Sudden, unexpected death due to glioblastoma: report of three fatal cases and review of the literature
© Riezzo et al.; licensee BioMed Central Ltd. 2013
Received: 17 March 2013
Accepted: 21 April 2013
Published: 2 May 2013
Sudden death from an undiagnosed primary intracranial neoplasm is an exceptionally rare event, with reported frequencies in the range of 0.02% to 2.1% in medico-legal autopsy series and only 12% of all cases of sudden, unexpected death due to primary intracranial tumors are due to glioblastomas. We present three cases of sudden, unexpected death due to glioblastoma, with different brain localization and expression. A complete methodological forensic approach by means of autopsy, histological and immunohistochemical examinations let us to conclude for an acute central dysregulation caused by glioblastoma and relative complication with rapid increase of intracranial pressure as cause of death. Although modern diagnostic imaging techniques have revolutionized the diagnosis of brain tumors, the autopsy and the careful gross examination and section of the fixed brain (with coronal section) is still the final word in determining exact location, topography, mass effects and histology and secondary damage of brain tumor and contributed the elucidation of the cause of death. Immunohistochemistry and proteomic analysis are mandatory in such cases.
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Glioblastoma is the most common malignant primary brain neoplasm, representing about 12-20% of all intracranial tumors and accounting for about 50-60% of all astrocytic neoplasms . The astrocytic neoplasms occur in patients of all ages and arise at all levels of the neuraxis. In adults, most occur in the cerebral hemispheres, whereas in children typically occur in the brain stem [2–5] or thalamus [6–9]. Less commonly affected sites in both children and adults include the spinal cord [10–13] and cerebellum [14–16]. The 2007 World Health Organization (WHO) grading system designed three lesions of diffusely infiltrating astrocytic tumors: diffuse astrocytoma (grade II), anaplastic astrocytoma (grade III) and glioblastoma (grade IV) . Among diffusely infiltrative astrocytomas of the cerebral hemispheres, a close correlation is observed between histologic grade and clinical variables: patient age, duration of symptoms and neurologic performance status. With occasional exceptions, lesions in older patients are more anaplastic, biologically aggressive, recently symptomatic, and destructive of neurologic function.
Sudden death from an undiagnosed primary intracranial neoplasm is an exceptionally rare event, with reported frequencies in the range of 0.02% to 2.1% in medico-legal autopsy series [18–24] and only 12% of all cases of sudden unexpected death due to primary intracranial tumors are due to glioblastomas .
We report three cases of sudden unexpected death due to undiagnosed glioblastoma grade IV according to WHO  with different brain localization and expression. Complete histological, immunohistochemical and proteomic examinations are presented, to improve diagnosis.
A 43-year-old Polish man was found dead in a slope near the track of the railway. Death scene investigation was unremarkable. A complete autopsy was performed 48 hs after death. The external examination revealed only same abrasions and bruises on the face, and the upper and lower limbs. The internal examination revealed polyvisceral stasis, heavy lungs and reddish colored foam on trachea and the main bronchi. The skull was entire. The examination of the brain (cm 21×16×6, g 1630) after fixation in buffered formalin revealed a cerebral edema and an increase in volume of the left frontal lobe. On coronal sections, the cerebral hemispheres were asymmetrical with deviation of midline structures from left toward right. In the left frontal lobe a spherical mass (cm 3.5×3×1.5), with variegated appearance and contained regions of necrosis and haemorrhage was found. The blood alcohol concentration was 0.8 g/l.
Western blot analysis
The exitus was attributed in the second and third case to brain oedema and massive haemorrhage into the glioblastoma from erosion of vessels, with an increase in intracranial pressure and compression of cerebrospinal fluid circulation, whereas in the first case death can be explained by distortion and compression of the medulla by the tumour with consequent acute central dysregulation due to glioblastoma corresponding to WHO grade IV.
Glioblastoma is highly malignant astrocytic glioma that appears to arise either de novo or in transition from diffuse astrocytoma and anaplastic astrocytoma. Glioblastomas that arise in transition from an often sizable, better-differentiated astrocytic tumor have been referred to as secondary glioblastomas . Other glioblastomas, primary glioblastomas, are densely cellular and homogeneously anaplastic, and exhibit none of the less cellular and better-differentiated components seen in secondary tumors. It remains a matter of debate whether these “primary” variants are truly malignant de novo or have overrun and obscured a precursor lesion.
Cases of sudden death due to glioblastoma multiforme published in the current literature
Size of tumor (cm)
Sutton JT et al. (2010)
Right frontal lobe
2 hours before death complying of a headache
Vougiouklakis T. et al. (2006)
Third ventricle, at level of the foramen of Monro
No neurological symptoms. The man was found unconscious in bed
Shiferaw K. et al. (2006)
Right frontal lobe
Patient with schizophrenia. Five day prior death, the man was disoriented, slow, and somnolent.
Elgamal EA. et al. (2006)
Left parietal lobe
Irritability excessively for 1 day and large vomit
Matschke J. et al. (2005)
Right fronto-parietal lobe
No neurological symptoms. The woman was found dead in her apartment
Left cingulated gyrus with infiltration of the thalamus
No neurological symptoms. The man suddenly collapsed at home
Left cerebellar hemisphere with infiltration of adjacent brainstem structures
No neurological symptoms. The man was found lying dead in his bed
Eberhart C.G. et al. (2001)
left frontal lobe
No neurological symptoms. The man was found unresponsive on the bathroom
Right cerebral hemisphere showed a large mass lesion, involving the basal ganglia and internal capsule
No neurological symptoms. The man was found unresponsive
Right frontal lobe
The man died after his automobile left the road at a high rate of speed and impacted a tree.
Matsumoto H. (1993)
Left temporal lobe
Right medulla and right temporal lobe
Headache, confusional state and difficulty in walking few hours before the death
Left temporal lobe
Confusion, slackening, sleepiness, and tremor of the upper limbs start few days before the death
Left frontal lobe
No neurological symptoms. The man was found dead in a slope near the track of the railway.
In the presented cases, the third one showed no neurological symptoms before the death and in the others cases there was a mild neurological symptomatology few hours before the death.
In recent years the concept of two distinct glioblastoma subtypes has been developed, combining clinical, morphological and genetic data. From this concept has emerged a clinical/molecular distinction of “primary” and “secondary” glioblastomas, although it is unclear how to distinguish this differentiation, or the extent to which it is therapeutically and prognostically relevant [31–33]. On the whole secondary types present in younger patients, more often women who have a longer duration of symptoms, and usually lie in the cerebral hemispheres. These tumors have a high frequency of mutation of p53 tumor suppressor gene on chromosome 17p with accumulation of p53 protein, but infrequent amplification of epidermal growth factor receptor (EGFR) involved in control of cell proliferation [32–35]. Loss of chromosome 19q in the region of a presumed tumor suppressor gene(s) as yet unidentified is more common in secondary tumors .
In the cases of our observation, the clinical and morphological data are in agreement to the diagnosis of primary glioblastoma. In all cases, in fact, the tumor was very aggressive and there weren't clinical symptoms before the death. Like astrocytomas of lower grade, glioblastomas may be discovered on evaluation for seizures or headache but unlike lower-grade lesions whose infiltrating and insinuating qualities carry the cells unobtrusively into intact parenchyma with little resultant mass effect, at least initially, glioblastoma are often expansive and edema generating. As a result, they are more likely to produce frank neurological deficits and sign of increased intracranial pressure: a subset present in sudden, stroke-like fashion as a consequence of intratumoral hemorrhage.
The features of intratumoral vascular proliferations, in fact, have a constant correlation with the prognosis. In glioblastoma vascular proliferation assumes two forms. Most common is a well-known variant that forms globular masses resembling the glomerular tufts of the kidney, this proliferation, now referred to as “microvascular proliferation”. The second form of vascular hyperplasia has a more legitimate claim to the term “endothelial proliferation” since it is intraluminal and consists largely of endothelial cells within small to medium-sized vessels. Endothelial proliferation is less common than glomeruloid microvascular proliferation and it appears to have a more constant correlation with high-grade gliomas and a poor prognosis.
When evaluating cases of sudden death due to undiagnosed glioblastoma there were several problems in defining the most probable causes of death. Although modern diagnostic imaging techniques have revolutionized the diagnosis of brain tumors, the autopsy and the careful gross examination and section of the fixed brain (with coronal section) is still the final word in determining exact location, topography, mass effects and histology and secondary damage of brain tumor and contributed the elucidation of the cause of death . Immunohistochemistry and proteomic analysis are mandatory in such cases [41–43].
Written informed consent was obtained from the patient's relatives for publication of this case report and any accompanying images.
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