Primary Supratentorial Atypical Teratoid/Rhabdoid Tumor in Children

Case Reports

Case 1

A 3-year-old boy complained of a headache accompanied by projectile vomiting, with weakness and unsteadiness of both lower limbs, for 2 months. A magnetic resonance scan demonstrated a solid, ring-enhancing mass in the septum pellucidum, extending laterally into each lateral ventricle and down into the upper anterior third ventricle, obstructing the foramina of Monro and causing hydrocephalus (Figure 1). A ventriculoperitoneal shunt was placed and then a right frontal craniotomy was done, with incisions in the right frontal lobe and the corpus callosum exposing the tumor through the right lateral ventricle. A gross total excision was performed, with multiple pieces of soft gray tumor, together 1.5 × 1.5 × 1.5 cm sent for histopathologic examination.

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Figure 1.

Axial (A) and sagittal (B) contrast-enhanced T1-weighted magnetic resonance images of case 1 showing a solid, ring-enhancing mass in the septum pellucidum, obstructing the foramina of Monro. This lesion caused dilation of the lateral and third ventricles with cerebrospinal fluid seepage.

The tumor was a highly cellular malignant neoplasm with 2 different admixed components. Most of it was composed of large polygonal cells with large nuclei, conspicuous nucleoli, and abundant eosinophilic cytoplasm. Some tumor cells had typical rhabdoid eosinophilic cytoplasmic inclusions displacing the nuclei to 1 side of the cell (Figure 2A). The other minor component was mesenchymal, consisting of bundles of spindle cells with mucinous/myxoid stroma. A sparse lymphocytic infiltrate in the tumor was also present. There were foci of necrosis and clusters of foamy macrophages. There was no tumor resembling primitive neuroectodermal tumor and none with overt epithelial differentiation.

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Figure 2.

Light microscopic findings of case 1. (A) Hematoxylin and eosin (H&E) showed rhabdoid tumor cells intermixed with a lymphocytic infiltrate (×400). (B) Strong and diffuse reactivity (both membranous and cytoplasmic positivity) for epithelial membrane antigen (×400). (C) Tumor cells showing no labeling with positive internal control (endothelial cells and lymphocytes) by INI1.

Immunohistochemical stains showed that the tumor cells were strongly and diffusely immunoreactive for epithelial membrane antigen (Figure 2B), and focally but strongly immunopositive for vimentin, synaptophysin, S-100 protein, and neuron-specific enolase. There was patchy positivity for pan-cytokeratin. Immunostains for pan-neurofilament protein cocktail, glial fibrillary acidic protein, melanosome, pan-actin, desmin, myoglobin, and the germ cell markers placental alkaline phosphatase, cluster of differentiation 117, and cluster of differentiation 30 were all negative. There was loss of nuclear immunopositivity for the INI1 protein, with preserved immunopositivity in endothelial cells and some lymphocytes infiltrating in the tumor (Figure 2C).

After the diagnosis of atypical teratoid/rhabdoid tumor was rendered, he was treated with craniospinal radiation, but he died 2 years after surgery.

Case 2

A 3-year-old female infant presented with headache, dizziness, nausea, and vomiting together with limb weakness for 1 month with gradual worsening of the symptoms. Physical and neurologic examination on admission revealed unequal dilated pupils (left: right = 2.0: 4.0) and neck stiffness. Her magnetic resonance imaging (MRI) showed a large, heterogeneously enhancing mass located in the right parietooccipital region. The tumor had associated perilesional edema and a midline shift. The splenium of corpus callosum, thalamus, and right lateral ventricle were compressed anteroinferiorly (Figure 3). Postcontrast MRI showed strong heterogeneous enhancement. Craniotomy was performed, and as no border was discernible between the tumor and surrounding brain tissue, the tumor was removed subtotally. She died of postoperative intracranial infection 1 month after the diagnosis.

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Figure 3.

Axial T2-weighted (A) and sagittal contrast-enhanced T1-weighted (B) magnetic resonance images of case 2 showing a large mass located in the right parietooccipital region. The tumor had associated perilesional edema and a midline shift. The corpus callosum, thalamus, and right lateral ventricle were compressed anteroinferiorly.

Histopathologically, the most striking feature was the rhabdoid cells with eccentrically placed nuclei containing vesicular chromatin, prominent nucleoli, and eosinophilic cytoplasm (Figure 4A). Neoplastic spindle cells with high mitotic activity were interspersed with rhabdoid cells, all infiltrating adjacent brain parenchyma and leptomeninges (Figure 4B). The tumors lacked primitive neuroectodermal tumor-like components or epithelial differentiation.

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Figure 4.

Light microscopic findings of case 2. (A) Diffuse sheets of rhabdoid tumor cells with eccentric nuclei, prominent nucleoli, eosinophilic cytoplasm, and cytoplasmic inclusions (H&E ×400). (B) Spindle cells showing high mitotic activity and mixed with scattered rhabdoid cells (H&E ×400). (C-E) Diffuse immunoreactivity for synaptophysin (C ×200) and S-100 protein (D ×400), focal but strong immunoreactivity for vimentin (E ×400). (F). Ki-67 staining showed Ki-67 index was 30% (×200).

The immunohistochemical results were similar to the case 1, except that epithelial membrane antigen and pan-cytokeratin were completely negative in this case (Figures 4C-F). Loss of nuclear immunoreactivity for INI1 protein was also observed (Table 1).

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Table 1.

Immunohistochemical Results of the 2 Cases.

	Case 1	Case 2
Epithelial membrane antigen	+++	–
Vimentin	+	+
S-100	+++	++
Synaptophysin	+	+
Neuron-specific enolase	++	+
Pan-cytokeratin	+	–
Glial fibrillary acidic protein	–	–
Ki-67 index	10%	30%
INI1	–	–

Discussion

Atypical teratoid/rhabdoid tumor is a rare, highly malignant embryonal tumor in the central nervous system. Although cases of older children and adults have been increasingly reported, ^{7 –9} atypical teratoid/rhabdoid tumor is primarily a disease of young children, usually less than 3 years of age. ⁴ Atypical teratoid/rhabdoid tumor represents approximately 1.3% of pediatric brain tumors, and constitutes as many as 20% of all embryonal tumors. ^10,11

Most reports suggest that the majority of atypical teratoid/rhabdoid tumors arise in the posterior fossa, with only about 40% at most in the cerebrum. ¹² However, some recent studies have demonstrated that supratentorial atypical teratoid/rhabdoid tumors are slightly more common, with a ratio of supratentorial to infratentorial tumors of 1.3:1. ¹³ The supratentorial examples are usually within the tissues of the cerebral hemisphere; those originating in the suprasellar region and pineal area may involve the ventricles by direct extension, but primary intraventricular atypical teratoid/rhabdoid tumor is very infrequent. Donovan et al reported an atypical teratoid/rhabdoid tumor of the velum interpositum involving the lateral and third ventricles, ¹⁴ and 1 of 4 cases of atypical teratoid/rhabdoid tumor described by Ertan et al was located in the third ventricle. ¹⁵ In this paper, we have described 1 case of atypical teratoid/rhabdoid tumor arising in the septum pellucidum and involving both lateral ventricles and the top of the third ventricle.

Histopathologically, atypical teratoid/rhabdoid tumors are usually composed of heterogeneous mixtures of rhabdoid cells and fields of more or less classic primitive neuroectodermal cells, plus foci with epithelial tissue or mesenchymal neoplastic tissue. This histologic diversity can lead to misdiagnosis, as medulloblastoma, primitive neuroectodermal tumor, high-grade glioma, melanoma, rhabdoid meningioma, or a variety of metastatic tumors. The grim prognosis requiring more aggressive therapy associated with atypical teratoid/rhabdoid tumor makes it extremely important to establish the correct diagnosis.

Immunohistochemical features are essential for identifying the disease but vary depending on the cellular composition of the tumor. Rhabdoid cells characteristically demonstrate consistent expression of vimentin, epithelial membrane antigen, with only slightly less frequent expression of smooth muscle actin. Expression of glial fibrillary acidic protein, neurofilament protein, synaptophysin, and keratins is also commonly observed. The primitive neuroectodermal cells variably express neurofilament protein, glial fibrillary acidic protein, keratins, or desmin. By contrast, germ cell markers are not typically expressed. In our patients, immunohistochemical results were similar to the studies reported in the literature, except that the rhabdoid cells in case 2 were not immunoreactive for epithelial membrane antigen.

Molecular studies have revealed that in most atypical teratoid/rhabdoid tumors, the INI1 (hSNF5/SMARCB1) gene, located in chromosome band 22q11.2, is inactivated by deletions and/or mutations. ^16,17 INI1 is a component of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex and functions as a tumor suppressor by positively regulating transcription of a particular set of eukaryotic genes, possibly including the c-Myc target genes involved with differentiation and apoptosis. ¹⁸ Strong correlation between molecular genetic status of atypical teratoid/rhabdoid tumor (deletion, mutation) and loss of INI1 expression by immunostaining has been reported. ¹⁹ It is believed that immunohistochemical staining for loss of INI1 expression is a sensitive and specific approach for identifying atypical teratoid/rhabdoid tumor and has become a gold standard procedure to differentiate this entity from other morphologically similar tumors, as mentioned earlier.

The prognosis of pediatric patients with atypical teratoid/rhabdoid tumor is generally considered to be dismal, because it has a high rate of dissemination throughout the cerebrospinal fluid pathways, and is associated with a very poor prognosis. Treatment approaches are now focusing on aggressive resection combining with high-dose chemotherapy. Although studies have shown that a variety of chemotherapeutic regimens may result in tumor stabilization and in some cases objective tumor shrinkage, they have not resulted in consistent long-term disease control. ¹¹ The median survival duration for children with atypical teratoid/rhabdoid tumor is approximately 17 months. ²⁰

In conclusion, our cases particularly emphasize that atypical teratoid/rhabdoid tumor should be considered in the diagnosis of a high-grade tumor showing rhabdoid features, regardless of tumor location. The presence of the characteristic loss of INI1 immunoreactivity is crucial to the diagnosis.