High-Grade Gliomas

High-grade gliomas (HGGs) are aggressive primary malignant brain tumors that include Anaplastic Astrocytoma (WHO Grade 3) and Glioblastoma Multiforme (GBM, WHO Grade 4). These tumors are characterized by rapid growth, diffuse infiltration of surrounding brain tissue, and poor prognosis despite multimodal treatment. Management requires a multidisciplinary approach involving maximal safe surgical resection, radiotherapy, chemotherapy, and supportive care. Molecular characterization has become an essential component of diagnosis, prognostication, and treatment planning.

Epidemiology

High-grade gliomas are among the most common malignant primary brain tumors in adults. Glioblastoma is the most frequent and most aggressive subtype. The incidence increases with age, with peak occurrence between the sixth and seventh decades of life. Glioblastoma occurs slightly more commonly in males than females.

Risk factors

Risk factors for high-grade gliomas include:

• Increasing age

• Previous exposure to ionizing radiation

• Family history of glioma

• Li-Fraumeni syndrome

• Neurofibromatosis type 1

• Turcot syndrome

• Lynch syndrome

• Previous low-grade glioma with malignant transformation

Pathophysiology

High-grade gliomas originate from glial cells and demonstrate rapid cellular proliferation, diffuse infiltration, angiogenesis, necrosis, and marked genetic heterogeneity. Tumor expansion produces mass effect, cerebral edema, increased intracranial pressure, seizures, and progressive neurological deficits. Molecular markers such as IDH mutation, ATRX mutation, and 1p/19q codeletion provide important diagnostic and prognostic information.

Clinical presentation

Patients usually present with rapidly progressive neurological symptoms caused by tumor infiltration, cerebral edema, and raised intracranial pressure. Clinical manifestations depend on the tumor location.

Symptoms

• Seizures

• Progressive headache

• Progressive neurological symptoms according to tumor location

• Nausea and vomiting

• Cognitive decline

• Personality or behavioural changes

• Limb weakness

• Speech disturbance

• Visual disturbances

• Gait imbalance

Clinical signs

• Focal neurological deficits

• Motor weakness

• Sensory deficits

• Aphasia

• Cranial nerve deficits

• Papilloedema

• Altered mental status

• Cognitive impairment

• Signs of raised intracranial pressure

Differential diagnosis

• Low-grade glioma

• Brain metastases

• Primary central nervous system lymphoma

• Brain abscess

• Tumefactive demyelinating disease

• Cerebral infarction

• Meningioma

• Primary CNS vasculitis

Diagnostic criteria

The diagnosis of high-grade glioma is established through clinical assessment, neuroimaging, histopathology, and molecular characterization.

Diagnosis is based on:

• Clinical features suggestive of an aggressive intracranial lesion.

• MRI or CT demonstrating features consistent with a high-grade glioma.

• Histopathological confirmation following biopsy or surgical resection.

• Molecular testing including IDH mutation, ATRX mutation, and 1p/19q codeletion where available.

Investigations

Laboratory investigations

• Full blood picture (FBP)

• Serum electrolytes

Histopathological and molecular studies

• Histopathological examination

• Immunohistochemistry studies:

  • IDH mutation

  • 1p/19q codeletion

  • ATRX mutation

Imaging

• CT scan of the brain

• MRI of the brain (preferred investigation)

• MR spectroscopy

• CT angiography or MR angiography

• Functional MRI (fMRI)

Management

Management aims to maximize survival, preserve neurological function, control symptoms, and maintain quality of life.

Initial management includes:

• Assess airway, breathing, and circulation in unstable patients.

• Perform comprehensive neurological assessment.

• Control seizures according to established guidelines.

• Reduce cerebral edema when indicated.

• Obtain appropriate neuroimaging and histological diagnosis.

• Discuss treatment through a multidisciplinary neuro-oncology team.

Non-pharmacological treatment

Surgical management

• Complete excision of the tumor should be attempted whenever safely feasible, as maximal safe resection is associated with improved survival.

• Preoperative and intraoperative techniques should be used to maximize the extent of safe resection, including:

  • Brain mapping

  • Intraoperative fluorescein guidance to improve resection margins

  • Intraoperative neuromonitoring

• Extent of tumor resection should be assessed using postoperative CT or MRI.

Radiotherapy

Patients should undergo CT-based treatment planning with contrast administration.

Planning recommendations include:

• CT planning with 3–5 mm slice thickness from the vertex to the base of the skull.

• Large volume planning target volume (PTV) should encompass the enhancing lesion identified on preoperative T2/FLAIR imaging with an approximately 2 cm margin.

• Small volume PTV (PTV2) should be based on gadolinium-enhanced T1-weighted MRI demonstrating the enhancing lesion with a 1–2 cm margin.

Recommended radiotherapy schedules:

• Large volume: 2.0 Gy × 23 fractions = 46 Gy, administered 5 days per week.

• Small volume (PTV2): 2.0 Gy × 7 fractions = 14 Gy.

• Total dose: 60 Gy in 30 fractions.

Alternative schedules for patients older than 65 years include:

• 40 Gy in 15 fractions (hypofractionated radiotherapy).

• 5 Gy × 5 fractions.

MR spectroscopy may be useful during follow-up to distinguish tumor recurrence from post-radiotherapy treatment changes.

Pharmacological treatment

Seizure management

• Treat seizures according to established anticonvulsant guidelines.

Concurrent chemoradiotherapy

• Temozolomide – 75 mg/m² – PO – once daily during radiotherapy.

Then:

• Temozolomide – 150–200 mg/m² – PO – once daily on days 1–5 – every 28 days – for 6 cycles after completion of radiotherapy.

Supportive treatment during chemotherapy:

• Oral steroids and Ondansetron should be administered 30 minutes before each Temozolomide dose.

• Temozolomide tablets should be taken first thing in the morning on an empty stomach.

• Co-trimoxazole – one tablet – PO – twice daily – during daily Temozolomide treatment for prophylaxis against Pneumocystis jirovecii pneumonia (PCP).

Management according to underlying cause

Newly diagnosed high-grade glioma

• Maximal safe surgical resection.

• Concurrent radiotherapy and Temozolomide chemotherapy.

• Adjuvant Temozolomide following completion of radiotherapy.

Recurrent disease

• Repeat surgery should be considered in selected patients to relieve symptoms, improve performance status, improve quality of life, and reduce corticosteroid requirements.

• Repeat radiotherapy may be considered depending on previous radiation dose and lesion size.

• Where surgery or repeat radiotherapy is unsuitable, palliative chemotherapy may be offered.

Active chemotherapy regimens include:

• BCNU

• PCV

• Temozolomide

• Irinotecan

• Bevacizumab

Referral

Refer all patients with suspected or confirmed high-grade glioma urgently to a neurosurgical and neuro-oncology specialist.

Urgent referral is indicated for patients with:

• New-onset or uncontrolled seizures

• Rapid neurological deterioration

• Progressive focal neurological deficits

• Features of raised intracranial pressure

• Altered level of consciousness

• Radiological evidence of aggressive tumor growth

• Suspected recurrent disease requiring specialist management

Complications

• Raised intracranial pressure

• Cerebral edema

• Recurrent seizures

• Progressive neurological deficits

• Cognitive impairment

• Tumor recurrence

• Radiation necrosis

• Treatment-related myelosuppression

• Endocrine dysfunction involving the pituitary gland following cranial irradiation

• Venous thromboembolism

Prognosis

High-grade gliomas carry a poor prognosis despite aggressive multimodal treatment. Prognosis depends on age, functional status, molecular characteristics (particularly IDH mutation status), extent of surgical resection, and response to chemoradiotherapy. Maximal safe resection followed by concurrent radiotherapy and Temozolomide remains the standard treatment associated with the best survival outcomes.

Prevention

There are no established methods for preventing high-grade gliomas. Early recognition of progressive neurological symptoms and prompt neuroimaging facilitate early diagnosis and treatment. Long-term follow-up with clinical assessment and serial MRI is essential for detecting recurrence, monitoring treatment response, and identifying endocrine dysfunction after cranial radiotherapy.