Acta Neurochir (2009) 151:653–657 DOI 10.1007/s00701-009-0286-5
SHORT ILLUSTRATED REVIEW
Cerebellar glioblastomas: pathophysiology, clinical presentation and management Gordan Grahovac & Damir Tomac & Smiljka Lambasa & Arijana Zoric & Mario Habek
Received: 6 April 2008 / Accepted: 28 October 2008 / Published online: 25 March 2009 # Springer-Verlag 2009
Summary Glioblastoma multiforme usually affects the cerebral hemispheres with the peak age of onset in the sixth or seventh decade, while cerebellar glioblastoma multiforme is a rare tumour especially in younger patients. Most result from de-differentiation from low grade astrocytoma (secondary glioblastoma) or can develop de novo (primary glioblastoma). Primary glioblastomas develop in older patients while secondary glioblastomas develop in younger patients and contain TP53 mutations as the earliest detectable change. We report a 28 year old patient with primary multi-focal cerebellar glioblastoma multiforme and
Study concept and design: Grahovac and Habek. Acquisition of data: Grahovac, Tomac, Lambasa and Zoric. Analysis and interpretation of data: Grahovac, Tomac, Lambasa and Zoric. Drafting of the manuscript: Grahovac and Habek. Critical revision of the manuscript for important intellectual content: Grahovac, Tomac, Lambasa, Zoric and Habek. Administrative, technical, and material support: Grahovac and Habek. G. Grahovac (*) : D. Tomac Department of Neurosurgery, University Hospital Dubrava, HR-10000 Zagreb, Croatia e-mail:
[email protected] S. Lambasa Department of Pathology, University Hospital Dubrava, Zagreb, Croatia A. Zoric Laboratory of Molecular Oncology, Division of Molecular Medicine, Ruder Boskovic Institute, Zagreb, Croatia M. Habek University Department of Neurology, Zagreb School of Medicine and University Hospital Center, Zagreb, Croatia
review the pathophisiology, clinical presentation, diagnosis and treatment of cerebellar glioblastomas. Keywords Glioblastoma multiforme . Cerebellum . Primary glioblastoma . p53 . p73
Introduction Glioblastoma multiforme is the most common primary brain tumour in adults. It usually affects the cerebral hemispheres and the peak age of onset is the sixth or seventh decade [4]. Few examples of cerebellar glioblastoma in adults have been published so far [5, 12]. The aim of this report is to give an overview of pathophysiology, clinical presentation, diagnosis and treatment of cerebellar glioblastomas, together with an illustrative clinical example which highlights all the diagnostic problems.
Literature review All articles containing the search term “Glioblastoma” and “Cerebellum” from 1975–2008 were obtained from the Medline database (PubMed, http://www.ncbi.nlm.nih.gov/ PubMed/, accessed on March 29, 2008). This approach yielded 163 titles and the abstracts of those related to cerebellar glioblastoma were read. Only articles in English were reviewed in detail. References were also selected from the authors' files. On the basis of abstract content, relevant papers were read specifically to provide context for this review rather than to comprehensively catalogue all publications. This review summarises the pathophisiology, clinical presentation, diagnosis and treatment of cerebellar glioblastomas.
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Illustrative clinical example A twenty eight year old female patient presented to our emergency room with occipital headache of increasing intensity over one week associated with vomiting. Her previous medical history was unremarkable and she had never had headaches before. Neurological examination showed only minor instability in the Romberg’s position. Enhanced brain CT revealed an irregular, hypodense lesion in the left cerebellar hemisphere with surrounding oedema and obstructive hydrocephalus due to obstruction of the fourth ventricle. Cranial MR imaging was performed which showed non-homogeneous enhancement of the lesion. On T1, T2, FLAIR and T1 post-contrast brain MRI sequences two mass lesions were visible: one in the medio-sagittal line near the IV ventricle, 12 × 10 × 10 mm in size, with homogeneous post-gadolinium enhancement; a second 22 mm in diameter localised more laterally in the left cerebellar hemisphere with ring-like, post-gadolinium enhancement and a central necrotic area. Both lesions were surrounded with oedema and causing herniation of the cerebellar tonsils caudally into the foramen magnum. Obstructive hydrocephalus due to compression of the fourth ventricle was present (Fig. 1A and B). Sub-occipital craniotomy was performed and both lesions were resected. However, radical resection was not possible due to the location and size of the tumours. During resection of the tumour, the roof of the fourth ventricle was opened. Since we opened not only the fourth ventricle but also the cerebello-medullary cistern, it was decided that a ventriculo-peritoneal shunt was not required. Histopathological examination revealed a pseudo-palisade pattern of low differentiated glial cells with a high mitotic index, microvascular proliferation and occasional necrosis (Fig. 2A). Infiltration of the subarachnoid spaces with tumour cells was prominent. Immuno-histochemistry with Glial Fibrillary Acidic Protein (GFAP) (Fig. 2B), TP53 (Fig. 2C) and p73 (Fig. 2 D) was performed, together with positive and negative controls. The patient underwent postoperative radiotherapy to the posterior cranial fossa. However, the tumour recurred eight months later and she underwent another operation and died seven months after the second intervention.
Discussion Glioblastoma multiforme is the most common primary central nervous system (CNS) tumour with a frequency of approximately 50% of all primary CNS tumours. Occurrence of glioblastoma multiforme in the cerebellum is extremely rare, with a frequency of 0% to 3.4% [10, 17]. The male to female ratio is 2:1 [6].
Fig. 1 A) Coronal post-contrast T1 weighted MRI image showing two rounded hyperintense areas with oedema and local compression; B) axial post-contrast T1 weighted MRI image showing primary glioblastoma multiforme with one focus in the left cerebellar hemisphere and another in the vermis
Pathophysiology Based on the clinical and genetic data, there are two subsets of glioblastoma multiforme [3]. Glioblastomas may develop de novo (primary type) or from previous low grade astrocytomas (secondary type) [9, 14]. Secondary glioblastomas develop more frequently in younger patients and often contain TP53 mutation (65%), while primary glioblastomas affect most elderly patients and are generally characterised by absence of heterozygosity 10q (LOH 10q) (70%), EGFR amplification (36%) and TP53 mutation at a frequency lower than 30% [14]. In the pathway to primary or secondary glioblastomas LOH 10q is the most frequent location of genetic alteration, but the loss of the entire chromosome 10 is typical for primary glioblastomas. Pathway p16INK4a/RB1 also plays an important role in both primary and secondary glioblastomas. While TP53 has a crucial role in the development of
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Fig. 2 A) Photomicrograph of a specimen characterised by atypical cells, pathological vascularisation and necrosis (HE stain, original magnification x 100); B) Photomicrograph of a specimen characterised by positive tumour cells positive for Glial Fibrillary Acidic Protein (GFAP staining, original magnification x 100); C) Photomicrograph of a specimen characterised by negative tumour cells negative for TP53 (original magnification x 100); D) Photomicrograph of a specimen characterised by tumour cells positive for p73 (original magnification x 100)
secondary glioblastoma, mutations of TP53 occur also in primary glioblastomas but with a lower frequency. EGFR/ PTEN/Akt/mTor is the key signalling pathway in the development of a primary glioblastoma. [1]. Also, p73 is a member of the p53 family with the function of inducing apoptosis and cell cycle arrest. There are some reports describing that p73 expressions have been higher in some carcinomas than in normal tissue. Mutation analyses of p73 in gliomas was performed but only a few samples showed gene mutation [1], suggesting that p73 may not play a major role as a tumour suppressor in gliomas, although in our patient there was a high expression of this gene. However, there was no TP53 mutation, indicating that it was a primary tumour. The role of p73 remains unclear and warrants further investigation. Although the microscopic appearance of glioblastoma is variable, histopathological confirmation still remains a “sine qua non” for the final diagnosis. Key diagnostic features are necrosis, pseudo-palisading and vascular hyperplasia [13]. All of these features were clearly present in our patient, confirming the diagnosis. The recognition of a secondary glioblastoma can be very difficult, but pathological evidence of low-grade tumour in the surgical specimen occasionally can help in diagnosis [4]. The cause of de-differentiation of an astrocytoma to a glioblastoma remains unclear, but some published examples suggest that radiation therapy up to 50 years previously may be a risk factor [19].
Clinical presentation and imaging findings Symptomatology of a glioblastoma multiforme of the cerebellum, like any other cerebellar tumour, includes headache, gait disturbance, vertigo, nausea, vomiting and ataxia [5]. Unfortunately, all these symptoms are nonspecific and can occur in many diseases. Rarely, symptoms may mimic brainstem infarction with the classical clinical picture of the Wallenberg’s syndrome [2]. Imaging of cerebellar tumours also presents a challenge. The presence of a large cerebellar mass with little mass effect and lack of peri-tumoural oedema should suggest cerebellar glioma in contrast to metastatic disease; the latter typically having more peri-tumoural oedema, mass effect on the fourth ventricle and hydrocephalus [21]. There is a similar problem with MRI interpretation in patients with cerebellar glioblastoma multiforme, as it is often very difficult to differentiate from other tumours, including metastasis as well as an abscess. However, the combination of heterogeneous morphology, ring-like enhancement, midline location, poorly defined margin, tumoural haemorrhage and multicentric or multifocal lesions serve as good indicators towards the correct diagnosis [10]. Diagnostic difficulty also arises when there are several lesions, like in our patient, when other causes like abscesses, granulomas or metastases should be considered. As the posterior fossa is a small compartment, it is very difficult to be absolutely certain that these two lesions were completely distinct.
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They were probably two focal areas of tumour connected with each other. As it was not possible to resect both lesions en bloc there was no evidence to prove the true multifocality nature of this tumour. However, some authors have found that multi-focal cerebellar glioblastomas account for up to 6% of all such cerebellar neoplasms [6, 15]. Survival of patients with glioblastoma multiforme is poor, with younger patients having the better outcome. Recently, it has been suggested that the site of tumour is also a prognostic factor and that tumours in the frontal lobe have a better prognosis [11].
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In patients with recurrent disease as in our patient, management depends on the age, performance score, response to initial therapy, time since original diagnosis, and whether the recurrence is local or diffuse. If recurrent tumour is local, repeated resection should be performed with or without a BCNU-impregnated wafer placed locally. In the case of an unresectable lesion, systemic chemotherapy with Temozolomide or nitrosurea-based regimens with re-irradiation can be performed. In a patient with diffuse disease systemic chemotherapy is recommended. Conclusion
Treatment The treatment of cerebellar glioblastomas does not differ much from treatment of glioblastomas at other locations. It is usually palliative and encompasses surgery, radiotherapy, and chemotherapy. According the guidelines of the National Comprehensive Cancer Network, the treatment of choice with the best outcome for patients is removal of the tumour as much as possible but keeping surgical morbidity to a minimum. The decision regarding surgery for glioblastoma depends on the patient’s age, performance status, proximity to “eloquent” areas of brain, feasibility of decreasing the mass effect, resectability of the tumour and in a patient with recurrent disease, the time since previous surgery [16]. Surgical options include stereotactic or open biopsy and debulking with sub-total or gross resection. Surgery will achieve a diagnosis, decrease intracranial pressure, increase survival and reduce the need for corticosteroid use by decreasing intracranial pressure. Extent of resection increases survival especially in patients older than 50 years, with a Karnofsky performance score higher than 70 and in patients with recurrent high-grade gliomas [7, 8]. If, during surgery, the diagnosis of glioblastoma is confirmed by frozen section, administration of a biodegradable BCNU wafer in the surgical cavity is also recommended. The extent of tumour debulking is confirmed 72 h after surgery with a contrast MR. After surgical excision or biopsy the patient can be treated with fractionated external beam radio-therapy. Total doses of 54–60 Gy in 1.8 to 2.0 Gy fractions are administered to the gross tumour volume. Patients with good performance score should be treated with daily Temozolomide (75 mg/m2) administered with post-operative radiation therapy followed by 6 months using a dose of 150–200 mg/m2/day times 5 days each month [18]. BCNU wafers can be re-inserted in the event of delayed tumour recurrence to prevent tumour recurrence avoiding the systemic toxicity of parenteral chemotherapy. They are active locally for three weeks. Currently, the chemotherapy of choice is Temozolomide, although BCNU, CCNU or PCV can also be used [20].
In conclusion, cerebellar glioblastoma multiforme, although rare, should be considered in the differential diagnosis of a cerebellar mass lesion. Primary or secondary cerebellar glioblastomas are genetically different entities, but a significant difference in survival in patients with primary or secondary cerebellar glioblastomas is not certain. That said, prompt and aggressive surgical treatment along with radiation therapy remains the established management strategy.
Conflict of interest statement
There is no conflict of interest
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