-
Acta Neuropathologica Communications Nov 2023As the progression of low-grade diffuse astrocytomas into grade 4 tumors significantly impacts patient prognosis, a better understanding of this process is of paramount...
As the progression of low-grade diffuse astrocytomas into grade 4 tumors significantly impacts patient prognosis, a better understanding of this process is of paramount importance for improved patient care. In this project, we analyzed matched IDH-mutant astrocytomas before and after progression to grade 4 from six patients (discovery cohort) with genome-wide sequencing, 21 additional patients with targeted sequencing, and 33 patients from Glioma Longitudinal AnalySiS cohort for validation. The Cancer Genome Atlas data from 595 diffuse gliomas provided supportive information. All patients in our discovery cohort received radiation, all but one underwent chemotherapy, and no patient received temozolomide (TMZ) before progression to grade 4 disease. One case in the discovery cohort exhibited a hypermutation signature associated with the inactivation of the MSH2 and DNMT3A genes. In other patients, the number of chromosomal rearrangements and deletions increased in grade 4 tumors. The cell cycle checkpoint gene CDKN2A, or less frequently RB1, was most commonly inactivated after receiving both chemo- and radiotherapy when compared to other treatment groups. Concomitant activating PDGFRA/MET alterations were detected in tumors that acquired a homozygous CDKN2A deletion. NRG3 gene was significantly downregulated and recurrently altered in progressed tumors. Its decreased expression was associated with poorer overall survival in both univariate and multivariate analysis. We also detected progression-related alterations in RAD51B and other DNA repair pathway genes associated with the promotion of error-prone DNA repair, potentially facilitating tumor progression. In our retrospective analysis of patient treatment and survival timelines (n = 75), the combination of postoperative radiation and chemotherapy (mainly TMZ) outperformed radiation, especially in the grade 3 tumor cohort, in which it was typically given after primary surgery. Our results provide further insight into the contribution of treatment and genetic alterations in cell cycle, growth factor signaling, and DNA repair-related genes to tumor evolution and progression.
Topics: Humans; Brain Neoplasms; Retrospective Studies; Glioma; Astrocytoma; Mutation; Temozolomide; Genomics; Isocitrate Dehydrogenase
PubMed: 37932833
DOI: 10.1186/s40478-023-01669-9 -
CNS Oncology 2015
Topics: Astrocytoma; Brain Neoplasms; Humans; Wnt Signaling Pathway
PubMed: 26497968
DOI: 10.2217/cns.15.24 -
Acta Neuropathologica Jun 2015Pilocytic astrocytomas (PAs) were recognized as a discrete clinical entity over 70 years ago. They are relatively benign (WHO grade I) and have, as a group, a 10-year... (Review)
Review
Pilocytic astrocytomas (PAs) were recognized as a discrete clinical entity over 70 years ago. They are relatively benign (WHO grade I) and have, as a group, a 10-year survival of over 90%. Many require merely surgical removal and only very infrequently do they progress to more malignant gliomas. While most show classical morphology, they may present a spectrum of morphological patterns, and there are difficult cases that show similarities to other gliomas, some of which are malignant and require aggressive treatment. Until recently, almost nothing was known about the molecular mechanisms involved in their development. The use of high-throughput sequencing techniques interrogating the whole genome has shown that single abnormalities of the mitogen-activating protein kinase (MAPK) pathway are exclusively found in almost all cases, indicating that PA represents a one-pathway disease. The most common mechanism is a tandem duplication of a ≈2 Mb-fragment of #7q, giving rise to a fusion between two genes, resulting in a transforming fusion protein, consisting of the N-terminus of KIAA1549 and the kinase domain of BRAF. Additional infrequent fusion partners have been identified, along with other abnormalities of the MAP-K pathway, affecting tyrosine kinase growth factor receptors at the cell surface (e.g., FGFR1) as well as BRAF V600E, KRAS, and NF1 mutations among others. However, while the KIAA1549-BRAF fusion occurs in all areas, the incidence of the various other mutations identified differs in PAs that develop in different regions of the brain. Unfortunately, from a diagnostic standpoint, almost all mutations found have been reported in other brain tumor types, although some retain considerable utility. These molecular abnormalities will be reviewed, and the difficulties in their potential use in supporting a diagnosis of PA, when the histopathological findings are equivocal or in the choice of individualized therapy, will be discussed.
Topics: Astrocytoma; Central Nervous System Neoplasms; Genetic Predisposition to Disease; Humans; Models, Molecular; Molecular Biology; Neuroimaging
PubMed: 25792358
DOI: 10.1007/s00401-015-1410-7 -
Cirugia Y Cirujanos 2017Pilocytic astrocytoma is a rare tumour, usually occurring in paediatric ages, and mainly located in the posterior fossa. It can cause hydrocephalus and intracranial... (Review)
Review
BACKGROUND
Pilocytic astrocytoma is a rare tumour, usually occurring in paediatric ages, and mainly located in the posterior fossa. It can cause hydrocephalus and intracranial hypertension and, less frequently, seizures, or a focal neurological deficit. The main imaging study by magnetic resonance imaging, which shows a tumour with solid and cystic components without peri-lesional swelling. The election treatment is surgical, and the patient is considered cured if a total resection is accomplished.
CLINICAL CASE
The case is presented of 22-year-old female patient with a supratentorial pilocytic astrocytoma and epilepsy. Histopathology reported a low grade glial proliferation, with an extensive fibrillar matrix, small cells without atypia, extensive calcifications and piloid areas consisting of bipolar fusiform cells, and some Rosenthal fibres. There were also spongiotic areas consisting of multipolar cells and associated microcysts. The final report was a pilocytic astrocytoma.
CONCLUSIONS
Pilocytic astrocytoma is more frequent in paediatric patients and in the posterior fossa. The case presented is of a young female adult with supratentorial location, making it a special case. The surgery achieved a total resection. The long-term prognosis is good, but it is necessary to perform a follow-up, particularly in adult patients because of a higher risk of recurrence.
Topics: Anticonvulsants; Astrocytoma; Cholecystitis, Acute; Craniotomy; Female; Humans; Levetiracetam; Magnetic Resonance Imaging; Neuroimaging; Piracetam; Remission Induction; Seizures; Supratentorial Neoplasms; Young Adult
PubMed: 27417707
DOI: 10.1016/j.circir.2016.05.009 -
Pathology Jun 2023Homozygous deletion (HD) of the CDKN2A/B locus has emerged as an unfavourable prognostic marker in diffuse gliomas, both IDH-mutant and IDH-wild-type. Testing for...
Homozygous deletion (HD) of the CDKN2A/B locus has emerged as an unfavourable prognostic marker in diffuse gliomas, both IDH-mutant and IDH-wild-type. Testing for CDKN2A/B deletions can be performed by a variety of approaches, including copy number variation (CNV) analysis based on gene array analysis, next generation sequencing (NGS) or fluorescence in situ hybridisation (FISH), but questions remain regarding the accuracy of testing modalities. In this study, we assessed: (1) the utility of S-methyl-5'-thioadenosine phosphorylase (MTAP) and cellular tumour suppressor protein pl61NK4a (p16) immunostainings as surrogate markers for CDKN2A/B HD in gliomas, and (2) the prognostic value of MTAP, across different histological tumour grades and IDH mutation status. One hundred consecutive cases of diffuse and circumscribed gliomas (Cohort 1) were collected, in order to correlate MTAP and p16 expression with the CDKN2A/B status in the CNV plot of each tumour. IDH1 R132H, ATRX and MTAP immunohistochemistry was performed on next generation tissue microarrays (ngTMAs) of 251 diffuse gliomas (Cohort 2) for implementing survival analysis. Complete loss of MTAP and p16 by immunohistochemistry was 100% and 90% sensitive as well as 97% and 89% specific for CDKN2A/B HD, respectively, as identified on CNV plot. Only two cases (2/100) with MTAP and p16 loss of expression did not demonstrate CDKN2A/B HD in CNV plot; however, FISH analysis confirmed the HD for CDKN2A/B. Moreover, MTAP deficiency was associated with shortened survival in IDH-mutant astrocytomas (n=75; median survival 61 vs 137 months; p<0.0001), IDH-mutant oligodendrogliomas (n=59; median survival 41 vs 147 months; p<0.0001) and IDH-wild-type gliomas (n=117; median survival 13 vs 16 months; p=0.011). In conclusion, MTAP immunostaining is an important complement for diagnostic work-up of gliomas, because of its excellent correlation with CDKN2A/B status, robustness, rapid turnaround time and low costs, and provides significant prognostic value in IDH-mutant astrocytomas and oligodendrogliomas, while p16 should be used cautiously.
Topics: Humans; Cyclin-Dependent Kinase Inhibitor p16; Oligodendroglioma; Homozygote; DNA Copy Number Variations; Sequence Deletion; Gene Deletion; Glioma; Biomarkers; Phosphorylases; Astrocytoma; Brain Neoplasms; Isocitrate Dehydrogenase; Mutation
PubMed: 37032198
DOI: 10.1016/j.pathol.2023.01.005 -
Indian Journal of Pathology &... May 2022The fifth edition of the World Health Organization (WHO) Classification of Tumors of the Central Nervous System (WHO CNS5) features several changes in the... (Review)
Review
A review of adult-type diffuse gliomas in the WHO CNS5 classification with special reference to Astrocytoma, IDH-mutant and Oligodendroglioma, IDH-mutant and 1p/19q codeleted.
The fifth edition of the World Health Organization (WHO) Classification of Tumors of the Central Nervous System (WHO CNS5) features several changes in the classification, diagnostic criteria, nomenclature, and grading of diffuse gliomas. Adult-type diffuse gliomas are genetically defined and include astrocytoma, isocitrate dehydrogenase (IDH)-mutant, oligodendroglioma, IDH-mutant and 1p/19q codeleted, and glioblastoma, IDH-wildtype. This review briefly discusses two tumor types: astrocytoma, IDH-mutant, and oligodendroglioma, IDH-mutant and 1p/19q codeleted, with emphasis on relevant changes in their classification and defining molecular genetic alterations. A simplified approach to the diagnosis of these tumors is provided.
Topics: Adult; Astrocytoma; Brain Neoplasms; Glioma; Humans; Isocitrate Dehydrogenase; Mutation; Oligodendroglioma; World Health Organization
PubMed: 35562130
DOI: 10.4103/ijpm.ijpm_34_22 -
Acta Neuropathologica Communications Jun 2021Primary spinal cord astrocytomas are rare, hence few data exist about the prognostic significance of molecular markers. Here we analyze a panel of molecular alterations...
Primary spinal cord astrocytomas are rare, hence few data exist about the prognostic significance of molecular markers. Here we analyze a panel of molecular alterations in association with the clinical course. Histology and genome sequencing was performed in 26 spinal astrocytomas operated upon between 2000 and 2020. Next-generation DNA/RNA sequencing (NGS) and methylome analysis were performed to determine molecular alterations. Histology and NGS allowed the distinction of 5 tumor subgroups: glioblastoma IDH wildtype (GBM); diffuse midline glioma H3 K27M mutated (DMG-H3); high-grade astrocytoma with piloid features (HAP); diffuse astrocytoma IDH mutated (DA), diffuse leptomeningeal glioneural tumors (DGLN) and pilocytic astrocytoma (PA). Within all tumor entities GBM (median OS: 5.5 months), DMG-H3 (median OS: 13 months) and HAP (median OS: 8 months) showed a fatal prognosis. DMG-H3 tend to emerge in adolescence whereas GBM and HAP develop in the elderly. HAP are characterized by CDKN2A/B deletion and ATRX mutation. 50% of PA tumors carried a mutation in the PIK3CA gene which is seemingly associated with better outcome (median OS: PIK3CA mutated 107.5 vs 45.5 months in wildtype PA). This exploratory molecular profiling of spinal cord astrocytomas allows to identify distinct subgroups by combining molecular markers and histomorphology. DMG-H3 tend to develop in adolescence with a similar dismal prognosis like GBM and HAP in the elderly. We here describe spinal HAP with a distinct molecular profile for the first time.
Topics: Adolescent; Adult; Aged; Astrocytoma; Child; Female; High-Throughput Nucleotide Sequencing; Humans; Male; Middle Aged; Molecular Diagnostic Techniques; Retrospective Studies; Spinal Cord Neoplasms; Young Adult
PubMed: 34193285
DOI: 10.1186/s40478-021-01222-6 -
Brain Tumor Pathology Apr 2019Many breakthroughs have been made in the past decade regarding our knowledge of the biological basis of the diffuse gliomas, the most common primary central nervous... (Review)
Review
Many breakthroughs have been made in the past decade regarding our knowledge of the biological basis of the diffuse gliomas, the most common primary central nervous system (CNS) tumors. These tumors as a group are aggressive, associated with high mortality, and have a predilection for adults. However, a subset of CNS glial and glioneuronal tumors are characterized by a more circumscribed pattern of growth and occur more commonly in children and young adults. They tend to be indolent, but our understanding of anaplastic changes in these tumors continues to improve as diagnostic classifications evolve in the era of molecular pathology and more integrated and easily accessible clinical databases. The presence of anaplasia in pleomorphic xanthoastrocytomas and gangliogliomas is assigned a WHO grade III under the current classification, while the significance of anaplasia in pilocytic astrocytomas remains controversial. Recent data highlight the association of the latter with aggressive clinical behavior, as well as the presence of molecular genetic features of both pilocytic and diffuse gliomas, with the recognition that the precise terminology remains to be defined. We review the current concepts and advances regarding histopathology and molecular understanding of pilocytic astrocytomas, pleomorphic xanthoastrocytomas, and gangliogliomas, with a focus on their anaplastic counterparts.
Topics: Anaplasia; Astrocytoma; Brain Neoplasms; Carcinoma; Central Nervous System Neoplasms; Ganglioglioma; Glioma; Humans; Neuroglia; Proto-Oncogene Proteins B-raf
PubMed: 30859342
DOI: 10.1007/s10014-019-00336-z -
Radiation Oncology (London, England) May 2022We sought to clarify the optimal follow-up, therapeutic strategy, especially the role of reirradiation, and the diagnostic impact of isocitrate dehydrogenase (IDH) 1 and...
BACKGROUND
We sought to clarify the optimal follow-up, therapeutic strategy, especially the role of reirradiation, and the diagnostic impact of isocitrate dehydrogenase (IDH) 1 and 2 mutation status in patients with radiation-induced glioma (RIG).
METHODS
We retrospectively reviewed the clinical characteristics and treatment outcomes of 11 patients with high-grade glioma who satisfied Cahan's criteria for RIG in our database during 2001-2021. IDH 1/2 mutations were analyzed by Sanger sequencing and/or pyrosequencing.
RESULTS
The RIGs included glioblastoma with IDH 1/2 wild-type (n = 7), glioblastoma not otherwise specified (n = 2), anaplastic astrocytoma with IDH1/2 wild-type (n = 1), and anaplastic astrocytoma not otherwise specified (n = 1). The median period from primary disease and RIG diagnosis was 17 years (range: 9-30 years). All patients underwent tumor removal or biopsy, 5 patients postoperatively received reirradiation combined with chemotherapy, and 6 patients were treated with chemotherapy alone. The median progression-free and survival times were 11.3 and 28.3 months. The median progression-free survival time of patients treated with reirradiation and chemotherapy (n = 5) tended to be longer than that of patients that received chemotherapy alone (n = 6) (17.0 vs 8.1 months). However, the median survival time was similar (29.6 vs 27.4 months). Local recurrence was observed in 5 patients treated with chemotherapy alone, whereas in 2 patients among 4 patients treated with reirradiation and chemotherapy. None of the patients developed radiation necrosis. In one case, the primary tumor was diffuse astrocytoma with IDH2 mutant, and the secondary tumor was glioblastoma with IDH 1/2 wild-type. Based on the difference of IDH2 mutation status, the secondary tumor with IDH 1/2 wild-type was diagnosed as a de novo tumor that was related to the previous radiation therapy.
CONCLUSIONS
RIG can occur beyond 20 years after successfully treating the primary disease using radiotherapy; thus, cancer survivors should be informed of the long-term risk of developing RIG and the need for timely neuroimaging evaluation. Reirradiation combined with chemotherapy appears to be feasible and has favorable outcomes. Determining the IDH1/2 mutational status is useful to establish RIG diagnosis when the primary tumor is glioma.
Topics: Astrocytoma; Brain Neoplasms; Glioblastoma; Glioma; Humans; Isocitrate Dehydrogenase; Re-Irradiation; Retrospective Studies
PubMed: 35505351
DOI: 10.1186/s13014-022-02054-x -
CNS Oncology Mar 2021Adult pilocytic astrocytoma (PA) is less prevalent than pediatric PA and is associated with a worse prognosis. In a literature review, we found that 88.3% of the... (Review)
Review
Adult pilocytic astrocytoma (PA) is less prevalent than pediatric PA and is associated with a worse prognosis. In a literature review, we found that 88.3% of the molecular alterations in adult PA are associated with MAPK pathway dysregulation. The most common alterations are fusions of . Understanding of the mechanisms underlying this pathway has evolved substantially, heralding advancements in specific targeted therapy. Here, we review clinical and molecular features of adult PA, characteristics predicting aggressive behavior and approaches to standard and investigational therapies. We highlight epigenetic profiling and integrated diagnosis as an essential component of classifying PA.
Topics: Adult; Astrocytoma; Brain Neoplasms; Child; Humans; Prognosis; Proto-Oncogene Proteins B-raf
PubMed: 33448230
DOI: 10.2217/cns-2020-0027