Glioblastoma: Symptoms, Types, Causes and Treatment

Glioblastoma is the most common and aggressive form of primary brain cancer in adults. Its rapid progression, complex biology, and resistance to treatment make it a uniquely challenging disease for patients, families, and clinicians. In this comprehensive guide, we'll walk through the key aspects of glioblastoma—its symptoms, major types, underlying causes, and current treatment strategies—empowering you with up-to-date, evidence-based insights drawn from leading clinical research.

Symptoms of Glioblastoma

Glioblastoma's symptoms can be subtle, varied, and often overlap with other neurological conditions. Recognizing these signs early is crucial for timely diagnosis and intervention. Symptoms arise from the tumor's location, size, and rate of growth, often reflecting increased pressure within the brain or disruption of normal neural pathways.

Symptom	Description	Prognostic Value	Source(s)
Headache	Persistent, worse when lying down, may worsen with coughing or straining	May be associated with longer survival, but not independently predictive	1 2 3
Seizures	New-onset, focal or generalized	Sometimes linked to earlier diagnosis and longer overall survival (not independent in multivariate analysis)	1 2 3
Weakness	Muscle weakness, often on one side	Predicts earlier diagnosis and diminished survival	2 3
Cognitive Dysfunction	Memory loss, confusion, personality changes	Independently associated with shorter survival and less aggressive treatment	1 2 3
Visual Changes	Blurred vision, double vision, vision loss	Can suggest raised intracranial pressure	1 2
Speech Changes	Difficulty speaking or understanding	Can occur depending on tumor location	2
Psychiatric Symptoms	Mood/behavioral changes, psychosis	Impact quality of life and sometimes lead to treatment discontinuation	4

Table 1: Key Symptoms

Common Presenting Symptoms

Glioblastoma often manifests with headaches, which may be worse in the morning or when lying down. These headaches can be associated with nausea, vomiting, or visual disturbances—classic signs of raised intracranial pressure. However, not every patient experiences all these symptoms, making diagnosis challenging in the early stages 1.

Seizures are another frequent presenting symptom, especially when the tumor is located near the brain's cortex. New-onset seizures in adulthood always warrant investigation for a possible brain tumor 1 2 3.

Focal Neurological Deficits

Depending on where the tumor is situated, patients may develop:

• Weakness or numbness, typically affecting one side of the body
• Speech and language difficulties
• Visual problems, including loss of vision or double vision
• Difficulty with balance or coordination

Notably, weakness and cognitive dysfunction (such as confusion or memory loss) are not only common but also linked with poorer survival outcomes and may influence the type and aggressiveness of treatment offered 2 3.

Cognitive and Psychiatric Changes

Cognitive impairment—including memory loss, confusion, and personality changes—can be an early or prominent symptom. These changes are especially significant, as patients presenting with cognitive dysfunction tend to have shorter survival and may not be candidates for more aggressive therapies 3.

A smaller subset of patients also develop psychiatric symptoms, including mood changes, behavioral disturbances, or even psychosis. These can seriously impact quality of life and at times lead to discontinuation of treatment. Risk factors for psychiatric symptoms include a prior psychiatric history, certain tumor locations, and some medications used during treatment 4.

Symptom Progression and Red Flags

Symptoms often progress over weeks to months. Any combination of persistent headache with cognitive impairment, new weakness, or personality changes should prompt urgent medical evaluation. New-onset seizures or rapidly worsening neurological symptoms are particularly concerning 1.

Types of Glioblastoma

Glioblastoma encompasses several subtypes, each with distinct biological and clinical features. Understanding these types can help guide prognosis and, increasingly, therapeutic decisions.

Type/Subtype	Key Features	Typical Age Group	Source(s)
Primary (de novo)	Rapid onset, no precursor lesion, EGFR amplification common	Older adults	5 10 15
Secondary	Evolves from lower-grade astrocytoma, TP53 mutations early	Younger adults	5 10
IDH-wildtype	Lacks IDH mutation, most common, poorer prognosis	Mostly adults	5 15
IDH-mutant	Has IDH mutation, better prognosis	Some younger adults	13 14 15
Pediatric Subtypes	Distinct molecular drivers (e.g., H3, MYCN, EGFR)	Children/adolescents	6

Table 2: Major Glioblastoma Types

Primary vs. Secondary Glioblastoma

Primary glioblastoma accounts for the vast majority of adult cases (>90%). These tumors develop rapidly without evidence of a less malignant precursor and typically affect older adults. Molecular features commonly include EGFR gene amplification, loss of chromosome 10q, and PTEN mutations 5 10 15.

Secondary glioblastoma arises from the progression of lower-grade astrocytomas or anaplastic astrocytomas and is more commonly seen in younger patients. TP53 mutations are a hallmark of this pathway, often present in early tumor stages. Despite sharing a similar appearance under the microscope, primary and secondary glioblastomas have distinct genetic and molecular signatures 5 10.

Molecular Subtypes: IDH Status and Beyond

Recently, molecular profiling has refined glioblastoma classification, with IDH (isocitrate dehydrogenase) mutation status being a critical factor:

• IDH-wildtype: Most common in adult glioblastoma, associated with a poorer prognosis.
• IDH-mutant: Less common, tends to occur in younger patients and is linked with a better prognosis 13 14 15.

Other molecular markers, such as MGMT promoter methylation, EGFR variants, and others, can further stratify tumors and predict response to specific therapies 5 13 14 15.

Pediatric Glioblastoma

Glioblastoma in children (pediatric glioblastoma) is biologically distinct from adult forms. Molecular subtypes in children can be defined by alterations in histone 3 variants, MYCN amplification, and others, which affect prognosis and potential therapeutic targets 6. These subtypes show unique genetic and epigenetic features, underlining the necessity of tailored approaches in pediatric patients.

Tumor Heterogeneity

Within a single glioblastoma, there is often significant diversity in cell types and genetic alterations. This intratumoral heterogeneity contributes to treatment resistance and rapid disease progression, making management particularly complex 7 8 13.

Causes of Glioblastoma

Despite decades of research, the exact causes of glioblastoma remain only partially understood. Both genetic and environmental factors play roles, but most cases are sporadic with no clear predisposing event.

Cause/Factor	Role in Glioblastoma	Comments	Source(s)
Genetic Mutations	Key driver (e.g., TP53, EGFR, PTEN)	Vary by subtype	10 12 13
Inherited Disorders	Rare (NF1, Li-Fraumeni, TSC)	Small proportion of cases	11 15
Ionizing Radiation	Only established environmental risk	Previous therapeutic exposure	11 15
Age & Gender	Incidence rises with age, male > female	Not direct causes, but risk factors	5 14 15
Other Environmental	Occupational exposures, cell phones (inconclusive)	No strong evidence	11 15
Immune Factors	Role in tumor microenvironment	Active area of research	8 15

Table 3: Factors Associated with Glioblastoma

Genetic Drivers and Molecular Pathways

Glioblastoma develops through the accumulation of genetic mutations:

• Primary glioblastomas often harbor EGFR amplification, PTEN mutations, and loss of chromosome 10q.
• Secondary glioblastomas are driven by early TP53 mutations, followed by additional genetic alterations as the tumor progresses 10 13.

The identification of cancer stem cells within glioblastomas has revealed their crucial role in tumor initiation, maintenance, and resistance to therapy 12.

Inherited and Environmental Risks

Although most glioblastomas are sporadic, a minority are linked to inherited syndromes such as neurofibromatosis type 1, Li-Fraumeni syndrome, and tuberous sclerosis. These inherited conditions increase the risk but account for only a small portion of cases 11 15.

The only well-established environmental risk factor is exposure to high-dose ionizing radiation, typically from prior therapeutic interventions for other conditions 11 15.

Age, Gender, and Other Factors

Incidence increases with age and is higher in men than women. Some studies have found that a history of allergies or atopic disease may be associated with reduced risk, but the mechanism is unclear 5 11 14 15.

Speculation around occupational exposures or cell phone use as risk factors has not been substantiated by strong evidence 11 15.

Tumor Microenvironment

Recent research highlights the importance of the tumor microenvironment—particularly immune cells such as tumor-associated macrophages—in influencing tumor growth and treatment response. This is an active area of investigation, with implications for future therapies 8 15.

Treatment of Glioblastoma

Managing glioblastoma requires a multimodal approach, combining surgery, radiation, chemotherapy, and supportive care. Despite aggressive treatment, prognosis remains poor, but ongoing research continues to push the boundaries of what's possible.

Treatment Modality	Key Elements	Role/Comments	Source(s)
Surgery	Maximal safe resection of tumor	Improves survival, usually first step	1 9 14 15 18
Radiotherapy	Fractionated external beam radiation	Standard post-surgery	1 9 14 15 18
Chemotherapy	Temozolomide (oral), sometimes with lomustine	Concomitant and adjuvant phases	1 9 14 15 18
Tumor-Treating Fields	Low-intensity alternating electric fields	Approved adjunct to temozolomide	14 18
Bevacizumab	Anti-VEGF antibody	May prolong progression-free survival, not overall survival	14 15 18
Local Therapies	Direct tumor cavity treatments, novel delivery	Under clinical investigation	17
Immunotherapy	Checkpoint inhibitors, CAR T cells, vaccines	Experimental/clinical trials	16 18
Supportive Care	Corticosteroids (edema), antiepileptics, palliative care	Essential throughout disease course	1 4 14

Table 4: Glioblastoma Treatment Modalities

Surgical Management

The primary goal is maximal safe resection—removing as much tumor tissue as possible while preserving neurological function. Surgery not only alleviates symptoms from mass effect but also provides tissue for definitive diagnosis and molecular profiling 1 9 14 15 18.

Radiation and Chemotherapy

After surgery, standard therapy includes:

• Radiotherapy: Fractionated external beam radiation, adapted to patient age, performance status, and tumor location.
• Chemotherapy: Temozolomide, administered concurrently with radiotherapy and continued as adjuvant therapy. The benefit of temozolomide is greater in patients whose tumors show MGMT promoter methylation 1 9 14 15 18.

Some patients may receive lomustine in addition to temozolomide, particularly if their tumor has a hypermethylated MGMT promoter 18.

Tumor-Treating Fields

This novel modality involves the application of low-intensity, alternating electric fields to the scalp. It is approved as an adjunct to adjuvant temozolomide and has shown efficacy in extending progression-free survival 14 18.

Management at Recurrence

Glioblastoma almost always recurs, typically near the original tumor site. Options at recurrence include repeat surgery, re-irradiation, and systemic therapies such as bevacizumab. However, no standard of care exists for recurrent disease, and treatment is tailored to the individual's circumstances 14 18.

Emerging and Local Therapies

Innovative strategies under investigation include:

• Local therapies: Delivering drugs or other treatments directly into the tumor cavity, aiming to maximize local effect and minimize systemic toxicity 17.
• Immunotherapy: Immune checkpoint inhibitors, CAR T-cell therapy, vaccine therapy, and oncolytic viruses are all being tested in clinical trials, with combinatorial approaches offering new hope 16 18.
• Targeted therapies: Attempts to target genetic mutations or specific pathways (e.g., EGFR, PI3K/AKT/mTOR) have so far been unsuccessful in altering the disease course, likely due to tumor heterogeneity and compensatory mechanisms 15.

Supportive and Palliative Care

Given the incurable nature of glioblastoma, supportive care is essential throughout the disease trajectory:

• Corticosteroids help control cerebral edema and reduce symptoms.
• Antiepileptic drugs are used if seizures occur.
• Psychiatric and palliative care teams play a vital role in symptom management, advance care planning, and supporting patients and families 1 4 14.

Conclusion

Glioblastoma is a formidable disease, but advances in research are gradually improving our understanding and management. Here’s a summary of the key points covered:

• Symptoms are diverse, ranging from headaches and seizures to cognitive changes and psychiatric symptoms. Early recognition and multidisciplinary management are crucial.
• Types of glioblastoma include primary and secondary forms, with further stratification by molecular features such as IDH status. Pediatric glioblastoma is biologically distinct.
• Causes are mainly genetic, with most cases arising sporadically. Inherited syndromes and ionizing radiation are rare established risk factors.
• Treatment is multimodal, combining surgery, radiation, chemotherapy, and supportive care. Novel therapies—including immunotherapy and local treatments—are under active investigation.

In summary:

• Glioblastoma remains a major clinical challenge due to its aggressiveness and resistance to therapy.
• Early symptom recognition and molecular classification are essential for optimal care.
• There is an urgent need for continued research into targeted and immune-based therapies.
• Holistic, patient-centered supportive care is vital at every stage of the disease.

With ongoing progress in understanding tumor biology and the development of innovative therapies, there is hope for improved outcomes for patients facing this difficult diagnosis.