The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary.
Harvard University1, University of California, San Francisco2, University of Düsseldorf3, Heidelberg University4, Aix-Marseille University5, Ludwig Institute for Cancer Research6, International Agency for Research on Cancer7, German Cancer Research Center8, University of Zurich9, St. Jude Children's Research Hospital10
TL;DR: The 2016 World Health Organization Classification of Tumors of the Central Nervous System is both a conceptual and practical advance over its 2007 predecessor and is hoped that it will facilitate clinical, experimental and epidemiological studies that will lead to improvements in the lives of patients with brain tumors.
Abstract: The 2016 World Health Organization Classification of Tumors of the Central Nervous System is both a conceptual and practical advance over its 2007 predecessor. For the first time, the WHO classification of CNS tumors uses molecular parameters in addition to histology to define many tumor entities, thus formulating a concept for how CNS tumor diagnoses should be structured in the molecular era. As such, the 2016 CNS WHO presents major restructuring of the diffuse gliomas, medulloblastomas and other embryonal tumors, and incorporates new entities that are defined by both histology and molecular features, including glioblastoma, IDH-wildtype and glioblastoma, IDH-mutant; diffuse midline glioma, H3 K27M-mutant; RELA fusion-positive ependymoma; medulloblastoma, WNT-activated and medulloblastoma, SHH-activated; and embryonal tumour with multilayered rosettes, C19MC-altered. The 2016 edition has added newly recognized neoplasms, and has deleted some entities, variants and patterns that no longer have diagnostic and/or biological relevance. Other notable changes include the addition of brain invasion as a criterion for atypical meningioma and the introduction of a soft tissue-type grading system for the now combined entity of solitary fibrous tumor / hemangiopericytoma-a departure from the manner by which other CNS tumors are graded. Overall, it is hoped that the 2016 CNS WHO will facilitate clinical, experimental and epidemiological studies that will lead to improvements in the lives of patients with brain tumors.
Citations
More filters
Nationwide Children's Hospital1, University of North Carolina at Chapel Hill2, Henry Ford Health System3, University of Texas MD Anderson Cancer Center4, Broad Institute5, Walter Reed National Military Medical Center6, Buck Institute for Research on Aging7, New York University8, University of Pittsburgh9, Sage Bionetworks10, University of California, San Francisco11, Institute for Systems Biology12
TL;DR: These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale.
1,928 citations
Cites methods from "The 2016 World Health Organization ..."
...Indeed, the clinical and molecular work of this paper factored into evidence used by the World Health Organization (WHO) to support their 2016 diagnostic update for glioma (Louis et al., 2016)....
[...]
TL;DR: This article aims to present a comprehensive and critical overview of emerging analytical technologies for EV detection and their clinical applications.
Abstract: Extracellular vesicles (EVs) are diverse, nanoscale membrane vesicles actively released by cells Similar-sized vesicles can be further classified (eg, exosomes, microvesicles) based on their biogenesis, size, and biophysical properties Although initially thought to be cellular debris, and thus under-appreciated, EVs are now increasingly recognized as important vehicles of intercellular communication and circulating biomarkers for disease diagnoses and prognosis Despite their clinical potential, the lack of sensitive preparatory and analytical technologies for EVs poses a barrier to clinical translation New analytical platforms including molecular ones are thus actively being developed to address these challenges Recent advances in the field are expected to have far-reaching impact in both basic and translational studies This article aims to present a comprehensive and critical overview of emerging analytical technologies for EV detection and their clinical applications
902 citations
University of Zurich1, Erasmus University Rotterdam2, Ludwig Maximilian University of Munich3, Medical University of Vienna4, Umeå University5, Aix-Marseille University6, University Hospital Heidelberg7, VU University Amsterdam8, Institut Gustave Roussy9, University of Cambridge10, University of Portsmouth11, University of Bonn12, Leiden University13, University of Lausanne14, University of Hamburg15, University of Düsseldorf16, German Cancer Research Center17
TL;DR: The European Association for Neuro-Oncology guideline provides recommendations for the clinical care of adult patients with astrocytic and oligodendroglial gliomas, including glioblastomas, based on the 2016 WHO classification of tumours of the central nervous system and on scientific developments since the 2014 guideline.
Abstract: The European Association for Neuro-Oncology guideline provides recommendations for the clinical care of adult patients with astrocytic and oligodendroglial gliomas, including glioblastomas. The guideline is based on the 2016 WHO classification of tumours of the central nervous system and on scientific developments since the 2014 guideline. The recommendations focus on pathological and radiological diagnostics, and the main treatment modalities of surgery, radiotherapy, and pharmacotherapy. In this guideline we have also integrated the results from contemporary clinical trials that have changed clinical practice. The guideline aims to provide guidance for diagnostic and management decisions, while limiting unnecessary treatments and costs. The recommendations are a resource for professionals involved in the management of patients with glioma, for patients and caregivers, and for health-care providers in Europe. The implementation of this guideline requires multidisciplinary structures of care, and defined processes of diagnosis and treatment.
773 citations
TL;DR: In this paper, the authors profile 4,347 single cells from six IDH1 or IDH2 mutant human oligodendrogliomas by RNA sequencing and reconstruct their developmental programs from genome-wide expression signatures.
Abstract: Although human tumours are shaped by the genetic evolution of cancer cells, evidence also suggests that they display hierarchies related to developmental pathways and epigenetic programs in which cancer stem cells (CSCs) can drive tumour growth and give rise to differentiated progeny. Yet, unbiased evidence for CSCs in solid human malignancies remains elusive. Here we profile 4,347 single cells from six IDH1 or IDH2 mutant human oligodendrogliomas by RNA sequencing (RNA-seq) and reconstruct their developmental programs from genome-wide expression signatures. We infer that most cancer cells are differentiated along two specialized glial programs, whereas a rare subpopulation of cells is undifferentiated and associated with a neural stem cell expression program. Cells with expression signatures for proliferation are highly enriched in this rare subpopulation, consistent with a model in which CSCs are primarily responsible for fuelling the growth of oligodendroglioma in humans. Analysis of copy number variation (CNV) shows that distinct CNV sub-clones within tumours display similar cellular hierarchies, suggesting that the architecture of oligodendroglioma is primarily dictated by developmental programs. Subclonal point mutation analysis supports a similar model, although a full phylogenetic tree would be required to definitively determine the effect of genetic evolution on the inferred hierarchies. Our single-cell analyses provide insight into the cellular architecture of oligodendrogliomas at single-cell resolution and support the cancer stem cell model, with substantial implications for disease management.
772 citations
TL;DR: Supportive and palliative care remain important considerations throughout the disease course in the multimodality approach to management, and innovative clinical trial designs with biomarker-enrichment strategies are needed to ultimately improve the outcome of patients with glioblastoma.
Abstract: Glioblastoma is the most common malignant primary brain tumor. Overall, the prognosis for patients with this disease is poor, with a median survival of <2 years. There is a slight predominance in males, and incidence increases with age. The standard approach to therapy in the newly diagnosed setting includes surgery followed by concurrent radiotherapy with temozolomide and further adjuvant temozolomide. Tumor-treating fields, delivering low-intensity alternating electric fields, can also be given concurrently with adjuvant temozolomide. At recurrence, there is no standard of care; however, surgery, radiotherapy, and systemic therapy with chemotherapy or bevacizumab are all potential options, depending on the patient's circumstances. Supportive and palliative care remain important considerations throughout the disease course in the multimodality approach to management. The recently revised classification of glioblastoma based on molecular profiling, notably isocitrate dehydrogenase (IDH) mutation status, is a result of enhanced understanding of the underlying pathogenesis of disease. There is a clear need for better therapeutic options, and there have been substantial efforts exploring immunotherapy and precision oncology approaches. In contrast to other solid tumors, however, biological factors, such as the blood-brain barrier and the unique tumor and immune microenvironment, represent significant challenges in the development of novel therapies. Innovative clinical trial designs with biomarker-enrichment strategies are needed to ultimately improve the outcome of patients with glioblastoma.
766 citations
References
More filters
TL;DR: The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class.
Abstract: BACKGROUND: Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas.
METHODS: We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes.
RESULTS: Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma.
CONCLUSIONS: The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.)
2,346 citations
"The 2016 World Health Organization ..." refers background in this paper
...It is important to recognize, however, that diffuse astrocytoma, IDH-wildtype is an uncommon diagnosis and that such cases need to be carefully evaluated to avoid misdiagnosis of lower grade lesions such as gangliogliomas; moreover, anaplastic astrocytoma, IDH-wildtype is also rare, and most such tumors will feature genetic findings highly characteristic of IDH-wildtype glioblastoma [6, 38]....
[...]
..., IDH mutation and 1p/19q codeletion status) and phenotype to diagnose these tumors results in nearly all of them being compatible with either an astrocytoma or oligodendroglioma [6, 44, 48], with only rare reports of molecularly “true” oligoastrocytomas consisting of histologically and genetically distinct astrocytic (IDH-mutant, ATRX-mutant, 1p/19q-intact) and oligodendroglial (IDH-mutant, ATRX-wildtype and 1p/19q-codeleted) tumor populations [14, 49]....
[...]
...In the setting of an anaplastic oligodendroglioma with non-diagnostic genetic results, careful evaluation for genetic features of glioblastoma may be undertaken [6]....
[...]
TL;DR: It is anticipated that the molecular classification of medulloblastoma will continue to evolve and diversify in the future as larger cohorts are studied at greater depth, and herein is outlined the current consensus nomenclature, and the differences between the medullOBlastoma subgroups.
Abstract: Medulloblastoma, a small blue cell malignancy of the cerebellum, is a major cause of morbidity and mortality in pediatric oncology. Current mechanisms for clinical prognostication and stratification include clinical factors (age, presence of metastases, and extent of resection) as well as histological subgrouping (classic, desmoplastic, and large cell/anaplastic histology). Transcriptional profiling studies of medulloblastoma cohorts from several research groups around the globe have suggested the existence of multiple distinct molecular subgroups that differ in their demographics, transcriptomes, somatic genetic events, and clinical outcomes. Variations in the number, composition, and nature of the subgroups between studies brought about a consensus conference in Boston in the fall of 2010. Discussants at the conference came to a consensus that the evidence supported the existence of four main subgroups of medulloblastoma (Wnt, Shh, Group 3, and Group 4). Participants outlined the demographic, transcriptional, genetic, and clinical differences between the four subgroups. While it is anticipated that the molecular classification of medulloblastoma will continue to evolve and diversify in the future as larger cohorts are studied at greater depth, herein we outline the current consensus nomenclature, and the differences between the medulloblastoma subgroups.
1,501 citations
"The 2016 World Health Organization ..." refers background in this paper
..., desmoplastic/nodular, medulloblastoma with extensive nodularity, large cell, and anaplastic) and it is now widely accepted that there are four genetic (molecular) groups of medulloblastoma: WNTactivated, SHH-activated, and the numerically designated “group 3” and “group 4” [46]....
[...]
TL;DR: To identify somatic mutations in pediatric diffuse intrinsic pontine glioma (DIPG), whole-genome sequencing of DNA from seven DIPGs and matched germline tissue and targeted sequencing of an additional 43 DIPG and 36 non-brainstem pediatric glioblastomas (non-BS-PGs) were performed.
Abstract: To identify somatic mutations in pediatric diffuse intrinsic pontine glioma (DIPG), we performed whole-genome sequencing of DNA from seven DIPGs and matched germline tissue and targeted sequencing of an additional 43 DIPGs and 36 non-brainstem pediatric glioblastomas (non-BS-PGs). We found that 78% of DIPGs and 22% of non-BS-PGs contained a mutation in H3F3A, encoding histone H3.3, or in the related HIST1H3B, encoding histone H3.1, that caused a p.Lys27Met amino acid substitution in each protein. An additional 14% of non-BS-PGs had somatic mutations in H3F3A causing a p.Gly34Arg alteration.
1,362 citations
TL;DR: Data is summarized on incidence rates, survival, and genetic alterations from population-based studies of astrocytic and oligodendrogliomas that were carried out in the Canton of Zurich, Switzerland to suggest that the acquisition of TP53 mutations in these glioblastoma subtypes may occur through different mechanisms.
Abstract: Published data on prognostic and predictive factors in patients with gliomas are largely based on clinical trials and hospital-based studies. This review summarizes data on incidence rates, survival, and genetic alterations from population-based studies of astrocytic and oligodendrogliomas that were carried out in the Canton of Zurich, Switzerland (approximately 1.16 million inhabitants). A total of 987 cases were diagnosed between 1980 and 1994 and patients were followed up at least until 1999. While survival rates for pilocytic astrocytomas were excellent (96% at 10 years), the prognosis of diffusely infiltrating gliomas was poorer, with median survival times (MST) of 5.6 years for low-grade astrocytoma WHO grade II, 1.6 years for anaplastic astrocytoma grade III, and 0.4 years for glioblastoma. For oligodendrogliomas the MSTwas 11.6 years for grade II and 3.5 years for grade III. TP53 mutations were most frequent in gemistocytic astrocytomas (88%), followed by fibrillary astrocytomas (53%) and oligoastrocytomas (44%), but infrequent (13%) in oligodendrogliomas. LOH 1p/19q typically occurred in tumors without TP53 mutations and were most frequent in oligodendrogliomas (69%), followed by oligoastrocytomas (45%), but were rare in fibrillary astrocytomas (7%) and absent in gemistocytic astrocytomas. Glioblastomas were most frequent (3.55 cases per 100,000 persons per year) adjusted to the European Standard Population, amounting to 69% of total incident cases. Observed survival rates were 42.4% at 6 months, 17.7% at one year, and 3.3% at 2 years. For all age groups, survival was inversely correlated with age, ranging from an MST of 8.8 months ( 80 years). In glioblastomas, LOH 10q was the most frequent genetic alteration (69%), followed by EGFR amplification (34%), TP53 mutations (31%), p16INK4a deletion (31%), and PTEN mutations (24%). LOH 10q occurred in association with any of the other genetic alterations, and was the only alteration associated with shorter survival of glioblastoma patients. Primary (de novo) glioblastomas prevailed (95%), while secondary glioblastomas that progressed from low-grade or anaplastic gliomas were rare (5%). Secondary glioblastomas were characterized by frequent LOH 10q (63%) and TP53 mutations (65%). Of the TP53 mutations in secondary glioblastomas, 57% were in hot-spot codons 248 and 273, while in primary glioblastomas, mutations were more evenly distributed. G:C-->A:T mutations at CpG sites were more frequent in secondary than primary glioblastomas, suggesting that the acquisition of TP53 mutations in these glioblastoma subtypes may occur through different mechanisms.
1,272 citations
"The 2016 World Health Organization ..." refers background in this paper
...Historically, the prognostic differences between WHO grade II diffuse astrocytomas and WHO grade III anaplastic astrocytomas were highly significant [31]....
[...]
TL;DR: IDH1 mutations are the earliest detectable genetic alteration in precursor low-grade diffuse astrocytomas and in oligodendrogliomas, indicating that these tumors are derived from neural precursor cells that differ from those of primary glioblastomas.
Abstract: Glioblastoma is the most frequent and malignant brain tumor. The vast majority of glioblastomas (~90%) develop rapidly de novo in elderly patients, without clinical or histologic evidence of a less malignant precursor lesion (primary glioblastomas). Secondary glioblastomas progress from low-grade diffuse astrocytoma or anaplastic astrocytoma. They manifest in younger patients, have a lesser degree of necrosis, are preferentially located in the frontal lobe, and carry a significantly better prognosis. Histologically, primary and secondary glioblastomas are largely indistinguishable, but they differ in their genetic and epigenetic profiles. Decisive genetic signposts of secondary glioblastoma are IDH1 mutations, which are absent in primary glioblastomas and which are associated with a hypermethylation phenotype. IDH1 mutations are the earliest detectable genetic alteration in precursor low-grade diffuse astrocytomas and in oligodendrogliomas, indicating that these tumors are derived from neural precursor cells that differ from those of primary glioblastomas. In this review, we summarize epidemiologic, clinical, histopathologic, genetic, and expression features of primary and secondary glioblastomas and the biologic consequences of IDH1 mutations. We conclude that this genetic alteration is a definitive diagnostic molecular marker of secondary glioblastomas and more reliable and objective than clinical criteria. Despite a similar histologic appearance, primary and secondary glioblastomas are distinct tumor entities that originate from different precursor cells and may require different therapeutic approaches.
884 citations
"The 2016 World Health Organization ..." refers background in this paper
...Glioblastomas are divided in the 2016 CNS WHO into (1) glioblastoma, IDH-wildtype (about 90 % of cases), which corresponds most frequently with the clinically defined primary or de novo glioblastoma and predominates in patients over 55 years of age [30]; (2) glioblastoma, IDH-mutant (about 10 % of cases), which corresponds closely to socalled secondary glioblastoma with a history of prior lower grade diffuse glioma and preferentially arises in younger patients [30] (see Table 4); and (3) glioblastoma, NOS, a diagnosis that is reserved for those tumors for which full IDH evaluation cannot be performed....
[...]