scholarly journals IDH-wildtype lower grade diffuse gliomas: the importance of histological grade and molecular assessment for prognostic stratification

2020 ◽  
Author(s):  
Giulia Berzero ◽  
Anna Luisa Di Stefano ◽  
Susanna Ronchi ◽  
Franck Bielle ◽  
Chiara Villa ◽  
...  
Keyword(s):  
Histological Grade ◽  
Lower Grade ◽  
Who Grade ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Prognostic Stratification ◽  
Grade Ii ◽  
Definition Of ◽  
Promoter Mutations ◽  
Grade Iii

Abstract Background IDH-wildtype (IDHwt) grade II gliomas are a rare and heterogeneous entity. Survival and prognostic factors are poorly defined. Methods We searched retrospectively all patients diagnosed with diffuse WHO grade II and III gliomas at our center (1989-2020). Results Out of 517 grade II gliomas, 47 were “diffuse astrocytomas, IDHwt”. Tumors frequently had fronto-temporo-insular location (28/47, 60%) and infiltrative behavior. We found TERT promoter mutations (23/45, 51%), whole chromosome 7 gains (10/37, 27%), whole chromosome 10 losses (10/41, 24%), and EGFR amplifications (4/43, 9%) but no TP53 mutations (0/22, 0%). Median overall survival (OS) was 59 months (vs. 19 months for IDHwt grade III gliomas (p< 0.0001). Twenty-nine patients (29/43, 67%) met the definition of molecular glioblastoma according to cIMPACT-NOW update3. Median OS in this subset was 42 months, which was shorter compared to patients with IDHwt grade II gliomas not meeting this definition (median OS: 57 months), but substantially longer compared to IDHwt grade III gliomas meeting the definition for molecular glioblastoma (median OS: 17 months, p<0.0001). Most patients with IDHwt grade II gliomas met cIMPACT criteria because of isolated TERT promoter mutations (16/26, 62%), which were not predictive of poor outcome (median OS: 88 months). Actionable targets, including 5 gene fusions involving FGFR3, were found in 7 patients (24%). Conclusions Our findings highlight the importance of histological grading and molecular profiling for the prognostic stratification of IDHwt gliomas and suggest some caution when assimilating IDHwt grade II gliomas to molecular glioblastomas, especially those with isolated TERT promoter mutation.

scholarly journals OS10.1 Survival analysis of IDH wildtype astrocytomas with molecular features of glioblastoma, WHO grade IV

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii20-iii20 ◽  
Author(s):  
C M S Tesileanu ◽  
J A F Koekkoek ◽  
L Dirven ◽  
H J Dubbink ◽  
J M Kros ◽  
...  
Keyword(s):  
Molecular Data ◽  
Lower Grade ◽  
Who Grade ◽  
Historical Cohort ◽  
Molecular Features ◽  
Tert Promoter ◽  
Significant Difference ◽  
Tert Promoter Mutations ◽  
Grade Ii ◽  
Promoter Mutations

Abstract BACKGROUND Recently, isocitrate dehydrogenase wildtype (IDHwt) lower grade gliomas (LGGs) that have a telomerase reverse transcriptase (TERT) promoter mutation and/or gain of chromosome 7 combined with loss of chromosome 10 and/or epidermal growth factor receptor amplification have been reclassified as IDHwt astrocytomas with molecular features of glioblastoma, WHO grade IV (‘astrocytomas IDHwt, WHO IV’). Survival of these tumors meeting the criteria of these tumors is less well studied. The objective of this study is to compare the overall survival (OS) between the IDHwt astrocytomas, WHO IV and histological glioblastomas (GBMs). MATERIAL AND METHODS In this retrospective multicenter cohort study, all adult patients with a newly diagnosed IDHwt LGG (histologically WHO grade II or III) and with molecular data available were selected from the Erasmus MC and the LUMC from October 2002 to April 2019. LGG patients showing contrast enhancement with necrosis on the MRI at the time of histological diagnosis were excluded. Molecular data were determined using a diagnostic NGS panel. A historical cohort of 195 patients with IDHwt GBMs with molecular data available was used to compare OS. OS was measured from the date of the first diagnostic MR scan. RESULTS 79 IDHwt LGG patients were identified of which 62 patients had molecular features of glioblastoma (‘astrocytomas IDHwt, WHO IV’), 11 patients did not have these molecular features (‘astrocytomas IDHwt, WHO II & III’). In the remaining 6 patients the molecular data were not conclusive (astrocytomas IDHwt, WHO NOS). Patients with astrocytomas IDHwt, WHO IV were slightly older at diagnosis (median age = 57 years) than patients with GBMs IDHwt in the reference cohort or astrocytomas IDHwt, WHO II & III (respectively: median age 55 years, p=0.032 and 47 years, p=0.035). The relatively young age of our GBM IDHwt cohort reflects more extensive molecular testing in younger patients and histologically lower grade tumors. The median OS of astrocytomas IDHwt, WHO IV (23.8 months) was similar to the median OS of GBMs (19.2 months, log-rank test p=0.37). The median OS in 19 patients with only TERT promoter mutations was 16.8 months, similar to GBMs (p=0.94). CONCLUSION There is no statistically significant difference between the OS of IDHwt astrocytomas with molecular features of glioblastoma and the OS of true glioblastomas. Grade II and III IDHwt astrocytoma with molecular features of glioblastoma should be designated WHO grade IV. The presence of TERT promoter mutations alone in this histological context also qualifies for this designation.

scholarly journals TERT promoter mutations in primary and secondary WHO grade III meningioma

2020 ◽  
Author(s):  
Andrea Daniela Maier ◽  
Adam Stenman ◽  
Fredrika Svahn ◽  
Christian Mirian ◽  
Jiri Bartek ◽  
...  
Keyword(s):  
Who Grade ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Promoter Mutations ◽  
Who Grade Iii ◽  
Grade Iii

Radiological Characteristics and Natural History of Adult IDH-Wildtype Astrocytomas with TERT Promoter Mutations

Neurosurgery ◽  
2018 ◽  
Vol 85 (3) ◽  
pp. E448-E456 ◽  
Author(s):  
Cristina Izquierdo ◽  
Marc Barritault ◽  
Delphine Poncet ◽  
Stéphanie Cartalat ◽  
Bastien Joubert ◽  
...  
Keyword(s):  
Natural History ◽  
Contrast Enhancement ◽  
Slow Growth ◽  
Gliomatosis Cerebri ◽  
Lower Grade ◽  
Tert Promoter ◽  
Anaplastic Transformation ◽  
Tert Promoter Mutations ◽  
History Of ◽  
Promoter Mutations

Abstract BACKGROUND Adult IDH-wildtype astrocytomas with TERT promoter mutations (TERTp) are associated with a poor prognosis. OBJECTIVE To analyze the radiological presentation and natural history of adult IDH-wildtype astrocytomas with TERTp. METHODS We retrospectively reviewed the characteristics of 40 IDH-wildtype TERTp-mutant astrocytomas (grade II n = 19, grade III n = 21) and compared them to those of 114 IDH-mutant lower grade gliomas (LGG), of 92 IDH-wildtype TERTp-mutant glioblastomas, and of 15 IDH-wildtype TERTp-wildtype astrocytomas. RESULTS Most cases of IDH-wildtype TERTp-mutant astrocytomas occurred in patients aged >50 yr (88%) and presented as infiltrative lesions without contrast enhancement (73%) that were localized in the temporal and/or insular lobes (37.5%) or corresponded to a gliomatosis cerebri (43%). Thalamic involvement (33%) and extension to the brainstem (27%) were frequently observed, as was gyriform infiltration (33%). This radiological presentation was different from that of IDH-mutant LGG, IDH-wildtype TERTp-mutant glioblastomas, and IDH-wildtype TERTp-wildtype astrocytomas. Tumor evolution before treatment initiation was assessable in 17 cases. Ten cases demonstrated a rapid growth characterized by the apparition of a ring-like contrast enhancement and/or a median velocity of diametric expansion (VDE) ≥8 mm/yr but 7 cases displayed a slow growth (VDE <8 mm/yr) that could last several years before anaplastic transformation. Median overall survival of IDH-wildtype TERTp-mutant astrocytomas was 27 mo. CONCLUSION IDH-wildtype TERTp-mutant astrocytomas typically present as nonenhancing temporo-insular infiltrative lesions or as gliomatosis cerebri in patients aged >50 yr. In the absence of treatment, although rapid tumor growth is frequent, an initial falsely reassuring, slow growth can be observed.

scholarly journals The Expression of Progesterone Receptors in Meningiomas of Different Grades

2019 ◽  
Vol 8 (2) ◽  
pp. 65-69
Author(s):  
Mohammad Tahir ◽  
Tehreem Atif ◽  
Summaya Sohail ◽  
Arfa Nawazish ◽  
Huma Mushtaq
Keyword(s):  
Progesterone Receptor ◽  
Treatment Options ◽  
Progesterone Receptors ◽  
Lower Grade ◽  
Immunoperoxidase Method ◽  
Nuclear Staining ◽  
Who Grade ◽  
Grade Ii ◽  
Who Grade Iii ◽  
Grade Iii

Background: Meningiomas are slow growing intracranial and intraspinal neoplasms with a tendency to recur locally. WHO grades them as I (benign), II (atypical) and III (anaplastic) in order of their increasing aggressiveness, based on histological parameters and brain parenchymal invasion. Progesterone receptors (PR) are more prevalent amongst the lower grade meningiomas. The objective of this study was to determine the immunohistochemical expression of progesterone receptors in meningiomas of different grades.Material and Methods: A total of 100 cases were selected over a period of 2.5 years. Three to five microns’ thick sections stained with Hematoxylin and Eosin were examined microscopically by a team of two Histopathologists and graded into grades I, II and III, according to 2016 WHO classification criteria. Another section of the original tumor was stained with progesterone receptor antibody using the conventional immunoperoxidase method. Stained slides were than examined by the same team of Histopathologists and declared positive (if nuclear staining was observed in more than 10% of tumor cells) or negative. Statistical analysis was done using SPSS version 21.Results: Out of a total of 100 cases of meningioma, there were 79 cases of benign/typical WHO grade I, 15 cases of atypical/ WHO grade II and 6 cases of anaplastic/ WHO grade III tumor. PR status was positive in 89.8 % (71/79) of grade I meningiomas and 46.6 % (7/15) of grade II/Atypical meningiomas. The 06 cases of Anaplastic/WHO grade III tumors were negative for PR. There was a higher prevalence of Progesterone receptors in female patients (89.8%; 53/59) as compared to male meningioma patients (60.9%; 25/41).Conclusion: We observed a decreased expression of progesterone receptor in higher grades of meningioma in this study. It is an effort to explore conservative treatment options for inoperable lesions, as anti-progesterone therapy may hold a promise as a new treatment option in the near future.

TERT promoter mutations in progressive treatment-resistant meningiomas.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2047-2047 ◽  
Author(s):  
Tareq A. Juratli ◽  
Christian Thiede ◽  
Dietmar Krex ◽  
Priscilla Kaliopi Brastianos ◽  
Hiroaki Wakimoto ◽  
...  
Keyword(s):  
Initial Diagnosis ◽  
Lower Grade ◽  
Treatment Resistant ◽  
Mutation Status ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Promoter Gene ◽  
History Of ◽  
Promoter Mutations

2047 Background: Recurrent meningiomas often undergo a grade-progression to become atypical or malignant upon recurrence. Detailed study of progressive meningioma has been hampered by the lack of available paired specimens. Here, we sequenced the TERT promoter ( TERTp) in a large series of patients with treatment-resistant meningiomas at initial diagnosis as well as their sequential recurrences. Methods: We scored 77 meningiomas from 36 patients for TERTp mutations. All patients in this study developed recurrences during the median follow-up of 13.3 years (range 6.4 - 25.5 years) and underwent three surgeries on average (range 2-8). Additionally, we screened geographically distinct sites of all TERTp-mutant meningiomas to interrogate intratumoral heterogeneity. Results: TERTp mutations were detected in 18 tumor samples (18/77 = 23.3%) from 12 patients, but not in any of the matched blood sample DNAs, excluding germline mutations. Notably, the TERTp mutations were absent in the initial lower-grade tumor and were present in the subsequent recurrent tumors. Moreover, we observe emergent spatial heterogeneity in the form of mixed populations of recurrent tumor cells containing different mutation status of the TERT promoter gene in three cases. Patients with emergence of TERTp -mutant meningiomas had a significantly shorter overall survival than their TERTp wild-type counterparts, when measured from the time of initial diagnosis (2.4 vs 11.1 years, 95% CI 0.25-4.54 vs 9.3- 16.8 years p = 0.007). Conclusions: Our data confirm the high frequency of TERTp mutations and the emergence of TERT promoter mutation in recurrent progressive meningiomas, strongly indicating the presence of ongoing evolution impacting the natural history of these tumors. TERTp mutations are mostly associated with poor outcome. Finally, our study provides important insight into the complexity of tumor heterogeneity and has important implications for targeted therapy in treatment-resistant meningiomas.

151 TERT Promoter Mutations in Progressive Treatment-resistant Meningiomas

Neurosurgery ◽  
2017 ◽  
Vol 64 (CN_suppl_1) ◽  
pp. 236-237
Author(s):  
Tareq A Juratli ◽  
Ganesh Shankar ◽  
Mara Koerner ◽  
Shilpa Tummala ◽  
Hiroaki Wakimoto ◽  
...  
Keyword(s):  
Initial Diagnosis ◽  
Lower Grade ◽  
Treatment Resistant ◽  
Mutation Status ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Promoter Gene ◽  
History Of ◽  
Promoter Mutations

Abstract INTRODUCTION Recurrent meningiomas often undergo a grade-progression to become atypical or malignant upon recurrence. Detailed study of progressive meningioma has been hampered by the lack of available paired specimens. Here, we sequenced the TERT promoter (TERTp) in a large series of patients with treatment-resistant meningiomas at initial diagnosis as well as their sequential recurrences. METHODS We scored 77 meningiomas from 36 patients for TERTp mutations. All patients in this study developed recurrences during the median follow-up of 13.3 years (range 6.4-25.5 years) and underwent three surgeries on average (range 2–8). Additionally, we screened geographically distinct sites of all TERTp-mutant meningiomas to interrogate intratumoral heterogeneity. RESULTS >TERTp mutations were detected in 18 tumor samples (18/77 = 23.3%) from 12 patients, but not in any of the matched blood sample DNAs, excluding germline mutations. Notably, the TERTp mutations were absent in the initial lower-grade tumor and were present in the subsequent recurrent tumors. Moreover, we observe emergent spatial heterogeneity in the form of mixed populations of recurrent tumor cells containing different mutation status of the TERT promoter gene in three cases. Patients with emergence of TERTp-mutant meningiomas had a significantly shorter overall survival than their TERTp wild-type counterparts, when measured from the time of initial diagnosis (2.4 vs 11.1 years, 95% CI 0.25-4.54 vs 9.3- 16.8 years P = 0.007). CONCLUSION Our data confirm the high frequency of TERTp mutations and the emergence of TERT promoter mutation in recurrent progressive meningiomas, strongly indicating the presence of ongoing evolution impacting the natural history of these tumors. TERTp mutations are mostly associated with poor outcome. Finally, our study provides important insight into the complexity of tumor heterogeneity and has important implications for targeted therapy in treatment-resistant meningiomas.

scholarly journals TERT PROMOTER MUTATIONS CONTRIBUTE TO PROGNOSTIC SUBGROUPS OF LOWER GRADE ASTROCYTOMAS

2014 ◽  
Vol 16 (suppl 3) ◽  
pp. iii45-iii45
Author(s):  
H. K. Ng ◽  
A. Chan ◽  
Y. Yao ◽  
D. Chan
Keyword(s):  
Lower Grade ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Promoter Mutations

Pathology of Spinal Ependymomas

Neurosurgery ◽  
2013 ◽  
Vol 73 (2) ◽  
pp. 247-255 ◽  
Author(s):  
Phiroz E. Tarapore ◽  
Peter Modera ◽  
Agne Naujokas ◽  
Michael C. Oh ◽  
Beejal Amin ◽  
...  
Keyword(s):  
Adjuvant Radiotherapy ◽  
Histological Grade ◽  
Progression Free Survival ◽  
Extent Of Resection ◽  
World Health ◽  
Subtotal Resection ◽  
Who Grade ◽  
Grade Ii ◽  
Health Organization ◽  
Grade Iii

AbstractBACKGROUND:Ependymomas constitute approximately 40% of primary intraspinal tumors. Current World Health Organization (WHO) grading may not correlate with observed progression-free survival (PFS).OBJECTIVE:This retrospective study of prospectively collected data examines whether PFS is influenced by the histological grade or by the extent of resection. It also analyzes the usage and effectiveness of postoperative adjuvant radiotherapy.METHODS:We reviewed 134 consecutive patients with ependymomas of all grades. Pathology slides were re-reviewed and the histological grades were confirmed by a single neuropathologist. Postoperative residual or recurrence was evaluated with follow-up magnetic resonance imaging.RESULTS:There were 85 male and 49 female patients, ranging from 10 to 79 (median 41) years of age. Thirty patients had WHO grade I tumors, 101 had grade II tumors, and 3 had grade III tumors. Kaplan-Meier analysis of PFS demonstrated a mean duration of 6 years for grade I, 14.9 years for grade II, and 3.7 years for grade III (P &lt; .001). In grade II ependymomas, mean PFS was 11.2 years with subtotal resection and 17.8 years with gross total resection (P &lt; .01). PFS of patients who underwent subtotal resection was not significantly changed by adjuvant radiotherapy (P &lt; .36).CONCLUSION:Patients with grade II ependymoma have significantly longer PFS than patients with grade I ependymoma. The extent of resection did not affect PFS in grade I ependymoma but it did in grade II. Contrary to its higher grade, WHO grade II ependymoma carries a better prognosis than WHO grade I ependymoma.

scholarly journals TERT promoter mutations contribute to subset prognostication of lower-grade gliomas

2014 ◽  
Vol 28 (2) ◽  
pp. 177-186 ◽  
Author(s):  
Aden Ka-Yin Chan ◽  
Yu Yao ◽  
Zhenyu Zhang ◽  
Nellie Yuk-Fei Chung ◽  
Joseph Shu-Ming Liu ◽  
...  
Keyword(s):  
Lower Grade ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Promoter Mutations

scholarly journals Lesion location implemented magnetic resonance imaging radiomics for predicting IDH and TERT promoter mutations in grade II/III gliomas

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Hideyuki Arita ◽  
Manabu Kinoshita ◽  
Atsushi Kawaguchi ◽  
Masamichi Takahashi ◽  
Yoshitaka Narita ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Resonance Imaging ◽  
Lesion Location ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Grade Ii ◽  
Promoter Mutations
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