Abstract

Background: Glioblastoma multiforme (GBM) is a highly aggressive malignant tumor known to be a great mimicker. Multicystic metastasis and cystic GBM are not rare but multicystic diffuse GBM was never reported before.

Case Description: We describe here the clinical course, the radiological characteristics, and the management of a patient with a diffuse cystic brain lesion. Even though the comprehensive bacterial, fungal, and parasitic work-up came back negative twice, the radiological and biological findings of the case presented in this work mislead an experienced multidisciplinary team. In a somewhat unexpected way, the pathological results showed a high-grade glial tumor.

Conclusion: The case reported herein is an important reminder of the highly multimorph characteristics of GBM and the challenging differential diagnosis of cystic brain lesions.

Keywords: Cystic brain lesion, Cystic glioblastoma, Multicentric glioblastoma, Multifocal glioblastoma

INTRODUCTION

Cystic brain lesions present a challenging differential diagnosis, including infectious and tumoral entities.[ 31 , 32 ] Among them, glioblastoma multiforme (GBM) is a highly aggressive malignant tumor known as a great mimicker.[ 6 , 10 , 26 , 27 , 32 ] Cystic GBM is considered a rare subtype or atypical form, with its prevalence reported between 7 and 23% of all GBM cases.[ 6 , 22 , 25 , 27 , 36 ] It typically manifests as a large primary cystic lesion accompanied by smaller heterogeneous solid/ cystic “sister” lesions, rarely invading both hemispheres, and is genetically indistinguishable from typical GBM.[ 7 , 17 , 27 , 29 , 32 ] A recent meta-analysis identified the cystic component as being positively associated with overall survival, larger tumor volume, slower growth, and younger age at diagnosis.[ 27 ] Although cystic GBM masquerading as an infectious process has been previously reported, diffuse bihemispheric cystic GBM perfectly mimicking parasitic multifocal cystic lesions has never been documented before.[ 22 , 30 , 32 ] Here, we report a unique case of multifocal/multicentric cystic GBM that does not align with the previously described characteristics and radiologically mimics parasitic-like cystic lesions, initially escaping multidisciplinary work-up.

CASE REPORT

The patient, a 60-year-old man with no notable comorbidities or medical history but with extensive travel experience as a former diplomat deployed to Central America, the Middle East, and Southeast Asia, presented to the emergency department of a peripheral hospital after an inaugural episode of a left upper arm myoclonic seizure. The neurological examination did not reveal any deficit. The Karnofsky Performance Status (KPS) at presentation was 90.

Imaging

Computed tomography (CT) scan followed by magnetic resonance imaging (MRI) revealed bihemispheric supratentorial intra-axial multicystic periventricular, intraventricular, and subcortical ring-enhancing lesions infiltrating mainly the frontal lobes with fronto-mesial predominance, as well as the corona radiata and corpus callosum [ Figures 1 and 2 ]. These lesions were iso/ hypointense on T1 sequences, associated with hyperintense T2 signal and mild perilesional edema, without attenuation on fluid-attenuated inversion recovery (FLAIR) imaging or diffusion restriction on diffusion-weighted imaging and apparent diffusion coefficient sequences. Some eccentric susceptibility-weighted imaging (SWI) hypointensities were observed, along with significant ring enhancement following Gadolinium injection [ Figures 1 and 3a-c ]. The CT scan did not show any calcifications of the cystic lesions.

Figure 1:

Diagnostic axial magnetic resonance imaging images. (a) T1-weighted; (b) T2-weighted; (c) T2 fluid-attenuated inversion recovery; (d) diffusion-weighted imaging; (e) apparent diffusion coefficient; (f) susceptibility-weighted imaging; and (g-i) T1 gadolinium-enhanced imaging. Notice the diffuse, multifocal and bihemispheric extension on (a-i). Notice the local perilesional edema on (b and c). Notice the multicystic component without diffusion restriction but the presence of susceptibility-weighted imaging intracystic excentric signal drops on (d-f). Notice the annular contrast enhancement of all cysts and of the main solid supracallosal component on (g).

Figure 2:

3D reconstruction of the skin of the head, ventricles and the lesions (iPlan, Brainlab). (a) lateral oblique view. (b) dorsal view. Skin is colored in pink. Ventricles are colored in blue. Tumoral lesions are colored in yellow.

Figure 3:

Pre- and post-oncological treatment MRI images. (a-c) sagittal-coronal-axial T1 gadolinium-enhanced images obtained before biopsy and oncological treatment. (d-f) sagittal-coronal-axial T1 gadolinium-enhanced images obtained at 6 months after the first oncological treatment. Notice the decreased pericystic contrast enhancement and the volumetric progression of the initially small supracallosal solid lesion (plain white arrow).

Multidisciplinary discussion and biological work-up

Given the lesion characteristics and the patient’s extensive travel history, an infectious etiology was initially suspected. The patient was started on antiepileptic treatment and referred to our institution for extensive blood and cerebrospinal fluid (CSF) work-up as well as a brain biopsy. During the first multidisciplinary discussion involving infectious disease specialists, parasitologists, radiologists, and neurosurgeons, neurocysticercosis (Taenia solium) was considered less likely due to the homogeneous intracystic content and the presence of eccentric SWI hypointensities on MRI. Cryptococcus neoformans was also considered, as the lesions were near the midline, following the Virchow-Robin spaces, without FLAIR attenuation; however, lumbar puncture did not reveal meningitis, and repeated polymerase chain reaction tests for Cryptococcus antigen were negative.[ 4 , 21 ] Cerebral amebiasis (Entamoeba histolytica) was also discussed. Tumoral lesions were initially deemed less probable. A complete biological work-up, including blood and CSF analysis, was negative twice for any viral, bacterial, fungal, or parasitic infection [ Table 1 ].

Table 1:

Biological workup.

Pathology

Given these results, an open biopsy of the main right frontal paramedian cyst was performed through a right frontal paramedian craniotomy without complications. Unexpectedly, pathology revealed a high-grade glial tumor. Combined histo-molecular analysis confirmed a diagnosis of glioblastoma, central nervous system (CNS) World Health Organization (WHO) grade 4, IDH-wildtype, with a PIK3CA mutation, an unknown EMK4::MCF2L fusion, and intermediate MGMT promoter methylation status.

Oncology

In light of the pathological results, multidisciplinary consensus deemed local treatment inappropriate due to the diffuse multifocal disease. Temozolomide therapy was initiated. After 1 month, the patient developed symptomatic cerebral edema requiring corticosteroids. Bevacizumab was added, and temozolomide was replaced by Lomustine following evidence of radiological progression. Follow-up MRI showed significant response with disappearance of the cystic lesions’ contrast ring-enhancement but progression of the main tumor focus centered on the right cingulate gyrus [ Figure 3 ]. Subsequently, palliative whole-brain radiotherapy (30 Gy) was administered. The patient developed gait instability with frequent falls leading to multiple hospitalizations. After 9 months of second-line treatment, further progression was confirmed, and targeted therapy against PIK3CA using Idelalisib was initiated. Unfortunately, 2 weeks later, he developed mechanical ileus related to a suspected (but unconfirmed) colorectal cancer. A palliative colostomy was performed. At that point, the KPS was 50. The patient died 1 month later from gastrointestinal complications.

DISCUSSION

GBM is a highly aggressive tumor characterized by poor prognosis due to its infiltrative nature, genetic heterogeneity, and multiform presentation.[ 6 , 27 ] Among its subtypes, cystic GBM is relatively rare, comprising 7–23% of cases.[ 33 ] Despite its distinctive radiological appearance, cystic GBM is not classified as a separate entity in the 2021 WHO classification of CNS tumors.[ 33 ] Two main hypotheses have been proposed regarding its development: transformation from a cystic low-grade glioma, more frequently observed in younger patients, and central necrotic liquefaction within the tumor mass.[ 15 , 28 , 32 ] Cystic GBMs are often associated with a highly inflammatory and invasive environment and are noted to have a distinct intracystic protein signature.[ 8 , 12 , 28 ] Some studies suggest that cystic features might reduce tumor invasiveness, potentially contributing to longer survival,[ 5 , 20 , 25 , 27 , 34 ] although others report no significant survival advantage even following surgical resection.[ 12 , 14 , 28 ]

An even rarer presentation is multifocal and multicentric GBM (mGBM), accounting for <2% of malignant gliomas.[ 15 , 16 ] Multifocal GBM refers to multiple lesions connected by T2/FLAIR hyperintensities, indicating infiltration along white matter tracts, whereas multicentric GBM is characterized by independent tumor foci separated by at least 1 cm with no visible connection.[ 19 ] Although the precise pathogenic mechanisms underlying mGBM remain unclear, it is believed that malignant glial cells in mGBM have an enhanced capacity for dissemination, potentially spreading along white matter fibers, ventricles, or the cerebral cortex.[ 35 ] Due to the diffuse and infiltrative nature of mGBM, the role of cytoreductive surgery in improving survival remains controversial.[ 9 , 11 , 16 , 24 ]

When both cystic and multifocal/multicentric features coexist, as in cystic mGBM, the presentation becomes exceedingly rare and even more diagnostically challenging.[ 15 , 17 , 27 , 30 , 32 ] In our case, the multicystic GBM closely mimicked a parasitic infection, initially misleading the multidisciplinary team and delaying the correct diagnosis.

The molecular landscape of multicystic GBM remains poorly defined. Among identified alterations, Cytochrome B5 reductase 2 (CYB5R2) gene hypomethylation and subsequent overexpression have been associated with poor survival outcomes in mGBMs, likely due to enhanced invasiveness and altered immunoregulation.[ 23 ] In contrast, while PIK3CA mutations – identified in our patient – are known to promote glioma cell survival, they have not been consistently linked to worsened prognosis in mGBM.[ 1 , 3 , 13 ]

Treatment options for mGBM are limited and challenging. Whole-brain radiotherapy combined with concurrent temozolomide has been considered a safe approach.[ 16 , 18 ] However, therapeutic response can be unpredictable; for instance, bevacizumab, although frequently used, has been associated with phenomena such as pseudoprogression or pseudoresponse, complicating assessment of treatment efficacy.[ 2 ] In our patient, initial rapid progression occurred under temozolomide, yet stabilization was achieved for nearly a year with a combination of lomustine, bevacizumab, and radiotherapy.

CONCLUSION

The specific molecular profile, optimal management strategies, and prognosis of cystic mGBM remain unknown. The unique case reported herein highlights the polymorphic nature of GBM, reinforcing its inclusion in the differential diagnosis of cystic brain lesions, even when diffuse multicystic features are present.

Authors’ contributions:

D.K-B. and M.W. Wrote the main manuscript text and prepared the figures. All authors collected and analyzed the data. All authors reviewed the manuscript.

Ethical approval:

The Institutional Review Board approval is not required. All procedures performed were in accordance with the 1964 Helsinki Declaration and its later amendments.

Declaration of patient consent:

The authors certify that they have obtained all appropriate patient consent.

Financial support and sponsorship:

Nil.

Conflicts of interest:

There are no conflicts of interest.

Use of artificial intelligence (AI)-assisted technology for manuscript preparation:

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

Disclaimer

The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Journal or its management. The information contained in this article should not be considered to be medical advice; patients should consult their own physicians for advice as to their specific medical needs.

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