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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KeywordsGlioblastoma Sudden death Immunohistochemistry stains Western blotting
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.
- Vougiouklakis T, Mitselou A, Agnantis NJ: Sudden death due to primary intracranial neoplasms. A forensic autopsy study. Anticancer Res. 2006, 26: 2463-2466.PubMedGoogle Scholar
- Albright AL, Guthkelch AN, Packer RJ, Price RA, Rourke LB: Prognostic factors in pediatric brain-stem gliomas. J Neurosurg. 1986, 65: 751-755. 10.3171/jns.1986.65.6.0751.View ArticlePubMedGoogle Scholar
- Albright AL, Price RA, Guthkelch AN: Brain stem gliomas of children. A clinicopathological study. Cancer. 1983, 52: 2313-2319. 10.1002/1097-0142(19831215)52:12<2313::AID-CNCR2820521226>3.0.CO;2-I.View ArticlePubMedGoogle Scholar
- Burger PC: Pathology of brain stem astrocytomas. Pediatr Neurosurg. 1996, 24: 35-40. 10.1159/000121012.View ArticlePubMedGoogle Scholar
- Fisher PG, Breiter SN, Carson BS, Wharam MD, Williams JA, Weingart JD, Foer DR, Goldthwaite PT, Tihan T, Burger PC: A clinicopathologic reappraisal of brain stem tumor classification. Identification of pilocystic astrocytoma and fibrillary astrocytoma as distinct entities. Cancer. 2000, 89: 1569-1576. 10.1002/1097-0142(20001001)89:7<1569::AID-CNCR22>3.0.CO;2-0.View ArticlePubMedGoogle Scholar
- Amin MR, Kamitani H, Watanabe T, Ishibashi M, Ogawa T, Funakoshi T, Miyata H, Ohama E: A topographic analysis of the proliferating tumor cells in an autopsied brain with infiltrative thalamic glioma. Brain Tumor Pathol. 2002, 19: 5-10. 10.1007/BF02482449.View ArticlePubMedGoogle Scholar
- Burger PC, Cohen KJ, Rosenblum MK, Tihan T: Pathology of diencephalic astrocytomas. Pediatr Neurosurg. 2000, 32: 214-219. 10.1159/000028937.View ArticlePubMedGoogle Scholar
- Di Rocco C, Iannelli A: Bilateral thalamic tumors in children. Childs Nerv Syst. 2002, 18: 440-444. 10.1007/s00381-002-0609-9.View ArticlePubMedGoogle Scholar
- Krouwer HG, Prados MD: Infiltrative astrocytomas of the thalamus. J Neurosurg. 1995, 82: 548-557. 10.3171/jns.1995.82.4.0548.View ArticlePubMedGoogle Scholar
- Epstein FJ, Farmer JP, Freed D: Adult intramedullary astrocytomas of the spinal cord. J Neurosurg. 1992, 77: 355-359. 10.3171/jns.1992.77.3.0355.View ArticlePubMedGoogle Scholar
- Kim MS, Chung CK, Choe G, Kim IH, Kim HJ: Intramedullary spinal cord astrocytoma in adults: postoperative outcome. J Neurooncol. 2001, 52: 85-94. 10.1023/A:1010680924975.View ArticlePubMedGoogle Scholar
- Santi M, Mena H, Wong K, Koeller K, Olsen C, Rushing EJ: Spinal cord malignant astrocytomas. Clinicopathologic features in 36 cases. Cancer. 2003, 98: 554-561. 10.1002/cncr.11514.View ArticlePubMedGoogle Scholar
- Strik HM, Effenberger O, Schäfer O, Risch U, Wickboldt J, Meyermann R: A case of spinal glioblastoma multiforme: immunohistochemical study and review of the literature. J Neurooncol. 2000, 50: 239-243. 10.1023/A:1006415703881.View ArticlePubMedGoogle Scholar
- Bernhardtsen T, Laursen H, Bojsen-Møller M, Gjerris F: Sub-classification of low-grade cerebellar astrocytoma: is it clinically meaningful?. Childs Nerv Syst. 2003, 19: 729-735. 10.1007/s00381-003-0825-y.View ArticlePubMedGoogle Scholar
- Gupta V, Goyal A, Sinha S, Singh AK, Tatke M, Kumar S, Singh D, Sachdeva PK: Glioblastoma of the cerebellum. A report of 3 cases. J Neurosurg Sci. 2003, 47: 57-164.Google Scholar
- Hayostek CJ, Shaw EG, Scheithauer B, O’Fallon JR, Weiland TL, Schomberg PJ, Kelly PJ, Hu TC: Astrocytomas of the cerebellum. A comparative clinicopathologic study of pilocytic and diffuse astrocytomas. Cancer. 1993, 72: 856-869. 10.1002/1097-0142(19930801)72:3<856::AID-CNCR2820720335>3.0.CO;2-K.View ArticlePubMedGoogle Scholar
- Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007, 114: 97-109. 10.1007/s00401-007-0243-4.PubMed CentralView ArticlePubMedGoogle Scholar
- Di Maio TM, Di Maio DJ: Sudden death due to colloid cysts of the third cerebral ventricle. N Y State J Med. 1974, 74: 1832-1834.PubMedGoogle Scholar
- Di Maio SM, Di Maio VJ, Kirkpatrik JB: Sudden unexpected deaths due to primary intracranial neoplasms. Am J Forensic Med Pathol. 1980, 1: 29-45. 10.1097/00000433-198003000-00007.View ArticleGoogle Scholar
- Eberhart Ch G, Morrison A, Gyure KA, Frazier J, Smialek JE, Troncoso JC: Decreasing incidence of sudden death due to undiagnosed primary central nervous system. Arch Pathol Lab Med. 2001, 125: 1024-1030.Google Scholar
- Huntington RW, Cummings KL, Moe TI, O’Connell HV, Wybel R: Discovery of fatal primary intracranial neoplasms at medico-legal autopsies. Cancer. 1965, 18: 117-127. 10.1002/1097-0142(196501)18:1<117::AID-CNCR2820180117>3.0.CO;2-4.View ArticlePubMedGoogle Scholar
- Schreiber D, Warsok R: Localization of brain tumors in autopsy. Part I: Tumor of the temporal lobe. Zentralbl Neurochir. 1981, 42: 241-250.PubMedGoogle Scholar
- Tiszlavicz L: Multiple primary intracranial tumors and association of intra and extracranial tumors. An autopsy study. Clin Neuropathol. 1993, 12: 204-210.PubMedGoogle Scholar
- Turillazzi E, Bello S, Neri M, Riezzo I, Fineschi V: Colloid cyst of the third ventricle, hypothalamus, and heart: a dangerous link for sudden death. Diagn Pathol. 2012, 7: 144-10.1186/1746-1596-7-144.PubMed CentralView ArticlePubMedGoogle Scholar
- Matschke J, Tsokos M: Sudden unexpected death due to undiagnosed glioblastoma: report of three cases and review of the literature. Int J Legal Med. 2005, 119: 280-284. 10.1007/s00414-005-0551-y.View ArticlePubMedGoogle Scholar
- Burger PC, Scheithauer BW: Tumors of the Central Nervous System. AFIP Atlas of Tumor pathology. Fourth Series. 2007, 7: 55-Google Scholar
- Matsumoto H, Yamamoto K: A case of sudden death by undiagnosed glioblastoma multiforme. Nihon Hoigaku Zasshi. 1993, 47: 336-369.PubMedGoogle Scholar
- Shiferaw K, Pizzolato GP, Perret G, Harpe RL: Sudden, unexpected death due to undiagnosed frontal glioblastoma in a schizophrenic patient. Forensic Sci Int. 2006, 158: 200-203. 10.1016/j.forsciint.2005.08.006.View ArticlePubMedGoogle Scholar
- Elgamal EA, Richards PG: Sudden death in children due to intracranial mass lesion. Childs Nerv Syst. 2006, 22: 305-309. 10.1007/s00381-005-1215-4.View ArticlePubMedGoogle Scholar
- Sutton JT, Cummings PM, Ross GW, Lopes MB: Sudden death of a 7-year-old boy due to undiagnosed glioblastoma. Am J Forensic Med Pathol. 2010, 31: 278-280. 10.1097/PAF.0b013e3181e8d0ef.View ArticlePubMedGoogle Scholar
- Kleihues P, Ohgaki H: Primary and secondary glioblastomas: from concept to clinical diagnosis. Neuro Oncol. 1999, 1: 44-51.PubMed CentralPubMedGoogle Scholar
- Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre PL, Burkhard C, Schüler D, Probst-Hensch NM, Maiorka PC, Baeza N, Pisani P, Yonekawa Y, Yasargil MG, Lütolf UM, Kleihues P: Genetic pathways to glioblastoma: a population-based study. Cancer Res. 2004, 64: 6892-6899. 10.1158/0008-5472.CAN-04-1337.View ArticlePubMedGoogle Scholar
- Ohgaki H, Kleihues P: Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and ologodendroglial gliomas. J Neuropathol Exp Neurol. 2005, 64: 479-489.PubMedGoogle Scholar
- Tohma Y, Gratas C, Biernat W, Peraud A, Fukuda M, Yonekawa Y, Kleihues P, Ohgaki H: PTEN (MMAC1) mutations are frequent in primary glioblastomas (de novo) but not in secondary glioblastomas. J Neuropathol Exp Neurol. 1998, 57: 684-689. 10.1097/00005072-199807000-00005.View ArticlePubMedGoogle Scholar
- Watanabe K, Tachibana O, Sata K, Yonekawa Y, Kleihuses P, Ohgaki H: Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. Brain Pathol. 1996, 6: 217-223. 10.1111/j.1750-3639.1996.tb00848.x.View ArticlePubMedGoogle Scholar
- Fujisawa H, Reis RM, Nakamura M, Colella S, Yonekawa Y, Kleihues P, Ohgaki H: Loss of heterozygosity on chromosome 10 is more extensive in primary (de novo) than in secondary glioblastomas. Lab Invest. 2000, 80: 65-72. 10.1038/labinvest.3780009.View ArticlePubMedGoogle Scholar
- Jung CS, Unterberg AW, Hartmann C: Diagnostic markers for glioblastoma. Histol Histopathol. 2011, 10: 1327-1341.Google Scholar
- Ohgaki H, Kleihues P: Genetic pathways to primary and secondary glioblastoma. Am J Pathol. 2007, 5: 1445-1453.View ArticleGoogle Scholar
- Riemenschneider MJ, Jeuken JWM, Wesseling P, Reifenberger G: Molecular diagnostics of gliomas: state of the art. Acta Neuropathol. 2010, 120: 567-584. 10.1007/s00401-010-0736-4.PubMed CentralView ArticlePubMedGoogle Scholar
- Silbergeld DL, Rostomily RC, Alvord ECJ: The cause of death in patients with glioblastoma is multifactorial: clinical factors and autopsy findings in 117 cases of supratentorial glioblastoma in adults. J Neuro-Oncol. 1991, 10: 179-185. 10.1007/BF00146880.View ArticleGoogle Scholar
- Salvati M, Pichierri A, Piccirilli M, Floriana Brunetto GM, D’Elia A, Artizzu S, Santoro F, Arcella A, Giangaspero F, Frati A, Simione L, Santoro A: Extent of tumor removal and molecular markers in cerebral glioblastoma: a combined prognostic factors study in a surgical series of 105 patients. J Neurosurg. 2012, 117: 204-211. 10.3171/2012.4.JNS101702.View ArticlePubMedGoogle Scholar
- Turtoi A, Musmeci D, Naccarato AG, Scatena C, Ortenzi V, Kiss R, Murtas D, Patsos G, Mazzucchelli G, De Pauw E, Bevilacqua G, Castronovo V: Sparc-like protein 1 is a new marker of human glioma progression. J Proteome Res. 2012, 11: 5011-5021. 10.1021/pr3005698.View ArticlePubMedGoogle Scholar
- Wang Q, Deng J, Yuan J, Wang L, Zhao Z, He S, Zhang Y, Tu Y: Oncogenic reg IV is a novel prognostic marker for glioma patient survival. Diagn Pathol. 2012, 7: 69-10.1186/1746-1596-7-69.PubMed CentralView ArticlePubMedGoogle Scholar
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