Giant cell glioblastoma in the pediatric age group: Report of two cases.

Giant cell glioblastoma multiforme is a rare subgroup of glioblastoma multiforme. It constitutes about 5% of all glioblastoma cases. Pediatric giant cell glioblastoma is extremely rare. We report two such cases of giant cell glioblastoma in pediatric age group (≤18 years). The pertinent literature is reviewed regarding this uncommon entity.

Introduction

Glioblastoma multiforme (GBM) is by far the most common and most malignant of the glial tumors. Glioblastoma is also one of the most lethal central nervous system (CNS) primary tumor. Composed of a heterogenous mixture of poorly differentiated neoplastic astrocytes, glioblastomas primarily affect adults and are preferentially located in the cerebral hemispheres.[1]

Malignant gliomas including GBM are extremely rare in children as compared to the adult population, comprising only 5–10% of all childhood intracranial neoplasms.[1] Giant cell glioblastoma (GCG) is a rare subgroup of GBM, which constitutes around 5% of all GBMs.[2] It is characterized by the presence of abundant bizarre, multinucleated giant cells along with abundant reticulin stroma and high frequency of p53 mutations. GCG more commonly involve the supratentorial cerebral hemisphere and portends a better prognosis than the conventional GBM.[2] Out of 70 cases of pediatric glioblastomas operated at our center from 2002–2009, there were two cases of pediatric GCG (3%).

Clinical Details

Case 1

A 10-year-old girl presented with history of two episodes of focal seizures with secondary generalization in the last 6 months and with recent onset headache and vomiting from last 10 days. On examination, the patient did not have any focal neurological deficit. Magnetic resonance imaging (MRI) brain revealed a mass lesion in the right temporo-parietal region, hypointense on T1 and hyperintense on T2 with ring enhancement on contrast administration. It was associated with perilesional edema and mass effect. The radiological features were suggestive of high grade glioma [Figure 1]. The patient underwent right temporo-parietal craniotomy and gross total excision of the tumor. She had an uneventful peri-operative course and was discharged on 7th post-operative day. Histopathological examination was suggestive of GCG. MIB-1 labeling index was 10%. The patient received post-operative radiotherapy and chemotherapy including temozolamide. She was well for 27 months before she was lost to follow-up.

Figure 1

Contrast MRI brain axial (a) and sagittal images (b) showing a ring-enhancing lesion in right temporo-parietal region

Case 2

An 18-year-old male patient presented with focal seizure involving right upper limb since past 1 month and right-sided hemiparesis. Neurological examination revealed right-sided hemiparesis with a power of 4/5 (Medical Research Council grading). MRI brain revealed a mass lesion in the left frontal region; hypointense on T1, hyperintense on T2, and FLAIR images with inhomogenous post-contrast enhancement [Figure 2]. It was associated with perilesional edema and mass effect. The patient underwent left fronto-parietal craniotomy and gross total excision of tumor. He had an uneventful peri-operative course and was discharged on 7th post-operative day. Histopathological examination was suggestive of GCG. MIB-1 labeling index was 25%. The patient received post-operative radiotherapy and chemotherapy including temozolamide. He was well for 30 months when he had a recurrence of tumor in frontoparietal region and died 1 month later.

Figure 2

FLAIR (a) and Contrast axial (b) MR image showing left frontal tumour with inhomogenous post-contrast enhancement with perilesional edema and mass effect

Histopathology

Histopathogical examination of both specimens revealed pleomorphic giant astrocytes with focal areas of necrosis. The neoplasic giant astrocytes were positive for glial fibrillary acid protein (GFAP). The MIB-1 labeling index was 10% in Case 1 and 25% in Case 2 [Figure 3].

Figure 3

Photomicrograph (a and b) showing pleomorphic giant astrocytes with focal area of necrosis (H and E, ×100). Immunostaining for GFAP showing positivity in giant cells (×100) (c). Immunostaining for MIB-1 showing indices of 25% (d)

Discussion

GCG is a rare tumor subgroup, a variant of GBM with an incidence of about 0.8% of all brain tumors and about 5% of all GBMs.[2]

Previously termed as monstrocellular tumor due to the macro size of its cells, the glial origin of these tumors has now been confirmed on electron microscopy and immunohistochemistry.[34] GCG, defined as glioblastoma with predominance of giant cells, is a rare subgroup and is often considered as a variant of GBM, classified as grade 4 tumor of WHO classification, although they might be considered as midway between grade 3 and grade 4 gliomas as they are prognostically better in terms of survival than the grade 4 GBM.

The mean age at presentation is 42 years with male to female ratio at 1.6 and 35% occur in patients <40 years.[5] Some authors have proposed a possible association between genetic disorders such as neurofibromatosis type 1[6] and tuberous sclerosis[7] and one study in primates hypothesized a possible etiological agent in the form of JC virus or progressive multifocal leukoencephalopathy.[8]

They have no preferential location, but are more commonly supratentorial, temporal lobe being the most common.[9] Other locations include frontal lobe, parietal lobe, cerebellum, lateral ventricles, optic chiasma, and rarely multifocal.[51011] They are often well-circumscribed tumors, with a tendency to affect younger individuals than does conventional GBM[2] and portending a better prognosis than GBM with longer median survival periods being reported in the literature.[12-14] Few cases of giant cell GBM have a reported survival up to 17 years.[14]

GCG′s don′t differ much in the clinical presentation from the classical GBM, although the duration of symptoms may be short. From the imaging perspective, GCG has been described as a well-circumscribed lesion, possibly due to the fibrous stroma, although no distinguishing features can be found when compared to classic GBM.[2] MRI usually reveals a contrast enhancing heterogeneous mass, with solid and cystic areas, hypo intense on T1 and hyper intense on T2 sequences with a surrounding edema.

Microscopically, they are highly cellular lesions comprising of abundant giant cells reaching size up to 500 nm with nuclei of varying sizes, shapes, and number; abundant stromal reticulin fibers can be found in many along with necrosis, mainly in a pseudo-pallisading or large ischemic forms. The correct origin and classification of these tumors have been elucidated by means of immunohistochemistry profiles. The glial origin of these tumors has been supported by means of positivity for Glial Fibrillary Acidic Protein (GFAP), thus abandoning the usage of the previous term monstrocellular tumor. Immunohistochemistry studies have also shown positivity for S-100, vimentin, alpha 1 anti-chymotrypsin.[15] Pathologically, they are characterized by the abundance of bizarre, multinucleated giant cells, reticulin stroma,[5] and high degree of p53 mutations.[16]

An important differential diagnosis both clinically and histologically to be considered is pleomorphic xanthoastrocytoma (PXA). The features which are in favor of GCG are quicker evolution of seizures, numerous great-sized giant cells, numerous mitoses, atypical mitoses, and pseudo-pallisading pattern of necrosis. Immunohistochemical profiles such as neuronal antigens and p53 will also aid in differentiating between the two with positivity for p53 and negativity for neuronal nuclear antigen, neurofilament protein, and synaptophysin favoring GCG.[1718]

Conclusion

GCG is very rare in pediatric age group, but when diagnosis is confirmed, it offers better hope for such patients because they usually have a longer survival period than classic GBM patients.