Fig. 10.1
(a–c) A 12-year-old female with GBM. (a) Axial T1, (b) axial T1 with gadolinium, (c) axial T2. (d–f) A 15-year-old male with malignant glioma. (d) Axial T1, (e) axial T1 with gadolinium, and (f) axial T2. Both tumors demonstrate minimal contrast enhancement
Conventional MRI features of HGG are varied and can resemble LGG. These tumors are usually solitary or rarely can be multifocal. Cortical tumors usually have an irregularly enhancing rim surrounding a necrotic core or can be poorly marginated with diffuse infiltration into white matter tracts such as the corpus callosum and anterior and posterior commissures. On pre-contrast T1-weighted sequences, these tumors are iso- or hypointense. Post-contrast T1-weighted sequences typically show an irregular enhancing rim surrounding a non-enhancing area of central necrosis. Intra-tumoral hemorrhage may be present in grade IV tumors. The enhancing rim typically represents highly proliferative, invasive, and radio-resistant tumor cells. T2-weighted and FLAIR sequences usually show a heterogeneous mass with variable signal intensity surrounded by bright areas representing a zone of vasogenic edema. It is important to note that infiltrating malignant tumor cells extend far beyond the area of enhancement. Giant cell glioblastoma and gliosarcoma tend to be more demarcated than other glioblastomas. In gliomatosis cerebri at least three cerebral lobes are typically involved, and these tumors are usually bilateral and extend into deep gray matter structures. Gliomatosis may extend to involve the posterior fossa or even the spinal cord. Lesions are characteristically hyperintense on T2 and FLAIR MR imaging. Imaging of the neuraxis is indicated when there is concern for disseminated disease throughout the brain and spinal cord.
Functional Neuroimaging
Conventional MRI which gives information based largely on tumor structure and anatomic location is increasingly being supplemented by methods commonly referred to by the collective term “functional imaging” [7]. A range of functional imaging techniques for brain tumors that provide information on cellularity, tissue ultrastructure, metabolism, and vascularity are available and best acquired as part of a multimodal protocol. There has been an increased interest in using functional imaging to assist in the diagnosis, management, and determination of treatment response of HGG. Some of the commonly used functional imaging techniques and their clinical uses are:
(a)
Diffusion MRI with two different techniques: diffusion-weighted imaging (DWI) and diffusion tensor imaging (DTI). DWI uses apparent diffusion coefficient (ADC) histograms and has been valuable in the grading of gliomas (especially LGG). Low ADC values correlate with high cellularity and proliferation, most often seen in aggressive tumors. DTI has been shown to be useful in discriminating LGG from HGG and also in presurgical evaluation and radiosurgical planning of white matter tracts surrounding the tumor (DT tractography). Fractional anisotropy (FA) using DTI may prove helpful for the assessment of treatment-induced white matter changes in children during follow-up.
(b)
Perfusion MRI (pMRI) provides a surrogate for neo-angiogenesis, which is a key feature of many malignant gliomas. An indirect measurement of pMRI, the relative cerebral blood volume (rCBV), has been shown to correlate with tumor vascularity and HGGs tend to have higher rCBV values than low-grade tumors.
(c)
Functional MRI (fMRI) is a commonly used technique for identifying the eloquent gray matter in cortical HGGs prior to surgery. This approach may be limited to older children and adolescents.
(d)
Magnetic resonance spectroscopy (MRS) measures the chemical composition of tissue and provides semiquantitative information about major cellular metabolites. A common pattern in brain tumors is a decrease in N-acetylaspartate (NAA), a neuron-specific marker, a decrease in creatine (Cr), and an increase in choline (Cho), lactate (Lac), and lipids (L). The concentration of Cho is a reflection of the turnover of cell membranes (due to accelerated synthesis and destruction) and is more elevated in regions with a high neoplastic activity. Lactate is the end product of nonoxidative glycolysis and a marker of hypoxia and possibly necrosis in tumor tissue. Tumor hypoxia is now recognized as a major promoter of tumor angiogenesis and invasion. MRS may be used in distinguishing tumor from non-tumor masses (abscess, infections, and metabolic disorders) or from radiation necrosis and in characterizing tumor grade (high grade vs. low grade). Multivoxel MRS imaging (MRSI) has the advantage of improved characterization of heterogeneous tumors but is technically more demanding, may be less reproducible, and is not widely available except in tertiary or quaternary treatment centers.
(e)
Positron emission tomography using fluorodeoxyglucose or F18 (FDG-PET) is another noninvasive molecular imaging modality that aids in the diagnosis of malignant tumors and may distinguish active tumor from radionecrosis. Besides F18, other radioisotopes, such as C11, are under the increasing use in adults and children.
Functional imaging techniques are becoming more widely available in clinical practice and have an important role in aiding the clinical management of children with HGG. They are increasingly used preoperatively to differentiate between tumor and non-tumor pathology (MRS, pMRI), high- and low-grade tumors (MRS, DWI), and primary HGG and metastatic lesions to the brain (MRS). These adjunct studies may also improve diagnostic accuracy of a biopsy by determining the most abnormal region of the tumor (MRS, DWI) and to define tumor margins for both surgical resection and radiation fields (fMRI, DTI). In the intraoperative and postoperative periods, functional imaging is most commonly used to identify eloquent areas of the brain especially in cortical tumors (fMRI, DTI) and for treatment planning for surgery, stereotactic radiosurgery, and radiation therapy (DT tractography). Monitoring for therapy-induced white matter changes and related toxicities (DTI), radiation necrosis versus residual/recurrent tumor, (MRS, DWI), and especially treatment response monitoring, including pseudoresponse (PsR) and pseudoprogression (PsP), is enhanced by these MRI- or PET-related imaging modalities [7]. The Response Assessment in Neuro-Oncology (RANO) criteria uses conventional MRI to assess treatment response of patients with gliomas (Table 10.1) [8]. Pediatric RANO (RAPNO) criteria are under development [9].
Table 10.1
Response Assessment in Neuro-Oncology (RANO)
First progression | Definition |
|---|---|
Progressive disease <12 weeks after completion of chemoRT | • Progression can only be defined using diagnostic imaging if there is new enhancement outside of the radiation field (beyond the high-dose region or 80 % isodose line) or if there is unequivocal evidence of viable tumor on histopathologic sampling (e.g., solid tumor areas [i.e., > 70 % tumor cell nuclei in areas], high or progressive increase in MIB-1 proliferation index compared with prior biopsy, or evidence for histologic progression or increased anaplasia in tumor) |
• Given the difficulty of differentiating true progression from pseudoprogression, clinical decline alone, in the absence of radiographic or histologic confirmation of progression, will not be sufficient for definition of progressive disease in the first 12 weeks after completion of concurrent chemoRT | |
Progressive disease >or equal to 12 weeks after completion of chemoRT | • New contrast-enhancing lesion outside of radiation field on decreasing, stable, or increasing doses of corticosteroids |
• Increase by >or equal to 25 % in the sum of the products of perpendicular diameters between the first post-radiotherapy scan, or a subsequent scan with smaller tumor size, and the scan at 12 weeks or later on stable or increasing doses of corticosteroids | |
• Clinical deterioration not attributable to concurrent medication or comorbid conditions is sufficient to declare progression on current treatment but not for entry onto a clinical trial for recurrence | |
• For patients receiving antiangiogenic therapy, a significant increase in T2/FLAIR non-enhancing lesion may also be considered progressive disease. The increased T2/FLAIR must have occurred with the patient on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy and not been a result of comorbid events (e.g., effects of radiation therapy, demyelination, ischemic injury, infection, seizures, postoperative changes, or other treatment effects) |
Pathology
Pediatric HGGs are less common than many other brain tumors occurring in infancy, childhood, and adolescence. Based upon the CCG-945 study and others, central neuropathology review can often result in a reclassification of HGG to an LGG or other histopathological entity [10–12].
Morphology
Macroscopically HGGs, particularly GBM, tend to have a heterogeneous appearance, forming obvious masses, often containing areas of hemorrhage and/or necrosis. They typically have a mottled tan, red, and brown coloration with alternating firm and softened zones. Gliosarcomas may be quite firm in consistency, due to the presence of sarcomatous components.
Histology
Microscopically, HGGs are distinguished from LGG by the presence of four important histologic criteria: nuclear atypia, mitotic activity (WHO grades III and IV), necrosis (grade IV), and/or microvascular proliferation (grade IV). Tumor grade is established based on the area of the greatest anaplasia. AAs (grade III) are hypercellular astrocytomas that in addition to nuclear atypia have increased mitotic activity. Vascular proliferation and necrosis are absent. Cells with large pleiomorphic or multiple nuclei may be present. GBM (grade IV), in addition to findings listed for AA, display necrosis (typically pseudopalisading necrosis) or microvascular proliferation. Atypical mitotic figures may be present. Gliosarcoma (grade IV) is a biphasic high-grade glioma with both malignant astrocytic (GBM) and sarcomatous components. The sarcomatous portion is frequently fibrosarcoma, though it may include malignant fibrous histiocytoma, chondrosarcoma, osteosarcoma, leiomyosarcoma, rhabdomyosarcoma, or even liposarcoma. Trichrome and reticulin stains are frequently helpful. Gliomatosis cerebri (GC, grade III) is most frequently astrocytic tumors, though infrequently may contain oligodendroglial elements. Nuclei tend to be elongated and hyperchromatic, and pleiomorphic forms are not uncommon. Secondary structures are frequently present. Mitotic activity is variable. Areas resembling GBM may be present in some cases.
Immunohistochemistry
Expression of the intermediate filament glial fibrillary acidic protein (GFAP) reflects the glial origin of these tumors and sometimes the extent of cytoplasmic development and is present in the intervening fibrillary matrix of these lesions. S100 often shows diffuse nuclear and cytoplasmic positivity, and another intermediate filament vimentin is similarly positive. The proliferation marker Ki–67 (or MIB–1) is variably positive, reflecting the low (grade II) to brisk (grades III and IV) proliferative activity of these lesions, respectively. Neurofilament staining of intra-tumoral neuritic processes provides evidence of the infiltrative pattern of these neoplasms. Pancytokeratin is often positive at least focally in higher grade lesions, showing cross-reactivity with glial intermediate filaments. More specific cytokeratin antibodies are usually negative. Sarcomatous portions of gliosarcoma, though not positive for GFAP, are consistently vimentin positive and tend to take on the staining properties of the particular sarcoma element present (muscle, fat, cartilage, etc.). Gliomatosis is variably positive for GFAP and S100 expression [1]. It may sometimes be a challenge for the neuropathologist to distinguish pediatric HGG from supratentorial primitive neuroectodermal tumors (sPNET), mandating central review for patients entered on a clinical trial.
Molecular Biology
In adults, GBM is typically classified as either primary or secondary based on clinical and biological features. The vast majority of GBM (approximately 90 %) develop rapidly de novo in middle-aged or elderly patients, without clinical or histological evidence of a less malignant precursor lesion (primary glioblastomas). Secondary GBM progress stepwise from low-grade diffuse astrocytoma (grade II) or anaplastic astrocytoma (grade III). Histologically, primary and secondary glioblastomas may be indistinguishable, but they differ in their genetic and epigenetic profiles. Isocitrate dehydrogenase IDH1 mutations are classically seen only in secondary glioblastoma [13] and associated with a hypermethylation phenotype [14].
Based on the histological similarity and recurrent genomic aberrations, pediatric GBM (pGBM) were historically thought to more closely resemble the secondary adult GBM (aGBM). PDGFRA mutations and focal amplifications are often present. Paugh et al. discovered somatic activating mutations in 14.3 % of pediatric non-brainstem HGG [15]. In another study using FISH, PDGFRA amplification was noted in 29.3 % pediatric and 20.9 % adult HGG, but amplification was not prognostic in children [16]. EGFR amplification and EGFRvIII and PTEN mutations are less common in pGBM than aGBM [17, 18]. MGMT methylation as assessed by MGMT overexpression [19, 20] or methylation-specific PCR assays [21] has been correlated with improved EFS but has not yet been validated as either an independent predictive or prognostic marker for pediatric HGG when compared to adult GBM [22].
Rapid advances in the field of genomics (exome and whole genome sequencing studies) and international collaborative efforts (providing access to a large number of pediatric tumors) have led to greater understanding of HGG in children and adults. It is now clear that in the majority of cases described to date, pGBM is biologically distinct from aGBM [23, 24]. The majority of pediatric GBM arise de novo and have characteristic clinical, genetic, and epigenetic features. Recurrent somatic driver mutations in the H3F3A gene, which encodes the replication-independent histone 3 variant (H3.3), lead to amino acid substitutions at key residues, namely lysine (K) 27 (K27M) and glycine 34 (G34R/V), identify distinct subgroups of pediatric GBM, and are seen in 30–45 % of cases [23–25]. H3.3 K27M mutations are more frequent in subcortical regions such as the thalamus and brainstem, whereas the H3.3 G34R/V lesions tend to be in hemispheric locations [26]. IDH1/2 mutations are very rare in childhood GBM (<10 %) [27]. Moreover mutations in H3F3A and IDH1 are mutually exclusive anatomically and across specific age groups: in children (K27M mutations), adolescents (G34R/V mutations), and young adult patients (IDH1 mutations) locations [26].
Whole exome sequencing studies of pediatric GBM identified mutations in α-thalassemia/mental retardation syndrome X-linked (ATRX) and death domain-associated protein (DAXX) genes in 45 % of cases [6]. These genes encode two subunits of a chromatin-remodeling complex required for H3.3 incorporation in pericentric heterochromatin and telomeres. ATRX and/or DAXX mutations have a strong association with TP53 mutations and alternative lengthening of telomeres (ALT) [23, 24]. IDH1/2 mutations lead to overproduction of 2-hydroxyglutarate (2-HG) which inhibits demethylases required for modification of histones and DNA and may thereby block differentiation and tumorigenesis. The H3F3A mutations (K27M leading to transcriptional derepression and G34R leading to altered gene expression, such as of MYCN; [28] are hypothesized to induce epigenetic reprogramming leading to tumorigenesis [29], although the exact mechanisms remain to be fully elucidated. Very recently, mutations were identified in SETD2, a H3K36 trimethyltransferase, in pediatric HGGs localized to the cerebral hemispheres. SETD2 mutations are specific to HGG in children (15 %) and adults (8 %). In HGG these mutations are mutually exclusive with H3F3A mutations but sometimes overlap with IDH1 mutations [30].
Of interest, activating BRAF mutations such as BRAF V600E are also present in 15–20 % of pediatric HGG (reviewed in [31]). The genetic differences of HGGs across the age spectrum are summarized in Table 10.2 [32].
Table 10.2
Integrated genomic classification of GBM
Subgroup | K27 | G34 | RTKI | IDH | Mesenchymal | RTKII (classic) |
|---|---|---|---|---|---|---|
Clinical features | ||||||
Age distribution in years (median, range) | 10.5 (5–23) child/adolescent | 18 (9–42) adolescent/young adult | 36 (8–74) adolescent/young adult, with another peak in adult/elderly | 40 (13–71) young adult/adult | 47 (2–85) adult, with a smaller peak in childhood | 58 (36–81) adult/elderly |
Tumor location | Midline/deep | Cortical | Cortical | Cortical | Cortical | Cortical |
- ST 70–80 % (thalamus, basal ganglia) | T > P > O | F > P > T | F>> > T > P | F = P > T | F = T > P | |
- IT 60 % (brainstem, spinal cord) | ||||||
Gender ratio (M/F) | ~ 1:1 | ~ 1:1 | ~ 1:1 | 1:1.7 | ~ 1:1 | 1.46:1 |
Histology | GBM | GBM | GBM | GBM | GBM | GBM |
Survival | Very poor | Poor | Poor/fair | <10 % long-term survivors | <10 % long-term survivors | <10 % long-term survivors |
Genomic features | ||||||
Mutations/cytogenetics | H3F3A (K27M) | H3F3A (G34R/V) | PDGFRA (ampl/mut) | IDH1(R132H) | − | EGFR(ampl) |
CDKN2A/B (del) | Copy number variations (low) | Chr 7 (gain) | ||||
Chr 10q (loss) | ||||||
CDKN2A(del) | ||||||
TP53 | +++ | +++ | − | +++ | + | ++ |
ATRX | ++ | +++ | − | ++ | − | − |
DAXX | + | +++ | − | − | − | − |
ALT | NR | +++ | NR | NR | NR | NR |
SETD2 | − | − | + | + | ||
Gene expression signature | Proneural | Mixed | Proneural | Proneural | Mesenchymal | Classical |
Immunohistochemistry (FOXG1/OLIG2) | FOXG1 −/OLIG2+ | FOXG1+/OLIG2 − | FOXG1+/OLIG2+ | IDH1 R132H | FOXG1+/OLIG2+ | FOXG1+/OLIG2+ |
Epigenetic features | ||||||
DNA methylation | CHOP+ | G-CIMP+ | ||||
Therapy
Treatment of HGGs requires a multidisciplinary approach and involves surgery, radiation therapy (RT), and chemotherapy.
Surgery
Patients presenting with signs of increased ICP may require emergent neurosurgical intervention to relieve obstructive hydrocephalus with several alternatives in addition to tumor debulking: placement of external ventricular drain (EVD) or a ventriculoperitoneal shunt (VP shunt) or by means of a third ventriculostomy, and the latter via the use of a neurosurgical endoscope. The use of preoperative corticosteroids, usually dexamethasone, can significantly decrease peri-tumoral edema, thus decreasing focal symptoms and often eliminating the need for emergency surgery. Tumor resection is safer when performed 1–2 days following reduction in edema and ICP by these means. Seizures are treated with anticonvulsants. Prophylactic anticonvulsants in patients who do not present with seizures are not recommended, and antiseizure medications are usually tapered and discontinued in the postoperative period.
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