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glioblastoma multiforme (GBM) or astrocytoma grade IV

Etiology: - prior exposure to radiation therapy only consistent risk factor [3] Epidemiology: - ~12-15% of intracranial neoplasms - 20% of primary CNC tumors - ~50-60% of astrocytic tumors - any age, peak incidence from 45-70 years of age Pathology: 1) may occur as primary glioblastoma or progression from diffuse or anaplastic astrocytoma 2) most often occur in subcortical white matter of cerebral hemispheres 3) infiltrative, poorly delineated 4) may be hemorrhagic [3] 5) may cross corpus callosum into other hemisphere ('butterfly glioma'), similar rapid spread seen in other white matter tracts - internal capsule, fornix, anterior commisure 6) extension and infiltration along perivascular spaces seen 7) metastasis: a) tends not to invade subarachnoid space & rarely b) metastasizes through CSF c) metastases outside the CNS are rare Microscopic Pathology: 1) increased cellularity 2) nuclear atypia 3) mitoses 4) endothelial proliferation 5) necrosis The presence of 3 of the above criteria (excluding #1) is sufficient for diagnosis of GBM; presence of necrosis is not necessary. Genetics: - chromosome 9p loss in 50% of anaplastic astrocytomas & GBMs primarily affecting CDKN2A gene - chromosome 13q loss in 1/3 - 1/2 of high grade astrocytomas RB gene inactivated in 20% of anaplastic astrocytomas, 35% GBMs - chromosome 12q13-14 amplification in 15% malignant gliomas including gene for CDK4 - allelic loss on chromosome 19q in up to 40% of anaplastic astrocytomas & GBMs - chromosome 10 loss in 60-95% of GBMs - PTEN mutations in ~10% of GBMs - DMBT1 gene - EGFR gene amplification in ~40% of primary GBMs less commonly amplified genes: N-myc, gli, c-myc, myb, K-ras, PDGF receptor alpha, MDM2 - homozygous deletion in chromosome 6q21 results in expression of a GOPC-ROS1 chimeric protein with constitutive receptor tyrosine kinase activity - chromosomal translocation t(10;19)(q26;q13.3) involving ZNF320 with BRWD2/WDR11 - diminished or absent expression of PHF3, JARID1B, THEM4, RIG - expression of STAT3 & c-ebpb portend poor prognosis - other implicated genes: MMP24, MMP25 Two subtypes based on clinical characteristics: 1) primary GBM associated with a) ink4A loss b) EGFR gene amplification in ~40% of primary GBMs (rare in secondary GBMs) c) PTEN loss >30% (rare in secondary GBM) - PTEN upstream open reading frame MP31 penetrates the blood-brain barrier & inhibits mice glioblastoma xenografts without neurological toxicity, suggesting a potential role in glioblastoma treatment [19] d) MDM2 amplification 2) secondary GBM associated with a) initially 1] p53 loss 2] PDGF/PDGFR overexpression b) progressing with 1] RB loss 2] CDK4 amplification Clinical manifestations: case report [14] - unilateral weakness of extremity - drooping of contralateral face - slurred speech - urinary incontinence - progressive functional decline & cognitive decline Laboratory: 1) biopsy (tissue needed for diagnosis) a) stereotactic needle biopsy b) open biopsy 2) autoantibodies: PHF20 Radiology: 1) magnetic resonance imaging (MRI)* - ring-enhancing lesion - areas of central necrosis & hemorrhage [3] 2) computed tomography (CT) 3) in general, higher grade astrocytic tumors show contrast enhancement * MRI images [14,20] Management: 1) surgery: a) debulking if patient will not suffer neurologic deficit b) not clear that debulking of tumor enhances survival c) intermittent pneumatic compression immediately after surgical resection [3] 2) radiation therapy a) 5000-6500 cGy - 60 Gy over a period of 6 weeks [10] - shorter course of 40 Gy in 15 fractions [10] b) prolongs survival c) administered in multiple fractions to an area around the tumor d) radiation necrosis may produce clinical picture indistinguishable from recurrent high-grade tumor 3) adjunct chemotherapy with radiation therapy a) temozolomide (Temodar) is treatment of choice [5,6,9,10] - combined chemoradiation beneficial to patients > 65 years of age (mean survival 9 months vs 4-5 months for either radiation or chemotherapy alone [9] - survival improved when temozolomide is given in morning rather than in the evening (17 vs 13.5 months) [18] b) lomustine [13] c) bevacizumab [3] - lomustine + bevacizumab without survival advantage over lomustine alone [13] d) BCNU 4) low-intensity alternating electric fields applied to the scalp as maintenance therapy after completing chemoradiation, extends survival progression-free (7 vs 4 months) & overall (21 vs 16 months) vs maintenance chemotherapy [8] - patient-operated Optune device continuously delivers alternating electrical fields to the brain at an intermediate frequency - it is thought to disrupt mitosis & cell division in tumor cells [11] 5) role for PTEN upstream open reading frame MP31 ? Prognosis: 1) 1-2 months without surgery 2) 4 months with surgery alone 3) 6-9 months with surgery plus radiation 4) 10-12 months with surgery plus radiation plus chemotherapy - 17 months with temozolomide given in morning [18] 5) 80% recur after surgical resection plus whole brain irradiation 6) radiation plus brachytherapy may give best results (18 months) 7) prognosis better in younger patients with minimal residual tumor after resection who receive post-operative chemotherapy & radiation therapy [3] Clinical trials: - attenuated HSV-1 in clinical trials (Univ of Alabama) - zika virus has oncolytic activity against glioblastoma stem cells [12] (no report of clinical trial yet) - oncolytic adenovirus allows 20% of patients to survive at least 3 years [15] - recombinant poliovirus-rhinovirus chimera allows 21% of patients to survive at least 3 years [17] - autologous tumor lysate-pulsed dendritic cell vaccine (DCVax-L) may be of benefit as adjunct to standard therapy [16]

Interactions

disease interactions

Specific

giant cell glioblastoma gliosarcoma

General

astrocytoma (astrocytic neoplasm) malignant glioma

References

  1. OMIM 137800
  2. Mark Felmus, M.D., Ph.D., Dept. of Medicine, UCSF Fresno
  3. Medical Knowledge Self Assessment Program (MKSAP) 11, 16, 18, 19. American College of Physicians, Philadelphia 1998, 2012, 2018, 2021
  4. Levin et al, Neoplasms of the central nervous system, in: Cancer: Principles & Practice of Oncology, DeVita et al, eds, Lippincott, Williams & Wilkins, Philadelphia, 2001, pg 2100
  5. Stupp R, Hegi ME, Gilbert MR, Chakravarti A. Chemoradiotherapy in malignant glioma: standard of care and future directions. J Clin Oncol. 2007 Sep 10;25(26):4127-36. PMID: 17827463
  6. Stupp R, Hegi ME, Mason WP et al Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009 May;10(5):459-66 PMID: 19269895
  7. WHO Classification Tumours of the Nervous System. Kleihues & Cavenee eds. IARC Press 2000
  8. Stupp R et al Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for GlioblastomaA Randomized Clinical Trial. JAMA. 2015;314(23):2535-2543 PMID: 26670971 http://jama.jamanetwork.com/article.aspx?articleid=2475463 - Sampson JH Alternating Electric Fields for the Treatment of Glioblastoma. JAMA. 2015;314(23):2511-2513 PMID: 26670969 http://jama.jamanetwork.com/article.aspx?articleid=2475446
  9. Rusthoven CG et al. Combined-modality therapy with radiation and chemotherapy for elderly patients with glioblastoma in the temozolomide era: A National Cancer Database analysis. JAMA Neurol 2016 May 23 PMID: 27214765
  10. Perry JR, Laperriere N, O'Callaghan CJ Short-Course Radiation plus Temozolomide in Elderly Patients with Glioblastoma. N Engl J Med 2017; 376:1027-1037. March 16, 2017 PMID: 28296618 http://www.nejm.org/doi/full/10.1056/NEJMoa1611977
  11. Stupp R, Hegi ME, Idbaih A et al CT007 - Tumor treating fields added to standard chemotherapy in newly diagnosed glioblastoma (GBM): Final results of a randomized, multi-center, phase III trial. American Association for Cancer Research. 2017 Annual Meeting. Session CTMS01 - Breast Cancer, Ovarian Cancer, and Glioblastoma Clinical Trials. April 2, 2017 http://www.abstractsonline.com/pp8/#!/4292/presentation/12353
  12. Zhu Z, Gorman MJ, McKenzie LD Zika virus has oncolytic activity against glioblastoma stem cells. J Experimental Med. Sept 5, 2017 PMID: 28874392 http://jem.rupress.org/content/early/2017/09/05/jem.20171093
  13. Wick W, Gorlia T, Bendszus M et al Lomustine and Bevacizumab in Progressive Glioblastoma. N Engl J Med 2017; 377:1954-1963. November 16, 2017 PMID: 29141164 http://www.nejm.org/doi/full/10.1056/NEJMoa1707358
  14. Siddiqui J, Krishnan AS. (images) Butterfly Glioma. N Engl J Med 2018; 378:281. January 18, 2018 PMID: 29342386 http://www.nejm.org/doi/full/10.1056/NEJMicm1704713
  15. Fuerst ML Glioblastoma: 'Smart Bomb' Virus Induces Durable Responses. Adenovirus engineered to attack recurrent disease allowed 20% of patients to live at least 3 years, probably due to direct oncolytic effects. MedPage Today. ASCO Reading Room 04.12.2018 https://www.medpagetoday.com/reading-room/asco/immunotherapy/72284 - Lang FF, Conrad C, Gomez-Manzano C,et al Phase I study of DNX-2401 (Delta-24-RGD) oncolytic adenovirus: Replication and immunotherapeutic effects in recurrent malignant glioma. J Clin Oncol. 2018 Feb 12 PMID: 29432077
  16. Castellino AM Dendritic Vaccine for Glioblastoma: Hope Hyped, Say Some. Medscape - Jun 13, 2018. https://www.medscape.com/viewarticle/898007 - Liau LM, Ashkan K, Tran DD et al First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma. Journal of Translational Medicine. 2018. 16:142 PMID: 29843811 Free PMC Article https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-018-1507-6
  17. Desjardins A, Gromeier M, Herndon JE 2nd et al Recurrent Glioblastoma Treated with Recombinant Poliovirus. N Engl J Med. June 26, 2018 PMID: 29943666 https://www.nejm.org/doi/full/10.1056/NEJMoa1716435 - Longo DL, Baden LR Exploiting Viruses to Treat Diseases. N Engl J Med. June 26, 2018 PMID: 29943655 https://www.nejm.org/doi/full/10.1056/NEJMe1807181
  18. Nelson R Morning (vs Evening) Dosing and Better Survival in Glioblastoma. Medscape - Apr 08, 2021 https://www.medscape.com/viewarticle/948959
  19. Huang N, Li F, Zhang M, Zhou H et al An Upstream Open Reading Frame in Phosphatase and Tensin Homolog Encodes a Circuit Breaker of Lactate Metabolism. Cell Metab. 2021 Jan 5;33(1):128-144.e9 PMID: 33406399
  20. Khanna O, Ghobrial GM, Farrell CJ 10 Brain Lesions to Recognize (MRI images) Medscape. October 25, 2021 https://reference.medscape.com/slideshow/brain-lesions-6013313
  21. Schaff LR, Mellinghoff IK Glioblastoma and Other Primary Brain Malignancies in Adults. A Review. JAMA. 2023;329(7):574-587 PMID: 36809318 https://jamanetwork.com/journals/jama/fullarticle/2801673

Databases, Figures & Images

OMIM 137800 Genetic abnormalities leading to GBM, simplified images related to glioblastoma multiforme