Pitfalls in Surgical Neuropathology
Moderators: Dr. Arie Perry and Dr. Richard A. Prayson
Case 1 -
Multifocal Glioblastoma (WHO Grade IV)
Pieter Wesseling, MD, PhD
Nijmegen Medical Centre
Nijmegen, The Netherlands
Clinical History and Radiology
A 63-year-old woman presented with a history of disturbed
ocular motility and nausea. T1 weighted MR images with contrast revealed multiple, contrast-enhancing intracerebral
lesions (corpus callosum, left frontal lobe, left cerebellar peduncle and hemisphere; see
below). A needle biopsy was taken of the lesion in the corpus callosum. Review of the MR
flare images suggested a connection between the different lesions via white matter tracts.
Case 1 - Figure 1
The small biopsy fragments show a highly cellular glial tumor. The tumor cells generally
have astrocytic features with eosinophilic cytoplasm and cell processes. There is moderate to marked
nuclear pleiomorphism and mitoses are readily found. Occasionally round nuclei with clear perinuclear
halo's can be identified, but this was found to be insufficient for recognition of an oligodendroglial
component. Dispersed florid microvascular proliferation and areas of necrosis (focally surrounded by
pseudopallisading of tumor cell nuclei) are present. Histopathological diagnosis: Glioblastoma
Multifocal and multicentric gliomas
The differential diagnosis of multiple lesions in the central nervous system includes metastases,
infectious/inflammatory diseases, demyelinating disorders, vascular diseases, malignant lymphoma, but
also glioma. Multiple gliomas can occur as synchronous (diagnosed at initial presentation) and
metachronous (appearing some time after initial diagnosis) lesions . Metachronous
dissemination of gliomas may well be increasing as patients live longer . Only a small
percentage of glioma patients (estimated by some authors as 2%) show multiple, seemingly independent
lesions at initial presentation
Glioblastomas relatively frequently present as multiple
synchronous lesions . This finding may be explained by the relatively high
incidence  and by the aggressive biological behavior of this type of glioma.
In the literature, multiple gliomas are often designated as multifocal or multicentric
Multifocal gliomas are considered to be the result of dissemination of glioma
cells via cerebrospinal fluid pathways, meninges, or white matter tracts, while multicentric gliomas are
widely separated lesions that can not be attributed to the pathways just mentioned. The distinction
between multifocal and multicentric gliomas is, however, not straight forward. It has been suggested
that supra- and infratentorial co-occurrence of multiple gliomas indicates true
multicentricity . However, a recent study suggests that migration of glioma cells may very
well occur via cerebro-cerebellar white matter tracts . In some studies, classification of
gliomas as multicentric is based on histopathological differences between the different lesions. Gliomas
are, however, often heterogeneous with marked spatial differences in cellular phenotype and malignancy
grade. Since molecular genetic studies demonstrated a common origin in such different components, these
heterogeneous gliomas are considered as clonal lesions
Moreover, a post mortem study
using whole brain sections showed that multifocal glioblastomas can emerge in the background of a better
differentiated astrocytic neoplasm . More recently, the occurrence of cerebellar
glioblastoma was described to arise in a patient with supra- and infratentorial gliomatosis
One study reported that using MRI, CT, or both, only in 12 of the 26 patients with multiple foci of
glioma at initial diagnosis various patterns of spread were evident or suggested (subarachnoid >
intraventricular > direct brain penetration) . However, glioma cells can migrate
(sometimes over long distances) via white matter tracts with relative preservation of the original tissue
architecture. Conventional radiological techniques tend to underestimate the extend of such diffuse
infiltrative growth, especially when the blood-brain barrier is still intact and, consequently,
contrast-enhancement is absent. In this setting, multifocal malignant progression may radiologically
result in multiple contrast-enhancing lesions and falsely suggest the presence of multiple independent
lesions. The best way to prove that "multicentric" gliomas are indeed polyclonal is by showing an
independent origin of the different lesions . One study performing genetic analysis of
multifocal glioblastoma multiforme indicated a monoclonal origin .
Recent studies suggest that the multifocality of gliomas as detected by radiological investigations
implies worse prognosis
The management of patients with multifocal or multicentric
glioma is controversial. Some authors advocate and others reject an aggressive surgical
approach . The benefit of the newer generation of chemotherapeutics and of targeted therapy
is not yet clear.
Take home message
Gliomas in adults
- often show diffuse (sometimes extremely diffuse) infiltration in the neuropil;
- can be heterogeneous lesions;
- occasionally present as multiple lesions in the CNS.
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