Key-words:
Cerebral imaging - diagnosis - glioblastoma - headache - magnetic resonance imaging - occult brain tumor
Introduction
Glioblastomas (GBs) are the most common malignant tumors of the brain with high mortality. Primary or de novo GBs are tumors with no evidence of a low-grade precursor tumor and are typically diagnosed in <3 months in 68% and <6 months in 86% of cases after the emergence of the first symptoms.[[1]] Nevertheless, the presenting signs and symptoms of GBs manifest rapidly and exhibit differences owing to the tumor's location and expansion, displacement, or infiltrative destruction of the neural structures. These signs and symptoms include progressive and pulsating headaches, new-onset epileptic seizures, focal neurological deficits, and altered mental status.[[2]] Magnetic resonance imaging (MRI) is the conventional noninvasive diagnostic tool for GBs.[[3]] A typical GB exhibits central necrosis, remarkable edema, mass effect, and a strong contrast enhancement indicating blood–brain barrier disruption on T1-weighted images, with a hyperintense appearance on T2-weighted images.
However, patients presenting with neurological symptoms, albeit with normal computed tomography (CT) or MRI findings, might be harboring occult brain tumors like GB.[[4]] Notably, GBs can manifest variously. Notably, patients in whom the tumor was detected within days had exhibited acute neurological signs and symptoms, such as acute-onset transient hemiparesis,[[5]] vomiting, headache, and seizure.[[6]] Therefore, in patients with negative findings, the average time until a diagnosis could range from days[[5]],[[6]] to months.[[4]],[[7]]
This paper describes two cases of GBs diagnosed 3.5 and 4 months, respectively, after an initial completely normal MRI imaging. Both patients presented with no neurological signs and symptoms even at their second admission, except for a headache.
Case Reports
Case 1
A 51-year-old woman presented with persistent right frontal headache. She was previously admitted to another medical center for her headache and discharged home with medication 4 months ago. Her initial cranial CT and magnetic resonance (MR) images were all within normal limits [[Figure 1]]a, [[Figure 1]]b, [[Figure 1]]c. Her neurological examination was unremarkable, but a mass lesion with heterogeneous contrast enhancement and necrosis was detected in the right frontal lobe on T1-weighted MR images of the patient. In addition, the T2-weighted images revealed hyperintense areas with severe edema [[Figure 1]]d, [[Figure 1]]e, [[Figure 1]]f. The patient underwent a right frontal craniotomy and gross total resection of the tumor, with a final pathological diagnosis of GB.
Figure 1: Case 1. Initial noncontrast axial computed tomography (a) and T1-weighted (b), and coronal T2-weighted magnetic resonance imaging (c) with no abnormality. Noncontrast T1-weighted magnetic resonance imaging demonstrated a mass lesion in the right frontal lobe (d), with heterogeneous contrast enhancement and necrosis on postcontrast axial T1-weighted magnetic resonance imaging (e) and hyperintense areas with strong edema on coronal T2-weighted magnetic resonance imaging (f) 4 months later
Case 2
A 60-year-old woman was admitted with a severe right-sided headache. She had a headache 3.5 months earlier and had undergone MR imaging with normal findings [[Figure 2]]a and [[Figure 2]]b. The patient's neurological examination was within normal limits; however, she had an epileptic seizure just before the radiological examination. MR images revealed a well-demarcated mass lesion in the right temporal lobe with strong contrast enhancement on T1-weighted images [[Figure 2]]c. In addition, the sulci were closed, and the midline structures were swollen because of edema in the right cerebral hemisphere. The patient underwent a right temporal craniotomy and gross total resection of the tumor, with a final pathological diagnosis of GB.
Figure 2: Case 2. Initial noncontrast axial T1-weighted (a) and T2-weighted magnetic resonance imaging (b) with no abnormality. A well-demarcated mass lesion in the right temporal lobe showing strong contrast enhancement on T1-weighted magnetic resonance imaging (c) 3.5 months later; the sulci were closed and midline structures were swollen because of edema in the right cerebral hemisphere
Discussion
The two cases presented herein reveal that even the most malignant and deadly brain tumors can remain occult on neuroimaging. Unfortunately, it took 3–4 months to detect brain tumors in these two women after their initial admissions, and a headache was still the only symptom in both patients at their second presentation. Notably, GBs are known to not exhibit any specific symptoms. However, any emergence of neurological deficit or onset of epileptic seizure should warrant an evaluation.[[4]]
Several studies in the literature have described negative CT scan investigations at initial clinical presentations; however, a considerable number of these studies belong to the era with significantly lesser technological advancement.[[8]],[[9]],[[10]] On the other hand, it is well known that the advent of MRI has not entirely improved the situation of delayed diagnosis of occult brain tumors,[[4]],[[7]] and there are insufficient data to determine the precise point of radiographic transformation of the tumors – from the last “negative” image to the first “positive” image.[[4]] Typically, GBs might not be radiologically detected until they cause visible changes in the cerebral tissue or structural abnormalities.[[8]] Therefore, most often, it is impossible to accurately diagnose occult tumors even though some clues are observed on MRI, such as poorly demarcated lesions; inhomogeneous hyperintensity on T2-weighted images with diffuse perilesional edema;[[11]] hyperintensity involving the cortex, subcortical, or both on T2-weighted MRI images;[[3]] subtle hyperintense areas;[[12]] multiple nonenhancing abnormalities; and T2-weighted hyperintensity.[[7]] Moreover, the radiological features of GB lesions are either not recognized or misdiagnosed as a demyelinating process, cerebral infarction,[[11]],[[13]],[[14]] encephalitis,[[11]],[[13]] and venous thrombosis.[[13]] Therefore, a mass exhibiting heterogeneous enhancement, central necrosis, and ill-defined, small isointense-to-hypointense lesions on T1-weighted and hyperintense lesion on T2-weighted images without edema and contrast enhancement should be considered typical for developing GBs.[[11]],[[13]]
It was reported that advanced MRI techniques to evaluate the physiological or metabolic properties of lesions, such as diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI), and to measure cerebral blood volume, such as dynamic susceptibility contrast MRI, may help to locate the extremely small tumor nests that remain undetected.[[15]],[[16]] Although Ideguchi et al.[[13]] found no abnormalities in the outcomes of DWI performed on a patient presenting with a headache in the left frontal lobe, Baehring et al.[[15]] showed that increased signal intensity on DWI was very useful in identifying early stage of malignant gliomas. Furthermore, MR spectroscopy (MRS) and positron emission tomography (PET) with 11C-methionine (MET) (MET–PET) are very valuable imaging techniques for patients with any identifiable or challenging lesions.[[16]],[[17]] Increased choline and reduced N-acetylaspartate levels detected and revealed MET uptake in the lesion in MRS and MET-PET, respectively, are important indicators for GBs.[[17]] Currently, standard brain MR imaging protocols in most radiology centers include DWI but not PWI. It is clear that the use of modern supplementary MR sequences with PET and MET–PET may facilitate accurate and early diagnosis of these tumors, especially in suspicious or challenging cases.
Both cases presented here only had conventional MRI without advanced techniques, and no abnormal or suspicious radiological findings were detected until their second admission. The characteristic radiological appearance of brain malignancy was based on the findings of strong contrast enhancement and necrosis on T1-weighted images, and hyperintensity on T2-weighted images, and mass effect with edema on both. Nevertheless, GBs could have been detected earlier with repeated neuroimaging in both cases, and the patients could have been treated without any delay. Therefore, early diagnosis of GB is significant in that it provides a chance of timely treatment, including gross total resection, thereby prolonging the progression-free and overall survivals.[[18]]
Therefore, new onset of seizures or a transient neurological deficit even in the absence of any other risk factor is recommended to be considered as glioma in patients, specifically those older than 40 years.[[9]] Moreover, a single high-quality neuroimaging study performed in the emergency setting might be insufficient to detect all malignant primary brain tumors. Hence, it is advised that patients who present with new neurological symptoms should undergo repeat imaging studies even if they had normal radiological findings a short time before.[[4]],[[7]],[[13]] Chittiboina et al.[[4]] reported that the seizures were crucial indicators of shorter time to imaging diagnosis and a worse tumor grade.
Conclusions
GBs might clinically reveal themselves before they emerge radiologically, even if they are not recognized. Therefore, it should be borne in mind that persistent headache could be the only sentinel sign of GBs before they become radiologically visible. Hence, follow-up imaging studies should be performed at short intervals to accurately diagnose the tumor and provide timely treatment to patients because even a single symptom-free moment can provide priceless peace of mind to these patients.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
