glioblastoma multiforme (GBM) or astrocytoma grade IV

Etiology

• prior exposure to radiation therapy only consistent risk factor

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

• may occur as primary glioblastoma or progression from diffuse or anaplastic astrocytoma
• most often occur in subcortical white matter of cerebral hemispheres
• infiltrative, poorly delineated
• may be hemorrhagic
• may cross corpus callosum into other hemisphere ('butterfly glioma'), similar rapid spread seen in other white matter tracts
  • internal capsule, fornix, anterior commisure
• extension and infiltration along perivascular spaces seen
• metastasis:
  • tends not to invade subarachnoid space & rarely
  • metastasizes through CSF
  • metastases outside the CNS are rare

Microscopic pathology

• increased cellularity
• nuclear atypia
• mitoses
• endothelial proliferation
• 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:

• primary GBM associated with
  • ink4A loss
  • EGFR gene amplification in ~40% of primary GBMs (rare in secondary GBMs)
  • 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
  • MDM2 amplification
• secondary GBM associated with
  • initially
    • p53 loss
    • PDGF/PDGFR overexpression
  • progressing with
    • RB loss
    • CDK4 amplification

Clinical manifestations

case report

• unilateral weakness of extremity
• drooping of contralateral face
• slurred speech
• urinary incontinence
• progressive functional decline & cognitive decline

Laboratory

• biopsy (tissue needed for diagnosis)
  • stereotactic needle biopsy
  • open biopsy
• autoantibodies: PHF20

Radiology

• magnetic resonance imaging (MRI)*
  • ring-enhancing lesion
  • areas of central necrosis & hemorrhage
• computed tomography (CT)
• in general, higher grade astrocytic tumors show contrast enhancement

* MRI images

Management

• surgery:
  • debulking if patient will not suffer neurologic deficit
  • not clear that debulking of tumor enhances survival
  • intermittent pneumatic compression immediately after surgical resection
• radiation therapy
  • 5000-6500 cGy
    • 60 Gy over a period of 6 weeks
    • shorter course of 40 Gy in 15 fractions
  • prolongs survival
  • administered in multiple fractions to an area around the tumor
  • radiation necrosis may produce clinical picture indistinguishable from recurrent high-grade tumor
• adjunct chemotherapy with radiation therapy
  • temozolomide (Temodar) is treatment of choice
    • combined chemoradiation beneficial to patients > 65 years of age (mean survival 9 months vs 4-5 months for either radiation or chemotherapy alone
    • survival improved when temozolomide is given in morning rather than in the evening (17 vs 13.5 months)
  • lomustine
  • bevacizumab
    • lomustine + bevacizumab without survival advantage over lomustine alone
  • BCNU
• 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
  • 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
• role for PTEN upstream open reading frame MP31 ?

Prognosis:

• 1-2 months without surgery
• 4 months with surgery alone
• 6-9 months with surgery plus radiation
• 10-12 months with surgery plus radiation plus chemotherapy
  • 17 months with temozolomide given in morning
• 80% recur after surgical resection plus whole brain irradiation
• radiation plus brachytherapy may give best results (18 months)
• prognosis better in younger patients with minimal residual tumor after resection who receive post-operative chemotherapy & radiation therapy

Clinical trials

• attenuated HSV-1 in clinical trials (Univ of Alabama)
• zika virus has oncolytic activity against glioblastoma stem cells (no report of clinical trial yet)
• oncolytic adenovirus allows 20% of patients to survive at least 3 years
• recombinant poliovirus-rhinovirus chimera allows 21% of patients to survive at least 3 years
• autologous tumor lysate-pulsed dendritic cell vaccine (DCVax-L) may be of benefit as adjunct to standard therapy

More general terms

• malignant glioma
• astrocytoma (astrocytic neoplasm)

More specific terms

• giant cell glioblastoma
• gliosarcoma

Patient information

glioblastoma multiforme patient information

Database

• OMIM: https://mirror.omim.org/entry/137800