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Glioblastoma multiforme

Glioblastoma multiforme, (GBM) also known as grade 4 astrocytoma is the most common and aggressive type of primary brain tumor, accounting for 52 percent of all primary brain tumors cases. more...

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Treatment can involve chemotherapy, radiotherapy and surgery. The 5 year survival rate of the disease has remained unchanged over the past 30 years, and stands at less than three percent. Even with complete resection of the tumor, combined with the best available treatment, the survival rate for GBM remains very low. Chromosomal aberrations like PTEN mutation, MDM2 mutation, and p53 mutation are commonly seen in these tumors. Growth factor aberrant signaling associated with EGFR, and PDGF are also seen. Tumors of this type may also infiltrate across the corpus callosum, producing a butterfly glioma.

Glioblastoma multiformes are characterized by the presence of small areas of necrotizing tissue that is surrounded by highly anaplastic cells. This characteristic differentiates the tumor from Grade 3 astrocytomas, which do not have necrotic tissue regions. Although glioblastoma multiforme can be formed from lower grade astrocytomas, post-mortem autopsies have revealed that most glioblastoma multiforme are not caused by previous lesions in the brain. Metastasis of GBM beyond the Central Nervous System is extremely rare.

A variant of glioblastoma multiforme is known as gliomatosis cerebri. Instead of a solid tumor, the cancerous cells are more scattered and diffuse. This variant preserves the architecture of the brain, but causes the affected portion of the brain to swell. It is extremely difficult to diagnose.


Although common symptoms of the disease can include seizure, headache, and hemiparesis, the single most prevalent symptom is a progressive memory, personality, or neurological deficit. The kind of symptoms produced highly depends on the location of the tumor, more so than on its pathological properties. The tumor can start producing symptoms quickly, but occasionally is asymptomatic until it reaches an enormous size. Unlike oligodendrogliomas, glioblastoma multiformes can form in either the gray matter or white matter of the brain. The symptoms can be relieved, on a primary approach, by the administration of chorticotherapy. These drugs act by rearranging the blood-brain barrier and thus reducing brain oedema. Apart from this, not many different drugs have any kind of importance on this situation. Anti-convulsants, analgesics and stomach protection drugs are usually prescribed.

A Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) scan is necessary to characterize the anatomy of this tumor (size, location, heter/homogeneity). However, final diagnosis of this tumor, like most tumors, relies on histopathologic examination (biopsy examination) after biopsy or surgery.


Treatment of primary brain tumors and brain metastases consists of both supportive and definitive therapies.


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Alzheimer pathology in elderly patients with glioblastoma multiforme
From Archives of Pathology & Laboratory Medicine, 12/1/02 by Nelson, James S

* Context.-Alzheimer disease (AD) and glioblastoma multiforme (GBM) have similar peak, age-specific incidence rates; however, to my knowledge, only 1 case of GBM associated with AD has been reported to date. The frequency of AD pathology, including neuritic plaques, diffuse plaques, neurofibrillary tangles, and cerebral amyloid angiopathy in patients with GBM is unknown. Studies of cancer occurrence in patients with AD are contradictory, with frequencies reported as equal to and as less than that in the general population. The GBM/AD nonconcordance may reflect underreporting of AD pathology or other factors.

Objective.-To compare the frequency and extent of neocortical AD pathology in autopsy cases involving patients aged 60 to 82 years, both with and without GBM.

Design.-Case-control study.

Setting.-Pathology department of a university hospital.

Patients.-Thirty-six autopsy cases of GBM patients aged

60 to 82 years; 54 cases of patients in the same age group without GBM or other primary brain tumors.

Methods-Examination of tumor sections for GBM and of neocortical sections for AD pathology according to Consortium to Establish a Registry for Alzheimer Disease (CERAD) guidelines.

Results.-Glioblastoma multiforme was confirmed in all tumor cases. Alzheimer disease pathology was present in 42% of cases with GBM and in 48% of cases without GBM; 28% of GBM cases had CERAD age-related plaque scores indicative or suggestive of AD; 43% of cases without GBM had CERAD age-related plaque scores indicative or suggestive of AD.

Conclusions.-Alzheimer disease pathology was underreported in both GBM and non-GBM patients. The influence of neurodegenerative processes on GBM symptoms and therapy in elderly patients requires further study.

(Arch Pathol Lab Med. 2002;126:1515-1517)

The probability of coexisting major diseases affecting an individual patient (comorbidity) increases with advancing age. In the United States, the highest age-specific incidence of dementia occurs from 65 to 95 years of age. An estimated 6% to 10% of persons in this age range are severely demented; 50% to 75% of these individuals have Alzheimer disease (AD).1 Histopathologic lesions characteristic of AD, including neuritic plaques (NPs) and neurofibrillary tangles (NFTs), are demonstrable at autopsy in the neocortex. According to recommendations for the postmortem diagnosis of AD from the National Institute on Aging and the Reagan Institute Working Group, these lesions are considered pathologic and are among the criteria used for the diagnosis of AD.2 The precise frequency of neocortical plaques and tangles in the general autopsy population has not been established conclusively. In 4 autopsy studies on nondemented or mildly demented elderly persons, neocortical neuritic or senile plaques occurred in 38% to 69% of cases and neocortical NFTs were noted in 0% to 67% of cases.3-6

The age-specific incidence rate for glioblastoma multiforme (GBM) or malignant astrocytoma in the United States begins to rise at 50 years of age and reaches its highest levels between 65 and 85 years of age.7 If, aside from their tumors, patients between 60 and 85 years of age with GBM or malignant astrocytoma are similar to the general population, then approximately 3 to 8 of every 100 elderly GBM patients should also have AD. Surprisingly, only 1 case of GBM and AD has been reported to date.8 The frequency of histopathologic AD lesions in GBM patients has not been reported. Although little information is available about primary malignant brain tumors in AD patients, several studies have compared the frequency of cancer in AD or demented patients with the general population or with nondemented control subjects. The results of these studies are contradictory. For example, demented and cognitively normal members of the Canadian Study of Health and Aging cohort had similar mortality rates for cancer.9 In other studies, however, cancer occurred less frequently in AD patients than in the general population.10-12 If these observations are extended to primary malignant brain tumors, such as GBM, then the Canadian Study of Health and Aging data would support underreporting of AD as the basis for the apparent lack of AD/GBM comorbidity, whereas reports of decreased cancer frequency in AD patients would suggest that additional factors are involved.

This study assessed the frequency of AD-related neocortical lesions comprising NPs, diffuse plaques, NFTs, and cerebral amyloid angiopathy (CAA) in 36 autopsy cases of GBM patients aged 60 to 82 years. The results are compared with similar observations on 54 autopsy cases of patients in the same age group without GBM or other primary brain tumors to determine whether AD pathologic lesions are significantly less frequent in elderly GBM patients than in patients of similar age without GBM.


Thirty-six cases of patients with GBM aged 60 to 82 years (average, 68 years) were collected from the 1956-1981 autopsy files of the Department of Pathology, Louisiana State University Health Sciences Center, New Orleans, La, and 54 cases of patients in the same age group without GBM or other primary brain tumors were collected from the 1979-1981 departmental files. The patients had died and were autopsied at the Medical Center of Louisiana in New Orleans (formerly Charity Hospital). During the 1956-1981 period, the autopsy rate was at or above 50%. Both groups consisted of all cases in each time period for which slides and paraffin blocks of tumor and neocortex were still available. None of the cases had been evaluated previously for Alzheimer pathology. The GBM patients had received only surgical treatment for their tumors. Information concerning mental status and the specific areas of cerebral cortex represented by the neocortical blocks was not available. Eight-micrometer-thick histologic sections of neocortex were cut from all neocortical blocks from every case, stained with thioflavin S, and examined by fluorescence microscopy for histologic evidence of Alzheimer pathology according to the Consortium to Establish a Registry for Alzheimer Disease (CERAD) neuropathology protocol modified by the substitution of generic neocortical sections for sections of frontal, temporal, and parietal neocortex specified in CERAD guidelines. The CERAD protocol involves determination of an NP score of "absent," "sparse," "moderate," or "frequent" for each neocortical section by comparing a 1-mm2 microscopic field of maximum NP density in the section with published cartoons of the 4 grades of NP density.13 The single highest NP score among all the neocortical sections of a case is correlated with the age of the patient to obtain an age-related plaque score of A, uncertain histologic evidence of AD; B, histologic findings suggest AD; or C, histologic findings indicative of AD.13 The subarachnoid and parenchymal locations of blood vessels with amyloid deposits were recorded. The extent of the CAA at each location was graded according to the number of affected vessels as follows: 1 to 2, sparse; 3 to 5, moderate; 6+, frequent. Hematoxylin-eosin stains of the tumor sections from each of the GBM cases and the neocortical sections from both the GBM and non-GBM cases were examined by conventional light microscopy.


Cases With GBM

The diagnosis of GBM was confirmed in all 36 cases. Histologic lesions associated with AD were present in the neocortical sections from 15 (42%) of 36 cases. Neuritic plaques occurred in 11 (31%) of 36 cases. Ten of these cases (28%) had an age-related plaque score either indicative (6 cases) or suggestive (4 cases) of AD. The remaining NP case had uncertain histologic evidence of AD. Five NP cases had sparse to moderate NFTs, 4 had moderate diffuse plaques, and 5 had sparse to moderate subarachnoid and parenchymal CAA. The 4 cases without NP included 3 with diffuse plaques only and 1 with sparse subarachnoid CAA. There were no cortical Lewy bodies.

Cases Without GBM

Histologic lesions associated with AD were present in neocortical sections from 26 (48%) of 54 cases. Neuritic plaques occurred in 23 (43%) of 54 cases with age-related plaque scores either indicative (8 cases) or suggestive (15 cases) of AD. Six NP cases had sparse to frequent NFTs, 13 had sparse to moderate diffuse plaques, and 7 had sparse to moderate subarachnoid and parenchymal CAA. The 3 cases without NPs included 2 with diffuse plaques only and 1 with sparse parenchymal CAA. There were no cortical Lewy bodies.


The characteristic histopathologic lesions associated with AD, particularly NPs and NFTs, are widely but not uniformly distributed throughout the cerebral cortex. Sections of the middle frontal, superior temporal, and inferior parietal gyri are specified in the CERAD neuropathology protocol as optimal sites for determination of the age-related plaque score. In the present study, only neocortical sections from unspecified sites were available for analysis. Despite this sampling limitation, the frequencies of NPs and NFTs among the patients with GBM are not markedly different from those observed among non-GBM patients of similar age from a subset of the same autopsy population. The NP and NFT values from both groups in the present study also lie within the range of NP and NFT frequencies reported in the 4 autopsy studies on nondemented and mildly demented persons cited previously.3-6 These observations demonstrate that histopathologic lesions characteristic of AD and the cellular mechanisms underlying their formation occur with comparable frequency in autopsied GBM and non-GBM patients of similar age. The apparent lack of AD/GBM comorbidity is the result of underreporting of AD pathology in GBM cases; in this study, the underreporting also involved the comparison group.

The criteria for definitive diagnosis of AD include clinical evidence of dementia. Recently, the occurrence of a preclinical form of AD has been inferred, based on examination of brains from persons with the mildest form of clinically recognizable dementia and from nondemented persons in the same age group.14 Because the brains from the patients with minimal dementia already contain large numbers of NPs and NFTs, the development of the AD process with formation of NPs and NFTs must begin before any clinical evidence of dementia is apparent. Consequently, some of the brains from a group of nondemented persons with detailed cognitive studies should have minimal or no AD-related lesions, while other brains from this group might include significant AD-related pathology and represent preclinical forms of AD.14 Several studies of brains from elderly patients with detailed cognitive studies confirm the occurrence of these 2 general types of neuropathologic findings and lend support to the concept of preclinical AD.4,5,14

Whether an interaction between the coexisting neurodegenerative and neoplastic processes may influence the expression of neurological symptoms or the clinical course in GBM cases with AD pathology is uncertain. In cases of AD combined with other neurodegenerative disorders or cerebrovascular disease, the extent of the AD pathology associated with cognitive impairment or dementia is less than in cases of AD alone.15,16 Comorbidity has not been investigated extensively in elderly patients with brain tumors. There are, however, some observations that suggest the possibility of comorbid processes affecting these individuals. Lowry et al17 reported that patients 65 years of age and older with primary malignant brain tumors have distinctively different presenting symptoms and shortened survival compared with younger patients. The older patients were more likely to present with confusion, aphasia, or memory loss, whereas the younger patients most often presented with headache or seizure. Other than advancing age, the conditions influencing these differences are unknown. Possibly, a subclinical or early phase of a neurodegenerative process, including AD, in elderly patients may be a factor. In a preliminary study, we noted an increase in posttreatment neurological morbidity in elderly patients with glioblastoma when AD pathology is identifiable in sections of neocortex included with the surgically resected tumor.18 Further studies are needed to clarify the role of comorbidity in the natural history and treatment of malignant brain tumors in the elderly.

This work was supported by grant HL54280 from the US Public Health Service, Washington, DC.


1. Kawas CH, Katzman R. Epidemiology of dementia and Alzheimer disease. In: Terry RD, Katzman R, Bick KL, Sisodia SS, eds. Alzheimer Disease. 2nd ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1999:95-116.

2. Consensus recommendations for the postmortem diagnosis of Alzheimer's disease. The National Institute on Aging and Reagan Institute Working Group on Diagnostic Criteria for Neuropathological Assessment of Alzheimer's Disease. Neurobiol Aging. 1997;18(suppl 4):51 -S2.

3. Ulrich J, Stahelin HB. The variable topography of Alzheimer type changes in senile dementia and normal old age. Gerontology. 1984;30:210-214.

4. Hulette CM, Welsh-Bohmer KA, Murray MG, Saunders AM, Mash DC, McIntyre LM. Neuropathological and neuropsychological changes in "normal" aging: evidence for preclinical Alzheimer disease in cognitively normal individuals. J Neuropathol Exp Neurol. 1998;57:1168-1174.

5. Davis DG, Schmitt FA, Wekstein DR, Markesbery WR. Alzheimer neuropathologic alterations in aged cognitively normal subjects. J Neuropathol Exp Neurol. 1999;58:376-388.

6. Xuereb JH, Brayne C, Dufouil C, et al. Neuropathological findings in the very old: results from the first 101 brains of a population-based longitudinal study of dementing disorders. Ann N Y Acad Sci. 2000;903:490-496.

7. Radhakrishnan K, Mokri B, Parisi JE, O"Fallon WM, Sunku J, Kurland LT. The trends and incidence of primary brain tumors in the population of Rochester, Minnesota. Ann Neurol. 1995;37:67-73.

8. Poole EC, Kepes JJ. Glioblastoma multiforme of the hippocampus in advanced Alzheimer's disease. Neuropathol Appl NeurobioL 1991;17:509-513.

9. Ostbye T, Hill G, Steenhuls R. Mortality in elderly Canadians with and without dementia. Neurology. 1999;53:521-526.

10. Molsa PK, Marttila RJ, Rinne UK. Survival and cause of death in Alzheimer's disease and multi-infarct dementia. Acta Neurol Scand. 1986;74:103-107.

11. Beard CM, Kokmen E, Sigler C, Smith GE, Petterson T, O'Brien PC. Cause of death in Alzheimer's disease. Ann Epidemiol. 1996;6:195-200.

12. Yamada M, Sasaki H, Mimori Y, et al. Prevalence and risks of dementia in the Japanese population: RERF's adult health study subjects. Radiation Effects Research Foundation. JAm Geriatr Soc. 1999;47:189-195.

13. Mirra SS, Gearing M, Heyman A. CERAD Guide to the Assessment of Alzheimer's Disease and Other Dementias. Durham, NC: CERAD; 1994.

14. Price JL, Morris JC. Tangles and plaques in nondemented aging and "preclinical" Alzheimer's disease. Ann Neurol. 1999;45:358-368.

15. Nagy Z, Esiri MM, Jobst KA, et al. The effects of additional pathology on the cognitive deficit in Alzheimer disease. J Neuropathol Exp Neurol. 1997;56: 165-170.

16. Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease: The Nun Study. JAMA. 1997;277:813-817.

17. Lowry JK, Snyder JJ, Lowry PW. Brain tumors in the elderly: recent trends in a Minnesota cohort study. Arch Neurol. 1998;55:922-928.

18. Nelson JS, Scott CB, Constine LS, Fu K, Murray KJ. Alzheimer related lesions and neural morbidity in glioblastoma patients: data from Radiation Therapy Oncology Group glioma trials. Lab Invest. 1998;78:161 A.

James S. Nelson, MD

Accepted for publication June 21, 2002.

From Pacific Health Research Institute, Honolulu, Hawaii, and the Department of Pathology, Louisiana State University Health Sciences Center, New Orleans, La.

Reprints: James S. Nelson, MD, Pacific Health Research Institute, 846 S Hotel St, Suite 303, Honolulu, HI 96813 (e-mail: jnelson@

Copyright College of American Pathologists Dec 2002
Provided by ProQuest Information and Learning Company. All rights Reserved

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