Grade II gliomas

Grade II gliomas, tumors of the central nervous system derived from the glial lineage (astrocytes and oligodendrocytes), are classically classified as "low-grade gliomas" alongside grade I gliomas. However, unlike the latter, they have an infiltrative character and spontaneously and inexorably evolve toward anaplasia and their transformation into high-grade gliomas. They are therefore now considered true malignant lesions, and their management has shifted from a wait-and-see approach to a decidedly aggressive stance. Due to the imprecision of histological classifications of gliomas, their epidemiological characteristics are vague. However, the incidence of grade II gliomas is generally estimated at 1 case per 100,000 inhabitants per year.

Histological Types According to WHO (2000)

Gliomas are very heterogeneous, and the histological criteria are not very practical. As a result, their classification is difficult and suffers from a lack of reproducibility. However, the World Health Organization (WHO) distinguishes:

Infiltrating Diffuse Astrocytomas

Grade II astrocytomas are characterized by a high degree of astrocytic differentiation, slow growth, and diffuse infiltration of adjacent parenchyma. They preferentially occur in young adults. Spontaneous progression to anaplastic astrocytoma (grade III) and then to glioblastoma (grade IV). Three types have been defined by the WHO:

• Fibrillary Astrocytoma: the most common, distinguished only by the presence of nuclear atypia compared to normal astrocytes.
• Gemistocytic Astrocytoma: defined by the presence of > 20% of neoplastic gemistocytic astrocytes (abundant, glassy, eosinophilic cell bodies + globular shape + eccentric nucleus) – its transformation into high-grade glioma is particularly rapid.
• Protoplasmic Astrocytoma: very rare. Its existence is even debated.

Oligodendrogliomas

Oligodendrogliomas are well-differentiated, diffusely infiltrating tumors in adults, typically located in the cerebral hemispheres and composed of cells resembling oligodendrocytes. Frequent presence of calcifications, possible cystic formations, and hemorrhagic changes.

Oligoastrocytomas

These tumors consist of two cell types, morphologically resembling cells from grade II astrocytomas and oligodendrogliomas, intermingled or distinct.

Clinical

The median age at diagnosis is approximately 35 years with no sexual predominance. The median overall survival with treatment is around 10 years, although this data should be viewed with caution due to the heterogeneity of evolutionary profiles.

Long asymptomatic period → inaugural clinical phase:

• Seizures: revealing in ≈ 80% of cases, ++ partial +- secondary generalization
  • → an inaugural seizure in an adult should always raise suspicion of a grade II glioma and prompt a brain MRI (unless clinical and electroencephalogram typical of idiopathic epilepsy)
• Focal deficits: rare, usually minimal. Minor or moderate cognitive disturbances are frequently noted (++ working memory and attention) as well as behavioral issues.
• Signs of intracranial hypertension (ICH): exceptional (slow growth)

→ inevitable spontaneous transformation towards anaplasia (exceptional as long as the tumor volume is < 50 cc) → focal deficits, intracranial hypertension, worsening of seizure phenomena → death.

Functional prognosis depends on the speed of tumor growth (exceeding plasticity capacities and mass effect), localization, and infiltrative nature (destruction of neural networks). Vital prognosis depends on mass effect and anaplastic transformation.

Complementary Examinations

Cerebral CT Scan

Very low sensitivity and specificity. Possible hypodensity not taking contrast +- calcifications.

Brain MRI = Gold Standard

→ T1 hypointensity, ++ homogeneous, T2 and FLAIR hyperintensity. Contrast uptake argues for a high-grade tumor… but is found (++ low intensity or punctate) in nearly 30% of grade II gliomas. The volume at diagnosis is generally 60-70 cc.

Perfusion MRI → demonstrates neovascularization and angiogenesis, correlated with grade.

Preferred localizations: frontal (++ pre-rolandic) and insular.

Methionine PET Scan (/ FDG)

Methionine → Its uptake is highly predictive of glioma aggressiveness.

FDG → May have utility in cases of diagnostic uncertainty with lymphoma.

Pathology

On the total piece if (sub)-total resection surgery is possible. Otherwise, on stereotactic biopsy or if there is diagnostic uncertainty with a non-tumoral lesion or lymphoma.

Miscellaneous

To be defined according to possible differential diagnoses and tumor localization. Possible pre-operative assessment. Systematic neuropsychological assessment.

Prognostic Factors

The median overall survival with treatment is around 10 years. However, the heterogeneity of evolutionary profiles of grade II gliomas makes any individual prediction precarious. Nevertheless, various factors modulating prognosis have been well established.

Cellular Proliferation Index (expression of Ag Ki67 studied via Ac MIB-1)

Correlated to histological grade… on average:

• Grade II Astrocytomas: 3.8%
• Grade III Astrocytomas: 18.4%
• Grade IV Astrocytomas: 31.6%

Inverse correlation to survival…:

• Grade II Astrocytomas: median survival of 72 months if < 3%, 23 months if > 3%
• Grade II and III Oligodendrogliomas: median survival of 3.4 years if < 5%, 1.1 years if > 5%

Chromosomal Factors

Different studies suggest longer survival in the presence of a 1p deletion (++ if associated with a 19q deletion) for grade II or III oligodendrogliomas. However, some consider a 19q deletion as a marker of anaplastic transformation...

Clinical Factors

Are poor prognostic factors (rapid anaplastic transformation):

• Age > 40 years
• Occurrence of focal deficits

Imaging-Derived Factors

Are poor prognostic factors (rapid anaplastic transformation):

• Greater tumor diameter > 6 cm
• Crossing the midline
• Tumor growth rate > 8 mm/year (→ median survival of 5 years versus 15 years otherwise)
• Methionine uptake (intensity and dispersion)

Surgical Possibility Factors

Total or subtotal surgical resection (less than 10 cc of residue) has been shown to effectively delay neoplastic transformation (variable benefit depending on cases but can extend to several decades). It should therefore be considered whenever possible (co-morbidities, age, accessibility, and localization of the tumor).

Therapeutic Principles - Treatments

The goals of therapeutic management are to preserve quality of life as much as possible and delay anaplastic transformation.

Management should be discussed for each case among oncologists, radiotherapists, surgeons, and radiologists. Roughly, surgery is preferred as the first intention. In case of inoperability, inoperable recurrence, or incomplete resection, radiotherapy will be discussed. Early chemotherapy, which can delay radiotherapy, should be systematically considered.

Surgery = Gold Standard

To be performed whenever possible provided that:

• Total or subtotal resection (residual < 10 cc) is possible, the only condition effectively delaying anaplastic transformation. Otherwise, surgery has no interest except for symptomatic aims (in case of significant mass effect, signs of intracranial hypertension) or in case of localization allowing iterative resections.
• Favorable benefit/risk ratio (accessibility, functional areas)

Radiotherapy

Current consensus = no indication in case of total resection → to be kept for non-accessible recurrences. No consensus for other scenarios… To be delayed as much as possible due to its neurotoxicity.

Chemotherapy

Its role is poorly defined. Current trend = early chemotherapy aiming to delay radiotherapy. The most commonly used regimens are PCV (Procarbazine, Lomustine, Vincristine) or Temozolomide.

Miscellaneous

Antiepileptics should be permanently established in case of seizure occurrence. However, there is no justification for initiating prophylactic treatment (except to discuss transiently post-operatively). Regarding the choice of antiepileptic during chemotherapy, a positive role on tumor evolution of valproate in combination with temozolomide has been discussed for several years... without producing convincing results in terms of survival.

Corticosteroids may be useful in case of peritumoral edema or immediate post-operative.

Bibliography

Bradley WG et al., Neurology in clinical practice, 5th ed., Butterworth-Heinemann, e-dition, 2007

EMC, Traité de neurologie, 2018

Louis DN et al., Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors, UpToDate, 2024

Osborn AG, Diagnostic imaging : brain, Amirsys, USA, 2d ed., 2009