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Introduction to Supratentorial Adult Brain Neoplasms

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1 Introduction to Supratentorial Adult Brain Neoplasms
Jay J. Pillai, M.D. Director of Functional MRI Associate Professor Neuroradiology Division The Russell H. Morgan Department of Radiology and Radiological Science Johns Hopkins Univ. School of Medicine

2 General classification
Primary Intra-axial Tumors: Astrocytic Neuroepithelial tumors Diffuse Infiltrative: Fibrillary, anaplastic, GBM, Gliomatosis cerebri Localized: Pilocytic, PXA, SGCA Non-astrocytic Neuroepithelial tumors Oligodendroglioma Ependymal tumors (ependymoma II, subepend I), choroid plexus lesions Neuronal / mixed Ganglioglioma (gangliocytoma) DIG, DNET, Central neurocytoma Embryonal tumors: PNET, medulloblastoma Lymphoma Primary Extra-axial tumors: Tumors of the meninges Tumors of meningothelial cells: meningioma Mesenchymal non-meningothelial tumors: sarcomas, MFH, lipomas, hemangioma Primary melanocytic tumors: melanocytoma, melanoma Neurogenic tumors Neurofibromas, schwannomas Metastases We only will discuss intra-axial tumors—both glial and non-glial and exclude extra-axial tumors, metastases and sellar/suprasellar tumors due to time constraints

3 Gliomas Astrocytomas Oligodendrogliomas Ependymomas
Choroid plexus tumors (mixed gliomas – oligoastrocytomas)

4 Astrocytomas Cell of origin: Astrocytes Most common CNS malignancy
75% of the neuroepithelial tumors Grades: Low grade: Gr I & II (circumscribed vs. diffuse) High grade: Gr III & IV (anaplastic vs glioblastoma)

5 Astrocytic tumors Pilocytic Astrocytoma – low grade (WHO Gr I)
Cyst with a mural nodule – cerebellar (juvenile), hypothalamic-chiasmatic, thalamic Diffuse / Fibrillary Astrocytoma – (WHO Gr II) 1/3 FL, 1/3 TL; gemistocytic astro more aggressive than fibrillary, 80% conv to GB, excl supratent Anaplastic Astrocytoma (Gr III)--may prog to GB in 2yr Glioblastoma (Multiforme) (Gr IV)--m.c. astro (50-60% of astro, 15% of ic tumors) Subependymal Giant Cell Astrocytoma (Gr I)--TS Pleomorphic xanthoastrocytoma (Gr II) Gliomatosis cerebri

6 WHO Grade II Astrocytoma Diffuse / Low grade astrocytoma
Focal or diffuse enhancing white matter mass Supratentorial – commonly frontal or temporal in location, rare in occipital lobe Infratentorial – typically brainstem glioma Appear circumscribed on imaging (not at surgery) Low attenuation on CT wo enhanc Calcification and necrosis are rare May mimic subacute infarct on CT, but MRI is definitive

7 High Grade Gliomas Highly vascular tumors with areas of necrosis and breakdown of the blood-brain barrier Significantly worse prognosis Tendency for recurrence TYPES: Anaplastic Astrocytoma (WHO Grade III) Glioblastoma [multiforme] (WHO Grade IV)

8 Anaplastic Astrocytoma
WHO grade III Astrocytoma Infiltrating hemispheric mass with variable enhancement, commonly affecting white matter and located in the frontal and temporal lobes. Brainstem or thalamic locations in children Ill-defined margins with edema and mass effect. Calcification, hemorrhage and necrosis are rare. Enhancement – patchy or focal, sometimes none.

9 Glioblastoma 15-20% of all tumors – ~50% of astrocytomas
Frontal > temporal > parietal lobes Primary GBM or secondary (dedifferentiated) GBM—prim w worse prognosis, sec in younger pts w longer clin course Imaging : Typically is a mass that shows a thick irregular enhancing rim around a necrotic core with moderate vasogenic edema Butterfly configuration (extending across the CC) Multifocal or Multicentric (even wo NF1) Tendency to CSF spread/drop mets/subarachnoid & subependymal seeding Rare variant—gliosarcoma (poor prog, all supratent)

10 Glioblastoma 15-20% of all tumors – ~50% of astrocytomas
Frontal > temporal > parietal lobes Primary GBM or secondary (dedifferentiated) GBM—prim w worse prognosis, sec in younger pts w longer clin course Imaging : Typically is a mass that shows a thick irregular enhancing rim around a necrotic core with moderate vasogenic edema Butterfly configuration (extending across the CC) Multifocal or Multicentric (even wo NF1) Tendency to CSF spread/drop mets/subarachnoid & subependymal seeding Rare variant—gliosarcoma (poor prog, all supratent)

11 Value of perfusion imaging in evaluation of biological behavior of gliomas even when findings are not consistent with initial histopathologic and standard MR imaging Law M, Oh S, Johnson G, Babb JS, Zagzag D, Golfinos J, Kelly PJ. Perfusion magnetic resonance imaging predicts patient outcome as an adjunct to histopathology: a second reference standard in the surgical and nonsurgical treatment of low-grade gliomas. Neurosurgery Jun;58(6): ; discussion Danchaivijitr N, Waldman AD, Tozer DJ, Benton CE, Brasil Caseiras G, Tofts PS, Rees JH, Jäger HR. Low-grade gliomas: do changes in rCBV measurements at longitudinal perfusion-weighted MR imaging predict malignant transformation? Radiology Apr;247(1):170-8. PURPOSE: To prospectively perform longitudinal magnetic resonance (MR) perfusion imaging of conservatively treated low-grade gliomas to determine whether relative cerebral blood volume (rCBV) changes precede malignant transformation as defined by conventional MR imaging and clinical criteria. MATERIALS AND METHODS: All patients gave written informed consent for this institutional ethics committee-approved study. Thirteen patients (seven men, six women; age range, years) with biopsy-proved low-grade glioma treated only with antiepileptic drugs were examined longitudinally with susceptibility-weighted perfusion, T2-weighted, fluid-attenuated inversion recovery, and high-dose contrast material-enhanced T1-weighted MR imaging at 6-month intervals to date or until malignant transformation was diagnosed. Student t tests were used to determine differences in rCBV values between "transformers" and "nontransformers" at defined time points throughout study follow-up. RESULTS: Seven patients showed progression to high-grade tumors between 6 and 36 months (mean, 22.3 months), and disease in six patients remained stable over a period of months (mean, 23 months). Transformers had a slightly (but not statistically significantly) higher group mean rCBV than nontransformers at the point of study entry (1.93 vs 1.31). In nontransformers, the rCBV remained relatively stable and increased to only 1.52 over a mean follow-up of 23 months. In contrast, transformers showed a continuous increase in rCBV up to the point of transformation, when contrast enhancement became apparent on T1-weighted images. The group mean rCBV was 5.36 at transformation but also showed a significant increase from the initial study at 12 months (3.14, P = .022) and at 6 months (3.65, P = .049) before transformation. Rates of rCBV change between two successive time points were also significantly higher in transformers than in nontransformers. CONCLUSION: In transforming low-grade glioma, susceptibility-weighted MR perfusion imaging can demonstrate significant increases in rCBV up to 12 months before contrast enhancement is apparent on T1-weighted MR images. BJECTIVE: To determine whether relative cerebral blood volume (rCBV) can predict patient outcome, specifically tumor progression, in low-grade gliomas (LGGs) and thus provide a second reference standard in the surgical and postsurgical management of LGGs. METHODS: Thirty-five patients with histologically diagnosed LGGs (21 low-grade astrocytomas and 14 low-grade oligodendrogliomas and low-grade mixed oligoastrocytomas) were studied with dynamic susceptibility contrast-enhanced perfusion magnetic resonance imaging. Wilcoxon tests were used to compare patients in different response categories (complete response, stable, progressive, death) with respect to baseline rCBV. Log-rank tests were used to evaluate the association of rCBV with survival and time to progression. Kaplan-Meier time-to-progression curves were generated. Tumor volumes and CBV measurements were obtained at the initial examination and again at follow-up to determine the association of rCBV with tumor volume progression. RESULTS: Wilcoxon tests showed patients manifesting an adverse event (either death or progression) had significantly higher rCBV (P = 0.003) than did patients without adverse events (complete response or stable disease). Log-rank tests showed that rCBV exhibited a significant negative association with disease-free survival (P = ), such that low rCBV values were associated with longer time to progression. Kaplan-Meier curves demonstrated that lesions with rCBV less than 1.75 (n = 16) had a median time to progression of /- 433 days, and lesions with rCBV more than 1.75 (n = 19) had a median time to progression of 245 +/- 62 days (P < 0.005). Lesions with low baseline rCBV (< 1.75) demonstrated stable tumor volumes when followed up over time, and lesions with high baseline rCBV (> 1.75) demonstrated progressively increasing tumor volumes over time. CONCLUSION: Dynamic susceptibility contrast-enhanced perfusion magnetic resonance imaging may be used to identify LGGs that are either high-grade gliomas, misdiagnosed because of sampling error at pathological examination or that have undergone angiogenesis in the progression toward malignant transformation. This suggests that rCBV measurements may be used as a second reference standard to determine the surgical management/risk-benefit equation and postsurgical adjuvant therapy for LGGs.

12 Treatment of GBM Standard treatment: complete resection of CE tumor followed by chemoradiation (External Beam RT + temozolomide) --direct placement of chemotherapeutic agents into resection cavity (carmustine[BCNU] wafers—Gliadel ) or convection-enhanced delivery –intracerebral drug delivery via small intracranial catheters w pressure gradient to control infusion rates Newer experimental therapies: 1) Therapy targeting cancer stem cells 2) Antiangiogenic therapy (bevacizumab [targets VEGF-A], cediranib [targets VEGFR1-3, PDGFR-beta, c-Kit proto-oncogene], etc.) 3) Immunotherapy (IL4-P38KDEL, IL13-PE8QQR)—interleukins; natural toxins can be conjugated to drugs that bind to receptors overexpressed by certain tumor cells Lima FR, Kahn SA, Soletti RC, et al. Glioblastoma: Therapeutic challenges, what lies ahead. Biochim Biophys Acta 2012; 1826 (12):

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14 Pseudoeffects: Pseudoprogression & Pseudoresponse
There is a lot of interest and some recent literature on the subject of pseudo-effects following treatment of glioblastoma. In practice, often it comes down to obtaining a follow up MR to see how findings change longitudinally. RANO criteria has replaced older McDonald (2D meas—sum of products of perpend diam/25% incr CE for prog) and RECIST (1 D meas) criteria for assessment of treatment response. New RECIST + F criteria (considering maximum diameter of both CE and T2/FLAIR regions—takes into account pseudoresponse just as RANO criteria do) also proposed, but currently RANO criteria are most widely accepted.

15 Pseudoprogression in Glioblastomas Quant and Wen. RANO
Pseudoprogression in Glioblastomas Quant and Wen. RANO. Curr Oncol Rep (2011) 13:50–56 Pseudo-progression: An increase in contrast enhancement and/or edema on MRI without true tumor progression. May occur post XRT alone, but enhanced by the addition of temozolomide to radiotherapy (chemoradiation), particularly in GBM patients with methylated MGMT. Can occur in 40-50% pts on chemoradiation In half of patients, the increased CE w/wo increased edema eventually subsides despite continuing temozolomide, suggesting that the CE reflects transiently increased permeability of the tumor vasculature from irradiation. In some cases may progress to actual radiation necrosis, but if patient is asymptomatic, then may continue treatment. Critical to be aware to avoid premature discontinuation of an effective therapy based on apparently worsening MRI findings alone. MGMT= O6-methylguanine-DNA methyltransferase gene on chromosome 10 q26 encodes a DNA repair enzyme that can abrogate the effects of alkylating chemotherapy such as temozolomide. If the MGMT gene is active, the DNA damage in tumor cells is quickly repaired. However, if the gene is inactivated due to methylation of its promoter region, then a better response to chemotherapy is seen.

16 Pseudoresponse in GBMs Quant and Wen. RANO
Pseudoresponse in GBMs Quant and Wen. RANO. Curr Oncol Rep (2011) 13:50–56 Pseudo-response: decrease in enhancement on MRI without a true anti-tumor effect High permeability of HGG vasculature responsible for CE and peritumoral edema. Anti-angiogenic agents targeting VEGF pathway, such as bevacizumab or cediranib, significantly reduce vascular permeability >>>high apparent radiologic response rates of 25% to 60% in GBM. Bevacizumab (Avastin ®), is a monoclonal antibody targeting VEGF. Partly due to normalization of tumor vessel permeability resulting in decreased CE, not necessarily true anti-glioma effect. Progression of disease while on VEGF inhibitors results in more treatment-refractory invasive nature of GBM w much worse prog—frequently seen expanding T2/FLAIR abnormality despite reduced CE, with rebound phenomenon wrt edema after discontin of Avastin ( similar to corticosteroids). Risks of Avastin:Toxicities: neutropenia and thrombocytopenia. Intracranial hemorrhage can be a problem and a contra-indication (as also h/o GI bleeds). Overall, there was a 16% incidence of adverse effects, including thromboembolism, hypertension, wound breakdown, GI perforation, partial small bowel obstruction, seizure, and ischemic stroke.

17 Agreement among the 4 methods was high (kappa statistic >0
Agreement among the 4 methods was high (kappa statistic >0.75) for both determination of response and type of progression. RECIST= Response Evaluation Criteria in Solid Tumors

18 RANO Criteria--GBM Quant EC, Wen PY. Response Assessment in Neuro-Oncology. Curr Oncol Rep 2011; 13:50–56.

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20 RANO Surgery Task Force Recommendations:
Vogelbaum MA, Jost S, Aghi MK, et al., Application of novel response/progression measures for surgically delivered therapies for gliomas: Response Assessment in Neuro-Oncology (RANO) Working Group. Neurosurgery 2012; 70(1): ; discussion

21 RANO group proposed changes in terminology
Complete Resection of Enhancing Tumor (CRET) and Complete Resection of Detectable Tumor (CRDT) to replace ‘GTR’ Partial Resection of Enhancing Tumor (PRET) and Partial Resection of Detectable Tumor (PRDT) to replace ‘Subtotal Resection’ or ‘Partial Resection’ Takes into account currently available imaging technology & info needed for current clinical trials Vogelbaum MA, Jost S, Aghi MK, et al., Application of novel response/progression measures for surgically delivered therapies for gliomas: Response Assessment in Neuro-Oncology (RANO) Working Group. Neurosurgery 2012; 70(1): ; discussion

22 New RANO criteria for LGG

23 New RANO criteria---LGG
Van den Bent MJ, Wefel JS, Schiff D et al., Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-grade gliomas. Lancet Oncol 2011; 12(6):583—593.

24 Non Astrocytic Neuroepithelial tumors
Oligodendrogliomas Low grade (WHO grade II) High Grade or Anaplastic (WHO grade III) Neuronal tumors – Ganglioglioma Ependymal Tumors Subependymoma Ependymoma Choroid Plexus tumors Papilloma and carcinoma

25 Oligodendrogliomas 4-5th decade of life—mean age 35 y.o., sz, HA, half low grade Slow growing tumors that typically involve the cortex and subcortical white matter—can cause scalloping of inner table Calcifications in a large number ( ~ 80%) Enhancement may be mild or none Frontal lobe more common other lobes, rare in posterior fossa or spine. Mixed forms and high grade forms common Typically heterogeneous in signal intensity, frequently with cystic components, possibly hemorrhage 1p 19q co-deletion or LOH (loss of heterozygosity), i.e., combined allelic loss of chr arms 1p and 19q ---predictor of both chemosensitivity and prolonged overall and recurrence-free survival. 10q LOH (correlated with anaplastic grade), however, predicted a survival disadvantage. Ramirez C, Bowman C, Maurage C-A, Dubois F, Blond S, Porchet N, Escande F. Loss of 1p, 19w, and 10q heterozygosity prospectively predicts prognosis of oligodendroglial tumors---towards individualized tumor treatment? Neuro-Oncology 2010; 12(5):

26 Neuronal and mixed neuronal-glial tumors
Gangliocytoma (cerebellar – LD disease)--no risk of malignant degen; cerebral ctx or cbl; hyper NCCT w minim or no enhanc; iso T1, T2, hyper FLAIR Ganglioglioma (anaplastic ganglioglioma)--peds & young adults<30, m.c. mixed tumors;slow growth w bony remodel; sz;85% TL>FL, ant 3rd vent, cbl, cord, o.n.; cystic in 30-50%;1/3 calcif; 50% faint enhanc; cysts m.c. in younger [<10y.o.];mural nodule poss; may dediff into anaplastic ganglioglioma Desmoplastic Infantile Ganglioglioma--1st 2 yrs DNET-WHO gr I;TL(50-60%)>FL(30%);simil to ganglioglioma;2nd,3rd dec w sz; mult cysts, T2 hyper, enh <1/3 unlike DIG, no edema,may scallop inner table, septations poss, hypodense on CT, a/w FCD in >50%, rarely recur, may arise from septum pelluc, rarely infratent Central neurocytoma--calcif, may be cystic, lat or 3rd v, often attached to septum pellucidum, peak in 3rd decade, mean 29 y.o., mild to mod enhanc, flow voids---ddx intrav oligo


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