The median survival in the authors' cohort was significantly higher than that of all previously reported cases (27.5 vs 4.5 months, p = 0.003). Postoperative treatment in the authors' cohort included radiotherapy with concurrent temozolomide, bevacizumab, interleukin 13, CCNU, and/or etoposide.
Conclusions
Enhanced survival in the authors' 4 patients suggests that the current standard of care for the treatment of GB may be beneficial in rhabdoid GB cases, with postoperative radiotherapy and concomitant temozolomide treatment followed by adjuvant therapy. Due to the rapid tumor dissemination associated with these lesions, aggressive and timely therapy is warranted, with frequent surveillance and/or continued therapy despite stable disease. Additionally, patients should undergo full craniospinal imaging to monitor the development of distant metastatic disease.
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Affiliation(s)
- Ranjith Babu
- 1Departments of Surgery (Division of Neurosurgery),
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- 1Departments of Surgery (Division of Neurosurgery),
- 3Neurobiology, Duke University Medical Center; and
- 4Neurosurgery Section, Durham VA Medical Center, Durham, North Carolina
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Yamamoto J, Takahashi M, Nakano Y, Soejima Y, Saito T, Akiba D, Hirato J, Nakazato Y, Nishizawa S. Rapid progression of rhabdoid components of a composite high-grade glioma and rhabdoid tumor in the occipital lobe of an adult. Brain Tumor Pathol 2011; 29:113-20. [DOI: 10.1007/s10014-011-0069-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2011] [Accepted: 09/28/2011] [Indexed: 10/16/2022]
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