Introduction to Supratentorial Adult Brain Neoplasms

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: • AstrocyticNeuroepithelial tumors • Diffuse Infiltrative: Fibrillary, anaplastic, GBM, Gliomatosiscerebri • Localized: Pilocytic, PXA, SGCA • Non-astrocyticNeuroepithelial 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

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 (anaplasticvsglioblastoma)

5. Astrocytic tumors • PilocyticAstrocytoma – low grade (WHO Gr I) • Cyst with a mural nodule – cerebellar (juvenile), hypothalamic-chiasmatic, thalamic • Diffuse / FibrillaryAstrocytoma – (WHO Gr II) • 1/3 FL, 1/3 TL; gemistocyticastro more aggressive than fibrillary, 80% conv to GB, excl supratent • AnaplasticAstrocytoma (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 • Pleomorphicxanthoastrocytoma (Gr II) • Gliomatosiscerebri

6. WHO Grade II AstrocytomaDiffuse / 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 woenhanc • 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: • AnaplasticAstrocytoma (WHO Grade III) • Glioblastoma [multiforme] (WHO Grade IV)

8. AnaplasticAstrocytoma • 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 gliomaseven 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. 2006 Jun;58(6):1099-107; discussion 1099-107. • Danchaivijitr N, Waldman AD, Tozer DJ, Benton CE, BrasilCaseiras 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. 2008 Apr;247(1):170-8.

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. BiochimBiophysActa 2012; 1826 (12): 338-49.

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 perpenddiam/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 GlioblastomasQuant and Wen. RANO. CurrOncol 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/woincreased 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.

16. Pseudoresponsein GBMs Quantand Wen. RANO. CurrOncol 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).

17. Agreement among the 4 methods was high (kappa statistic >0.75) for both determination of response and type of progression.

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

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): 234-243; discussion 243-4.

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): 234-243; discussion 243-4.

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 AstrocyticNeuroepithelial 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):490-499

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 (anaplasticganglioglioma)--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 anaplasticganglioglioma • Desmoplastic Infantile Ganglioglioma--1st 2 yrs • DNET-WHO gr I;TL(50-60%)>FL(30%);simil to ganglioglioma;2nd,3rddec w sz; mult cysts, T2 hyper, enh <1/3 unlike DIG, no edema,may scallop inner table, septationsposs, 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---ddxintravoligo