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Table of Contents
Year : 2020  |  Volume : 3  |  Issue : 2  |  Page : 38-44

A contemporary molecular view of diffuse gliomas with implications for diagnosis

1 Department of Neurosurgery, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China
2 Department of Pathology, Robert H. Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

Date of Submission11-May-2020
Date of Acceptance01-Jun-2020
Date of Web Publication27-Jun-2020

Correspondence Address:
Dr. Daniel J Brat
Department of Pathology, Robert H. Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
Dr. Xuejun Yang
Department of Neurosurgery, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/glioma.glioma_11_20

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Diffuse gliomas are a family of neoplastic diseases characterized by widespread infiltration of central nervous system structures by tumor cells displaying glial differentiation. Traditionally characterized by morphologic features of lineage and histologic differentiation, we now understand that diffuse gliomas contain multiple discrete molecular subsets, each with their own clinical and genetic characteristics. In the current molecular era, the World Health Organization 4th Edition update introduced classes of diffuse glioma according to the status of isocitrate dehydrogenase mutation, 1p/19q co-deletion, histone H3 mutation, and BRAF mutation. Additional studies have demonstrated the subset-specific prognostic significance and grading implications of epidermal growth factor receptor amplification, CDKN2A/B homozygous deletion, TERT promoter mutations, and whole chromosome 7 gain and whole chromosome 10 loss (+7/−10). These findings represent the beginning of the molecular era of diagnosis and grading. Additional studies will likely refine our current conceptions and further advance our ability to stratify risk and direct therapies. In this review, we discuss the current understanding of the molecular classification of diffuse gliomas.

Keywords: Astrocytoma, classification, diagnosis, diffuse glioma, glioblastoma, isocitrate dehydrogenase, molecular, oligodendroglioma, prognosis

How to cite this article:
Li J, Wang X, Tong L, Yang X, Brat DJ. A contemporary molecular view of diffuse gliomas with implications for diagnosis. Glioma 2020;3:38-44

How to cite this URL:
Li J, Wang X, Tong L, Yang X, Brat DJ. A contemporary molecular view of diffuse gliomas with implications for diagnosis. Glioma [serial online] 2020 [cited 2022 Dec 8];3:38-44. Available from: http://www.jglioma.com/text.asp?2020/3/2/38/288176

Jiabo Li & Xuya Wang contributed equally.

  Introduction Top

Diffuse gliomas are a family of primary central nervous system (CNS) tumors. They are characterized by the individual tumor cells infiltrating into the brain and spinal cord structures. These neoplasms occur in patients of all ages throughout the neuro-axis but predominantly in the elderly people and in the cerebral hemispheres. Although diffuse gliomas are ultimately fatal since they cannot be completely resected by neurosurgery and they are only partially responsive to adjuvant therapies, clinical outcomes vary tremendously depending on patient age, extent of resection, and tumor type.[1] For over 100 years, pathologists have classified and graded these neoplasms based on morphologic features present on microscopic examination.[2],[3] While these classification and grading systems were based on the best available evidence at the time, they were widely criticized for their lack of reproducibility and their inability to accurately predict patient outcome in a manner that could be used to guide clinical care.[4],[5],[6]

Over the past decade, much has changed and we have now entered the molecular era, in which definitions of diffuse gliomas integrate molecular genetic alterations with morphologic features to generate a diagnosis that is much more reproducible and clinically relevant.[7],[8],[9],[10] An understanding of these changes is critical for everyone in the neuro-oncology community, including neuropathologists, neuroradiologists, neurosurgeons, radiation oncologists, neuro-oncologists, other members of the patient care team, and brain tumor investigators.

With overwhelming evidence from numerous large-scale, molecular profiling studies, the World Health Organization (WHO) introduced integrated diagnoses that included molecular alterations into the 2016 classification system.[2] In addition, the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) was created shortly after the 2016 WHO classification in order to accelerate the evaluation and implementation of clinically relevant advances in neuro-oncology research [Table 1].[11] Here, we provide an overview of our current understanding of the genetics and biology of diffuse glioma, with particular emphasis on changes introduced by the WHO and cIMPACT-NOW.
Table 1: World Health Organization classification of diffuse gliomas

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  Database Search Strategy Top

Literature review was performed using PubMed database. Most of the selected English language and full-text articles were published between July 2010 and May 2020. An ancient publication in 1926 was the first to explain the classification of gliomas. The following combinations of keywords were used to initially select the articles to be evaluated: brain tumor, diffuse glioma, glioblastoma, astrocytoma, oligodendroglioma, classification, diagnosis, prognosis, molecular, and cIMPACT-NOW.

  2007 World Health Organization Classification Was Based on Morphologic Features Top

2007 World Health Organization diffuse glioma classification

From the early 1900s to the 2016 WHO brain tumor classification, the classification of diffuse gliomas was according to the morphologic characteristics of individual tumor cells.[12],[13] Tumors that had microscopic features of astrocytic differentiation were referred to as astrocytoma, while those with features of oligodendrocytes were termed oligodendroglioma. If the neoplastic cells within a diffuse glioma displayed both astrocytic and oligodendroglial differentiation, this tumor was classified as oligoastrocytoma. Once the tumor was classified, other morphologic features (mitotic activity, histologic anaplasia, microvascular hyperplasia, and necrosis) were used for grading purposes. The best known and most frequent form of diffuse glioma, glioblastoma, WHO Grade IV, was a high grade diffusely infiltrative glioma with astrocytic differentiation that also displayed mitotic activity, as well as microvascular proliferation and/or necrosis.[2]

Morphologic classification of diffuse gliomas lacked reproducibility

While cytologic and histologic evaluation of diffuse gliomas represented the optimal approach for nearly a century, there were significant concerns about the reproducibility and predictive value of this system of classification and grading. One problem was the subjective nature of morphologic classification, since the designation of a tumor as an oligodendroglioma, astrocytoma, or oligoastrocytoma depended on characteristics such as nuclear roundness and regularity; cytoplasmic clearing and eosinophilia; and other features such as calcification, vascular features, and tissue patterns.[14] Making matters worse, grading schemes for oligodendroglioma and astrocytoma were not the same, so that a discrepancy in tumor classification could also lead to a discrepancy in tumor grade. Since patients with brain tumors often search out second and third opinions, multiple differing diagnoses could result. The subjective nature of classification and grading led a lack of interobserver reproducibility that created challenges for clinicians and patients.[5] Discordant diagnoses of diffuse gliomas based on morphology alone by neuropathologists were reported in 23%–48% of cases in the pre-WHO 2016 era.[15],[16]

Morphologic classification of diffuse gliomas did not optimally stratify risk

Morphology-based classification and grading schemes for diffuse gliomas did not demonstrate optimal risk stratification or predict clinical outcomes for patients with these diseases. The histologic diagnosis of glioblastoma has had relatively high interobserver reproducibility and also carried excellent risk stratification corresponding to dismal patient outcomes, most likely due to strong interobserver agreement with regard to pseudopalisading necrosis and microvascular hyperplasia.[5],[17] However, the predictive value of a diagnosis based on morphology alone was low for histologic Grade II and III oligodendroglioma, astrocytoma, and oligoastrocytoma.[6]

  the Development of 2016 World Health Organization Classification Top

The central significance of isocitrate dehydrogenase mutation

The molecular era for diffuse glioma classification was kicked off in earnest when recurrent mutations of isocitrate dehydrogenase 1 (IDH1) were reported in a small set of glioblastomas (GBMs) in 2008.[18] Those GBM patients who harbor a mutant form of IDH1 were younger and had much longer survival than patients with IDH-wildtype GBMs. These IDH-mutant GBMs are often developed from histologic Grade II and III diffuse gliomas. Several months later, in another article on the IDH-mutational statuses, it was reported that IDH mutations happened in more than 70% of the low-grade gliomas (LGGs, WHO Grade II and III diffuse gliomas) and secondary GBMs (those developed from LGG).[19] In contrast, IDH mutations rarely occurred in primary (denovo) GBMs. In addition, IDH mutations were related to much better clinical outcomes in patients with diffuse gliomas. Interestingly, patients with anaplastic astrocytomas, Grade III that were IDH-wildtype were found to have shorter overall survival than those with GBMs, Grade IV that were IDH-mutant, highlighting the central significance of these mutations in defining distinct patient outcomes and also foreshadowing the need for a new classification and grading scheme.[19] These findings indicated that IDH-wildtype and IDH-mutant diffuse gliomas are distinct diseases with differing genetic profiles and clinical outcomes. Large-scale molecular profiling of diffuse gliomas has confirmed that notion.[20]

Transcriptional classes of isocitrate dehydrogenase-wildtype glioblastomas

While IDH-wildtype GBMs among adults are now recognized as clinically aggressive and distinct from both IDH-mutant glioma and from most high-grade gliomas of childhood, they should not be considered a uniform group. For example, large-scale gene expression profiling has repeatedly identified three dominant transcriptional classes of IDH-wildtype GBMs: mesenchymal, proneural, and classical.[21] Although these transcriptional classes are not currently used for clinical classification or care, they point out distinctions among IDH-wildtype GBMs, which may be biologically relevant and eventually lead to targeted therapies. For example, some studies have indicated that the immune profiles of mesenchymal GBMs are distinct from other transcriptional classes and that immunotherapies may be more effective in the mesenchymal class.[22]

Most IDH-wildtype GBMs contain genetic alterations that affect four core pathways: retinoblastoma (RB), p53, receptor tyrosine kinase (RTK), and telomerase reverse transcriptase (TERT), which might seem to indicate a level of homogeneity.[9],[23],[24] Interestingly, transcriptional classes have moderately strong correlations with specific combinations of genomic alterations. Neurofibromin 1 (NF1), Rb1, and tumor protein p53 (TP53) mutations are typical of the mesenchymal subtype; platelet-derived growth factor receptor alpha amplifications are common in the proneural subtype; and epidermal growth factor receptor amplification and phosphatase and tensin homolog alterations are typical of the classical subtype.[21] Thus, even though each GBM may harbor genetic alterations that affect the same core pathways (TERT, p53, Rb1, and RTK), the specific combinations of altered genes within these pathways have differing downstream effects on gene expression and are closely linked to distinct transcriptional classes.

In addition to the influence of specific genetic alterations, there is also a strong contribution of the tumor micro-environment and nonneoplastic cell types to the gene expression and transcriptional class of GBM. Hypoxia, immune cell infiltrates, and the type and extent of angiogenesis are all thought to contribute to the transcriptional profile of GBMs.[21]

H3 K27 mutation

Another groundbreaking finding that was first uncovered in 2012 involved high-grade diffuse gliomas that occurred predominantly in pediatric patients.[25] Tumors that have traditionally been referred to as “diffuse intrinsic pontine glioma” and “thalamic glioma” in children, as well as other midline lesions involving the brain stem and diencephalon, have been found to be consistently characterized by H3F3A mutation and HIST1H3B mutation.[26] The most common of these are mutations at the H3 K27 locus, which are found in 70%–80% of pontine gliomas.[27] The presence of these mutations within a diffusely infiltrating glioma is nearly always associated with an aggressive clinical course and short patient survivals, leading to their designation as WHO Grade IV neoplasms.

Interestingly, the type of H3 mutation within a diffuse glioma appears to dictate the location of the neoplasm and its clinical outcome. Almost all diffuse gliomas with an H3 mutation at the K27 position locate in a brainstem or thalamus, and mostly happen in children, although not exclusively. H3 mutations at the G34 locus are associated with high-grade gliomas at cerebral hemispheres in patients that are adolescents or young adults.[28] What is more, the co-mutations with H3 mutations also affect the precise glioma location. For example, TP53 mutations co-exist with H3 mutations in cerebral hemispheric and thalamic tumors. Telomerase reverse transcriptase (ATRX) and death domain-associated protein (DAXX) mutations are strongly associated with H3 G34-mutant cerebral hemispheric tumors and H3 K27-mutant thalamic tumors, respectively. Activin A receptor type I (ACVR1) mutations are frequently present in histone H3 K27-mutant diffuse intrinsic pontine glioma.[29]

While high-grade diffuse gliomas in pontine and thalamus are well known for their occurrence in pediatric patients, and original studies have focused on the association of H3 K27 mutations in these tumors, it has become clear that diffuse midline gliomas carrying H3 K27 mutation also happen in adults, including patients into their 60s.[30] With greater experience, it appears that the midline location is more correlated with H3 K27 mutations than age. Thus, midline gliomas should be tested for H3 mutations independent of patient age.

Detection of H3 K27 by immunohistochemistry (IHC) showed 100% sensitivity and specificity and was superior to global reduction in H3K27 me3 as a biomarker in diagnosing H3 K27 mutations. However, testing for trimethylation mark in addition to H3 K27 IHC may provide confirmation in cases where results are equivocal.[31] The diffuse midline glioma, H3 K27M-mutant, and WHO Grade IV were included in the WHO 2016 classification, which represents the first specific mutation determining brain tumor type and grade.

Molecular subsets of low-grade gliomas

Following the recognition of IDH mutations as a primary distinguishing alteration that defined different types of GBM, two independent projects illustrated that molecular features rather than histology alone could determine more precise classifications for LGG. In these studies, it was determined that tumors diagnosed morphologically as oligodendroglioma, oligoastrocytoma, or astrocytoma of Grades II and III could be classified in a clinically more meaningful manner at the molecular level by the presence or absence of IDH mutations and 1p/19q co-deletions.[6],[32] Those diffuse gliomas carrying IDH mutations and 1p/19q co-deletions had distinct gene expression and methylation profiles and were also found to harbor mutations in CIC,FUBP1,Notch1, and the TERT promoter. They also were associated with the longest survival among the molecular classes. Those diffuse gliomas that had IDH mutations but lacked 1p/19q co-deletions were shown to be TP53-mutant and loss ATRX. These diffuse gliomas, now understood to represent IDH-mutant astrocytomas, were correlated with prognoses worse than IDH-mutant, 1p/19q co-deleted tumors.[6] Those IDH-wildtype diffuse gliomas in adults were found to be similar to IDH-wildtype GBMs in terms of genetic alterations.[17] In addition, the median survivals of both IDH-wildtype GBMs and IDH-wildtype diffuse gliomas were less than 18 months.[6] Thus, the molecular subsets had distinct clinical profiles and genetic alterations and provided strong evidence for a molecular-based classification of these diseases.

2016 World Health Organization classification of diffuse gliomas

With the convincing evidence mentioned above, the WHO integrated molecular alterations into the classification of brain tumor entities in 2016.[2] The entities that were included among the diffuse gliomas included IDH-wildtype diffuse astrocytoma, WHO Grade II; IDH-mutant diffuse astrocytoma, WHO Grade II; IDH-wildtype anaplastic astrocytoma, WHO Grade III; IDH-mutant anaplastic astrocytoma, WHO Grade III; IDH-wildtype GBM, WHO Grade IV; and IDH-mutant GBM, WHO Grade IV. For each of these categories, there was also a not otherwise specified (NOS) category, which could be used for diagnosis if molecular testing was not performed or could not be interpreted. On a practical level, the IDH mutational status can be determined in most cases by IHC for the IDH1-R132H-mutant protein, which accounts for over 90% of all IDH1 and IDH2 mutations. For patients under the age of 55 years old with a GBM, it was recommended that reflex testing should be performed for other IDH1 and IDH2 mutations if the results from IDH1-R132H IHC were negative. For those patients over 55 years old, the likelihood of having a non-IDH1-R132H mutation in a primary GBM is very low and testing may not be required.[33],[34] For children and adults with diffusely infiltrating gliomas that involve the midline, testing for the H3 K27M mutation should be performed, either by IHC for the mutant protein or by sequence analysis, in order to support the diagnosis of diffuse midline glioma, H3 K27M-mutant, WHO Grade IV, which was also introduced by the WHO in 2016.[2]

For those tumors that are IDH-mutant, there is a need to distinguish IDH-mutant astrocytoma from oligodendroglioma, IDH-mutant, 1p/19q co-deleted. As of 2016, the integrated diagnosis of oligodendrogliomas and anaplastic oligodendrogliomas requires the presence of IDH mutation and 1p/19q co-deletion. The diagnosis of IDH-mutant astrocytoma (Grades II, III and IV) is supported by TP53 mutation and ATRX loss or mutation.[6] From a practical standpoint, this can be achieved by an IHC panel that includes IDH1-R132H, p53, and ATRX.[6],[35],[36],[37] The vast majority of IDH-mutant astrocytomas show a loss of nuclear staining for ATRX in neoplastic cells, with retention in nonneoplastic cells serving as an internal positive control.[37] p53 is typically overexpressed in neoplastic cells in IDH-mutant astrocytomas. While the expression of p53 in the nuclei of neoplastic cells is not absolute proof of a mutation, the correlation is very strong in the setting of IDH-mutant astrocytomas if the percentage of neoplastic cells showing overexpression is >10%.[35]

Of note, the 2016 WHO excluded the diagnosis for oligoastrocytoma in integrated entities, since there was no evidence to support a molecular entity of such “mixed” tumors.[2] Those diffuse gliomas that were IDH-mutated were either 1p/19 co-deleted and considered oligodendrogliomas, IDH-mutant, 1p/19q co-deleted, or showed ATRX mutation or loss and TP53 mutation, and were considered IDH-mutant astrocytomas. The large majority of IDH-wildtype diffuse gliomas of histologic Grades II and III showed the genetic alterations and clinical behavior of IDH-wildtype GBM. Thus, there was no molecular support for the entity oligoastrocytoma.[6] The 2016 WHO retained oligoastrocytoma, WHO Grade II, NOS and anaplastic oligoastrocytoma, WHO Grade III, NOS as diagnostic entities that could be used in the absence of molecular testing.[2]

  Recent Advances in Addition to 2016 World Health Organization Classification Top

Consortium to inform molecular and practical approaches to central nervous system tumor taxonomy

While the 2016 WHO has taken an important step forward to incorporate genetic alterations into the integrated classifications, it was obvious that the updates in the WHO classification far lagged behind the advances in cancer genomics. Indeed, in the WHO publications between 2007 and 2016, numerous groundbreaking investigations fundamentally changed our concept of diffuse gliomas, yet a sanctioned mechanism that could more readily adopt these advances was needed to incorporate them into clinical practice.[6],[9],[17],[19],[23],[25],[26] This requirement led to the rise of cIMPACT-NOW a group of highly experienced neuropathologists aiming to evaluate and incorporate genomic advances into clinical practice in neuropathology.[11]

Starting in 2016 and continuing to the present, cIMPACT-NOW has provided published updates that address knowledge gaps, confusion, or advances in clinically relevant research that could be implemented into clinical practice.[38] For example, Update 1 clarified the use of the term NOS and proposed the use of the additional term not elsewhere classified (NEC), since there were large variations, sometimes unintended, in the manner in which the NOS term was applied. It was clarified that the term NOS implies that ancillary molecular testing was not performed or could not be interpreted, leading to a diagnosis based on morphology. The NEC term, on the other hand, was introduced to imply that testing was performed and interpreted, yet the results did not support the diagnosis of a WHO entity, and led to a diagnosis that was descriptive (not classified).[39] cIMPACT Update 2 clarified diagnostic criteria for diffuse midline glioma, H3 K27M-mutant and diffuse astrocytoma/anaplastic astrocytoma, IDH-mutant. It was emphasized that the finding of an H3 K27 mutation alone was not sufficient for the diagnosis of diffuse midline glioma, H3 K27M-mutant, since other tumor types have this mutation. It was also emphasized that 1p/19q testing was not mandatory in all IDH-mutant gliomas, since the tumor morphology and results from p53 and ATRX testing could support the diagnosis of an IDH-mutant astrocytoma, without having performed 1p/19q testing.[40] cIMPACT Update 4 focused on the diffuse gliomas of childhood that are both IDH-wildtype and H3-wildtype. Many of these tumors have overlapping morphologies with adult gliomas but have completely distinct clinical settings and genetic alterations and are usually associated with a more indolent clinical course. It was concluded that these diffuse gliomas should be referred to by their defining genetic alteration: diffuse glioma, BRAFV600E-mutant; diffuse glioma, MYB-altered; diffuse glioma, MYBL- altered; diffuse glioma, FGFR1-mutant; diffuse glioma, FGFR1 TKD-duplicated; or diffuse glioma, other MAPK pathway alterations.[41]

Incorporating molecular criteria for grading

With the substantial changes introduced by the 2016 WHO, especially with regard to the new integrated diagnoses for the diffuse gliomas, there was uncertainty about the clinical relevance of grading schemes that had previously been used for the diffuse gliomas based on morphological classification. In particular, there was concern that grading schemes were uncapable of optimally stratifying risk within the molecular classes of diffuse glioma. In cIMPACT Update 3, guidance was provided on the grading of IDH-wildtype gliomas,[42] while cIMPACT Update 5 provided guidance on the grading and terminologies of IDH-mutant astrocytomas.[43]

Isocitrate dehydrogenase-mutant astrocytomas

The grading standards provided by the 2016 WHO classification followed those in the 2007 WHO classification. Both IDH-mutant and IDH-wildtype gliomas were classified according to the same standards.[44],[45] Several independent projects have demonstrated that histologic grading standards probably cannot distinguish prognoses for patients with IDH-mutant astrocytomas in the WHO Grade II and III entities.[46],[47] In the contrary, some studies have concluded that traditional grading system is still able to stratify prognoses for these patients.[48],[49] cIMPACT-NOW evaluated these studies to determine whether the conclusions were evident to define molecular genetic entities that could steadily distinguish prognoses among patients with IDH-mutant diffuse astrocytic gliomas. cIMPACT-NOW also evaluated the evidence to identify gliomas that would behave as aggressively as GBM. They concluded that there was sufficient evidence to define an entity of homozygous deletion of CDKN2A/B for astrocytoma, IDH-mutant, Grade IV, along with necrosis and microvascular hyperplasia.[43] Homozygous deletion of CDKN2A/B was strongly associated with poor prognoses in patients with IDH-mutant astrocytomas and presenting a clinical behavior corresponding to Grade IV.[46],[47],[48],[49],[50],[51],[52]

Isocitrate dehydrogenase-wildtype astrocytomas

Among the IDH-wildtype astrocytomas, the 2016 WHO retained the provisional entities of diffuse astrocytoma, WHO Grade II, and anaplastic astrocytoma, WHO Grade III, and glioblastoma, WHO Grade IV.[2] Several studies have indicated that a subgroup of histologic Grade II and III IDH-wildtype astrocytic gliomas have an aggressive behavior, with overall survival time similar to that in IDH-wildtype glioblastoma.[6],[19],[32] cIMPACT-NOW evaluated the evidences and concluded that those histologic Grade II and III IDH-wildtype astrocytomas that carry EGFR amplification, +7/−10, or TERT promoter mutation have an aggressive clinical behavior, with clinical outcomes equal to or only slightly longer than patients with IDH-wildtype GBM, and should therefore be defined as Grade IV.[46],[53],[54] However, these gliomas were not designated as GBM, since such genomic alteration would be considered as an official WHO entity. This led to the classification of diffuse astrocytic glioma, IDH-wildtype, with molecular features of GBM, WHO Grade IV.[42]

  Conclusion Top

For over a hundred of years, the diagnoses of diffuse gliomas were predominantly based on morphologic features of lineage and histologic differentiation, yet recent molecular genetic advances have pushed a revolution of diagnostic definitions and classifications. In the current molecular era, integrated diagnoses are carried out by incorporating genetic features. The cooperation of neuropathologists, molecular pathologists, and clinicians aims to optimize clinical care by incorporating molecular alterations for diagnoses and therapies. As we learn more about molecular profiles and their relationship to clinical outcomes and responses to therapy, new guidelines will refine classification and grading criteria. Undoubtedly, the improved molecular profiling of diffuse gliomas has optimized our diagnostic strategies and risk stratification system and has taken an important step to the development of more precisely targeted treatments.

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Conflicts of interest

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