High-Grade Glioma

Steven H. Lin and Shiao Y. Woo

 Background

What % of primary CNS tumors are malignant?

~40% of primary brain tumors are considered malignant.

In adults, what is the most common malignant CNS neoplasm?

~85% of CNS neoplasms in adults are glioblastoma multiforme (GBM), which constitutes 20% of all primary tumors.

What are the WHO classifications for high-grade CNS tumors?

1. 
   

   WHO III: anaplastic astrocytoma (AA)/oligodendroglioma/oligoastrocytoma

   
   
2. 
   

   WHO IV: GBM

What are some common genetic changes seen in malignant brain tumors?

↑ EGFR (50%) and PTEN mutation (30%–40%)

What are the initial genetic changes associated with primary vs. secondary GBM?

1. 
   

   Primary: ↑ EGFR/MDM2 amplification/LOH10/p16 loss

   
   
2. 
   

   Secondary: p53 mutation → low-grade glioma (LGG) → LOH 19q/p16 loss → AA → LOH 10, DCC → 2^nd GBM

What % of GBMs are multicentric?

<5% of GBMs are multicentric.

What are the 4 pathologic characteristics that define GBM?

Pseudopalisading necrosis, vascular proliferation, ↑ mitotic rate, and pleomorphic nuclei

 Workup/Staging

What is the Cushing triad, and what does it represent in brain tumors?

HTN, bradycardia, respiratory irregularity. It represents ↑ ICP.

With what Sx do high-grade gliomas (HGGs) most commonly present?

HA (especially in the am, 50%), seizures (20%), focal neurologic dysfunction, and mental status change

What are the common imaging characteristics of HGGs on MRI?

Hypodense on T1, gadolinium enhancing, T2 enhancing, and +T2 FLAIR (edema)

 Treatment/Prognosis

What is the MS for LGG vs. HGG?

1. 
   

   Low grade: pure oligodendroglioma: 10 yrs; oligoastrocytoma: 7 yrs; anaplastic oligodendroglioma (AO): 5 yrs

   
   
2. 
   

   High grade: AA: 3 yrs; GBM: 14 mos

What are the most important factors used for the RTOG recursive partitioning analysis (RPA) stratification?

1. 
   

   Age 50 yrs, histology (AA or GBM), Karnofsky performance status (KPS) of 70, MS changes, and Sx greater or less than 3 mos

(Curran WJ et al., J Natl Cancer Inst 1993)

What constitutes RPA class III pts?

Age <50 yrs, AA with poor MS, or GBM with good KPS

What defines RPA class VI pts?

Any histology with KPS <70 and altered MS

What is the MS of a pt with RPA class I–II, III–IV vs. V–VI?

MS by RPA class:

1. 
   

   Class I–II: 40–60 mos (3–5 yrs)

   
   
2. 
   

   Class III–IV: 11–18 mos (1–1.5 yrs)

   
   
3. 
   

   Class V–VI: 5–9 mos

Under what RPA classes can GBM fall?

GBMs fall under classes III–VI:

1. 
   

   Class III: <50 yo, KPS 90–100

   
   
2. 
   

   Class IV: <50 yo, KPS <90 or >50 yo, good KPS

   
   
3. 
   

   Class V: >50 yo, KPS <70 but no change in MS

   
   
4. 
   

   Class VI: KPS <70 and MS change

On what is the current modified RPA based?

Outcomes with temozolomide (TMZ) (Mirimanoff RO, JCO 2006)

What is the 4-yr OS and MS for the adapted RPA groups for malignant gliomas (per Mirimanoff RO, ASTRO 2007 update)?

1. 
   

   Overall survival: class III (<50 yo, performance status [PS] 0): 28.4% vs. 6.4%; class IV: 11.3% vs. 3.3%; class V (>50 yo, Mini-Mental State Examination <27, Bx only): 6% vs. 1%

   
   
2. 
   

   Median survival: class III: 21 mos vs. 15 mos; class IV: 16 mos vs. 13 mos; class V: 10 mos vs. 9 mos

What additional factors did the European Nomogram (European GBM Calculator) investigate for stratification purposes?

MGMT methylation status and extent of resection; only MGMT, PS, and MS were prognostic (Gorlia T et al., Lancet Oncol 2008)

What is MGMT, and why is it important?

MGMT is a DNA repair enzyme that removes alkyl groups from the O⁶ position of guanine (when methylated/inactive, it leads to longer survival).

When should anticonvulsants be started?

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