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Timestamp: 2019-04-23 11:55:35+00:00

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complete chromosome 1p and 19q codeletion being particularly common in histologically classic oligodendrogliomas.
facilitate tailored treatments for individual patients.
growth’) into the neuropil, i.e., the dense network of neuronal and glial processes of the CNS parenchyma .
1 Relative frequency of histopathologically diagnosed oligodendroglial and oligoastrocytic tumors in the spectrum of glial tumors of the CNS: a in 95.5% ependymal tumors 11. oligodendroglial. It is now fully clear that certain molecular aberrations carry important diagnostic. Unequivocal histological typing and grading of diffuse gliomas is challenging however. 117]..8% pilocytic astrocytoma 5. florid microvascular proliferation (MVP.2% 13 pilocytic astrocytoma 33. anaplastic astrocytoma 6. and necrosis .e. i.564 patients of all age groups.1% oligoastrocytic tumors 1. 2007–2011  aspect of the microvessel walls).9% ‘unique astrocytoma variants’ 1.2% ependymal tumors 6. 65.3% anaplastic astrocytoma 3. e. This results in a high rate of interobserver variation in the diagnosis of diffuse gliomas. 1). such as pilocytic astrocytoma).4% malignant glioma. Oligodendrogliomas and oligoastrocytomas have been generally grouped together as oligodendroglial tumors and account for less than 10 % of the diffuse gliomas (Fig.8% .1% a diffuse astrocytoma 9. According to the WHO 2007 classification. these neoplasms are graded as WHO grade II/low grade. especially because the biological diversity of these tumors is difficult to capture in precise microscopic criteria. b in 10. NOS 7.. after typing a diffuse glioma as astrocytic. in children. or mixed. marked hypertrophy and hyperplasia of endothelial cells and pericytes resulting in a multilayered Fig.4% ‘unique astrocytoma variants’ 4. Microscopic features used for grading are the presence/absence of marked mitotic activity.	810 Acta Neuropathol (2015) 129:809–827 the most malignant form.0% malignant glioma.6% diffuse astrocytoma 11.7% oligodendrogliomas 2.0% oligoastrocytic tumors 3. glioblastoma. respectively. the knowledge on the genetic/ molecular underpinnings of gliomagenesis is rapidly expanding. biological behavior. prognostic and/or predictive information because they provide clinically relevant information on tumor type.274 children and adolescents (0–19 years).4% b glioblastoma 6. WHO grade III/anaplastic or WHO grade IV/ glioblastoma (WHO grade I being reserved for more circumscribed gliomas. For the past 20 years. including oligodendroglial tumors [36. Also. NOS 25.9% glioblastoma 55. and oligodendroglial tumors are rare (<4 % of the primary CNS tumors) . It is therefore to be expected that (like. Information extracted from CBTRUS statistical report: NPCR and SEER. glioma variants with a more circumscribed growth pattern are more frequent than diffuse gliomas. the samples provided for histopathological analysis are not always (fully) representative.3% oligodendrogliomas 5.g. Of note. and/ or expected response to a particular treatment regimen.
In anaplastic examples. such as clustering of tumor cells around the perikarya of preexistent neurons (satellitosis). delicate chromatin and small-to-inconspicuous nucleoli. oligoastrocytoma) . In this review. radiological and histopathological aspects of these neoplasms (‘Setting the stage’). see [71. Only a tiny fraction of oligodendroglial tumors is thought to be due to single-gene hereditary syndromes such as biallelic Lynch syndrome [37. we reconstruct the transition from a purely morphological to an integrated morphological and molecular scheme for classification of the heterogeneous group of oligodendroglial tumors. but the tumor still maintains an overall sense of regularity and nuclear roundness [80. a more vesicular chromatin pattern and more prominent nucleoli. although some architectural growth patterns also provide useful clues (Fig. the nuclei are generally round and uniform with crisp nuclear membranes. however. the diffuse infiltrative growth is easily appreciated. nuclear features are key for microscopic recognition of an oligodendroglial phenotype. 73]. 2).Acta Neuropathol (2015) 129:809–827	sarcomas and hematological malignancies) classification of CNS tumors will increasingly be based on the presence of particular molecular aberrations. 89]. including cortex connected to the genu of the corpus callosum. a mostly pediatric. relatively small cells. radiotherapy and chemotherapy) yields median survival times of 12–14 years even in WHO grade III examples. in less cellular areas at the tumor periphery. Setting the stage Gliomas originate from neural stem cells or glial progenitor cells that develop or maintain glial characteristics . In low-grade oligodendrogliomas. and surrounding cortical small vessels (perivascular aggregates).. The presence of a branching network of delicate capillaries (chicken-wire pattern) and extensive calcification are common. which is typically absent in frozen sections and rapidly fixed specimens. As originally described by Bailey and Bucy .e. Occasionally. Most oligodendroglioma patients present with seizures. Oligodendroglial tumors most commonly arise in the frontal lobe. After summarizing clinical. and oligodendroglial tumors are amongst the first in line for such a change. somewhat more frequently in males and with the peak incidence in the 5th and 6th decade. Furthermore. glioblastomas. often with prominent secondary structure formation. or mixed (i. 81]. oligodendrogliomas in children are histologically similar. but may involve unusual sites such as the posterior fossa and the spinal cord more frequently and lack the molecular background of adult counterparts . based on the resemblance of the tumor cells with non-neoplastic glial cells most diffuse gliomas can be typed as astrocytic. Robust enhancement is not a common feature in low-grade examples and suggests transformation to a higher histologic grade [61. extracranial metastases of oligodendroglial tumors occur (for recent reviews. indicating that the genu of the corpus callosum is a major pathway for seizure generalization . this patient category still substantially contributes to the high average number of ‘years of life lost’ for patients suffering from a CNS tumor . 13 . 42]. In the last part of this article (‘WHO’s next?’). under the pial surface (subpial aggregation). and pilocytic astrocytomas the reader is referred to companion articles in the present cluster. or rarely even signet-ring cell morphology [68. Oligodendroglial tumors are often highly cellular lesions in central regions with closely packed. Because of their locally aggressive behavior and the fact that they cannot be cured by current therapies. The combination of the round nuclei and perinuclear haloes results in a fried-egg appearance of individual cells and in a honeycomb architectural pattern of groups of evenly spaced cells. the oligodendrogliomas were located more caudolaterally in orbitofrontal and temporal lobes but typically sparing cortex connected to the genu. Rarely. However. Patients with a WHO grade II oligodendroglioma may survive even 811 longer. diffuse gliomas are considered one of the most devastating cancers . perinuclear halo that often is seen in oligodendroglial tumor cells is in fact an artifact of formalin fixation. According to the WHO 2007 classification. 78]). prognostic and/or predictive value of these aberrations will be discussed (‘Molecular mechanisms and markers’). Given the often young age at presentation. Rare oligodendroglial tumors show marked pleomorphism (‘polymorphic oligodendroglioma’) or cells arranged in a rhythmic/spongioblastic fashion. Typically. slowly progressive oligodendroglial-like proliferation presents as a diffuse leptomeningeal neoplasm [97. 69. the molecular underpinnings of oligodendroglial tumors and the diagnostic. For a review on similar aspects concerning diffuse astrocytomas. cells are frequently enlarged and epithelioid with nuclei that often show increased size and pleomorphism. we elaborate on how these markers can be used to reclassify oligodendroglial tumors more objectively. but sooner or later such tumors generally progress to a high-grade malignant glioma as well. but with some challenges and unanswered questions remaining. The clear. Progress has been made with oligodendroglioma patients such that current standard of care (surgery. Patients experiencing generalized tonic–clonic seizures were reported to more often have the greatest lesion load in mesial frontal regions. while in patients with partial seizures. part of the tumor cells in oligodendrogliomas may show a gliofibrillary or minigemistocytic phenotype with strong staining for glial fibrillary acidic protein (GFAP) of the cytoplasm. but not specific additional features in oligodendrogliomas. oligodendroglial.
macronucleoli. 1p19q codeleted) oligodendrogliomas include: a a honeycomb-like arrangement of evenly spaced tumor cells with uniformly rounded nuclei and clear haloes imparting a “fried egg” appearance. but a maintained general sense of nuclear roundness. most oligodendrogliomas show only limited p53 immunoreactivity (o) and retained ATRX expression (p) . and i foci of tumor necrosis. d tissue section). m Tumoral synaptophysin positivity is not uncommon and can include a paranuclear dot-like pattern. c. sharp nuclear membranes. l A stain for neurofilament protein often highlights the infiltrative growth pattern by showing entrapped neurons and axons.	812 Fig. e foci of anaplastic transformation with increased cellularity and enlarged cell size (left) in comparison to the low-grade precursor cells (right). b mucin-filled microcystic spaces. while others (k) show strong expression in gliofibrillary oligodendrocytes (perinuclear rim and variable tadpole-like tail) or minigemistocytes (not shown). more often consisting of collections of apoptotic cells rather than the pattern of pseudopalisading necrosis seen in glioblastomas. some cases are completely GFAP negative. h microvascular proliferation. additionally. and small nucleoli (c intra-operative smear. with only reactive astrocytes staining (j). Immunohistochemically. n A stain for IDH1-R132H mutant protein highlights perineuronal satellitosis in this positive tumor with cortical involvement. delicate “salt and pepper” chromatin. Anaplastic examples often feature: f enlarged epithelioid cells with increased pleomorphism. Unlike diffuse astrocytomas. there are branching capillaries (arrow) resembling chicken-wire. g increased mitotic index and occasional 13 Acta Neuropathol (2015) 129:809–827 “red crunchy” cells with brightly eosinophilic lysosomal inclusions (arrow). d minigemistocytes with small rounded bellies of eosinophilic cytoplasm and classic nuclear cytology including rounded countours. vesicular chromatin. 2 Common histopathologic patterns encountered in classic (IDH mutant.
In contrast. The latter may include the 1p19q codeletion pattern of adult oligodendroglioma. demonstration of IDH1 R132H mutant protein (d) and 1p19q codeletion confirmed the diagnosis in this case. but more frequently harbors 1p deletion without 19q loss [79. 3 Less common and sometimes diagnostically confusing histopathologic patterns encountered in classic (IDH mutant. however. 2. the histopathological diagnosis of oligoastrocytomas is based on the presence of neoplastic glial cells with morphological 13 . simulating a more astrocytoma-like pattern.Acta Neuropathol (2015) 129:809–827	813 Fig. the case with gangliogliomalike maturation featured areas of classic anaplastic oligodendroglioma (g note also the “red crunchy” cells). with immunohistochemical pitfalls including CD56 (b) and synaptophysin (c) positivity. As indicated by their name. However. Rare examples demonstrate more overt neuronal differentiation. including neurocytic (f) and ganglioglioma-like (g. h). 1p19q codeleted) oligodendrogliomas include: a–e a lobulated or nodular growth pattern can simulate a neuroendocrine tumor. FISH studies (not shown) revealed 1p19q codeletions not only in this component. e focal spindled cytology was also encountered. 3). Neurocytic foci often feature slightly smaller and more hyperchromatic nuclei surrounding central collections of delicate pink neuropil (i.. but in neoplastic ganglion cells (h) as well 100]. Histopathological typing of diffuse gliomas is relatively straightforward for tumors at the ‘prototypic ends’. 101]. there is a surprisingly wide morphological spectrum that includes both common and diagnostically misleading patterns (Figs.e. neurocytic rosettes).
demonstration of TERT mutation in IDH wild type (wt) diffuse gliomas as well as of EGFR amplification/EGFRvIII strongly indicates high-grade malignant astrocytic tumor/glioblastoma. florid MVP. A recently published algorithm proposes immunohistochemistry (IHC) as a first step. OA low-grade astrocytoma. In fact. See also text in this article and the other reviews in this cluster characteristics of both astrocytes and oligodendrocytes. Nevertheless.	814 Fig. A. oligodendroglioma. Introducing 1p/19q codeletion as a defining feature for oligodendrogliomas will in most cases allow for a clear distinction from astrocytic neoplasms and can be expected to drastically reduce the fraction of neoplasms diagnosed as mixed/oligoastrocytic (b).. a KIAA-BRAF fusion gene is typically found in pilocytic astrocytoma. oligodendroglioma. (neuro)pathologists who readily accept the existence of mixed gliomas will more liberally diagnose oligoastrocytomas. In practice. For instance. 4a) [16. According to the WHO criteria. c Molecular markers helpful in daily clinical practice for state-of-the-art classification of diffuse gliomas. although the latter form is rare . These cells may be diffusely mixed or separated. In oligodendrogliomas. Variable testing for other markers can be helpful as well: in IDH mutated (mut) diffuse gliomas demonstration of TERT mutation indicates oligodendroglioma and of TP53 mutation astrocytoma. oligoastrocytic/mixed glioma. how many mitoses are needed for “marked mitotic activity”? One 13 Acta Neuropathol (2015) 129:809–827 a oligoastrocytic oligodendroglial astrocytic WHO grade II b oligoastrocytic oligodendroglial astrocytic WHO grade II WHO grade III GBM-O GBM WHO grade IV AO AOA AA WHO grade III O OA A O A 1p/19q codel AO AA 1p/19q intact GBM WHO grade IV c astrocytic WHO grade II WHO grade III WHO grade IV oligoastrocytic oligodendroglial 1p/19q intact IDH mut ATRX IHCTERT wt TP53 mut 1p/19q codel IDH mutxxxxx ATRX IHC+xxxx TERT mutxxxxxx TP53 wtxxxxxxxxx 1p/19q intact IDH wt ATRX IHC+ TERT mut TP53 wt or mut study reported that finding six or more mitoses per ten high power fields allowed for recognition of oligodendrogliomas with more aggressive (WHO grade III) clinical behavior . those who readily accept the existence of mixed gliomas are likely to more liberally diagnose oligoastrocytomas than those skeptical that this entity exists (Fig. or marked mitotic activity is considered as WHO grade II. an oligodendroglioma without necrosis. AOA anaplastic astrocytoma. GBM-O glioblastoma with oligodendroglial component. AA. resp. O. GBM glioblastoma. resp. CNS tumors resembling classic oligodendrogliomas often lack 1p/19q codeletion. The diagnostic definitions of oligoastrocytomas have been subjective and their diagnosis is poorly reproducible. oligoastrocytic/mixed glioma. the significance of necrosis was unclear. Meanwhile. Ideally. In a large study published in 2006. both with regard to cell type (astrocytic. allowing for correct classification of esp. while the presence of one or more of these features generally warrants an anaplastic designation (WHO grade III). In mixed gliomas. and such tumors are still considered WHO grade III. delineation of oligoastrocytomas from (more) pure astrocytic and oligodendroglial tumors is poorly reproducible. subsequent molecular testing for 1p/19q codeletion status and/or other IDH1 and IDH2 mutations is performed. Especially. conceptual preferences of individual (neuro)pathologists further impact cell type determinations. Additional challenges arise because the grading criteria for astrocytomas differ and as such. AO. HIST1H3B/C indicate pediatric type high-grade gliomas (which may also harbor ATRX mutations and show loss of ATRX immunoreactivity). florid MVP and necrosis do not have the same unfavorable connotation as in diffuse astrocytic neoplasms. necrosis was found to be a statistically . different systems for the assessment of malignancy grade of oligodendroglial tumors were applied . the presence of florid MVP was similarly considered to be consistent with WHO grade III. the initial determination of astrocytoma versus oligodendroglioma is often critical to whether the same glioma will be considered lowor high-grade. whereas prior to the 2007 WHO classification. 73]. mixed) and malignancy grade. the best position for these ‘pediatric oligodendrogliomas’ in an improved taxonomy of CNS tumors requires further study. the IDH1 R132H mutant protein positive.. considerable problems arise in daily practice given the subjectivities of these definitions. 35]. For instance. While in the past. especially in children. oligodendroglial. while those who are skeptical that this entity exists will designate the vast majority of diffuse gliomas as either astrocytic or oligodendroglial (a). ATRX negative (and thus ATRX mutated) astrocytomas . the WHO classification has since gained world-wide acceptance [60. in other tumors. while mutations in the histone genes H3F3A. 4 Diffuse gliomas: from histopathologically to molecularly ▸ defined entities. Diffuse gliomas histopathologically form a spectrum.
While improved definitions of morphological features may be helpful in this respect . These data once again illustrate the fact that histopathological discrimination of mixed gliomas from pure counterparts remains subjective and at least partly explain differences in overall survival of patients with anaplastic oligoastrocytomas between various large prospective studies. 119]. 86. expression of phosphorylated cyclic-AMP responsive element binding protein (p-CREB. The presence of Rosenthal fibers and eosinophilic granular bodies in a glial tumor suggests pilocytic astrocytoma. 123]. Not infrequently.. but the sensitivity for identifying 1p19q codeleted oligodendrogliomas was only 70 % and the value of this tool for discrimination of diffuse gliomas awaits further elucidation.Acta Neuropathol (2015) 129:809–827	significant predictor of poor overall survival for patients with anaplastic oligoastrocytoma. but not for those with anaplastic oligodendroglioma . Other studies on GBM-O provided conflicting results (see for review ). immunohistochemical studies (e. more typical glioneuronal tumors can be challenging [91. particularly given their reportedly high frequencies of EGFR gene amplification. Examples are glial neoplasms like pilocytic astrocytoma and clear cell ependymoma. Olig2 expression was not found helpful for distinguishing oligodendrogliomas from diffuse astrocytomas. a more promising approach is to integrate molecular data in order to create a more objective and reproducible glioma classification. The better prognosis of patients with GBM-O compared to those with classic glioblastoma in this series may then at least partly be explained by the fact that these GBMOs were more often secondary glioblastomas with IDH mutation occurring in younger patients with dedifferentiated tumors . 27].3 trial and originally diagnosed as glioblastoma by a local pathologist. INA expression did not appear to provide the sensitivity and specificity needed for robust recognition of oligodendrogliomas [14. 114. While multiple studies show that distinctive histologic features in diffuse gliomas are associated with clinical outcome and with specific molecular alterations. a transcription factor involved in gliomagenesis) was described to be present in astrocytomas but largely absent in prototypic oligodendrogliomas . 93. 15 % was reclassified as GBM-O but this re-grouping lacked prognostic significance . indicating that the progenitor cells from which these tumors are derived are less strictly committed to glial lineage than previously thought [92. After initial optimism. Very recently. of 339 glioblastoma cases included in the EORTC_26981/ NCIC_CE. More recently described candidate markers in this respect are Olig2 (a murine bHLH transcription factor expressed in neural progenitors and oligodendroglia and considered to be essential for oligodendrocyte development) and the neuronal intermediate filament alpha internexin (INA). the concept of GBM-O had already been around for more than a decade . This situation results in undesirable clinical discrepancies . stratification into grade III and IV on the basis of absence or presence of necrosis was justified leading to a ‘glioblastoma with oligodendroglial component’ (GBM-O) category in the WHO 2007 classification . as well as neuronal or glioneuronal tumors such as neurocytomas and dysembryoplastic neuroepithelial tumors (DNTs). leading to the conclusion that for anaplastic oligoastrocytomas. 65]. Molecular mechanisms and markers Like other neoplasms. Acknowledging that histopathological distinction of GBM-O from small cell glioblastoma can be difficult. Appin et al. a clinical and molecular subtype already known for a better prognosis. More recently. 26. This may also explain that occasionally oligodendrogliomas are reported to display neurocytic or ganglioglioma-like maturation and that differentiation from other. even among experienced neuropathologists [36. the lack of robust histopathological criteria causes substantial diagnostic interobserver variability. Other features that are helpful in this respect include biphasic growth pattern (pilocytic astrocytomas). it is likely that the latter variant was overrepresented in some studies taking glioblastomas as a starting point. the formation of true rosettes or perivascular pseudorosettes (ependymal tumors) and the formation of specific glioneuronal elements (DNT). Furthermore. more frequently originate from lower grade precursors and are associated with longer survival. Others published similar observations [107. More precise classification of gliomas is urgently needed for adequate assessment of prognosis and appropriate planning of treatment. However. diffuse gliomas develop as a result of genetic and molecular alterations that further accumulate 13 . synaptophysin staining (for quite some time considered as sound evidence for neuronal rather than glial differentiation) has been described to occur in ‘bona fide’ oligodendrogliomas (and other gliomas) as well.g. 72. other primary CNS tumors may show oligodendroglioma-like features including fried-egg appearance of (part of) the tumor cells. 113].  reported that GBM-Os tend to arise in younger patients. Similarly. For example. Of note. nor from DNTs or pilocytic astrocytomas (although lack of Olig2 staining may aid in the diagnosis of neurocytoma or clear cell ependymoma rather than oligodendroglioma) [56. Unequivocal recognition of oligodendrogliomas is hindered by the lack of specific immunohistochemical markers for these tumors . dot-like staining for epithelial membrane antigen typically present in ependymal tumors) and occasionally electron microscopy (for ultrastructural demonstration of ependymal or neuronal differentiation) may be helpful 815 in problematic cases. 115]. although they can be rarely found in diffuse gliomas as well.
This explains why it is the loss of the entire arms of 1p and 19q that is related to clinical outcome. 77]. 40]. regardless of astrocytic or oligodendroglial cell type. supporting the hypothesis that these gliomas originate from a bipotential progenitor cell able to give rise to neurons and oligodendrocytes . Cairncross et al. 1p/19q codeleted grade III tumors. Recently. MGMT promoter methylation and G‑CIMP O6-alkylguanine-DNA-alkyltransferase (AGT). The biomarker value of immunohistochemistry for the repair enzyme itself is less clear [50. but better than grade II and III tumors without IDH mutations. Through an altered substrate specificity. rather than smaller terminal or interstitial deletions which occur by a completely different mechanism and are occasionally encountered in astrocytic tumors. 50 base pair single-end sequencing. IDH mutations give rise to metabolic alterations. using restriction fragment length polymorphism analysis. 116]. The high clinical relevance of 1p/19q loss became clear when this marker appeared to be associated with sensitivity to chemotherapy and improved outcome. In turn. however. This will. Application of ‘strict’ (as opposed to ‘relaxed’) histopathological criteria for recognition of oligodendrogliomas results in a higher correlation with 1p/19q codeleted tumors [2.	816 with tumor progression. Some of these molecular abnormalities carry important diagnostic. IDH status has major prognostic implications for patients with diffuse gliomas.395G>A (p. a high percentage (70–80 %) of IDH1 and IDH2 mutations were identified in diffuse grade II and III gliomas. including an increase in production of 2-hydroxyglutarate (2-HG) which can inhibit histone demethylation and induces a glioma hypermethylation phenotype (glioma CpG island methylated phenotype or G-CIMP) [45. 125]. 13 Acta Neuropathol (2015) 129:809–827 IHD1/IDH2 mutations Following the initial discovery of isocitrate dehydrogenase (IDH) gene mutations in a small subset of especially younger glioblastoma patients with prolonged survival. giving support for a major molecular component in future tumor characterization. In large prospective randomized studies on diffuse glioma. 124.  reported for the first time that many oligodendroglial tumors show loss of heterozygosity (LOH) for chromosome arms 1p and 19q. 127]. such as glioblastoma . Complete 1p/19q codeletion In 1994. Reifenberger et al. with c. 118. 135]. In a large series of ‘classic’ glioblastomas. and likely precedes the development of the 1p/19q codeletion. 75. Nearly all mutations involve codon 132 of IDH1 or the homologous codon 172 of IDH2. GBM-Os showed a similar low frequency of 1p/19q codeletion . Indeed. 51]. The IDH1 R132H mutant protein can be detected reliably using immunohistochemistry . whereas superimposed TP53 and ATRX mutations drive it towards the astrocytoma phenotype instead [3. The most promising markers for oligodendroglial tumors are briefly discussed below. In some studies. Later on. while others reported an increased frequency of codeletions in GBM-Os compared to conventional glioblastoma . and was suggested to be a better predictive factor for benefit to chemotherapy in the RTOG trial on adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors . Virtually all 1p/19q codeleted tumors have a pro-neural expression profile. methylation of very specific regions in the MGMT promoter was found to be highly correlated to MGMT expression [6. encoded by the O6-methylguanine-DNA-methyltransferase (MGMT) gene. this leads to a variety of downstream chromatin remodeling and transcriptional alterations. is a key repair enzyme that removes alkyl and methyl adducts from DNA. the latter possibly specifically driving a diffuse glioma towards the classic oligodendroglioma morphologic phenotype. 94]. 2–8 % of the primary/de novo and 0–13 % of secondary tumors were reported to show 1p/19q codeletion . with virtually all tumors responding. Further studies have shown that IDH mutation is an early event in gliomagenesis (‘driver mutation’). 48]. . IDH mutant tumors without 1p/19q codeletion have a worse outcome compared to IDH mutant. 124]. 1p/19q codeletion was demonstrated to be the only copy number aberration that was stable across spatial regions of low-grade diffuse gliomas and their recurrences . miss approximately 10 % of IDH mutations. Further studies have shown that 1p/19q loss in fact results from a non-balanced translocation t (1:19) (q10:p10) with subsequent loss of one of the derivative chromosomes [38.  were the first to point out that recurrent anaplastic oligodendrogliomas with 1p/19q codeletion were far more responsive to PCV (procarbazine–ccnu–vincristine) chemotherapy.R132H) representing >90 % of all IDH1 mutations [87. These aberrations allow the tumor to acquire assets for sustained survival and growth and to escape normal growth restraining influences [39. gliomas with MGMT promoter methylation were demonstrated to be more sensitive to the alkylating agent temozolomide (TMZ) . The IDH mutation rate in 1p/19q codeleted tumors approaches 100 % [96. 1p/19q codeletion was associated with improved overall survival but also with increased benefit of adjuvant PCV chemotherapy given after radiotherapy [18. making cells with functional enzyme less sensitive to alkylating and methylating chemotherapy than those incapable of repairing these adducts. by using genome-wide. prognostic and/or predictive information.
59]. respectively. 31]. 817 TERT and ATRX Two mutually exclusive mutations play a role in telomere maintenance in gliomas: telomerase reverse transcriptase (TERT) mutations in hot spot promoter regions C228T. but also after radiotherapy only [120. EGFR amplification mainly occurs in 1p/19q intact. CIC is a downstream component of receptor kinase (RTK) pathways (RTK–RAS–RAF–MAPK) and blocks transcription through binding to a regulatory region. but not with 1p/19q loss [58. The presence of EGFR amplification in histologically pure anaplastic oligodendrogliomas is indicative of glioblastoma . Recent data of The Cancer Genome Atlas (TCGA) consortium on lower grade (WHO grade II and III) gliomas show that IDH mutations in these gliomas are virtually mutually exclusive with homozygous deletion of CDKN2A and with amplification of EGFR [1. 131].. but about 10 % of G-CIMP positive tumors lack IDH mutation . 62. No CIC mutations were identified in tumors without 19q loss . C250T result in increased expression of telomerase. MGMT and G-CIMP status. and they are exceedingly rare in other brain tumors. PIK3CA mutations. supporting their putative roles as tumor suppressor genes . Virtually all 1p/19q codeleted tumors carry TERT mutations. 12]. Paradoxically. The small cell variant of glioblastoma has morphological similarities to anaplastic oligodendroglioma but carries EGFR amplification in 70 % of cases . highgrade astrocytomas) [121. CIC mutations occur almost invariably with IDH mutations. in particular 9p LOH and/or deletion of the CDKN2A gene (p16). Anaplastic oligodendrogliomas Anaplastic oligodendroglial tumors usually have additional genetic aberrations. FUBP1 mutations may result in MYC activation or ribosome biogenesis. 132]. Critical for normal telomere homeostasis. These include inactivating mutations in the homolog of the Drosophila capicua (CIC) and farupstream binding protein 1 (FUBP1) gene. a specific epigenetic pattern for IDH mutated and 1p/19q codeleted tumors can be identified [6. The higher rate of CIC mutations in pure oligodendrogliomas suggests CIC mutations may be related to the phenotypic characteristics of these tumors [10. The additional impact of these alterations on the outcome of patients with 1p/19q codeleted glioma is presently unclear. It is negatively regulated by RTK signaling which blocks the function of CIC through MAPK-mediated phosphorylation. IDH and TP53 mutations.Acta Neuropathol (2015) 129:809–827	Several studies have shown a high rate of MGMT promoter methylation in grade II and III gliomas. 121. These genes are located on the 19q (CIC) and 1p (FUBP1) chromosomal arms. which are instead seen in the majority of WHO grade II-III astrocytomas and secondary glioblastomas. which subsequently was demonstrated to be related to IDH mutational status and G-CIMP. Genome-wide methylation studies have shown that MGMT promoter methylation is usually part of the G-CIMP phenotype. 104. With the Illumina 450 HM beadchip. IDH wild type gliomas and 13 .e. Virtually all 1p/19q codeleted oligodendrogliomas show G-CIMP and MGMT promoter methylation. 13. considered to occur secondary to the unbalanced translocation and found to be present in ~50–70 % and 15–30 % of 1p/19q codeleted tumors. This suggests that these tumors follow a different oncogenic route from the start. This results in the degradation of CIC. 127]. these mutations are present in both 1p/19q codeleted oligodendrogliomas and in IDH wild type high-grade gliomas [5.e. have a very favorable outcome where the same TERT mutations in the absence of this codeletion or IDH mutations herald a grim prognosis (comparable to glioblastoma) . EGFR and chromosome 7 CIC and FUBP1 mutations Several other mutations have been identified in 1p/19q codeleted tumors. TERT mutations are mutually exclusive with ATRX (alpha thalassemia mental retardation syndrome X linked) mutations. 128. 54]. As discussed above. The presence of polysomy of chromosome 7 and amplification of the epidermal growth factor receptor (EGFR) gene is associated with TERT mutations and a prognosis similar to primary glioblastoma in general. In EORTC study 26951 on anaplastic oligodendroglial tumors the methylation of specific regions in the MGMT promoter was found to be the strongest predictive factor for benefit to PCV chemotherapy . These findings at least partly explain the favorable outcome of MGMT methylated tumors after not only chemotherapy or combined chemoradiotherapy.. 11. The mechanisms involved in escaping senescence in the remaining set of gliomas still await further elucidation. With combined analysis of IDH. oligodendrogliomas). it has become clear that the prognostic role of MGMT status in grade III tumors is related to IDH mutated tumors. 132]. Gliomas with TERT mutations in the presence of 1p/19q codeletion (i. whereas MGMT methylation status is predictive for benefit to alkylating chemotherapy in the absence of IDH mutations in both grade III and IV gliomas (i. and polysomies [10. these mutations are associated with the alternative lengthening of telomeres (ALT) phenotype. EGFR amplifications are virtually mutually exclusive with 1p/19q codeletion and with IDH mutations . 96. Most diffuse gliomas thus show either ATRX or TERT mutations.
clinicopathological predictions and therapeutic planning. a group of neuropathologists with ample expertise in histopathological and molecular diagnosis of CNS tumors reached consensus and formulated the International Society of Neuropathology-Haarlem consensus guidelines (ISN-Haarlem guidelines) on how molecular information could be incorporated into an updated version of the WHO classification. In a similar vein. (2) diagnoses should be ‘layered’ with histologic classification. Several studies have now demonstrated that the molecular classification corresponds better with outcome than histopathology. 109. The question then arises how to call tumors with clear discrepancy between morphology and molecular information. 122]. This is similar to many other pediatric neoplasms that resemble an adult counterpart. and predictive implications. 111]. 13 Acta Neuropathol (2015) 129:809–827 Who’s next? The distinct differences in outcome of the various molecularly defined subsets even within morphologically similar types and grades of diffuse gliomas summarized above is now ready to be translated into a refined. Based on the available data.	818 indicates the diagnosis glioblastoma. most of which will also have an IDH and a TERT mutation (Fig. Intratumoral genetic heterogeneity In a recent study sequencing the exomes of 23 low-grade gliomas and their recurrences. ‘canonical oligodendroglioma’ in adult patients could be defined as a diffuse glioma with complete 1p/19q codeletion. some young adult patients with tumors resembling oligodendroglioma. most of these are IDH mutated. these tumors have the best outcome in the group of diffuse gliomas and show increased sensitivity to adjuvant PCV chemotherapy. Adequate understanding of the consequences of such ITGH for the diagnosis and treatment of these tumors needs further study. tumors from 6 of 10 patients treated with the temozolomide (TMZ) were hypermutated and harbored driver mutations in the RB (retinoblastoma) and Akt-mTOR (mammalian target of rapamycin) pathways. better candidate markers being IDH mutation. 1p/19q status is most likely not the ultimate identifier of sensitivity to adjuvant (PCV) chemotherapy. and molecular information listed below an ‘integrated diagnosis’ (Table 1). 4b). 129]. However. including mutations considered to be driver mutations such as TP53 and ATRX. but lacking IDH mutations and 1p/19q codeletion may harbor the pediatric type of oligodendroglioma. (4) some pediatric entities should be separated from their adult counterparts . WHO grade. Of note. in 43 % of cases. These findings suggest that recurrent tumors are often seeded by cells derived from the initial tumor at a very early stage of their evolution . Pediatric oligodendroglial tumors Pediatric and some young adulthood oligodendrogliomas are different from oligodendrogliomas in adults in that they show neither IDH mutations nor combined 1p/19q codeletion and thus represent a different disease [21. 63. schemes were already proposed for a classification that is based on assessment of molecular aberrations rather than purely on histopathology . suggested or not needed for its definition. at least half of the mutations in the initial tumor were undetected at recurrence. Given that it is difficult to define entities by a lack of findings. generally without 19q deletion . suggesting that they indeed carry the adult type of oligodendroglioma. Some studies suggested shortened recurrence free survival times or poorer prognosis for oligodendroglial tumors with polysomy of 1p and 19q. disseminated oligodendroglioma-like leptomeningeal neoplasms (an entity that predominantly affects children) were reported to frequently harbor concurrent BRAF-KIAA1549 gene fusions and 1p deletion. Vice versa. but the exact importance of this finding is not yet clear [108. In the study of Johnson et al. more objective glioma classification with associated clinical. . but differ genetically and biologically [34. G-CIMP and MGMT promoter methylation. The layered diagnostic format allows to leave the ‘molecular layer’ empty and to state in the integrated diagnosis that molecular testing was not performed. 110]. thereby bearing the signature of TMZ-induced mutagenesis. Indeed. an objective definition for pediatric oligodendroglioma will likely remain a challenge until these tumors are better characterized at the molecular level. other groups reported substantial intratumoral genetic heterogeneity (ITGH) in diffuse gliomas [88. Diffuse gliomas with intact 1p/19q may have oligodendroglial phenotype. prognostic. particular (chemo) therapeutic strategies/compounds may elicit certain molecular aberrations in tumor cells. in many larger series on glioma a limited number of tumors diagnosed as low grade or anaplastic astrocytoma (5–10 %) has combined 1p/19q loss. (3) determinations should be made for each tumor entity as to whether molecular information is required. with the present status of molecular knowledge it is clear that . The rare childhood examples with IDH mutations and 1p19q codeletions almost always occur in adolescents. but have a less favorable outcome especially if no IDH mutation is present. Indeed. Salient recommendations of this group included that: (1) diagnostic entities should be defined as narrowly as possible to optimize interobserver reproducibility. 102. Moreover. Recently. In fact. Recently.
a recent study on adult diffuse low. even among expert neuropathologists. GBM-O is in fact nothing more than the grade IV variant of oligoastrocytoma and all of the caveats discussed above pertain.. molecular information: synoptic account of type of test(s) performed and the results obtained. 83]. Also. 133]. ATRX loss Layer 2. ATRX − (IHC) Example 1 and 2 are further illustrated in Figs. Further investigations are required to sort out if such ‘outliers’ justify the creation of separate diagnostic categories . evaluation of the 13 . this can be filled out initially as ‘pending’ Example 1: anaplastic oligodendroglioma (WHO grade III). Evidently. 53. Immunohistochemistry for p53 protein (strong staining of a large percentage of tumor cell nuclei) has been reported as a highly specific. Based on these conclusions. 1p/19q codeleted Example 2: low-grade astrocytoma (WHO grade II). integrated morphological and molecular definition of subgroups of diffuse gliomas will in itself already lead to a change in WHO grade in some cases (see Figs. canonical oligodendrogliomas typically being TERT mutated and TP53 wild type (Fig. PTEN deletion (FISH). GBM-O) category will largely disappear [32.and high-grade gliomas demonstrated that the integrated morphological and molecular diagnosis (incorporating information on ATRX. The suggestion that it is time to say farewell to oligoastrocytoma as a diagnosis immediately elicited case reports of tumors showing molecular features of composite oligodendroglioma and astrocytoma [46. WHO grade: reflecting natural history. 6 for examples).g. respectively IHC immunohistochemistry. FISH fluorescent in situ hybridization molecular information is required for optimal diagnosis of diffuse gliomas and that in this context for most cases an ‘empty molecular layer’ must be viewed as shortcoming. ‘not available’.Acta Neuropathol (2015) 129:809–827	819 Table 1 Layered format for integrated morphological and molecular diagnosis of CNS tumors as proposed in ISN-Haarlem guidelines  Layer 1. in case of positive ATRX staining of tumor cell nuclei and negative staining for IDH1 R132H) followed by 1p/19q analysis and subsequently by IDH sequencing . an algorithm was proposed for a stepwise diagnostic approach that could reduce the number of molecular analyses needed for a final diagnosis: initial immunohistochemistry for ATRX and IDH1 R132H mutant protein. the need for a separate mixed diffuse glioma (incl. but moderately sensitive surrogate marker for the presence of a TP53 mutation in gliomas . secondary/IDH mutated glioblastomas. 4c). IDH-mut. Several studies have now revealed that molecular and epigenetic/methylation characteristics allow reclassification of oligoastrocytomas or morphologically ambiguous diffuse gliomas into either oligodendroglioma or astrocytoma. when necessary (e. such as primary/IDH wild type glioblastomas. 1p/19q codeletion (FISH) Example 2: IDH1-R132H + (IHC). Acknowledging that ATRX mutations in IDH mutant diffuse gliomas almost never co-occur with 1p/19q codeletions and result in loss of immunohistochemical ATRX staining of tumor cell nuclei. assessment of TERT and/or TP53 mutations may be exploited for establishing such a prognostic classification. Alternatively. while molecular classification allows for more stringent definition of the vast majority of diffuse gliomas. histopathological diagnosis.. histological classification: standard microscopic diagnosis Example 1: glioblastoma with oligodendroglial component Example 2: low-grade mixed glioma Layer 3. IDH and 1p/19q codeletion) had significantly greater prognostic power for overall and progression-free survival than the original. and 1p/19q codeleted anaplastic oligodendrogliomas. Indeed. 5 and 6. e. Distinct molecular subsets can easily be carved out of the GBM-O category and placed into more clinically uniform subtypes. p53 ++ (IHC). 41.g. With the adoption of an integrated morphological and molecular diagnosis from a clinical perspective. Introducing a new. some authors suggest that it is time to say farewell to oligoastrocytoma as an entity [104. Elaborating on the suggestions in the ISN-Haarlem guidelines. ‘not considered necessary’. For molecular subtyping of diffuse gliomas several markers may be exploited (Fig. 134]. may temporarily be filled with ‘pending’ as well or with ‘not done’ (preferably with a reason. 5. the diagnosis of mixed gliomas has suffered amongst the greatest levels of discordance. 4c). there will always be single cases that do not readily fit into the scheme. Already in 1997 the finding that low-grade oligoastrocytomas generally have either 1p/19q codeletion or TP53 mutation made the authors question the presence of truly mixed gliomas . ‘insufficient tissue for testing’) Example 1: IDH1-R132H + (IHC). until molecular information becomes available. may be left out when uncertain or otherwise confusing Example 1: WHO grade III or IV (dependent on molecular information) Example 2: WHO grade II Layer 4. integrated diagnosis: integrating all ‘highlights’ from tissue-based information as described in layers 2–4.
previously diagnosed as GBM-O. Given the combined deletions of chromosome 1p (g.	820 Acta Neuropathol (2015) 129:809–827 Fig. c) and included necrosis (a) and microvascular proliferation (b). Other challenges that need to be tackled are how to put pediatric oligodendrogliomas (known to lack 1p/19q codeletions) in the taxonomy of oligodendroglial tumors and which platforms and cut-off levels are the most ideal to be used for demonstration of particular molecular aberrations. WHO grade III based on the most current recommendations exact criteria to be used for grading and the significance of such grading within molecular subgroups is warranted . this case would be reclassified as an anaplastic oligodendroglioma. whereas the PTEN deletion identified by FISH is more common in glioblastoma (f. however. WHO grade IV featured mostly cells resembling astrocytoma (a. This tumor. The expression of IDH1R132H mutant protein suggested that this represents either a secondary glioblastoma or an anaplastic oligodendroglioma. 5 Example of how ‘molecular reclassification’ may affect tumor grade. A recent study of 558 WHO grade II and III diffuse gliomas revealed that mitotic index was significantly associated with outcome in IDH wild type but not in IDH mutant tumors . 1p probe in orange and 1q probe in green) and 19q (19p probe in green and 19q probe in orange). centromere 10 probe in green and PTEN probe in orange). The different platforms for detection of the relevant 13 . Cells resembling oligodendroglioma were seen only focally (d).
It remains to be seen though if such noninvasive methods will ultimately provide information that is detailed and robust enough to replace tissue-based morphological and molecular analysis. we are now experiencing the transition towards an integrated morphological and molecular definition of diffuse gliomas. regarding how criteria for grading within the molecular groups should be adapted. In conclusion.Acta Neuropathol (2015) 129:809–827	821 Fig.g. acknowledging that our knowledge on the molecular underpinnings of cancer will continue to rapidly expand. The official updating process of the 4th edition of the WHO classification of CNS tumors has just begun and ‘the jury is still out’ with regard to what exactly the definitions for subgroups of diffuse gliomas will look like. the presence of an IDH mutation may provide an opportunity to apply specific. Importantly. since the benefits of near-total resection of diffuse gliomas have long been recognized. For instance. now that diffuse gliomas are increasingly diagnosed based on presence or absence of specific molecular aberrations. e. one can imagine that some of these tumors may be diagnosed by non.. IDH targeted treatment. after almost a century of a histopathologically based classification of CNS tumors.. with in some situations the clinical relevance of the molecular findings overriding the relevance of the histopathological diagnosis.g. WHO grade II based on strong p53 expression (c correlating well albeit imperfectly with TP53 mutation) and loss of ATRX expression (d note positive expression in nonneoplastic nuclei serving as a positive internal control) markers have their own strengths and weaknesses [45. ‘liquid biopsies’ may increasingly be used to detect particular markers in blood of glioma patients [9. tissue may continue to be obtained in most cases even if a diagnosis may be made by other means.or minimally invasive approaches. 106]. Moreover. it may 13 . for recognition of the clinically relevant 1p/19q codeletion. 66]. It can be expected that in the updated WHO classification (publication of which is scheduled early in 2016) demonstration of (complete) 1p/19q codeletion will indeed be required for the diagnosis of ‘canonical oligodendroglioma’ and that the (poorly reproducible) diagnosis of mixed gliomas will largely disappear. Also. how pediatric oligodendrogliomas should be defined. Alternatively. In the more distant future. Furthermore. assays capable of demonstrating wholearm losses are preferable. which platforms and cut-off levels should ideally be used for molecular diagnostics. 7). in order to minimize the risk of false positives from incomplete 1p and 19q losses (Fig. 6 Example where ‘molecular reclassification’ does not affect tumor grade. no matter if the diagnosis was astrocytoma or (1p/19q codeleted) oligodendroglioma [15. the therapeutic management of individual patients may be determined by their ‘cancer signature’ rather than by the traditional pathological diagnosis . This previously diagnosed oligoastrocytoma. and how to stay connected with centers/ countries where molecular testing is not available. IDH mutant gliomas) may be recognized as such by advanced magnetic resonance evaluation [28. 57]. 98]. thereby facilitating tailored treatment for individual patients. 30. Several groups already reported that molecular subgroups of gliomas (e. This integrated diagnostic approach allows for much more robust recognition of biologically different subgroups within the spectrum of diffuse gliomas. WHO grade II (a) with IDH1 R132H mutant protein (b) would now be reclassified as a diffuse astrocytoma. Such a change will bring new challenges as well.
19q13. probes for 15 loci on chromosome 1p and 8 loci on 19q are used to interrogate these chromosome arms for loss or gain [the rest of the probes (3 on 1q.1q22 (LMNA) 13.2 (PPAP2B) 04.1p36.43… 25.1p36.80 0.3 (CRB1) 19.60 0. a Example of an oligodendroglioma of which formalin-fixed. other copy number aberrations were only detected in some regions (most strikingly in area I.15q21 42.80 1. b Massively parallel sequencing (MPS) allows for much more detailed analysis of copy number aberrations in the (tumor) genome.14q24 37.19q13.11q22 33. this heterogeneity for copy number aberrations of other chromosomes cannot simply be explained by a difference in percentage of tumor cells in the different areas and must be interpreted as intratumoral genetic heterogeneity. 2 on 19p.00 1p probes 1q 19q probes 19p probes on other chromosomes (n=15) (n=3) (n=8) (n=2) (n=15) 1.19p13.2 (GTF2B) 05. In order to avoid detection of false-positive cases with partial 1p and/or 19q loss. 7 For unequivocal assessment of 1p/19q codeletion in oligodendroglial tumors.1q32.	822 Acta Neuropathol (2015) 129:809–827 a 2.40 43.1p13.1q31.32… 14.32… 24.1 (LPHN2) 02.17q21 41.1p36.1p31.13q14 35.17q11 39.19q13.00 01. Interestingly.1p21.1p36.3 (FAF1) 09.12p13 38. 15 on other chromosomes) serve as copy number references].19p13.33 (BAX) 23.19q13. see region marked by red box).2 (TGFB1) 20. detection of whole-arm losses is key.5q22 29. ideally a test is used that allows for analysis of multiple loci along each chromosome arm. while complete losses of chromosome arms 1p (indicated by the arrow) and 19q (arrowhead) were uniformly present in the different regions.8q24 31.1p32.40 1.3q29 32.1p32. As the deletions for 1p and 19q loss in the different regions are at a similar level.22 (MFN2) 11.14q22 40.2p16 30.19q13. This is an example of a low-grade oligodendroglioma of which four different regions were separately analyzed. paraffin-embedded tissue was analyzed for 1p/19q status by multiplex ligation-dependent probe amplification (MLPA).1 (TNNT2) 15. With this platform.20 b I IV I III IV II III II Fig.2 (LDLR) 26.2… 28.3 (DPYD) 0.1 (CYP2J2) 07.3p25 27.19q13.19q13.1p36.19q12 (CCNE1) 17.1p36.33… 16.33… 22.20 1.32 (TP73) 10.32 (PTAFR) 06.2 (NRAS) 03.1p12 (NOTCH2) 0.11… 21.33 (GNB1) 12.8q13 34.23 (PARK7) 08. Image b is modified from  .12 (UPK1A) 18.00 0.9q21 36. The test is performed in duplicate (hence the two lines) and demonstrates a clear loss for all 1p and 19q probes in this case (see  for technical 13 details).1p35.60 1.1p22.1p32.
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