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Diagnostic Pathology Feb 2019Gliomas with 1p/19q-codeletion as well as mutation of isocitrate dehydrogenase (IDH) 1 are typically characterized as oligodendrogliomas with comparatively good response... (Review)
Review
Widely metastatic IDH1-mutant glioblastoma with oligodendroglial features and atypical molecular findings: a case report and review of current challenges in molecular diagnostics.
BACKGROUND
Gliomas with 1p/19q-codeletion as well as mutation of isocitrate dehydrogenase (IDH) 1 are typically characterized as oligodendrogliomas with comparatively good response to treatment with radiation and chemotherapy.
CASE PRESENTATION
We present the case of a 28-year-old man with an IDH1 and TP53 mutant high grade glioma with abnormalities in chromosomes 1 and 19 suggestive of anaplastic oligodendroglioma that rapidly progressed to widespread metastatic disease. Biopsy of a liver lesion confirmed metastasis of the patient's known brain primary and chemotherapy with temozolomide was initiated. The patient's rapidly growing tumor burden with fulminant liver failure and tumor lysis led to multisystem failure of which the patient died. Further molecular testing illustrated features more consistent with glioblastoma: multiple large chromosomal aberrations including loss of whole chromosome 1 and 2q; gain/amplification of MYCN, MET, and CDK4; loss of CDKN2A/B; and an ATRX mutation.
CONCLUSION
This case illustrates the importance of higher level molecular diagnostic testing for patients with particularly aggressive disease progression that is not concordant with standard prognoses. Additional data on cases with atypical alterations of 1p and 19q are needed to better understand the distinct biology of these cancers so that appropriate therapies can be developed.
Topics: Adult; Brain Neoplasms; Chromosome Aberrations; Fatal Outcome; Glioblastoma; Humans; Isocitrate Dehydrogenase; Male; Mutation
PubMed: 30738431
DOI: 10.1186/s13000-019-0793-5 -
Neurology India 2018The plethora of biomarkers available for the diagnosis and prognostication of gliomas has refined the classification of gliomas. The new World Health Organization (WHO)...
BACKGROUND
The plethora of biomarkers available for the diagnosis and prognostication of gliomas has refined the classification of gliomas. The new World Health Organization (WHO) 2016 classification integrates the phenotypic and genotyping features for a more robust diagnosis.
MATERIALS AND METHODS
Fifty gliomas with oligodendroglial morphology according to the WHO 2007 classification were analyzed for isocitrate dehydrogenase 1 and 2 (IDH1/2) mutations by polymerase chain reaction, 1p/19q status by fluorescent in situ hybridization (FISH), and IDH1 and X-linked alpha-thalassemia retardation (ATRX) expression by immunohistochemistry. Tumors were reclassified into oligodendrogliomas, astrocytomas, and glioblastomas (GBMs) according to the new "integrated" diagnostic approach.
RESULTS
30% of previously diagnosed oligodendrogliomas and almost 90% of oligoastrocytomas were reclassified as astrocytomas. Twenty gliomas showed 1p/19q co-deletion, while 18 gliomas showed polysomy of chromosome 1/19. Polysomy of chromosome 1/19 was significantly associated with astrocytic tumors (P ≤ 0.001). Loss of ATRX expression was seen in 20 of 23 WHO grade II/III astrocytomas and 3 of 7 GBMs. All WHO grade II and III gliomas in our cohort showed IDH1/2 mutations. Moreover, 4 of 7 GBMs showed the wild-type IDH1/2 mutation, and 2 of 3 GBMs which showed IDH1/2 mutations were secondary GBMs. There was no significant difference in progression-free and overall survival between WHO grade II and III gliomas, possibly because all these tumors showed IDH1/2 mutations. In multivariate analysis, only the WHO grade (grade IV versus II and III combined) was significantly associated with increased risk of recurrence and death (P = 0.016 and 0.02).
CONCLUSION
The new integrated diagnosis provides a more meaningful classification, removing the considerable subjectivity that existed previously.
Topics: Adolescent; Adult; Astrocytoma; Biomarkers, Tumor; Brain Neoplasms; Female; Glioblastoma; Glioma; Humans; Isocitrate Dehydrogenase; Male; Middle Aged; Oligodendroglia; Oligodendroglioma; Prognosis; X-linked Nuclear Protein; Young Adult
PubMed: 30504574
DOI: 10.4103/0028-3886.246275 -
BMC Cancer Sep 2018The treatment recommendations for Low-grade Gliomas (LGG) underwent profound changes due to results from RTOG 9802 published in April 2016. This work aims to investigate...
BACKGROUND
The treatment recommendations for Low-grade Gliomas (LGG) underwent profound changes due to results from RTOG 9802 published in April 2016. This work aims to investigate whether the results from the trial were already incorporated into the treatment recommendations at German oncology centers before an update of the official guidelines.
METHODS
An online based questionnaire with questions covering all aspects of adjuvant treatments of LGGs was generated, including three cases with distinct clinical situations. We contacted all members of the neuro-oncologic working group (NOA) of the German Cancer Society (DKG) as well as all German-speaking members of the European Low-Grade Glioma Network via E-mail.
RESULTS
We collected 38 responses. All responders were at least specialists; they predominantly worked at tertiary hospitals with a high volume of LGGs treated annually (75% with more than 10 cases per year). All responders stated to consent treatment recommendation for LGGs within interdisciplinary oncologic boards. The treatment recommendations for LGGs changed profoundly between 2015 and 12/2016. There is a trend towards PCV-based multimodal treatments, especially for oligodendroglial LGGs, as well as a trend away from watchful-waiting-policies for astrocytic LGGs.
CONCLUSION
Neurooncologists do adapt results from clinical trials quickly. None the less, there is still an immense heterogeneity within the treatment recommendations, predominantly for astrocytic LGGs. Well planned clinical trials and concise treatment recommendations are warranted; additionally, individual counseling of patients is essential.
Topics: Adult; Combined Modality Therapy; Female; Germany; Glioma; Health Care Surveys; Humans; Male; Middle Aged; Multimodal Imaging; Neoplasm Grading; Neoplasm Staging; Practice Guidelines as Topic; Surveys and Questionnaires; Tertiary Care Centers
PubMed: 30241469
DOI: 10.1186/s12885-018-4825-4 -
The Neuroradiology Journal Feb 2019This article describes an unusual presentation of disseminated oligodendroglial-like leptomeningeal tumour. A previously healthy 23-year-old Caucasian woman presented...
This article describes an unusual presentation of disseminated oligodendroglial-like leptomeningeal tumour. A previously healthy 23-year-old Caucasian woman presented with headache, photophobia and recurrent seizures. Initial investigations were suggestive of subarachnoid haemorrhage. Her symptoms deteriorated rapidly and within weeks she developed complete blindness and diffuse sensory ataxia. The aim of this article is to increase awareness of this rare disease, especially in patients who present with acute, rapidly progressive neurological symptoms with signs of acute or chronic central nervous system bleeding.
Topics: Diagnosis, Differential; Female; Humans; Meningeal Neoplasms; Meningioma; Subarachnoid Hemorrhage; Young Adult
PubMed: 30091674
DOI: 10.1177/1971400918793530 -
JAMA Oncology Sep 2018Glioma is the most commonly occurring malignant brain tumor in the United States, and its incidence varies by age, sex, and race or ethnicity. Survival after brain tumor...
IMPORTANCE
Glioma is the most commonly occurring malignant brain tumor in the United States, and its incidence varies by age, sex, and race or ethnicity. Survival after brain tumor diagnosis has been shown to vary by these factors.
OBJECTIVE
To quantify the differences in incidence and survival rates of glioma in adults by race or ethnicity.
DESIGN, SETTING, AND PARTICIPANTS
This population-based study obtained incidence data from the Central Brain Tumor Registry of the United States and survival data from Surveillance, Epidemiology, and End Results registries, covering the period January 1, 2000, to December 31, 2014. Average annual age-adjusted incidence rates with 95% CIs were generated by glioma histologic groups, race, Hispanic ethnicity, sex, and age groups. One-year and 5-year relative survival rates were generated by glioma histologic groups, race, Hispanic ethnicity, and insurance status. The analysis included 244 808 patients with glioma diagnosed in adults aged 18 years or older. Data were collected from January 1, 2000, to December 31, 2014. Data analysis took place from December 11, 2017, to January 31, 2018.
RESULTS
Overall, 244 808 patients with glioma were analyzed. Of these, 150 631 (61.5%) were glioblastomas, 46 002 (18.8%) were non-glioblastoma astrocytomas, 26 068 (10.7%) were oligodendroglial tumors, 8816 (3.6%) were ependymomas, and 13 291 (5.4%) were other glioma diagnoses in adults. The data set included 137 733 males (56.3%) and 107 075 (43.7%) females. There were 204 580 non-Hispanic whites (83.6%), 17 321 Hispanic whites (7.08%), 14 566 blacks (6.0%), 1070 American Indians or Alaska Natives (0.4%), and 5947 Asians or Pacific Islanders (2.4%). Incidences of glioblastoma, non-glioblastoma astrocytoma, and oligodendroglial tumors were higher among non-Hispanic whites than among Hispanic whites (30% lower overall), blacks (52% lower overall), American Indians or Alaska Natives (58% lower overall), or Asians or Pacific Islanders (52% lower overall). Most tumors were more common in males than in females across all race or ethnicity groups, with the great difference in glioblastoma where the incidence was 60% higher overall in males. Most tumors (193 329 [79.9%]) occurred in those aged 45 years or older, with differences in incidence by race or ethnicity appearing in all age groups. Survival after diagnosis of glioma of different subtypes was generally comparable among Hispanic whites, blacks, and Asians or Pacific Islanders but was lower among non-Hispanic whites for many tumor types, including glioblastoma, irrespective of treatment type.
CONCLUSIONS AND RELEVANCE
Incidence of glioma and 1-year and 5-year survival rates after diagnosis vary significantly by race or ethnicity, with non-Hispanic whites having higher incidence and lower survival rates compared with individuals of other racial or ethnic groups. These findings can inform future discovery of risk factors and reveal unaddressed health disparities.
Topics: Adult; Black or African American; Aged; Brain Neoplasms; Female; Glioma; Health Status Disparities; Hispanic or Latino; Humans; Incidence; Male; Middle Aged; Population Surveillance; Registries; SEER Program; United States; White People
PubMed: 29931168
DOI: 10.1001/jamaoncol.2018.1789 -
Modern Pathology : An Official Journal... Oct 2018Pilocytic astrocytomas represent the most common glioma subtype in young patients and account for 5.4% of all gliomas. They are characterized by alterations in the...
Duplications of KIAA1549 and BRAF screening by Droplet Digital PCR from formalin-fixed paraffin-embedded DNA is an accurate alternative for KIAA1549-BRAF fusion detection in pilocytic astrocytomas.
Pilocytic astrocytomas represent the most common glioma subtype in young patients and account for 5.4% of all gliomas. They are characterized by alterations in the RAS-MAP kinase pathway, the most frequent being a tandem duplication on chromosome 7q34 involving the BRAF gene, resulting in oncogenic BRAF fusion proteins. BRAF fusion involving the KIAA1549 gene is a hallmark of pilocytic astrocytoma, but it has also been recorded in rare cases of gangliogliomas, 1p/19q co-deleted oligodendroglial tumors, and it is also a common feature of disseminated oligodendroglial-like leptomeningeal neoplasm. In some difficult cases, evidence for KIAA1549-BRAF fusion is of utmost importance for the diagnosis. Moreover, because the KIAA1549-BRAF fusion constitutively activates the MAP kinase pathway, it represents a target for drugs such as MEK inhibitors, and therefore, the detection of this genetic abnormality is highly relevant in the context of clinical trials applying such new approaches. In the present study, we aimed to use the high sensitivity of Droplet Digital PCR (DDPCR™) to predict KIAA1549-BRAF fusion on very small amounts of formalin-fixed paraffin-embedded tissue in routine practice. Therefore, we analyzed a training cohort of 55 pilocytic astrocytomas in which the KIAA1549-BRAF fusion status was known by RNA sequencing used as our gold standard technique. Then, we analyzed a prospective cohort of 40 pilocytic astrocytomas, 27 neuroepithelial tumors remaining difficult to classify (pilocytic astrocytoma versus ganglioglioma or diffuse glioma), 15 dysembryoplastic neuroepithelial tumors, and 18 gangliogliomas. We could demonstrate the usefulness and high accuracy (100% sensitivity and specificity when compared to RNA sequencing) of DDPCR™ to assess the KIAA1549-BRAF fusion from very low amounts of DNA isolated from formalin-fixed paraffin-embedded specimens. BRAF duplication is both necessary and sufficient to predict this fusion in most cases and we propose that this single analysis could be used in routine practice to save time, money, and precious tissue.
Topics: Astrocytoma; Brain Neoplasms; DNA, Neoplasm; Formaldehyde; Humans; Oncogene Proteins, Fusion; Paraffin Embedding; Polymerase Chain Reaction; Sensitivity and Specificity; Tissue Fixation
PubMed: 29802359
DOI: 10.1038/s41379-018-0050-6 -
BMC Cancer May 2018Carbonic anhydrase related proteins (CARPs) VIII, X and XI functionally differ from the other carbonic anhydrase (CA) enzymes. Structurally, they lack the zinc binding...
BACKGROUND
Carbonic anhydrase related proteins (CARPs) VIII, X and XI functionally differ from the other carbonic anhydrase (CA) enzymes. Structurally, they lack the zinc binding residues, which are important for enzyme activity of classical CAs. The distribution pattern of the CARPs in fetal brain implies their role in brain development. In the adult brain, CARPs are mainly expressed in the neuron bodies but only weaker reactivity has been found in the astrocytes and oligodendrocytes. Altered expression patterns of CARPs VIII and XI have been linked to cancers outside the central nervous system. There are no reports on CARPs in human astrocytomas or oligodendroglial tumors. We wanted to assess the expression of CARPs VIII and XI in these tumors and study their association to different clinicopathological features and tumor-associated CAs II, IX and XII.
METHODS
The tumor material for this study was obtained from surgical patients treated at the Tampere University Hospital in 1983-2009. CARP VIII staining was analyzed in 391 grade I-IV gliomas and CARP XI in 405 gliomas.
RESULTS
CARP VIII immunopositivity was observed in 13% of the astrocytomas and in 9% of the oligodendrogliomas. Positive CARP XI immunostaining was observed in 7% of the astrocytic and in 1% of the oligodendroglial tumor specimens. In our study, the most benign tumors, pilocytic astrocytomas, did not express CARPs at all. In WHO grade II-IV astrocytomas, CARPs were associated with molecular events related to more benign behavior, which was the case with CARP VIII in oligodendrogliomas and oligoastrocytomas as well.
CONCLUSIONS
The study observations suggest that the CARPs play a role in tumorigenesis of diffusively infiltrating gliomas. Furthermore, the molecular mechanisms beneath the cancer promoting qualities of CARPs have not yet been discovered. Thus, more studies concerning role of CARPs in oncogenesis are needed.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Astrocytoma; Biomarkers, Tumor; Brain; Brain Neoplasms; Carcinogenesis; Child; Humans; Middle Aged; Nerve Tissue Proteins; Oligodendroglioma; Young Adult
PubMed: 29792187
DOI: 10.1186/s12885-018-4493-4 -
Cancer Science Jul 2018IDH-mutant gliomas are classified into astrocytic or oligodendroglial tumors by 1p/19q status in the WHO 2016 classification, with the latter presenting with...
IDH-mutant gliomas are classified into astrocytic or oligodendroglial tumors by 1p/19q status in the WHO 2016 classification, with the latter presenting with characteristic morphology and better prognosis in general. However, the morphological and genetic features within each category are varied, and there might be distinguishable subtypes. We analyzed 170 WHO grade II-IV gliomas resected in our institution. 1p/19q status was analyzed by microsatellite analysis, and genetic mutations were analyzed by next-generation sequencing and Sanger sequencing. For validation, the Brain Lower Grade Glioma dataset of The Cancer Genome Atlas was analyzed. Of the 42 grade III IDH-mutated gliomas, 12 were 1p-intact/19q-intact (anaplastic astrocytomas [AA]), 7 were 1p-intact/19q-loss (AA), and 23 showed 1p/19q-codeletion (anaplastic oligodendrogliomas). Of the 88 IDH-wild type glioblastomas (GBMs), 14 showed 1p-intact/19q-loss status. All of the seven 1p-intact/19q-loss AAs harbored TP53 mutation, but no TERT promotor mutation. All 19q-loss AAs had regions presenting oligodendroglioma-like morphology, and were associated with significantly longer overall survival compared to 19q-intact AAs (P = .001). This tendency was observed in The Cancer Genome Atlas Lower Grade Glioma dataset. In contrast, there was no difference in overall survival between the 19q-loss GBM and 19q-intact GBM (P = .4). In a case of 19q-loss AA, both oligodendroglial morphology and 19q-loss disappeared after recurrence, possibly indicating correlation between 19q-loss and oligodendroglial morphology. We showed that there was a subgroup, although small, of IDH-mutated astrocytomas harboring 19q-loss that present oligodendroglial morphology, and also were associated with significantly better prognosis compared to other 19q-intact astrocytomas.
Topics: Adult; Aged; Astrocytoma; Brain Neoplasms; Chromosome Deletion; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 19; Female; Humans; Isocitrate Dehydrogenase; Kaplan-Meier Estimate; Male; Middle Aged; Mutation; Prognosis
PubMed: 29752851
DOI: 10.1111/cas.13635 -
Neuro-oncology Sep 2018Hyperactivation of phosphoinositide 3-kinase (PI3K) signaling is common in cancers, but the precise role of the pathway in glioma biology remains to be determined. Some...
BACKGROUND
Hyperactivation of phosphoinositide 3-kinase (PI3K) signaling is common in cancers, but the precise role of the pathway in glioma biology remains to be determined. Some understanding of PI3K signaling mechanisms in brain cancer comes from studies on neural stem/progenitor cells (NSPCs), where signals transmitted via the PI3K pathway cooperate with other intracellular pathways and downstream transcription factors to regulate critical cell functions.
METHODS
To investigate the role of the PI3K pathway in glioma initiation and development, we generated a mouse model targeting the inducible expression of a PIK3CAH1047A oncogenic mutant and deletion of the PI3K negative regulator, phosphatase and tensin homolog (PTEN), to NSPCs.
RESULTS
Expression of a Pik3caH1047A was sufficient to generate tumors with oligodendroglial features, but simultaneous loss of PTEN was required for the development of invasive, high-grade glioma. Pik3caH1047A-PTEN mutant NSPCs exhibited enhanced neurosphere formation which correlated with increased Wnt signaling, while loss of cAMP response element binding protein (CREB) in Pik3caH1047A-Pten mutant tumors led to longer symptom-free survival in mice.
CONCLUSION
Taken together, our findings present a novel mouse model for glioma demonstrating that the PI3K pathway is important for initiation of tumorigenesis and that disruption of downstream CREB signaling attenuates tumor expansion.
Topics: Animals; Brain Neoplasms; Carcinogenesis; Cell Cycle; Cell Movement; Cell Proliferation; Class I Phosphatidylinositol 3-Kinases; Cyclic AMP Response Element-Binding Protein; Mice; Mice, Knockout; Neural Stem Cells; PTEN Phosphohydrolase; Phosphatidylinositol 3-Kinases; Phosphorylation; Signal Transduction; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 29718345
DOI: 10.1093/neuonc/noy068 -
PloS One 2018The neurofibromatosis type 2 (NF2) tumor suppressor protein Merlin functions as a negative regulator of cell growth and actin dynamics in different cell types amongst...
The neurofibromatosis type 2 (NF2) tumor suppressor protein Merlin functions as a negative regulator of cell growth and actin dynamics in different cell types amongst which Schwann cells have been extensively studied. In contrast, the presence and the role of Merlin in oligodendrocytes, the myelin forming cells within the CNS, have not been elucidated. In this work, we demonstrate that Merlin immunoreactivity was broadly distributed in the white matter throughout the central nervous system. Following Merlin expression during development in the cerebellum, Merlin could be detected in the cerebellar white matter tract at early postnatal stages as shown by its co-localization with Olig2-positive cells as well as in adult brain sections where it was aligned with myelin basic protein containing fibers. This suggests that Merlin is expressed in immature and mature oligodendrocytes. Expression levels of Merlin were low in oligodendrocytes as compared to astrocytes and neurons throughout development. Expression of Merlin in oligodendroglia was further supported by its identification in either immortalized cell lines of oligodendroglial origin or in primary oligodendrocyte cultures. In these cultures, the two main splice variants of Nf2 could be detected. Merlin was localized in clusters within the nuclei and in the cytoplasm. Overexpressing Merlin in oligodendrocyte cell lines strengthened reduced impedance in XCELLigence measurements and Ki67 stainings in cultures over time. In addition, the initiation and elongation of cellular projections were reduced by Merlin overexpression. Consistently, cell migration was retarded in scratch assays done on Nf2-transfected oligodendrocyte cell lines. These data suggest that Merlin actively modulates process outgrowth and migration in oligodendrocytes.
Topics: Animals; Astrocytes; Cell Line; Cell Movement; Cell Nucleus; Cell Proliferation; Central Nervous System; Cytoplasm; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Neurofibromatosis 2; Neurofibromin 2; Neurogenesis; Neurons; Oligodendroglia; Schwann Cells; Transfection
PubMed: 29715273
DOI: 10.1371/journal.pone.0196726