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Epithelioid glioblastomas stratify into established diagnostic subsets upon integrated molecular analysis.

ABSTRACT: Epithelioid glioblastoma (eGBM) is a newly defined and rare GBM variant in the current WHO 2016 classification. BRAF V600E mutation is overrepresented in these tumors and there is known some morphological overlap with anaplastic epithelioid PXA (ePXA). In order to further elucidate this diagnostic category, we molecularly characterized 64 pediatric and adult examples initially diagnosed as "eGBM." Tumors were analyzed using array based methylation and direct sequencing of the BRAF and TERT genes. Our results demonstrated considerable molecular and clinical heterogeneity among eGBM cohort. Methylation patterns, copy number alterations, and mutational analysis data, in combination with clinical findings disclosed three different, well established tumor subtypes: (i) PXA-like tumors with favorable prognosis, predominantly in children and young adults (38), (ii) IDHwt GBM-like tumors with poor prognosis, mainly occurring in older adults, albeit with more frequent BRAF mutations (17), and (iii) RTK1 pediatric GBM-like neoplasms of intermediate prognosis in children and young adults, associated with chromothripsis and frequent PDGFRA amplifications (9). We conclude that the histopathologically defined eGBM do not represent a single diagnostic entity, but rather at least three molecularly and biologically distinct categories. Therefore, additional molecular testing through genome-wide molecular profiling is recommended to further stratify these rare cases.

SUBMITTER: Korshunov A

PROVIDER: S-EPMC7469088 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Epithelioid glioblastomas stratify into established diagnostic subsets upon integrated molecular analysis.

Korshunov Andrey A Korshunov Andrey A Chavez Lukas L Sharma Tanvi T Ryzhova Marina M Schrimpf Daniel D Stichel Damian D Capper David D Sturm Dominik D Kool Marcel M Habel Antje A Kleinschmidt-DeMasters Bette K BK Rosenblum Marc M Absalyamova Oksana O Golanov Andrey A Lichter Peter P Pfister Stefan M SM Jones David T W DTW Perry Arie A von Deimling Andreas A

Brain pathology (Zurich, Switzerland) 20171030 5

Epithelioid glioblastoma (eGBM) is a newly defined and rare GBM variant in the current WHO 2016 classification. BRAF V600E mutation is overrepresented in these tumors and there is known some morphological overlap with anaplastic epithelioid PXA (ePXA). In order to further elucidate this diagnostic category, we molecularly characterized 64 pediatric and adult examples initially diagnosed as "eGBM." Tumors were analyzed using array based methylation and direct sequencing of the BRAF and TERT genes ...[more]

PMID: 28990704

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Project description:Epithelioid hemangioendothelioma is a low-grade malignant vascular tumor with an intermediate clinical behavior between benign hemangiomas and high-grade angiosarcomas. Pathologic or molecular factors to predict this clinical heterogeneity are not well defined. A WWTR1-CAMTA1 fusion is present in most classic epithelioid hemangioendothelioma, regardless of their clinical behavior, suggesting that additional genetic abnormalities might be responsible in driving a more aggressive biology. A small subset of cases show distinct morphology and are characterized genetically by a YAP1-TFE3 fusion. Two histologic grades have been described in classic epithelioid hemangioendothelioma of the soft tissue. However, proposed criteria do not apply to other clinical presentations and have not been assessed in the YAP1-TFE3 positive tumors. Furthermore, no previous studies have compared the survival of these two molecular subsets. In this study we investigate the clinicopathologic and molecular findings of a large cohort of 93 translocation-positive epithelioid hemangioendothelioma managed at our institution. Patient characteristics, histologic features, treatment outcomes, and genetic abnormalities were investigated and these factors were correlated with overall survival. In 18 patients (15 with WWTR1-CAMTA1 and 3 with YAP1-TFE3) Memorial Sloan Kettering-IMPACT targeted DNA sequencing was performed to identify secondary genetic alterations showing more than half of tumors had a genetic alteration beyond the disease-defining gene fusion. Patients with conventional epithelioid hemangioendothelioma with WWTR1-CAMTA1 fusion had a less favorable outcome compared with the YAP1-TFE3 subset, the 5-year overall survival being 59% versus 86%, respectively. Soft tissue epithelioid hemangioendothelioma were frequently solitary, followed an uneventful clinical course being often managed with curative surgery. Multifocality, pleural involvement, lymph node or distant metastases had a significantly worse outcome. Patients with pleural disease or lymph node metastases had an aggressive clinical course akin to high-grade sarcomas, with 22% and 30%, respectively, alive at 5 years, compared with >70% survival rate in patients lacking these two adverse factors.

Project description:Epithelioid glioblastoma (E-GBM) is a rare aggressive variant of IDH-wildtype glioblastoma newly recognized in the 2016 World Health Organization classification, composed predominantly of monotonous, patternless sheets of round cells with laterally positioned nuclei and plump eosinophilic cytoplasm. Approximately 50% of E-GBM harbor BRAF V600E, which is much less frequently found in other types of glioblastomas. Most E-GBM are recognized as primary/de novo lesions; however, several E-GBM with co- or pre-existing lower-grade lesions have been reported. To better understand associations between E-GBM and the lower-grade lesions, we undertook a histological and molecular analysis of 14 E-GBM, 10 of which exhibited lower-grade glioma-like components (8 E-GBM with co-existing diffuse glioma-like components, 1 E-GBM with a co-existing PXA-like component and 1 E-GBM with a pre-existing PXA). Molecular results demonstrated that the prevalence of BRAF V600E, TERT promoter mutations and CDKN2A/B homozygous deletions in E-GBM were 13/14 (93%), 10/14 (71%) and 11/14 (79%), respectively, and concurrent BRAF V600E, TERT promoter mutations and CDKN2A/B homozygous deletions were observed in 7/14 (50%) of E-GBM. These alterations were also frequently seen in the lower-grade lesions irrespective of the histology. Genetic analysis including array comparative genomic hybridization performed for 5 E-GBM with co- and pre-existing lower-grade components revealed that all molecular changes found in the lower-grade components were also observed in the E-GBM components, and additional changes were detected in the E-GBM components. In conclusion, E-GBM frequently exhibit BRAF V600E, TERT promoter mutations and CDKN2A/B homozygous deletions and these alterations tend to coexist in E-GBM. Taken together with the facts that only one PXA preceded E-GBM among these lower-grade lesions, and that co-occurrence of BRAF V600E, TERT promoter mutations and CDKN2A/B homozygous deletions have been reported to be rare in conventional lower-grade diffuse gliomas, the diffuse glioma-like components may be distinct infiltrative components of E-GBM, reflecting intratumoral heterogeneity.

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Epithelioid glioblastomas stratify into established diagnostic subsets upon integrated molecular analysis.

Publications

Epithelioid glioblastomas stratify into established diagnostic subsets upon integrated molecular analysis.

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