2‐YEAR‐OLD GIRL WITH RIGHT LEG WEAKNESS

CLINICAL HISTORY

A previously healthy 2‐year‐old child first presented with a new limp and mild weakness of her right leg. Initial workup with X‐rays was negative. Her condition worsened over 2 weeks with new neurological deficits including worsening gait changes resulting in crawling rather than walking and holding her right arm in a flexed position. Magnetic resonance imaging (MRI) (T1 with contrast) showed a large solid and cystic intra‐axial mass with markedly heterogeneous enhancement centered within the frontoparietal region with extension into and expansion of the body of the corpus callosum (1, 2). Stereotactic biopsy for diagnosis and surgical decompression was performed. She was treated with steroids and anticonvulsants. Further chemotherapeutic treatment was scheduled, but she continued to worsen with lethargy and hypertonicity requiring hospitalization. She clinically deteriorated with unreactive pupils and cerebral posturing. MRI showed tumor progression with herniation. She expired 3 months after onset of her symptoms. A brain‐only autopsy was performed.

Figure 1.

Figure 2.

GROSS

Autopsy showed a markedly edematous brain weighing 1550 g fresh (fresh average weight 2‐year‐old brain 1064 g) with generalized flattening of the sulci and gyri. There was destruction and softening of the right temporal lobe consistent with uncal herniation. Serial coronal sections of the cerebral hemispheres revealed a soft, hemorrhagic, gelatinous tumor maximally measuring 11 cm anterior to posterior, involving both hemispheres, crossing the corpus callosum, involving both caudate nuclei and completely effacing both lateral ventricles. The thalamus and putamen were grossly spared. There was a generalized midline shift to the left (Figure 3).

Figure 3.

MICROSCOPIC

Histologic examination of the tumor revealed pleomorphic, hyperchromatic tumor cells with prominent nucleoli. There was no inflammatory infiltrate. The tumor displayed a mix of hypocellular and hypercellular areas (4, 5, respectively) with prominent Alcian blue staining in many of the hypocellular areas (Figure 6). Focal necrosis with surrounding pseudopalisading of tumor (Figure 7) and focal vascular proliferation (Figure 8) were identified. The tumor cells were immunoreactive for glial fibrillary acidic protein (GFAP) (Figure 9). Ki67 immunostaining demonstrated a high proliferation rate (Figure 10).

Figure 4.

Figure 5.

Figure 6.

Figure 7.

Figure 8.

Figure 9.

Figure 10.

DIAGNOSIS

Glioblastoma multiforme.

DISCUSSION

Brain tumors are the leading cause of cancer deaths in children, accounting for 20% of pediatric cancers. Gliomas contributing as much as 60% of this group (6). High‐grade gliomas include glioblastoma and anaplastic astrocytoma. Glioblastomas can occur in any area of the brain. In children, the brainstem is the most common site and the cerebellum the least. Clinical presentation is notable for an evolution of symptoms over weeks to months, consistent with a high‐grade lesion. The presenting symptoms are variable and related to the location of the tumor. Most commonly they include seizures, visual field defects, hemiparesis, headaches and increased intracranial pressure. Very young children may have non–specific symptoms such as irritability, macrocephaly, failure to thrive and lethargy (6). Glioblastomas are generally de novo lesions in children, especially in young children as in this case. One of the few definitive environmental risk factors associated with increased risk of secondary brain tumor in children is therapeutic radiation exposure. The resulting secondary brain tumors may present as early as 7–9 years after exposure or up to decades later (4).

The genetics of de novo glioblastoma in children are notably different from adult tumors. These tumors tend to have p53 inactivation and no significant epidermal growth factor receptor (EGFR) amplification. Although multiple genetic alterations have been implicated, these also involve the p53 pathway. One study of deep‐seated glioblastomas showed all nine cases with p53 mutations (3). A larger study of 54 patients with tumors from different anatomical sites had p53 immunoreactivity in 54% of cases, with EGFR overexpression in only 26%. Tumors showing p53 mutations were most frequently thalamic, less often cerebral lobar and least often brainstem in location (2).

Similar to tumors in adults, glioblastomas in children have a highly varied morphology. The tumor cells themselves are highly varied in morphology. Their appearance ranges from pleomorphic cells—with or without glassy cytoplasm—to small, uniform cells, to giant cell forms with lobed or multiple nuclei (1). Interestingly, this tumor had a prominent myxoid component that has been reported (1). Immunohistochemical staining is essential to confirm if the tumor cells are GFAP‐positive and to determine proliferation rate with Ki‐67.

Prognosis for glioblastoma is poor despite advances in diagnosis and treatment, with less than 20% survival at 5 years. The Ki‐67 rate has been shown to be a strong predictor of outcomes. A study of 98 patients showed a worse prognosis with increasing Ki‐67 labeling. The poorest 5‐year survival, approximately 11%, was seen in tumors with more than 36% Ki‐67 labeling (5). Unfortunately, the present case had at least 50% Ki‐67 labeling and followed the predicted aggressive course of a glioblastoma.

Multiple studies comparing treatment with surgery, radiation or chemotherapy have shown that children undergoing radical tumor resection have had a statistically significant improvement in progression‐free survival. A major complicating factor in radical resection, however, is that glioblastomas often have invaded the critical areas of the cerebrum, limiting patient candidacy. Radiation offers modest prolongation of survival, but is not indicated for children less than 3 years of age because of unacceptable effects on neurological development. As surgery and radiation are rarely curative, experimental chemotherapeutic trials with a variety of combination regimens are being studied. Currently, no therapeutic regimen has yet shown to improve outcomes (6).

ABSTRACT

A previously healthy two year girl presented with new neurological deficits including a limp and right leg weakness. Her deficits increased with a worsening gait and holding the right arm flexed. Radiological imaging revealed a large, heterogeneous supratentorial mass within the frontoparietal region. Despite medical management, her condition rapidly deteriorated due to rapid tumor progression with subsequent herniation. A brain‐only autopsy showed a markedly edematous brain with sulcal and gyral flattening and uncal herniation. Serial sectioning revealed a soft, hemorrhagic, gelatinous tumor involved both hemispheres which crossed the corpus callosum and effaced both ventricles. Microscopic examination revealed a glioblastoma multiforme. Glioblastomas in children present with a wide spectrum of symptoms based on the location of the lesion. The genetics of pediatric glioblastoma differ from adult tumors with p53 inactivation and no significant epidermal growth factor amplification. The Ki‐67 has been shown to be a strong predictor of outcomes, and unfortunately this case had an aggressive course as predicted with at least 50% tumor staining. Similar to adults, glioblastoma in children follows an aggressive course despite surgery, radiation and/or chemotherapy.