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Home , Anaplastic astrocytoma, Neoplasm

ANTICANCER RESEARCH 26: 2463-2466 (2006)

Sudden Death due to Primary Intracranial . A Forensic Study

THEODORE VOUGIOUKLAKIS1, ANTIGONY MITSELOU1 and NIKI J. AGNANTIS2

Departments of 1Forensic and 2Pathology, Medical School, University of Ioannina, Ioannina, Greece

Abstract. Although most fatal tumors are diagnosed well young adults aged 20 to 39 years, representing the third before a patient’s death, occasionally forensic pathologists leading -related death in the past two decades (6). encounter cases in which the presence of a of As a result of increasingly widespread access to modern the had not been suspected prior to and sensitive imaging technology, such as computed death. A search for cases of sudden death due to intracranial tomography (CT) and magnetic resonance imaging, sudden tumors from a total of 1985 from the archives of the death due to undiagnosed intracranial neoplasms probably Department of , University of Ioannina, accounts for fewer cases in forensic autopsy series (6, 7). In Greece, in the period 1998-2005, was undertaken. Two such this article, two patients, whose sudden demise could be cases in which a medico-legal autopsy had disclosed brain directly attributed to the effects of a previously augmented tumors were found. The first case was a 34-year-old man who intracranial pressure due to acute and severe hemorrhage had been found unconscious in bed, and died a few hours after of a , comprising a grade WHO- hospitalization. His autopsy had revealed a 7-cm glioblastoma IV and an grade WHO-III respectively, are at the level of the third ventricle. The second case involved a presented. The presence of astrocytic tumors is not 67-year-old man presenting with brain tumor, diagnosed 1.5 surprising since they are the most common type of brain months previously. The patient had died after 16 hours of tumors, accounting for more than 38% of all primary central hospitalization. A 4-cm astrocytoma of the left temporal lobe nervous systems (CNS) , and are generally fatal (6). had been found at autopsy. In both cases, the tumors may, The mechanisms of death included , acute directly or indirectly, have been the underlying of death. hemorrhage and herniation due to mass effect (8-11). The importance of a thorough neuropathological examination in all cases of sudden death, in which no extracerebral cause Materials and Methods had been found, is emphasized. A retrospective review of 1,985 autopsies, carried out at the Sudden death from an undiagnosed primary intracranial Department of Forensic Pathology, University of Ioannina, Ioannina, Greece, in the period 1998-2005 (through September, is an exceptionally rare event, with reported 2005), was performed to identify out-patient fatalities due to frequencies in the range of 0.02% to 2.1% in medico-legal primary brain tumors, which presented as sudden death. During autopsy series (1-6) (Table I). Lindboe et al., however, this period, there had been two cases (accounting for 0.1% of all pointed out that many of the individuals in these series had cases). In both cases, paraffin sections of the respective tumors had long-term clinical symptoms of an intracranial process were available and were re-evaluated according to the latest World and, therefore, their deaths could not be regarded as Health Organization (WHO) (11) classification of tumors of the unexpected; in fact, only a small minority of the patients had CNS as glioblastoma grade IV and astrocytoma grade III. The two cases fulfill the criteria of sudden death as death occuring in an actually been found dead or died instantaneously (7). asymptomatic person, with a maximum time-interval of 24 hours Mortality due to brain neoplasm is particularly high in after the onset of symptoms.

Case 1

Correspondence to: Prof. Niki J. Agnantis, MD, Ph.D., Department A 34-year-old man had been found unconscious in bed, in of Pathology, Medical School, University of Ioannina, Ioannina the military unit where he worked. He was rushed to the 45110, Greece. Tel: +30 26510 97792, Fax: +30 26510 97858, e- emergency department of the University Hospital. The mail: [email protected] patient appeared acutely ill, unresponsive with fixed dilated Key Words: Intracranial tumors, astrocytoma, glioblastoma, sudden pupils and had the minimun Glasgow coma scale score of 3; death, forensic autopsy. he was ventilated and admitted to the intensive care unit.

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Table I. Undiagnosed central nervous system tumor studies.

Study Location Years Autopsies CNS tumor deaths %

Huntington et al. (1) Kern County, California, USA 1950 - 1955 3543 0.42 Schreiber and Warsok (2) Erfurt, Germany 1953 - 1976 54946 2.7 Di Maio and Di Maio (4) Brooklyn, New York, USA 1960 - 1970 17404 0.16 Di Maio et al. (3) Dallas County, Texas, USA 1970 - 1977 10995 0.17 Tiszlavicz (5) Szeged, Hungary 1960 - 1990 37504 1.2 Eberhart et al. (6) Maryland, USA 1980 - 1999 54873 0.02 - 0.05 This study Ioannina, Greece 1998 - 2005 1985 0.1

The CT scan of the brain showed , dilatation of the Case 2 lateral ventricles, hydrocephalia and the existence of a hemorrhagic mass at the third ventricle. After 1 day in a A 67-year-old man had been admitted to the emergency coma, the patient died. Aproximately 2 months before his room with unresponsive, fixed, dilated pupils, a temperature death, the patient had consulted a doctor in the of 36.5ÆC, blood pressure of 110/40 mmHg, heart rate of neurological department of a hospital complaining of 60 bpm and a respiratory rate of 8 bpm. He had absent and neck . A diagnosis of tension headache papillary light, corneal and gag reflexes and had a Glasgow had been made and the possibility of brain tumor appears coma scale of 4. A head CT scan showed a mass in the left not to have been considered. One week before his temporal lobe, accompanied by hemorrhage and cerebral hospitalization, he had suffered loss of consciousness. edema. The patient died after 16 hours, following A forensic autopsy was conducted the day after the withdrawal of medical and mechanical life support. patient’s death. Apart from artifacts of resuscitation, no Reportedly, the patient had consulted a physician due to significant injury was found. Internally, the heart was of headache and occasional vomiting. A CT scan had revealed normal size and configuration with no evidence of anomaly, a tumor in the left parietal lobe, with no other while the lungs showed mild to moderate congestion and specifications. Some weeks later, the man had been found pulmonary edema. With the exception of the brain, the unconscious in front of his house. remaining organs were apparently healthy, with no evidence An autopsy was performed immediately after death. of macroscopic pathology. The brain weighed 1620 g and Internally, the heart was of normal configuration with no showed diffusely cerebral edema and swelling. A evidence of anomaly, was slightly hypertrophic and coronary hemorrhagic mass, of maximum diameter of 6.9 cm, was atherosclerosis grade II/III was observed. The lungs showed present at the third ventricle, at the level of the foramen of mild to moderate congestion and pulmonary edema and few Monro. On coronal sections of the brain, the cerebral foci of condensation at the lower lobes. The brain weighed hemispheres demonstrated widespread, marked flattening 1580 g and showed diffuse cerebral edema and cerebellar of the gyri and marked dilation of the lateral ventricles. The tonsillar herniation. Horizontal sections revealed a 4 x 4 x spherical mass was accompanied by massive fresh 5-cm, firm, variegated tan-brown mass, with areas of hemorrhage, measuring, in total, 6.9 x 5.2 x 3.4 cm. A cut hemorrhage and , arising from the left temporal surface revealed a friable mass, whitish in color, with lobe. The tumor extended well into the third lateral extensive areas of necrosis and hemorrhage. Micro- ventricle, compressing the lumen and infiltrating deeply into scopically, the tumor was composed of small- , structures. with areas of poorly-differentiated pleomorphic astrocytic The microscopic evaluation of the mass showed diffuse cells with nuclear atypia (Figure 1). Incipient microvascular replacement of the cerebral by neoplastic cells with proliferation was also present. Immunohistochemical the presence of small and large astrocytes, in some areas staining was performed with against glial dispersed and in others arranged in small or larger groups; fibrillary acidic protein (GFAP), synaptophysin, protein nuclear atypia and marked mitotic activity were present. and the proliferation-associated Ki-67 (MIB1). The The tumor was accompanied with foci of hemorrhage and tumor cells were GFAP-positive and synaptophysin- necrosis. Immunohistochemical evaluation indicated negative. The Ki-67/MIB1-labeling index (LI) was 6.7%. positive staining from GFAP. The Ki-67/MIB1 LI was 4.9% The percentage of the nuclei with accumulation of p53 and accumulation of p53 protein was 3.7 %. The final protein was 5.2%. The final diagnosis was glioblastoma diagnosis was anaplastic astrocytoma corresponding to corresponding to WHO grade IV. WHO grade III.

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Figure 1. Histological appearance of the tumor taken from patient 1, showing cellular with hyperchromatic irregular nuclei. H&E x 400.

Discussion accounting for about 50-60% of all astrocytic . Generally, the peak incidence age range is between 45 and Intracranial tumors are said to account for 8% of non- 75 years; while decidedly rare before 30, no age is exempt traumatic . About half of this may and cases may arise in childhood and even in the prenatal be the first manifestation and in a small proportion of these stage. The sex distribution shows a preponderance of males, cases the patients die suddenly (12). In our experience, sudden ranging from 2:1 to 3:2 (13). The white matter of the brain death is rare and only two cases were identified in the files of is characteristically involved and the distribution of the the Department of Forensic Pathology from 1998 to 2005. In tumor is wide. The frontal lobes are most often involved the literature, of the primary brain tumors glioblastoma and, generally, the forepart of the brain is implicated far multiforme (3) predominates; other tumors that have been more frequently than the posterior; the occipital lobes are reported to present in this way include anaplastic astrocytoma, a rare site (14). , , , Histopathologically, are heterogeneous and pituitary (4). are the most tumors, including small cells with minimal cytoplasm and frequent malignant primary brain tumors in adults. Clinically, round hyperchromatic nuclei, as well as large multi- this group of tumors can be divided into four World Health nucleated cells. Tumor necrosis in glioblastoma appears as Organization (WHO) grades. Pilocytic astrocytomas (WHO either foci of micronecrosis or broad necrotic zones, as in grade I) are generally slow growing and non-infiltrative our cases, surrounded by a hypercellular zone consisting pediatric tumors, which are rarely fatal. Grade II astrocytoma primarily of parenchymal infiltration, which is visible as a patients survive an average of over 5 years, but survival drops soft grey rim. The observation of a red and brown to 3 years for anaplastic (grade III). Grade IV coloration from extensive hemorrhaging, which often elicits astrocytomas account for about half of all astrocytic tumors, stroke-like symptoms, is common. In our cases, extensive with a median survival of less than a year (12). fresh hemorrhage had been observed both within and Glioblastoma, defined as the most malignant astrocytic surrounding the tumor. Another prominent characteristic of tumor, is a relatively frequent intracranial neoplasm, these tumors is the presence of thrombosed vessels representing about 12-20% of all intracranial tumors and surrounding and within the neoplasm (14, 15).

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The concept of two distinct glioblastoma subtypes has 4 DiMaio TM and DiMaio DJ : Sudden death due to colloid been developed in recent years, combining clinical, of the third cerebral ventricle. NY State Med J 74: 1832- morphological and genetic data (14, 16). Primary 1834, 1974. 5 Tiszlavicz L: Multiple primary intracranial tumors and glioblastomas, arising de novo with no apparent low-grade association of intra and extracranial tumors. An autopsy study. precursor , and in the majority of cases occuring in Clin Neuropathol 12: 204-210, 1993. older patients, with a mean age of 55 years. Secondary 6 Eberhart Ch G, Morrison A, Gyure KA, Frazier J, Smialek JE glioblastomas develop through progression from low-grade and Troncoso JC: Decreasing incidence of sudden death due to or anaplastic precursor astrocytoma in patients typically undiagnosed primary central nervous system. Arch Pathol Lab younger than 45 years. In contrast to the primary tumors, Med 125: 1024-1030, 2001. most secondly glioblastomas show significant accumulation 7 Lindboe CF, Svenes KB and Slordal L: Sudden, unexpected death in subjects with undiagnosed gliomas. Am J Forensic Med of the p53 protein, but lack immunoreactivity for EGFR, Pathol 18: 271-275, 1997. and PTEN is rare (16). In our case, significant 8 Prahlow JA, Teot LA, Lantz PE and Stanton CA: Sudden death immunostaining for the p53 protein, was observed. These in epilepsy due to an isolated subependymal giant cell data indicate that primary and secondary glioblastomas astrocytoma of the septum pellucidum. Am J Forensic Med carry different genetic alterations. Pathol 16: 30-37, 1995. WHO grade III astrocytomas are preferentially located in 9 Buttner A, Gall C, Mall G and Weiss S: Unexpected death in the cerebral hemispheres. The growth may be deep, persons with symptomatic epilepsy due to glial brain tumors: a report of two cases and review of the literature. Forensic Sci Int involving such structures as the corpus callosum, septum 100: 127-136, 1999. pellucidum and basal ganglia. They occur in adult patients 10 Byard RW, Bourne AI and Hanieh A: Sudden and unexpected (peak incidence 45-60 years). Microscopically, anaplastic death due to hemorrhage from occult central nervous system astrocytomas are characterized by signs of focal or diffuse lesions: a pediatric autopsy study. Pediatr Neurosurg 17: 88- , such as increased cellularity, nuclear atypia and 94, 1991. marked mitotic activity. The typical histological hallmarks of 11 Silbergeld DL, Rostomily RC and Alvord EC Jr: The cause of glioblastoma (microvascular proliferation and necrosis) are death in patients with glioblastoma is multifactorial: clinical factors and autopsy findings in 117 cases of supretentorial not yet present, but anaplastic astrocytomas tend to progress glioblastoma in adults. J Neurooncol 10: 179-185, 1991. to secondary glioblastomas, as mentioned above (12, 14). On 12 Kleihues P and Cavenee WK: Pathology and genetics of tumor cytogenetic analysis, most anaplastic astrocytomas of the nervous system. World Health Organization demonstrated deletions in chromosomes 6, 9p, 11p, 19q and Classification of Tumors. IARC, Lyon, 2000. 22q. When present, PTEN mutation indicates a poor 13 Black M and Graham DI: Sudden unexplained death in adults prognosis. The TP53 tumor-suppressor gene mutation caused by intracranial pathology. J Clin Pathol 55: 44-50, 2002. located at chromosome 17p13 is altered in anaplastic 14 McLendon RE, Enterline DS and Tien RD: Tumors of central neuroepithelial origin. In: Russell and Rubinstein’s Pathology astrocytomas (17, 18). of Tumors of the Nervous System, vol 1, 2nd edition. Bigner Over recent years, improvements in imaging techniques, DD, McLendon RE, Bruner JM (eds.). pp. 95-120, Arnold, notably the introduction of CT and magnetic resonance London, 1998. imaging, have resulted in increased early detection of CNS 15 Raza SM, Lang FF, Aggarwal BB, Fuller GN, Wildrick DM and neoplasms (6, 13). Furthermore, we observed a significantly Sawaya R: Necrosis and glioblastoma: a friend or a foe? A lower incidence of death due to undiagnosed CNS tumors review and a hypothesis. 51: 2-13, 2002. than reported in different studies (Table I). 16 Kleihues P and Ohgaki H: Primary and secondary glioblastomas: from concept to clinical diagnosis. Neurooncol 1: 44-51, 1999. In conclusion, autopsy of the brain is still definitive in 17 Kleihus P, Burger PC, Collins VP et al: Pathology and Genetics determining the exact location, topography, mass effects and of Tumors of the Nervous System. IARC Press, Lyon, 2000. of brain tumors (19). 18 Reifengerger G and Collins VP: Pathology and molecular genetics of astrocytic gliomas. J Mol Med 82: 656-670, 2004. References 19 Boguslavskii VL and Serebrennikov IM: The forensic medical significance of brain tumors. Sud Med Ekspert 36: 5-6, 1993. 1 Huntington RW, Cummings KL, Moe TI, O’Connell HV and Wybel R: Discovery of fatal primary intracranial neoplasms at medicolegal autopsies. Cancer 18: 117-127, 1965. 2 Schreiber D and Warsok R: Localization of brain tumors in autopsy. Part I: Tumor of the temporal lobe. Zentralbl Neurochir 42: 241-250, 1981. 3 DiMaio SM, DiMaio VJ and Kirkpatrik JB: Sudden unexpected Received December 5, 2005 deaths due to primary intracranial neoplasms. Am J Forensic Revised February 15, 2006 Med Pathol 1: 29-45, 1980. Accepted February 20, 2006

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