Neurosurgery notes/Tumours/Gliomas, Glioneuronal Tumors, and Neuronal Tumors/Adult type diffuse astrocytoma/Low grade gliomas

Low grade gliomas

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Parent item
Adult type diffuse astrocytoma
Sub-item
Astrocytoma, IDH mutant
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted
LGG treatment

General

  • Glioma of a grade lower than anaplastic
    • Astrocytomas
    • Oligodendrogliomas

Numbers

  • Incidence of DLGG: 1– 1.5/ 100 000 patients/ year
    • Astrocytic low grade glioma (LGG): 0.6– 1.2/ 100 000 patients/year
    • Oligodendroglial LGG, 0.3/ 100 000 patients/year
  • Accounting for 10– 15% of all primary brain tumours
  • Age of diagnosis: 45 years
    • Symptomatic diagnosis: 37.0 years
      • Likely to be in eloquent areas (lower threshold for triggering symptoms
        • Insula
        • SMA region
    • Incidental diagnosis 35.5 years
      • Incidence of GLGGs will likely increase with growing access to brain imaging worldwide.
      • Likely to be in non eloquent areas
  • M:F ; 3:2
    • Incidental: M:F, 2:3
      • It might be females area more likely to seek medical attention than men

Clinical presentation

Symptom
Overall N = 852 (%)
1960–1981 N = 281 (%)
1990–2011 N = 571 (%)
P value
Seizures
610 (72)
218 (78)
392 (69)
0.008
Headaches
258 (30)
130 (46)
128 (23)
<0.0001
Speech
61 (7)
26 (9)
35 (6)
0.12
Sensory/motor symptom
271 (32)
113 (40)
158 (28)
0.003
  • Asymptomatic
    • Due to
      • Slow growing allows neuroplasticity
      • Long time lag before seizure forms due to
        • LGG have minimal cerebral oedema
        • LGG are slow- growing
  • Seizures
    • >80% of patients
    • Cortically based tumours
      • Frontal
      • Temporal
      • Insular
  • Focal neurological deficits
    • Small numbers
    • Getting even rarer
  • Altered mental state
    • Disorders of
      • Executive functions
      • Attention
      • Concentration
      • Working memory
      • Emotion
    • Due to
      • Tumour
      • Seizures
      • Antiepileptic medications
    • A systematic assessment of higher mental functions and health related quality of life
      • Is now recommended before oncological treatment.
      • This serves several important purposes:
        • Detection of subtle neuropsychological deficits
        • Tailoring of the therapeutic strategy for a given individual
          • e.g. choosing neoadjuvant chemotherapy rather than surgery first in cases of very diffuse DLGG with cognitive disturbances
        • Devising of surgical strategy according to the detected deficit and location of the tumour (i.e. selection the optimal neurological tests that should be administrated during awake surgery);
        • Establishing of a pretreatment baseline that will allow detection of post- treatment deficit and facilitate planning of specific functional rehabilitation following surgery
  • Increased intracranial pressure

Radiological diagnosis

General

  • A diagnosis of LGG on imaging is usually possible in the context of the clinical picture and by repeating the scan, typically in 3 months or earlier,
    • Depending on the degree of suspicion of pathology other than LGGs and
    • Likelihood of harmful consequences of delayed diagnosis.

MRI

Standard

  • T1
    • Hypointense
  • T1+ C
    • Generally
      • Lack of enhancement = LGG
      • Contrast enhancement = grade 3 or 4 astrocytoma or GBM
    • BUT (Cavaliere et al., 2005)
      • >30% Grade 3/4 astrocytomas and GBM of cases with no contrast enhancement will be reclassified as grade 3 or 4 (there is no reference for this in oxford textbook)
        • Barker et al., 1997: Older you are, higher the likelihood of histological grade being higher than grade 2 in non- enhancing gliomas increases with age
        • Abd-elghany 2019 1.9% of GBM do not enhance
      • 15– 39% of DLGGs enhance
        • Enhancement is more common in oligodendrogliomas (20– 50%)
          • Anaplastic oligodendrogliomas enhancement: 62– 72%
        • Haemorrhage and calcifications are also more common in oligodendrogliomas.
        • Oligodendrogliomas
          • Grade 2: 25% have calcifications
          • Grade 3 oligodendrogliomas: 50% have calcifications
            • Consistent with their progression from low to higher grade over time (Khalid et al., 2012)
  • T2
    • Hyperintense
    • Flair
      • Best shows the tumour extent
      • LGG is a diffuse neoplastic disease and that glioma cells have been shown to be present beyond the FLAIR signal abnormality as far as 2 cm (Pallud et al., 2010c).
      • Post op FLAIR MRI
        • Is the gold standard for objective calculation of postoperative residual volume.

Functional MR

  • Helpful in preoperative planning
  • fMRI can establish:
    • Dominant hemisphere preoperatively
    • Serve as a starting point for identification of functional language cortex during direct cortical stimulation
  • However, fMRI has not been shown to be a suitable alternative to awake language mapping
  • Giussani 2010:
    • A meta-analysis of nine studies
    • Correlation between language fMRI and direct cortical stimulation found:
      • Sensitivity ranging from 59 to 100%
      • Specificity ranging from 0 to 97%
    • The inconsistency in these results may be due to the influence of the pathological features of gliomas on fMRI, such as parenchymal invasion and angiogenesis
    • Gliomas can cause both biochemical and architectural changes in the local cerebral microenvironment, including alterations in:
      • Neurotransmitter concentration
      • Cortical reorganization of eloquent function

DTI tractography

  • Helpful in preoperative planning.

Magnetoencephalography (MEG)

  • Helpful in preoperative planning.

Prognostic markers

  • Important prognostic factors associated with outcome of patients with DLGGs (overall survival and time to anaplastic transformation (TAT)
      • Variable
      OS
      TAT
      Age
      ✅
      ㅤ
      KPS
      ✅
      ㅤ
      Presence of neurological deficits
      ✅
      ㅤ
      Presenting with seizures
      ✅
      ㅤ
      Tumour volume
      ✅
      ㅤ
      Tumour crossing midline
      ✅
      ㅤ
      Tumour location - frontal
      ✅
      ㅤ
      Speed of growth
      ✅
      ✅
      rCBV
      ✅
      ㅤ
      Histology: astrocytoma rather than oligodendroglioma
      ✅
      ㅤ
      1p19q codeletion
      ✅
      ✅
      IDH mutations
      ✅
      ✅
      TERT mutation
      ✅
      ✅
      Degree of resection
      ✅
      ✅
    • Clinical prognostic markers
      • Age has also been associated with higher frequency of anaplasia in non-enhancing gliomas
      • Low performance status (KPS <70%)
    • Radiology prognostic markers
      • Eloquent areas tumour
        • Shorter OS because
          • Functional limitations to the extent of resection
          • Earlier development of neurological dysfunction
      • Large tumour size
        • Mass effect, focal deficits, and/ or intracranial hypertension leading to a poorer functional status are significant factors on univariate analysis but not on multivariate analysis, probably because they are related to tumour volume.
        • Limits therapeutic possibilities
        • Increases the risk of treatment- related complications
        • The volume of residual tumour serves as a predictor of AT
      • Speed of growth
        • Measured by velocity of diametric expansion (VDE)
          • A measurement reflecting both the initial tumour volume and the increase in volume
        • Pros VDE
          • A good monitoring tool as it takes into account the whole tumour therefore no sampling bias
          • Non- invasive
          • Simple
          • Reproducible
          • Relatively cheap.
        • An independent prognostic factor for (independent of histopathological findings & molecular status):
          • OS
          • Malignant PFS
      • PET
        • Negative 18F- FET PET studies = grade 2 astrocytomas
        • Positive 18F- FET PET studies = high- grade gliomas
      • MR spectroscopy
        • Presence of lactates and lipids on MR spectroscopy is related to more aggressive behaviour
        • Raised Choline- to- creatine ratio (Cho/ Cr) known to be correlated with tumour cell proliferation
        • Elevated 2- hydroxyglutarate (2HG) levels in gliomas with IDH1 mutations compared with wild type
      • High cerebral blood volume measured by MRI (rCBV)
        • Can detect signs of malignant transformation → shorter OS
    • Histological and molecular prognostic markers
      • Main mutations
        • IDH1 or IDH2
        • ATRX
        • TERT genes
        • Loss of 1p/ 19q chromosomal arms
      • Associated mutations
        • EGFR
        • EGFRvIII
        • PTEN
        • NF1 genes
        • RB1
        • PIK3CA
        • PIK3R1
      • In diffuse grade 2 and 3 tumours displaying
        • Data from
          • Cancer Genome Atlas Research Network et al., 2015
          • Mayo-UCSF study
        • Best prognosis (triple positive)-29%
          • IDH mutation
          • TERT mutated
          • 1p/ 19q codeletion (1p/ 19q- del)
        • Moderate prognosis - 5%
          • IDH mutation
          • TERT mutated
          • No 1p/ 19q- del.
        • Poor prognosis (Triple negative)-7% OS similar to GBM
          • IDH wild- type
          • TERT wild type
          • No 1p/ 19q- del.

Differential diagnosis

  • Radiological differential diagnosis:
    • Encephalitis
      • Rasmussen encephalitis: a very rare condition that involves long-term worsening inflammation (encephalitis) of one hemisphere
    • Cerebral ischaemia/ infarction
    • Other intrinsic low- grade tumours (e.g. DNET, ganglioglioma) or
    • Gliomas of higher grades
      • Defining malignant transformation
        • MRI+ C
          • Contrast enhancement
        • Positron emission tomography (PET)
          • Aid differentiating Radiation- treated gliomas
          • Identify potential anaplastic loci
        • MR spectroscopy
          • Differentiating low vs high grade (sensitivity and specificity: 80– 85%)
            • Cho/ Cr ratio
            • NAA (N- acetylaspartate)/ Cr ratio
        • Perfusion MRI
          • Use for routine monitoring and detection of malignant transformation
            • No radiation
            • No contrast
          • Perfusion MRI measuring the relative cerebral blood volume (rCBV) is more practical, especially if frequent (e.g. three- monthly) surveillance is required
  • Differentiating LLG from other diagnosis
    • Good clinical history
      • Will help differentiating most
    • Biopsy
      • Rarely needed
      • e.g. Rasmussen encephalitis
      • Sampling error
        • Kunz et al., 2011:
          • Anaplastic foci covering 4 – 44% of the entire visible tumour volume : biopsy can undergrade LGG
          • Sampling accuracy can be improved with the use of PET- directed guidance, both in the case of needle biopsy and resection.
    • An interval MRI scan
      • 3 months or less
      • Aid
        • Differential diagnosis,
        • Prognostic factor for LLG
          • As the speed of growth = aggressiveness
    • MR spectroscopy