Giant Cell Glioblastoma: Symptoms, Types, Causes and Treatment

Giant cell glioblastoma (GCGBM) is a rare subtype of glioblastoma, itself the most aggressive form of primary brain tumor. Although sharing many features with classic glioblastoma, GCGBM stands out for its distinctive cellular makeup, unique molecular characteristics, and, in some cases, a slightly better prognosis. In this article, we explore the symptoms, types, causes, and treatment options for GCGBM, drawing on the latest scientific research to provide a comprehensive and accessible overview.

Symptoms of Giant Cell Glioblastoma

Giant cell glioblastoma can present with a range of neurological and systemic symptoms. These symptoms are primarily driven by the tumor's location, size, and the rapidity with which it grows. Understanding the presentation is essential for timely diagnosis and management.

Main Symptom	Typical Presentation	Frequency/Context	Source
Seizures	Generalized or focal	Common initial symptom	1
Headache	Persistent, worsening over days	Often accompanied by nausea/vomiting	1
Vomiting	Often with headache	Indicates increased intracranial pressure	1
Hemiparesis	Weakness on one side	Depends on tumor location	1
Acute Deterioration	Rapid consciousness loss	Rare, linked to subdural hematoma	2

Table 1: Key Symptoms

Typical Clinical Presentations

Giant cell glioblastoma’s initial symptoms often overlap with other brain tumors but are notable for:

• Seizures: Frequently the first sign, especially generalized seizures, as reported in a 42-year-old patient who had a three-month history of seizures before diagnosis 1. Seizures result from the tumor's irritative effect on the surrounding brain tissue.
• Headaches and Vomiting: Headaches are common and tend to worsen over time, sometimes accompanied by vomiting, which signals increased intracranial pressure. The headaches may escalate rapidly, especially in the week prior to diagnosis 1.
• Neurological Deficits: Depending on the tumor's site—most commonly in the cerebral hemispheres, particularly the temporal and parietal lobes—patients can develop focal neurological signs such as hemiparesis (weakness of one side of the body) 1.

Rare and Acute Presentations

Though uncommon, GCGBM can present acutely:

• Sudden Neurological Collapse: In rare instances, GCGBM may cause acute subdural hematoma without trauma, leading to rapid loss of consciousness and other severe symptoms. This occurs due to invasion of blood vessels by the aggressive tumor 2.

Symptom Progression

• Short Clinical History: Unlike secondary glioblastomas, GCGBM often develops rapidly, with symptoms appearing and worsening over weeks to a few months 9.
• Cognitive and Personality Changes: As with other glioblastomas, patients may experience subtle personality changes, confusion, or memory loss if the tumor affects the frontal lobes.

Types of Giant Cell Glioblastoma

While GCGBM is itself a subtype of glioblastoma, further distinctions exist based on cellular, molecular, and histopathological features. Understanding these types is crucial for diagnosis, prognosis, and ultimately, management.

Subtype	Key Features	Prognosis/Notes	Source
Classic GCGBM	Multinucleated giant cells, p53 mutation	Slightly better than typical GBM	3 4 7 8 9 10
GCGBM with Calcification	Calcified tumor areas, younger patients	May indicate longer survival	1
GCGBM with Lipidization	Massive lipid accumulation	Linked to better outcomes	1
Overlap with PXA	Some histologic similarity to PXA	Requires careful distinction	5

Table 2: GCGBM Subtypes and Variants

Histopathological Subtypes

• Classic GCGBM: Defined by strikingly bizarre, multinucleated giant cells. These tumors are highly pleomorphic and display frequent mitoses 1 3 4.
• GCGBM with Calcification: Although calcification is rare in high-grade gliomas, when present in GCGBM, it may signal a better prognosis. Calcified GCGBM has been reported to occur in younger patients and is associated with longer survival—sometimes even in the absence of aggressive therapy 1.
• GCGBM with Lipidization: Some rare cases, especially in pediatric patients or those with neurofibromatosis, display massive lipidization within the tumor, a feature also linked to longer survival 1.

Molecular and Immunohistochemical Subtypes

• p53-Mutant GCGBM: The majority of GCGBMs harbor mutations in the TP53 gene. This molecular signature distinguishes them from classical primary glioblastomas (which often have EGFR amplification) and aligns them more closely with secondary glioblastomas and pleomorphic xanthoastrocytoma (PXA) 3 5 7 8 9 10.
• Overlap with PXA: Both GCGBM and PXA may show giant cells and some shared immunohistochemical features. However, strong p53 staining is more common in GCGBM, while PXAs more often express neuronal antigens 5. Accurate diagnosis relies on careful histological and molecular analysis.

Unique Clinical Contexts

• Pediatric GCGBM: Exceptionally rare but reported, sometimes with distinctive features (e.g., calcification, lipidization) and longer survival 1.
• GCGBM vs. Secondary Glioblastoma: While classic GCGBM typically arises de novo, some molecular features overlap with secondary glioblastomas, especially the high frequency of TP53 mutations and younger age at presentation 6 7 8 9.

Causes of Giant Cell Glioblastoma

The precise cause of GCGBM remains elusive, but significant advances in molecular genetics have illuminated the pathways that drive its development. Understanding these causes not only aids in diagnosis but may also guide future therapies.

Factor	Description	Impact/Notes	Source
TP53 Mutation	High frequency in GCGBM	Central to tumor development	3 7 8 9 10
EGFR Amplification	Rare in GCGBM, common in classic GBM	May explain better prognosis	3 6 7 8 9
IDH Mutation	Rare or absent in GCGBM	Indicates de novo origin	6 7 8
PTEN Mutation	Seen in ~30% of cases	Tumor suppressor loss	8
Other Genetic Changes	ATRX, RB1, NF1 alterations, low TML	Impacts prognosis and therapy	7

Table 3: Causative and Molecular Factors

Key Molecular Pathways

• TP53 Mutations: The overwhelming majority of GCGBMs exhibit mutations in the TP53 gene (encoding tumor suppressor protein p53), with rates as high as 75–100% reported across studies 3 7 8 9 10. These mutations disrupt normal cell cycle control and are central to tumorigenesis in this subtype.
• EGFR Pathway: Unlike classic primary glioblastoma, EGFR amplification is uncommon in GCGBM (seen in only about 6% of cases). This molecular difference may contribute to the relatively better prognosis of GCGBM, as EGFR amplification is linked to more aggressive tumor behavior 3 6 7 8 9.
• IDH Mutations: These are almost always absent in GCGBM, supporting the idea that this tumor arises de novo (primary glioblastoma) rather than evolving from lower-grade astrocytoma (secondary glioblastoma) 6 7 8.

Additional Genetic Alterations

• PTEN Mutations: Present in roughly one-third of GCGBM cases, PTEN loss further disrupts regulation of cell growth and survival 8.
• ATRX, RB1, NF1 Mutations: Recent studies have identified mutations in genes such as ATRX (involved in chromatin remodeling), RB1 (cell cycle regulation), and NF1 (neurofibromin), particularly in GCGBMs with a high number of giant cells. These add to the landscape of genetic changes influencing tumor behavior 7.
• Low Tumor Mutational Load (TML): Most GCGBMs have low TML, which may influence the response to immunotherapy. Rare ultra-mutated cases may benefit from immune checkpoint blockade 7.

Non-Genetic Factors

• Age and Gender: GCGBM tends to occur in younger individuals compared to classic GBM and shows a slight male preponderance 1 4.
• Environmental Risks: Aside from rare genetic predispositions (e.g., neurofibromatosis) and prior exposure to brain irradiation, no clear environmental risk factors for GCGBM have been identified 12.

Treatment of Giant Cell Glioblastoma

Treating GCGBM remains a challenge, as with all glioblastomas. However, certain aspects of GCGBM—such as its tendency to be more circumscribed and its distinct molecular profile—may offer therapeutic opportunities. Here, we outline the standard of care, emerging options, and future directions.

Treatment	Description	Impact/Outcome	Source
Surgical Resection	Maximal safe tumor removal	Improves survival	1 4
Radiotherapy	Adjuvant after surgery	Associated with better outcomes	4
Chemotherapy	Temozolomide is standard	Standard, prolongs survival	1 4 12
Immunotherapy	Checkpoint inhibitors, CAR T, vaccines	Experimental; some promising results in high TML	7 11 14
Targeted Therapy	PI3K/AKT/mTOR, BRAF, others	Under investigation	12 15
Nanomedicine	Drug delivery via dendrimers, etc.	Potential to enhance efficacy	13

Table 4: Treatment Approaches

Standard of Care

• Surgical Resection: The first step is maximal safe removal of the tumor. GCGBM's tendency to be more circumscribed than classic GBM may allow for more complete resection, which is associated with longer survival 1 4.
• Radiotherapy: Postoperative radiotherapy is standard and has been linked to improved outcomes. Adjuvant radiation is particularly important in maximizing disease control 4.
• Chemotherapy: Temozolomide, administered concurrently with radiotherapy and continued as maintenance, is the standard chemotherapeutic regimen for glioblastoma, including GCGBM 1 4 12.

Molecularly Targeted and Experimental Therapies

• Immunotherapy: While most glioblastomas respond poorly to immunotherapy due to a highly immunosuppressive microenvironment, rare GCGBMs with ultra-high mutational burdens may benefit from immune checkpoint inhibitors. Research is ongoing into vaccines, CAR T-cell therapy, and combination immunotherapies 7 11 14.
• Targeted Therapies: Inhibitors of pathways such as PI3K/AKT/mTOR, and agents targeting BRAF or NTRK fusions, are being studied in select cases. However, thus far, these targeted approaches have not significantly improved outcomes for the majority of patients 12 15.
• Nanomedicine: Novel drug delivery systems, such as dendrimer nanomolecules, are being developed to improve drug penetration across the blood-brain barrier and enhance tumor targeting. These approaches hold promise for the future treatment of glioblastoma, including GCGBM 13.

Prognosis and Special Considerations

• Prognosis: Patients with GCGBM generally have a better prognosis than those with classic GBM, with some achieving long-term survival, especially when complete resection and adjuvant therapies are possible 4. Histological features such as calcification, multinucleated giant cells, and robust lymphocytic infiltration are linked to improved outcomes 1.
• Personalized Medicine: The molecular profile of each tumor—such as the presence of TP53 mutations, low EGFR amplification, or high TML—may increasingly guide therapy choices in the future 7 12.

Conclusion

Giant cell glioblastoma is a rare, distinct, and complex brain tumor subtype, marked by unique clinical, pathological, and molecular features. While it often carries a grave prognosis, certain characteristics—such as the potential for more complete surgical removal and a slightly better response to therapy—offer hope for improved outcomes.

Key Points:

• GCGBM presents most often with seizures, headaches, vomiting, and focal neurological deficits, with a rapid progression of symptoms 1.
• It is defined by the presence of bizarre multinucleated giant cells and a high frequency of TP53 mutations, distinguishing it from classic glioblastoma 3 7 8 9 10.
• Subtypes include those with calcification or lipidization, and some overlap histologically with pleomorphic xanthoastrocytoma (PXA) 1 5.
• Causes are rooted in specific genetic alterations, especially TP53 mutations, and GCGBM typically arises de novo in younger adults 3 6 7 8 9 10.
• Treatment follows the standard glioblastoma approach: maximal safe resection, radiotherapy, and temozolomide chemotherapy, with emerging roles for immunotherapy and nanomedicine in select cases 1 4 7 11 12 13 14 15.
• Prognosis is somewhat better than classic GBM, especially when complete resection is achievable and favorable histological features are present 4.

Continued research into the molecular underpinnings and novel therapeutic strategies for GCGBM holds promise for further improving patient outcomes in the years ahead.