Primary Intracranial Atypical Teratoid/Rhabdoid Tumors

Materials and Methods

Results

Clinical Characteristics

The clinical data of the patients are shown in Table 1. There were 5 male and 3 female patients in this study. Age at diagnosis ranged from 18 to 264 months, with a median of 67 months, and 4 patients (50%) were younger than 3 years of age. One patient presented with deviation of the mouth and the eyes (case 1); 1 patient had right hemiparesis (case 2); and 6 patients (75%) had headache and/or vomiting, accompanied in 2 patients by seizures (cases 6 and 8), 1 patient with visual disturbance (case 5), and 1 patient with progressive gait disturbance (case 7). No patients were found to have an asymptomatic renal rhabdoid tumor.

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Table 1.

Clinical Information, Treatment, and Outcome of 8 Patients With an Atypical Teratoid/Rhabdoid Tumor.

Patient (no.)	Age (mo)	Gender	Initial symptoms	Tumor location	Tumor size (cm)	Surgical resection	Postoperative treatment	Survival time (mo)
1	24	Male	Deviation of the mouth and the eyes	Right cerebellopontine angle	3.0	Partial	None	2
2	26	Female	Right limbs weakness	Left frontal lobe	5.5	Total	None	11
3	18	Female	Vomiting	Vermis and the fourth ventricle	5.2	Total	None	1
4	108	Male	Headache, vomiting	Left occipital lobe	8.0	Total	Radiotherapy	11
5	264	Male	Headache, vomiting, visual disturbances	Left occipital lobe	6.0	Total	Radiotherapy and chemotherapy	15
6	24	Male	Nausea, vomiting, seizures	Left lateral ventricle	4.5	Partial	None	4
7	144	Female	Headache, vomiting, gait disturbance	Right cerebellar hemisphere	5.0	Subtotal	Radiotherapy and chemotherapy	10
8	144	Male	Headache, seizures	Right temporal lobe	2.5	Subtotal	Radiotherapy	9
Median	67				5.1			9.5
Range	18-264				2.5-8.0			1-15

Gross total resection was performed on 4 (50%) patients, subtotal resection on 2 patients (cases 7 and 8), and partial resection on 2 patients (cases 1 and 6). Two patients (cases 4 and 8) received 54 to 60 Gy of involved-field radiation over a 6-week period postoperatively, and 2 patients (cases 5 and 7) were treated with postoperative radiotherapy and chemotherapy using a regimen of vincristine, etoposide, cisplatin, and cyclophosphamide. Case 5 received 4 cycles of chemotherapy after 54 Gy of involved-field radiation. Case 7 received 2 cycles of chemotherapy after craniospinal irradiation using a total craniospinal dose of 36 Gy and a total dose of 54 Gy for the primary sites of disease. At the time of this review, 7 patients (88%) died of progressive disease, and 1 patient (case 3) died of pulmonary infection 1 month after the operation. The median overall survival duration was 9.5 months (range, 1-15 months). Only 1 patient (case 5) survived for longer than 1 year.

Neuroradiologic Findings

As presented in Table 1, 3 (38%) of the 8 tumors occurred in the posterior fossa, including the cerebellar hemispheres, the vermis, the fourth ventricle, and the right cerebellopontine angle, and 5 (62%) of the tumors occurred in supratentorial regions, including the occipital, frontal, and temporal lobes and the left lateral ventricle. The median tumor size was 5.1 cm (range, 2.5-8.0 cm). Most of the lesions (n = 6, 75%) were predominantly solid with cystic areas. One case (case 7) was entirely solid, and 1 (case 5) was mostly cystic. The CT scans generally showed inhomogeneous isodense (n = 4) or slightly hyperdense (n = 3) solid components (Figure 1A) containing hypodense cystic zones (n = 6). One tumor (case 5) was a predominantly cystic hypodense mass. Inhomogeneous enhancement was apparent in the 3 cases given intravenous contrast infusions (Figure 2A). Two of the 8 tumors contained calcifications. With T1-weighted MR imaging, the tumors were typically heterogeneously hypointense (n = 4) or isointense (n = 2) containing hyperintense foci (Figures 1B and 2B), whereas in T2-weighted images they were isointense or slightly hyperintense with hypointense foci (Figures 1C and 2C). The 6 cases for which MRI scans were done had mass effect and peritumoral edema. Of these 6 cases, 4 were given intravenous gadolinium infusions, and in these the tumors had heterogeneous contrast enhancement, with the solid components having moderate to strong enhancement and the cystic portions none (Figures 1D and 2D). Abnormal enhancement in the leptomeninges indicative of leptomeningeal dissemination of tumor was seen in 1 patient's scans (case 6) at the time of diagnosis. Finally, in fluid-attenuated inversion-recovery images, the tumors were isointense in 2 and slightly hyperintense relative to gray matter in 1 of the 3 cases so examined (Figure 2E).

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Figure 1.

Axial computed tomographic scan (A) of case 7 displaying a slightly hyperdense mass in the right cerebellar hemisphere. The mass was hypointense in axial T1-weighted images (B) and was hyperintense in T2-weighted images, along with evidence of edema in the surrounding brain tissue (C). Contrast-enhanced axial T1-weighted images (D) revealed strong enhancement within the mass.

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Figure 2.

Axial enhanced computed tomographic scan after contrast injection (A) of case 4, displaying a large, bulky mass involving the left occipital lobe with inhomogeneous enhancement and calcification. The mass was heterogeneously hypointense in axial T1-weighted images (B) and was slightly hyperintense in axial T2-weighted images (C). There was a prominent heterogeneous contrast enhancement in a contrast-enhanced axial T1-weighted image (D). Axial fluid-attenuated inversion-recovery images displaying isointense signal intensity relative to the gray matter (E).

Pathologic and Immunohistochemical Findings

Grossly, the tumors were soft, fleshy, pink-gray masses containing areas of necrosis or hemorrhage. Histologically, most of the tumors (n = 7) were predominantly composed of rhabdoid cells and undifferentiated small cells (Figure 3A), along with a mixture of mesenchymal (n = 5) and/or epithelial components (n = 2). Only 1 tumor (13%) was entirely composed of rhabdoid cells. The rhabdoid cells were intermediate-sized, round-to-oval, and characterized by abundant eosinophilic cytoplasm, eccentrically placed nuclei, and prominent nucleoli. These cells were generally arranged in cords, nests, or diffuse solid sheets. Frequently aberrant mitotic activity and extensive areas of necrosis were detected. Paranuclear eosinophilic inclusions could be seen in a minority of the rhabdoid cells. The undifferentiated small cells with hyperchromatic nuclei, scant cytoplasm, and indistinct cell borders resembling a medulloblastoma were diffusely arranged. Homer Wright rosettes (Figure 3B) were observed in 3 cases (38%). The mesenchymal components were arranged in a reticular pattern or in interweaving fascicles, mimicking a sarcoma. There was no well-differentiated epithelial structure, but epithelioid characteristics in the form of poorly formed glands were present in 2 cases (25%). Occasionally, cords of epithelioid cells were embedded within a mucinous background simulating a chordoma.

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Figure 3.

Histopathologic characteristics of atypical teratoid/rhabdoid tumors. (A) Tumor with prominent rhabdoid cells and undifferentiated small cells, resembling medulloblastoma (hematoxylin and eosin staining; magnification, ×200). (B) Rhabdoid cells with eccentrically placed nuclei and eosinophilic cytoplasm and Homer Wright rosettes formed by small cells (hematoxylin and eosin staining; magnification, ×400). (C) Strong cytoplasmic immunoreactivity for vimentin in the rhabdoid cells and small cells (magnification, ×400). (D) Membranous and cytoplasmic immunoreactivity for epithelial membrane antigen in the rhabdoid cells (magnification, ×400). (E) Loss of expression of INI1 in nuclei of tumor cells with retained expression in the endothelial and inflammatory cells (magnification, ×200). (F) Focal cytoplasmic immunoreactivity for cytokeratin in the rhabdoid cells (magnification, ×400).

The immunoreactivity profiles of the atypical teratoid/rhabdoid tumors are listed in Table 2. All tumor cells showed diffusely and strong cytoplasmic immunoreactivity for vimentin (Figure 3C), and showed at least focal membranous and cytoplasmic immunoreactivity for epithelial membrane antigen (Figure 3D), but were negative for INI1 (Figure 3E), desmin, and placental alkaline phosphatase in all of the specimens. Notably, although there was loss of nuclear expression of INI1 in tumor cells, nuclear INI1 expression was retained in intratumoral blood vessels and inflammatory cells. In most cases (n = 6), the rhabdoid cells showed at least focal smooth muscle actin positivity. Focal cytoplasmic immunoreactivity for cytokeratin (Figure 3F) (n = 6), glial fibrillary acidic protein (n = 5), neurofilament protein (n = 4), synaptophysin (n = 3), and CD99 (n = 5) was predominantly observed in the rhabdoid cells in variable cases. Moreover, regions of small cells, as well as mesenchymal or epithelial components, also showed variable expression of these markers singly or in clusters. In addition, staining for synaptophysin was also seen in a neuropil pattern in 3 cases. The mean MIB-1 labeling index was 48% (range, 20%-80%), indicating its malignant biologic behavior.

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Table 2.

Immunohistochemical Characteristics of Atypical Teratoid/Rhabdoid Tumors.^a

Patient (no.)	Vimentin	EMA	SMA	Cytokeratin	GFAP	NFP	Synaptophysin	CD99	Desmin	PLAP	INI1
1	+	+	+	+	+	+	–	–	–	–	–
2	+	+	–	+	+	–	+	+	–	–	–
3	+	+	+	+	–	–	+	+	–	–	–
4	+	+	+	+	+	+	–	–	–	–	–
5	+	+	+	–	+	+	–	–	–	–	–
6	+	+	+	+	–	–	+	+	–	–	–
7	+	+	+	+	+	+	–	+	–	–	–
8	+	+	–	–	–	–	–	+	–	–	–
Positive rate (%)	100	100	75	75	62.5	50	37.5	62.5	0	0	0

Abbreviations: EMA, epithelial membrane antigen; GFAP, glial fibrillary acidic protein; SMA, smooth muscle actin; NFP, neurofilament protein; PLAP, placental alkaline phosphatase; +, positive result of immunohistochemical assay; –, negative result.

^aThe antibody clones or catalog numbers are as follows: cytokeratin (polyclonal, Code Z0622, wide-spectrum screening), EMA (monoclonal, clone E29), vimentin (monoclonal, clone V9), SMA (monoclonal, clone 1A4), desmin (monoclonal, clone D33), GFAP (monoclonal, clone 6F2), NFP (monoclonal antibody to the 70-kDa subunit of neurofilament, clone 2F11), synaptophysin (monoclonal, clone SY38), PLAP (monoclonal, clone 8A9), CD99 (monoclonal, clone 12E7), Ki-67 (monoclonal, clone MIB-1), and INI1 (monoclonal, clone 25/BAF47).

Discussion

Atypical teratoid/rhabdoid tumors are rare, highly malignant intracranial tumors, representing less than 5% of all pediatric central nervous system tumors, but accounting for up to 20% of malignant central nervous system tumors in children younger than age 3 years. ^3,14,15 The tumors most commonly occur in the cerebellum, but they can arise anywhere in the central nervous system. ^{1 –3,14} Other rare sites of origin include the cerebellopontine angle, ⁶ the brainstem, ⁷ the pineal region, ^4,7 and the spine. ^1,15 There is a slight male predominance. ^1,2,11 In this study, 4 patients were younger than 3 years at diagnosis, and only 1 tumor occurred in an adult patient; the male-to-female ratio was 5:3, which was consistent with previous reports. ^{1 –3,11} However, posterior fossa predominance was not detected in this study: 3 tumors were infratentorial, and 5 tumors were supratentorial. Two of the 3 infratentorial tumors were cerebellar, and 1 was in the right cerebellopontine angle. The cerebral hemispheres were the most common supratentorial location. One tumor was located in the left lateral ventricle.

The clinical presentation of atypical teratoid/rhabdoid tumors depends on the age at presentation and the tumor location and is similar to that of primitive neuroectodermal tumor/medulloblastoma. ¹ However, patients with an atypical teratoid/rhabdoid tumor tend to be younger than those with a primitive neuroectodermal tumor/medulloblastoma. ⁶ In this study, headache was the most common symptom in children older than 3 years. Younger children presented with vomiting and/or seizures. One patient with a tumor in the right cerebellopontine angle developed seventh cranial nerve palsy, and 1 patient with a tumor in a frontal lobe developed hemiplegia. These results were consistent with previous reports. ^{1 –3}

The histogenesis and biological determinants of malignancy of atypical teratoid/rhabdoid tumors remain unclear. Based on the polyphenotypic histopathologic and immunohistochemical features, it has been speculated that this tumor may originate from highly malignant, transformed pluripotent precursor cells, ^{1 –3} which is further supported by the expression of stem cell–associated transcription factors in these tumors. ^16,17 It is now generally accepted that deletion and/or mutation of the INI1/hSNF5/SMARCB1 gene on chromosome band 22q11.2 may be responsible for tumorigenesis. ^3,5,11,12 The INI1/hSNF5 gene is a component of the ATP-dependent chromatin remodeling SWI/SNF complex and functions as a tumor suppressor gene by mediating cell cycle arrest. ¹⁸ Loss of the INI1/hSNF5/SMARCB1 gene may deregulate both the p16^INK4A and p14^ARF pathways, resulting in the repression of tumor suppressors. ¹⁹ These results provide insights into cell cycle dysregulation in the pathogenesis of atypical teratoid/rhabdoid tumors and may facilitate the development of more effective therapeutic strategies for these tumors. ¹⁹

The neuroimaging appearances of atypical teratoid/rhabdoid tumors reported so far consistently described bulky, isodense, or slight hyperdense lesions with zones of hypodense change and calcification in CT scans. ^{6 –8} In this study, the tumors were large (median 5.1 cm), and calcification was noted in 2 of 8 cases. Typically, the tumors are inhomogeneous, hypointense, to isointense in T1-weighted images with heterogeneous contrast enhancement, isointense to slightly hyperintense in T2-weighted images, and in fluid-attenuated inversion-recovery, as detected in this study, reflecting their histopathologic complexity as well as the frequent presence of more areas of apparent necrosis or cystic change than are evident with the typical medulloblastoma. ^{6 –8} Moreover, cerebellopontine angle involvement and intratumoral hemorrhage are more common in atypical teratoid/rhabdoid tumors than in medulloblastoma. ⁶ There is a high tendency for subarachnoid dissemination in 24% to 46% of the cases at presentation. ^1,7,8 In this study, intratumoral hemorrhage was present in 3 cases, 1 tumor involved in a cerebellopontine angle, and nodular leptomeningeal dissemination was seen in 1 of the 4 cases studied with MRI at the time of diagnosis. In addition, atypical teratoid/rhabdoid tumors were hyperintense in diffusion-weighted images, indicating restricted diffusion within these tumors, similar to primitive neuroectodermal tumors, and apparent diffusion coefficient values could not distinguish these types of tumor from each other. ^6,7 The proton MR spectra of both types of tumor typically show elevated levels of choline and decreased N-acetylaspartate. ⁷ The similarities of many imaging features of atypical teratoid/rhabdoid tumor with primitive neuroectodermal tumor may be due to the overlapping histologic features of these hypercellular tumors that contain neoplastic cells with increased nuclear-cytoplasmic ratios and small extracellular spaces. ^{1,6 –8} Therefore, for a bulky pediatric brain neoplasm that is heterogeneously contrast-enhancing in T1-weighted images, with more areas of apparent necrosis or cystic change, and with restricted diffusion in diffusion-weighted images, atypical teratoid/rhabdoid tumor should be taken into consideration in addition to primitive neuroectodermal tumor/medulloblastoma.

The definitive diagnosis of atypical teratoid/rhabdoid tumors should be based on pathologic and immunochemical findings and should require proof of loss of the INI1/hSNF5 protein or genes. ^{1 –3,9 –13} Cytologic examination may offer a useful alternative to that of frozen sections during the intraoperative consultation. ²⁰ Histopathologically, these tumors are characterized by the presence of nests or sheets of rhabdoid cells mixed with undifferentiated small cells, as well as epithelial or mesenchymal components in varying proportions, as seen in our cases, but lack germ cells and tissue differentiation characteristic of malignant teratomas. ^{1 –3,9,10,20} The rhabdoid cells have an eccentrically placed vesicular nucleus, a prominent nucleolus, and a pale or eosinophilic inclusion-like cytoplasm that is composed of intermediate filament whorls. The presence of rhabdoid cells and such tumoral heterogeneity are the histologic hallmarks of these tumors. A few of the cases (approximately 13%) contain a pure population of rhabdoid cells, mimicking a sarcoma. ¹ In the present study, 1 tumor was entirely composed of rhabdoid cells, 7 tumors consisted of a mixture of rhabdoid cells and undifferentiated small cells, as well as a spindle cell or fascicular architecture, or epithelioid features with myxoid changes within a given region.

The immunohistochemical findings in this study were similar to those reported in the literature. ^{1 –3,9 –12} Immunoreactivity for vimentin was consistently detected in all atypical teratoid/rhabdoid tumors. Most tumors displayed at least focal immunoreactivity for epithelial membrane antigen, cytokeratin, smooth muscle actin, glial fibrillary acidic protein, neurofilament protein, synaptophysin, or CD99. However, these tumors were typically immunonegative for placental alkaline phosphatase, desmin, and the INI1 protein. Immunophenotypic heterogeneity and loss of nuclear INI1 expression in these tumor cells were particularly unique and were crucial for the diagnosis. ^{10,12,13,21,22} INI1 immunostaining should be routinely performed in all malignant pediatric embryonic central nervous system tumors to test for a lack of INI1 protein, because patients with these tumors may benefit from intensified treatment. ²²

The differential diagnosis of atypical teratoid/rhabdoid tumors should include primitive neuroectodermal tumor/medulloblastoma, anaplastic ependymoma, choroid plexus carcinoma, malignant teratoma, and other embryonal tumors. ^{1 –3,9 –13} Tumors resembling metastatic carcinoma in an infant should prompt the consideration of an atypical teratoid/rhabdoid tumor even in the absence of classic rhabdoid cells. Large, bulky intracranial masses displaying a remarkably wide morphologic spectrum in a younger child should be suspect as well. The polyphenotypic immunoprofiles, along with deletion or mutation of the INI1/hSNF5 gene, can be critical for making these important distinctions. Although cytogenetic analysis was not performed in the present study, the pathologic and immunohistochemical findings in all of the specimens were compatible with atypical teratoid/rhabdoid tumors.

Atypical teratoid/rhabdoid tumors are highly aggressive malignancies with a median survival of only 17 months. ¹⁴ Their biological invasiveness and early leptomeningeal dissemination, occurrence in patients younger than 3 years, and a lesser extent of surgical resection have been reported to be associated with worse prognosis. ^7,14,15 There has hitherto been no satisfactory treatment for these tumors, although aggressive multimodality regimens, including immediate gross total resection followed by intensive chemotherapy and/or radiation therapy, have yielded limited success in some patients. ^15,23 In the present study, all of the patients died within a median of 9.5 months (range, 1-15 months) due to postoperative progressive disease or pulmonary infection. Only one 22-year-old patient, who received gross total resection followed by chemotherapy and radiotherapy, survived longer than 12 months; this patient died at 15 months after the operation, which suggested that the combination of postoperative chemotherapy and radiotherapy may be useful for older patients and was consistent with previous reports. ^14,15,23 We also found that the mean survival duration of 4 children younger than 3 years at diagnosis was 4.5 months (range, 1-11 months). Reluctance to use radiotherapy in such young children and a higher rate of disease progression in younger children may account for the poor prognosis. ^{1 –3,15} Therefore, specific, intensive multimodal treatment protocols that depend on the patient’s age and extent of the disease at diagnosis are needed for the treatment of atypical teratoid/rhabdoid tumor. ^14,15 Further cytogenetic studies should be focused on facilitating the ultimate design of tumor-specific therapies. ^{11,12,14,15,18,19}

Conclusions

Atypical teratoid/rhabdoid tumors are rare aggressive intracranial tumors that display nonspecific imaging characteristics, that should be considered during the differential diagnosis of large pediatric intracranial tumors. The pathologic findings, supported by immunochemistry and/or genetic analysis, are essential for making the final diagnosis. The efficacy of aggressive therapeutic modalities for these tumors should be further explored.