Search

Recent advances in molecular pathology have reshaped the practice of brain tumor diagnostics. The classification of gliomas has been restructured with the discovery of isocitrate dehydrogenase (IDH) 1/2 mutations in the vast majority of lower grade infiltrating gliomas and secondary glioblastomas (GBM), with IDH-mutant astrocytomas further characterized by TP53 and ATRX mutations. Whole-arm 1p/19q codeletion in conjunction with IDH mutations now define oligodendrogliomas, which are also enriched for CIC, FUBP1, PI3K, NOTCH1, and TERT-p mutations. IDH-wild-type (wt) infiltrating astrocytomas are mostly primary GBMs and are characterized by EGFR, PTEN, TP53, NF1, RB1, PDGFRA, and CDKN2A/B alterations, TERT-p mutations, and characteristic copy number alterations including gains of chromosome 7 and losses of 10. Other clinically and genetically distinct infiltrating astrocytomas include the aggressive H3K27M-mutant midline gliomas, and smaller subsets that occur in the setting of NF1 or have BRAF V600E mutations. Low-grade pediatric gliomas are both genetically and biologically distinct from their adult counterparts and often harbor a single driver event often involving BRAF, FGFR1, or MYB/MYBL1 genes. Large scale genomic and epigenomic analyses have identified distinct subgroups of ependymomas tightly linked to tumor location and clinical behavior. The diagnosis of embryonal neoplasms also integrates molecular testing: (I) 4 molecularly defined, biologically distinct subtypes of medulloblastomas are now recognized; (II) 3 histologic entities have now been reclassified under a diagnosis of "embryonal tumor with multilayered rosettes (ETMR), C19MC-altered"; and (III) atypical teratoid/rhabdoid tumors (AT/RT) now require SMARCB1 (INI1) or SMARCA4 (BRG1) alterations for their diagnosis. We discuss the practical use of contemporary biomarkers for an integrative diagnosis of central nervous system neoplasia.

Gliomas are a large and diverse group of primary brain tumors that include those that are diffusely infiltrative and others that are well-circumscribed and low grade. Diffuse gliomas are currently classified by the World Health Organization as astrocytomas, oligodendrogliomas, or oligoastrocytomas and range in grade from II to IV. Glioblastoma (GBM), World Health Organization grade IV, is the highest grade and most common form of astrocytoma. In the past, the diagnosis of gliomas was almost exclusively based on histopathologic features. More recently, improved understanding of molecular genetic underpinnings has led to ancillary molecular studies becoming standard for classification, prognostication, and predicting therapy response. Isocitrate dehydrogenase (IDH) mutations are frequent in grade II and III infiltrating gliomas and secondary GBMs. Infiltrating astrocytomas and secondary GBMs are characterized by IDH, TP53, and ATRX mutations, whereas oligodendrogliomas demonstrate 1p/19q codeletion and mutations in IDH, CIC, FUBP1, and the telomerase reverse transcriptase (TERT) promoter. Primary GBMs typically lack IDH mutations and are instead characterized by EGFR, PTEN, TP53, PDGFRA, NF1, and CDKN2A/B alterations and TERT promoter mutations. Pediatric GBMs differ from those in adults and frequently have mutations in H3F3A, ATRX, and DAXX, but not IDH. In contrast, circumscribed, low-grade gliomas of childhood, such as pilocytic astrocytoma, pleomorphic xanthoastrocytoma, and ganglioglioma, often harbor mutations or activating gene rearrangements in BRAF. Neuropathologic assessment of gliomas increasingly relies on ancillary testing of molecular alterations for proper classification and patient management.

Recent advances in neuroimaging techniques, particularly in magnetic resonance imaging, have led to substantially improved spatial anatomic resolution such that subtle or small central nervous system lesions, which could go undetected on gross examination of brain sections, are now readily identified on imaging. Although neuroimaging is generally considered the surrogate of gross neuropathology, it is still not a substitute for tissue diagnosis. Rather, it can be a valuable tool for the surgical pathologist in the process of formulating a differential diagnosis based on location and imaging features, as well as in identifying radiologic/pathologic discordance, such as the possible undersampling of a heterogenous glioma, which could lead to underestimation of the tumor grade. The following review focuses on the application of neuroimaging techniques, mainly magnetic resonance imaging, to the histologic diagnosis of central nervous system lesions, and the correlation of imaging features of infiltrative gliomas with histologic findings pertinent to tumor grading. The use of advanced functional magnetic resonance methods, specifically diffusion-weighted imaging, perfusion-weighted imaging, and magnetic resonance spectroscopy is also discussed, as well as the common pitfalls in imaging interpretation.

Glioblastoma multiforme (GBM) is the highest-grade infiltrative astrocytoma and also the most common. It is generally associated with a dismal prognosis (mean survival 11 months), yet individual patient survivals vary. Histologic parameters have had limited value in predicting survival among patients with GBM. The current view of GBM as a histopathologic entity consisting of several genetic subtypes raises the possibility that molecular alterations could be predictive of survival. Common genetic alterations in GBM include gene amplification of epidermal growth factor receptor (EGFR), mutations in the tumor suppressors TP53 and PTEN, and genetic losses on chromosome 10. Less common in GBMs is the combined loss of chromosomes 1p and 19q-a combination that has proven prognostically favorable in oligodendrogliomas. A recent article on prognostic factors in a series of 97 GBMs by Schmidt et al. finds that both TP53 mutations and young patient age at presentation are independent factors associated with a long survival. Loss of heterozygosity (LOH) of chromosome 10q was predictive of a poor outcome. Perhaps most intriguing, the finding of combined LOH of 1p and 19q, which was noted in only five GBMs, was associated with a significantly longer survival. Thus, combined losses of 1p and 19 may be associated with a favorable prognosis in a wider range of infiltrative gliomas that includes GBM. While these findings will be debated and need to be confirmed, it is clear that genotyping of infiltrative gliomas will be an important component of neuro-oncology in the future. Not only will genetic alterations offer prognostication, but they will also serve as targets for directed therapies. Treatments directed against tumors with EGFR amplification, TP53, mutations and PTEN mutations are being developed and tested in clinical trials. It remains to be seen if GBMs with 1p and 19q losses are chemosensitive in the same manner as oligodendrogliomas.

Infiltrative astrocytic neoplasms are the most common malignancies of the central nervous system. They remain clinically problematic because of their involvement of brain structures critical to proper cognitive, behavioral, and motor function; their widely invasive properties, which make them difficult to resect totally; and their nearly inevitable biologic progression in spite of adjuvant therapy. Glioblastoma multiforme (GBM, World Health Organization grade IV), the most malignant form of infiltrating astrocytoma, can present as a high-grade lesion from the outset (so-called de novo GBM) or can evolve from a lower grade precursor lesion (secondary GBM). Molecular genetic investigations suggest that GBM is best regarded as a clinicopathologic entity composed of multiple molecular genetic subsets. Molecular alterations associated with progression to GBM and that define genetic subsets include epidermal growth factor receptor amplifications, p53 mutations, retinoblastoma pathway alterations [most commonly, p16(CDKN2A) losses], and chromosome 10 alterations, including PTEN mutations. Despite the wide range of genetic events that ultimately lead to GBM, the vascular changes that evolve are remarkably similar. Microvascular hyperplasia is spatially and temporally associated with pseudopalisading necrosis in GBM and is believed to be driven by hypoxia-induced expression of proangiogenic cytokines such vascular endothelial growth factor. In addition, genetic alterations in GBM are thought to contribute directly or indirectly to angiogenic dysregulation. Both p53 mutations and genetic losses on chromosome 10 may tip the balance toward an angiogenic phenotype through upregulation of proangiogenic factors and/or downregulation of angiogenesis inhibitors. Understanding genetic events and their relation to angiogenic regulation in astrocytic neoplasms may eventually lead to therapies that are specifically directed at molecularly defined subsets of these diseases.

Grading schemes for meningiomas have traditionally designated tumors as "meningioma," "atypical meningioma," or "anaplastic (malignant) meningioma," depending upon the presence of histopathologic features thought to indicate aggressive behavior. In the past, most systems have considered brain invasion by tumor as the best evidence of malignancy. Perry et al. have recently investigated the significance brain invasion as a prognostic feature in meningiomas. The authors studied a series of 116 patients who had been diagnosed previously with "malignant meningioma" due to the presence of brain invasion, histologic anaplasia, or metastasis. On the basis of a multivariate analysis of histopathologic features and their relationship to tumor recurrence and patient survival, the authors concluded that brain invasion should be considered one of the diagnostic features of atypical meningioma. Accordingly, the diagnosis of malignant meningioma should be reserved for those tumors that are frankly anaplastic and/or contain (> = 20 mitoses per 10 high-power fields (HPF). Due in large part to the strength of evidence in this study, the World Health Organization (WHO) has adopted a grading scheme for meningiomas that incorporates many of the authors' proposals. New diagnostic criteria will result in improved reproducibility with fewer diagnoses of malignant meningioma (WHO grade III).