Butterfly Glioblastoma: Morphology, Diagnosis, and Treatment

Butterfly glioblastoma is a rare and aggressive brain tumor known for its rapid growth and poor prognosis. It spreads across both hemispheres through the corpus callosum, creating a symmetrical “butterfly” shape on imaging scans. Its deep location and invasive nature make treatment highly challenging, often resulting in limited survival despite medical intervention.

Understanding its morphology, diagnostic methods, and treatment options is crucial for improving patient outcomes.

Morphological And Anatomical Traits

Butterfly glioblastoma is distinguished by its infiltration of the corpus callosum, the dense bundle of nerve fibers connecting the brain’s hemispheres. This facilitates its bilateral spread, creating the characteristic symmetrical appearance seen on imaging. Unlike more localized glioblastomas, which remain confined to one hemisphere, butterfly glioblastoma extends across the midline, often affecting the frontal and parietal lobes. This widespread invasion disrupts interhemispheric communication, leading to cognitive impairment, motor dysfunction, and personality changes.

Histologically, it mirrors conventional glioblastoma, classified as a WHO grade 4 astrocytoma. It features a heterogeneous cellular structure with necrosis, microvascular proliferation, and pseudopalisading necrotic cells—hallmarks of its aggressive nature. Extensive necrosis reflects rapid tumor growth, outpacing its blood supply and creating hypoxic conditions that further drive malignancy. The high degree of microvascular proliferation leads to abnormal, leaky blood vessels, exacerbating peritumoral edema and increasing intracranial pressure.

The tumor’s diffuse infiltration into surrounding white matter tracts makes complete surgical resection nearly impossible. Tumor cells migrate along myelinated fibers, particularly through the corpus callosum’s anterior and posterior portions, allowing for widespread dissemination. This infiltration pattern contributes to resistance to conventional therapies, as malignant cells often extend beyond the visible tumor mass, leading to recurrence even after aggressive treatment.

Diagnostic Imaging Methods

Imaging is essential for identifying butterfly glioblastoma due to its deep-seated location and extensive infiltration. Magnetic resonance imaging (MRI) is the gold standard, offering detailed visualization of the tumor’s spread. T1-weighted MRI with contrast enhancement typically shows a heterogeneously enhancing lesion with irregular borders, reflecting the disrupted blood-brain barrier and abnormal vascular proliferation. The “butterfly” shape is most apparent on axial and coronal views. T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences highlight peritumoral edema, indicating widespread infiltration into surrounding white matter.

Advanced imaging techniques refine diagnosis and treatment planning. Diffusion tensor imaging (DTI) assesses white matter tract involvement, mapping displacement and disruption of major fiber pathways in the corpus callosum. Fractional anisotropy values from DTI reveal reduced integrity in affected regions. MR spectroscopy provides metabolic profiling, typically showing elevated choline, reduced N-acetylaspartate, and increased lactate, indicating high cellular turnover and anaerobic metabolism. These metabolic changes help distinguish butterfly glioblastoma from other midline lesions such as lymphoma or demyelinating diseases.

Perfusion-weighted MRI quantifies cerebral blood volume (CBV) and blood flow, with glioblastomas typically exhibiting increased CBV due to microvascular proliferation. Dynamic susceptibility contrast (DSC) imaging highlights abnormal perfusion, identifying the most aggressive tumor components for biopsy or targeted therapy. Positron emission tomography (PET) using radiotracers such as 18F-fluorodeoxyglucose (FDG) or 18F-fluoroethyl-l-tyrosine (FET) enhances diagnostic precision by assessing metabolic activity. Butterfly glioblastomas show intense FDG uptake, reflecting high glucose metabolism, while FET-PET delineates tumor margins more accurately than standard MRI.

Molecular And Genetic Markers

The molecular profile of butterfly glioblastoma aligns with conventional glioblastoma, though its midline infiltration suggests genetic factors influencing its aggressive spread. One of the most defining mutations is in the telomerase reverse transcriptase (TERT) promoter, present in most cases. This mutation drives unchecked proliferation by maintaining telomere length, allowing tumor cells to evade senescence. Epidermal growth factor receptor (EGFR) amplification, particularly EGFRvIII mutations, enhances tumor survival by activating oncogenic pathways such as PI3K/AKT and RAS/MAPK, promoting its invasive spread.

Loss of tumor suppressors like PTEN and CDKN2A further accelerates progression. PTEN deletions, found in nearly half of glioblastomas, activate the PI3K/AKT pathway, promoting cell survival and resistance to apoptosis. Similarly, homozygous deletion of CDKN2A disrupts cell cycle regulation by disabling the RB and p53 pathways, enabling unchecked proliferation. The absence of IDH1 and IDH2 mutations, common in lower-grade gliomas, is linked to poorer prognosis and a more infiltrative growth pattern, consistent with butterfly glioblastoma’s behavior.

Epigenetic modifications also play a role, with MGMT promoter methylation serving as a key biomarker for treatment response. MGMT encodes a DNA repair enzyme that counteracts the effects of alkylating agents like temozolomide, the standard chemotherapy for glioblastoma. Methylation silences MGMT, impairing DNA repair and improving chemotherapy efficacy. Patients with MGMT-methylated tumors experience longer progression-free survival, though resistance can still develop through alternative repair mechanisms.

Current Treatment Modalities

Treating butterfly glioblastoma is challenging due to its deep location and extensive infiltration. Standard therapy follows the Stupp protocol, combining maximal safe surgical resection, radiotherapy, and temozolomide chemotherapy. Complete resection is rarely possible, so surgery focuses on debulking while preserving neurological function. Even partial resection can improve short-term outcomes by reducing tumor burden and intracranial pressure, though recurrence remains inevitable.

Radiotherapy follows surgery, with a standard dose of 60 Gy over six weeks targeting residual tumor cells while minimizing damage to healthy tissue. Intensity-modulated radiation therapy (IMRT) and proton therapy improve precision, reducing exposure to surrounding brain structures. Concurrent temozolomide enhances radiosensitivity, with a maintenance phase extending up to six months. Patients with MGMT promoter methylation typically respond better to temozolomide, though resistance often develops, necessitating alternative strategies such as tumor-treating fields (TTFields), which disrupt cancer cell division through low-intensity electric fields.