General Child Neurology
May. 31, 2021
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Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant brain tumor that typically affects young children. Once considered rapidly fatal, intensive multimodal treatment regimens have resulted in improved survival for some patients. The Children’s Oncology Group (COG) published the largest series of prospectively treated patients with atypical teratoid/rhabdoid tumor, demonstrating significantly improved survival for patients younger than 3 years of age compared to historical cohorts. Atypical teratoid/rhabdoid tumor is the first pediatric brain tumor for which a candidate tumor suppressor gene, SMARCB1, was identified. Gene expression profiling analysis suggests that there are 3 distinct molecular subtypes of atypical teratoid/rhabdoid tumor.
• Atypical teratoid/rhabdoid tumor is often fatal, but subsets of patients are long-term survivors after intensive multimodal therapy.
• A somatic mutation of the SMARCB1 gene is found in nearly all atypical teratoid/rhabdoid tumors, and an immune-histochemical stain for the gene product can help pathologists readily identify the tumor.
• Patients with germline mutations for the SMARCB1 gene often have disseminated or synchronous tumors, and their disease may behave more aggressively.
• AT/RT appears to contain 3 to 4 subgroups with distinct epigenomic, transcriptional, and clinic-pathologic features.
• Studies that incorporated targeted biological therapies to treat atypical teratoid/rhabdoid tumor are underway.
Atypical teratoid/rhabdoid tumor of the central nervous system is a rare, highly malignant disease that occurs primarily in young children. The disease is often simply referred to as AT/RT. It was first identified by Rorke and colleagues as a unique tumor type in 1987 (29). Prior to that time, patients with atypical teratoid/rhabdoid tumor were often misdiagnosed as having medulloblastoma or other embryonal tumor. This is understandable as approximately two thirds of atypical teratoid/rhabdoid tumors have components that resemble medulloblastoma or other embryonal tumors (34). In addition to rhabdoid cells, atypical teratoid/rhabdoid tumors often contain malignant epithelial and mesenchymal components that further distinguish them from medulloblastoma or other embryonal tumors. Because it histologically resembles the rhabdoid tumor of the kidney, atypical teratoid/rhabdoid tumor was sometimes referred to as malignant rhabdoid tumor of the brain or central nervous system (15) before it was recognized as a distinct entity. The World Health Organization began classifying atypical teratoid/rhabdoid tumor an embryonal grade IV neoplasm in 1993 (25).
• Short history of progressive neurologic changes and symptoms of hydrocephalus should lead the clinician to evaluate for a malignant brain tumor.
As is the case with other brain tumors, patients with atypical teratoid/rhabdoid tumor present with signs and symptoms that reflect the location of the tumor. Approximately half of atypical teratoid/rhabdoid tumors arise in the posterior fossa (32). Young patients with posterior fossa tumors usually present with symptoms related to hydrocephalus, namely early morning headaches, vomiting, and lethargy. They may also develop ataxia or regression of motor skills. Cranial nerve palsies, particularly VI and VII, are not uncommon. Because young children have open sutures and fairly pliable skulls, a rapidly enlarging head size should alert the practitioner to evaluate the patient for a brain mass as this may be the only symptom at presentation. Patients with supratentorial tumors can present with signs and symptoms of hydrocephalus, enlarging head size, hemiparesis, seizures, or visual changes depending of the location of the tumors. Because atypical teratoid/rhabdoid tumor is a highly malignant tumor, patients typically have a fairly short history of progressive symptoms measured in days to weeks. It is unusual for symptoms to have been present for more than a few months. There are no data to support that clinical characteristics can separate atypical teratoid/rhabdoid tumors from other malignant brain tumors.
Imaging characteristics are also helpful but nonspecific for atypical teratoid/rhabdoid tumor. The CT appearance is typically that of a hyperdense mass that enhances intensely with contrast (32). On T1-weighted MRI, the tumor mass is typically isointense with frequent hyperintense foci secondary to intratumoral hemorrhage. The tumor does take up contrast intensely but in a heterogenous pattern. On T2-weighted and flair MRI, the tumor appears heterogenous as a result of the mixture of tumor cellularity, hemorrhage, necrosis, and cysts. Post-contrast flair imaging may reveal small tumor deposits. MR spectroscopy findings were similar to other embryonal tumors with marked elevation of choline and low or absent N-acetyl-aspartate and creatine. Hyperintensity of diffusion-weighted imaging suggests that the tumor is malignant. At least 2 cases of diffuse leptomeningeal disease have been reported (14; 39). Both patients had diffusely thickening and enhancing meninges without discrete primary mass.
Although clinical and radiographic findings can suggest atypical teratoid/rhabdoid tumor, the diagnosis is made pathologically. Pathological diagnosis is confirmed with immunohistochemical stain for the SMARCB1 (previously called INI-1) gene product. If the SMARB1 gene is altered, the tumor cells do not stain for the normal gene product. Over the past 2 decades, there has been increased awareness of atypical teratoid/rhabdoid tumors, especially at large pediatric centers. This has led to an increase in the diagnosis. The diagnosis of atypical teratoid/rhabdoid tumor should be considered in a young child, especially when the child is less than 3 years of age, with malignant brain tumor and appropriate histologic and genetic studies performed as detailed in the pathogenesis and pathophysiology section.
The reported prognosis for patients with atypical teratoid/rhabdoid tumor is guarded. In 2 large published series of 106 patients from the 1990s, most patients had died from their disease within the first year after diagnosis despite aggressive treatment (34; 07). A few patients have died of treatment-related complications from chemotherapy. More recent case series report long-term survivors (31; 40); they tend to be older patients who have had both radiation and chemotherapy. Other studies conclude that progression-free survival is improved with intensified multimodal therapy that includes intense systemic and intrathecal chemotherapy in addition to radiation (09) or intensive chemotherapy that includes stem cell transplant (17). The Children’s Oncology Group (COG) published the largest series of prospectively treated patients with atypical teratoid/rhabdoid tumor. The overall survival for the cohort was 43% (33).
Several studies suggest that methotrexate is an effective component of treatment. Methotrexate is associated with neurologic toxicity, particularly when combined with radiation therapy. Advances in radiation therapy technology, primarily in conformal treatment fields, offer the potential of decreasing the morbidity associated with radiation. Such combination therapy must be monitored closely, especially in very young children, which make up the majority of patients with atypical teratoid/rhabdoid tumor. A case series suggests that brain injury can occur from therapy and may mimic recurrent disease (18). In 2017, the Canadian ATRT registry reported its findings for patients diagnosed in first year of life (16). The registry found that in the first year of life, there was a much higher rate of palliation (46% vs. 10.8%) from the national registry in comparison to the literature cohort. The data also suggested that the subset of patients who received high dose chemotherapy with or without irradiation has similar survival rates observed in older children.
Studies that employ transcriptional and methylation profiling have found that atypical teratoid/rhabdoid tumor contains 3 subtypes (41; 21). These important findings may help predict outcome, risk-stratify, and help identify targeted treatments.
A 25-month-old, previously healthy girl presented to her pediatrician with a 2-week history of progressive vomiting. She was initially thought to have gastroenteritis, but vomiting progressed and began occurring on waking. She also developed acute balance difficulty and had fallen the evening prior to presentation. Because of her symptoms, an MRI was ordered that revealed a large necrotic-appearing brain tumor arising in the left parietal-occipital region, well demonstrated on the axial post-contrast image.
The patient underwent subtotal tumor resection. Pathologically, the tumor showed a markedly hypercellular neoplasm consistent with atypical teratoid/rhabdoid tumor. SMARCB1 staining demonstrated diffuse loss of expression among the tumor cells. Staging workup was negative for disseminated disease, and renal ultrasound showed normal kidneys without a renal mass. The patient was treated with 6 cycles of intensive chemotherapy, including methotrexate, cyclophosphamide, cisplatin, etoposide, and vincristine. Between the third and fourth cycles, 3D conformal field radiation was given to a dose of 50.4 Gy. Currently, the patient is more than 10 years from her original diagnosis. She had a moderate learning disability and seizure disorder but is making good developmental progress, and serial imaging shows treatment-related changes but no evidence of disease.
The etiology of atypical teratoid/rhabdoid tumor is unknown. The majority of tumors do have an alteration of the SMARCB1 gene but its function remains unknown. Patients with atypical teratoid/rhabdoid tumor can have a germline mutation of the SMARCB1 gene. These patients are classified as having rhabdoid tumor predisposition syndrome (30). This syndrome occurs in 10% to 35% of patients with atypical teratoid/rhabdoid tumor, and it increases the risk that the patient will have tumors in the kidney and other soft tissue sites (28; Bourdeaut et al 2011; 13).
Atypical teratoid/rhabdoid tumor is recognized as a distinct clinical entity because of its pathologic and genetic characteristics. Histologically, atypical teratoid/rhabdoid tumor contains sheets of rhabdoid cells against a background of primitive neuroectodermal cells, mesenchymal cells, or epithelial cells (24). Some tumors are composed entirely of rhabdoid cells, whereas others show a combination of rhabdoid cells and areas resembling primitive neuroectodermal tumor or medulloblastoma. Immunohistochemical features help to identify the disease but vary depending on the cellular composition of the tumor. Rhabdoid cells express vimentin and epithelial membrane antigen, neurofilament, glial fibrillary acidic protein, and keratin. The primitive neuroectodermal cells may express neurofilament protein, glial fibrillary acidic protein, or desmin. These are rapidly growing tumors that can have MIB-1 labeling indices of 50% to 100% (25). A study found a strong association with tumors that stained strongly for claudin-6 and poor outcome (12).
Work by Biegel and colleagues identified a candidate tumor suppressor gene, SMARCB1, which is abnormal in the majority of atypical teratoid/rhabdoid tumors (04). Cytogenetic studies of atypical teratoid/rhabdoid tumor demonstrate simple karyotypes, with loss of all or part of chromosome 22 as the primary and often solitary finding. The deletions target the SMARCB1 gene in chromosome band 22q11.2, which demonstrates biallelic mutations, deletions, or intragenic duplications in up to 98% of atypical teratoid/rhabdoid tumors (Bourdeaut et al 2013). Please note that there are several names given to the mutated gene in atypical teratoid/rhabdoid tumor. It is referred to here as SMARCB1 as this is now its official Human Genome Organisation (HUGO) name (23). Other names that have been used for the gene are SPF5, INI1, and BAF47.
SMARCB1 is a component of a SWI and SNF ATP-dependent chromatin-remodeling complex (04). The exact function of the gene is unknown, but it is likely that a mutation results in altered transcriptional regulation of downstream targets. It is believed that the presence of a SMARCB1 mutation in a tumor with histologic features suggestive of embryonal tumor without a clear rhabdoid component is sufficient to establish a diagnosis of atypical teratoid/rhabdoid tumor. As mentioned previously, patients with atypical teratoid/rhabdoid tumor should have germline testing for SMARCB1 to identify patients with rhabdoid tumor predisposition syndrome (03; 30). Patients with a germline mutation have a lower median age at diagnosis and a poorer prognosis (28; Reddy et al 2010; 30). SMARCB1 gene mutations have also been found in patients with renal and extrarenal rhabdoid malignancies (04).
Immunohistochemical staining for SMARCB1 is a useful tool in distinguishing atypical teratoid/rhabdoid tumor from other embryonal tumor/medulloblastoma and other CNS tumors that can be confused with atypical teratoid/rhabdoid tumor (22). Most pediatric centers now routinely stain primitive central nervous tumors for SMARCB1 as part of their evaluation as this stain is commercially available.
Atypical teratoid/rhabdoid tumor was initially thought to be extraordinarily rare. With the increased clinical awareness of this tumor and the utility of the immunohistochemistry assay for SMARCB1, it is now estimated that atypical teratoid/rhabdoid tumor accounts for at least 3% of brain tumors in children. All published series report a peak incidence in very young children, less than 3 years of age. Based on prior Children’s Cancer Group, Pediatric Oncology Group, and Pediatric Brain Tumor Consortium studies, approximately 10% of children younger than 36 months of age with malignant brain tumors have atypical teratoid/rhabdoid tumor (32). In a series from Taiwan, the ratio of atypical teratoid/rhabdoid tumors to primitive neuroectodermal tumors in children younger than 36 months of age was 1:3.8 (20). This group also reported a female predominance although no other series have found a gender difference. In an Austrian study of 311 newly diagnosed tumors, atypical teratoid/rhabdoid tumor was the sixth most common entity (6.1%) (44). A peak incidence was found in the birth to 2-year age group where they were as common as medulloblastoma. The number of reported patients with atypical teratoid/rhabdoid tumor has increased 5.5-fold in an analysis of the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) data from 1992 to 2008, likely reflecting greater awareness and improved diagnostic techniques (08). Although it is much less common in older children and adults, atypical teratoid/rhabdoid tumor has been reported with increasing frequency in these populations as well.
There is no known means to prevent the development of an atypical teratoid/rhabdoid tumor. Rhabdoid tumor predisposition syndrome (RTPS) is inherited in an autosomal dominant manner. Although most cases occur de novo, in rare cases, individuals inherited a SMARCB1 pathogenic variant from an unaffected parent. Parents of children with atypical teratoid/rhabdoid tumor and a germline mutation/rhabdoid tumor predisposition syndrome should consider genetic testing given the possibility, although extremely rare, that they carry a constitutional mutation of the SMARCB1 gene. Genetic counseling and psychological support should be provided to the family before genetic testing is done.
Atypical teratoid/rhabdoid tumor may be difficult to distinguish from other embryonal tumors, particularly medulloblastoma. Before atypical teratoid/rhabdoid tumor was widely recognized, many were misdiagnosed as such (34; 07). Other malignant nervous system tumors should also be considered in the differential diagnosis, including choroid plexus carcinoma and ependymoma. High-grade glial neoplasms can occur in young children but are extremely rare.
Patients with suspect atypical teratoid/rhabdoid tumor should undergo complete MRI imaging of the brain and spine prior to surgery unless emergent surgery precludes this being done. This is to quantify the radiographic extend of disease at diagnosis and is necessary for conformal radiation planning. Surgical resection is indicated for nearly all patients with atypical teratoid/rhabdoid tumor; this is for both diagnosis and treatment. The tumor should undergo pathologic and molecular genetic testing. Methylation profiling should be considered if adequate tumor is available. A lumbar puncture should be done as part of the staging evaluation to look for cerebrospinal fluid dissemination unless this is medically contraindicated. Routine studies and cytology should be performed on cerebral spinal fluid. This is usually done after surgery due to risks of performing a lumbar puncture in patients with a posterior fossa mass. It is recommended that patients with atypical teratoid/rhabdoid tumor be tested for a germline mutation, especially when they have both renal and central nervous system tumors. This study can be performed on serum or saliva. Consideration should also be given to performing a renal ultrasound on patients with atypical teratoid/rhabdoid tumor prior to starting treatment to rule out a renal mass.
• Regimens that include intensive multi-modal therapies improve survival.
• Targeted pathway inhibitors and other novel therapies are urgently needed.
Treatment of atypical teratoid/rhabdoid tumor has often paralleled that of infant medulloblastoma or other embryonal tumors. Most patients receive some form of multimodality therapy. Original data available from the atypical teratoid/rhabdoid tumor registry suggest that patients who have had a gross total resection have a longer median survival, albeit the difference was only 3 months (19). In the Children’s Oncology Group ACNS0333 trial, the goal of surgery was maximal safe tumor resection with second-look surgery after induction if indicated (33). In the study, 37 patients (55%) underwent gross total or near-gross total resection, whereas 29 (45%) underwent subtotal, partial, or biopsy. Although patients who had a gross total resection upfront had a slightly better 4-year overall survival, there was not a significant difference in event-free or overall survival based on degree of resection. It has been estimated that less than one third of patients have tumors that are amenable to complete resection. This may be because the tumor often invades cranial nerves at the cerebellopontine angle, and young patients often have large and invasive tumors at the time of diagnosis. Other studies have also found that degree of surgical resection did not significantly impact survival (Bartelheim et al 2007; 35).
Given the young age of most patients with atypical teratoid/rhabdoid tumor, chemotherapy has been the main form of postsurgical adjuvant therapy. Varieties of chemotherapeutic approaches have been utilized, with varying success. Many patients have also been treated with radiation, adding further complexity to evaluating the efficacy of a given chemotherapy regimen. Outcome for children treated with surgery and standard chemotherapy alone is extremely poor. Legacy cooperative group “baby brain” protocols employed dose intensified multi-agent chemotherapy to treat a variety of malignant brain tumors in very young children (Geyer et al 2005; 38). Pediatric Oncology Group (POG) 9233/4 and Children’s Cancer Group (CCG) 9921 enrolled 63 patients with atypical teratoid/rhabdoid tumor and achieved a 24-month event-free survival (EFS) of 6.4%. In both studies, however, early responses to chemotherapy were seen. Children’s Oncology Group ACNS0333 was the first prospective trial to treat atypical teratoid/rhabdoid tumor (33). The therapeutic regimen for the study was based on cases series and registry data that showed that high-dose chemotherapy (HDC) with peripheral blood stem cell (PBSC) rescue, early radiation therapy (RT), and methotrexate had activity against atypical teratoid/rhabdoid tumor (19; 17; 10). Patients from birth to 22 years of age were eligible for the study. Patients received 2 cycles of methotrexate containing multi-agent induction chemotherapy, followed by 3 cycles of consolidation high-dose chemotherapy with peripheral blood stem cell rescue. Radiation was required on study and was given after either following induction or consolidation depending on the age of the setting, patient, location of tumor, and presence of metastasis. Submission of tumor tissue and blood was required for SMARCB1 analysis. Sixty-five evaluable patients had a 4-year event-free survival and overall survival (OS) of 37% and 43%, respectively. For 54 patients less than 3 years of age, the ACNS0333 regimen significantly reduced the risk of event-free survival events compared to CCG9921 and POG 9233/4 (P < .0005; hazard rate, 0.43; 95% CI, 0.28 to 0.66). Patients older than 3 years of age had a 4-year progression-free survival of 57%. The study also examined potential prognostic variables and did not find a significant difference in outcome based on primary tumor location, presence of metastatic disease, or extent of resection. For patients who completed induction, there was no difference in survival based on the timing of radiation. The authors did report 2 cases of severe radiation necrosis that occurred in patients who received radiation between induction and consolidation and recommended that radiation be placed after consolidation to avoid this. Methylation profiling of tumor samples from ACNS0333 segregated into 3 subgroups supported the previous retrospective reports (41; 21).
Another therapeutic approach for patients with atypical teratoid/rhabdoid tumor that has been reported is based on the Intergroup Rhabdomyosarcoma Study III (31). A multicenter trial treated 20 children with atypical teratoid/rhabdoid tumor with intensive multimodality treatment that included the chemotherapy backbone of IRSIII with some modifications (09). The 2-year progression-free survival was 53%. These data are encouraging, but longer follow-up has not been published. A report from Austria described long-term survival of 9 patients who received dose-intensified chemotherapy that included both intrathecal chemotherapy and high-dose therapy with stem cell rescue as well as local irradiation (37).
Some form of radiation therapy appears to be an important component of therapy for atypical teratoid/rhabdoid tumor patients. At St. Jude Children’s Research Hospital, 9 children over the age of 36 months were treated with radiation therapy in addition to chemotherapy as part of their initial treatment (40). The 2-year progression-free survival was 78% +/- 14%. The authors concluded, however, that the patients’ older age led to improved survival. A study identified 144 patients with atypical teratoid/rhabdoid tumor in the National Cancer Institute’s Surveillance, Epidemiology, and End Results Database (08). The study confirmed a robust association between the use of radiation therapy and survival. Proton beam radiation may have an advantageous role in treating atypical teratoid/rhabdoid tumor. A series of very young patients treated with proton beam reported good disease control and increased sparing of healthy tissues such as cerebrum, temporal lobe, cochlea, and hypothalamus (11).
ACNS0333 led to significantly improved survival and confirms that some patient with atypical teratoid/rhabdoid tumor can be cured of their disease with intensive multimodal regimens that include high-dose chemotherapy with peripheral blood stem cell and radiation. More than half of patients with atypical teratoid/rhabdoid tumor, however, will not survive, and for those who do, there is significant risk of treatment-related sequelae. Further intensification with cytotoxic chemotherapy is likely not feasible. Pathway-specific and other novel therapies are desperately needed to improve outcome.
There are preclinical data that atypical teratoid/rhabdoid tumor may be a good candidate for pathway-specific therapies. Several preclinical studies have shown promising results. One study, for example, found that atypical teratoid/rhabdoid tumor cell lines commonly express the tyrosine kinase c-Abl (27). Treating the tumor cell with the tyrosine kinase inhibitor imatinib resulted in reduced cellular growth, suggesting a possible role for tyrosine kinase inhibitors in treating the disease. In another study, the inhibition of the Erb2-EGFR pathway by the small molecule inhibitor lapatinib led to inhibition of cell migration and apoptosis (36). In 2 other studies, histone deacetylase inhibitors increased radiosensitivity of atypical teratoid/rhabdoid tumor cells but not normal tissue, making this class of drugs another potential attractive weapon to treat atypical teratoid/rhabdoid tumors (05; 26). Additionally, inhibition of Aurora kinase A, which is elevated in atypical teratoid/rhabdoid tumor cells, induced cell death in tumor cells (42). These authors found that the Aurora kinase inhibitor MLN8237 (Millennium Pharmaceuticals, MA) strongly suppressed the ability of AT/RT cells to form colonies and enhanced radiation sensitivity to the tumor cells. In a series of 4 patients with recurrent or progressive atypical teratoid/rhabdoid tumor, single-agent alisertib produced marked and durable regression in disease burden, as detected by brain and spine MRI and by evaluation of spinal fluid cytology (43). Overexpression of the polycomb repressive complex 2 (PRC2) subunit enhancer of zeste 2 (EZH2) is associated with tumor progression and invasive growth in atypical teratoid/rhabdoid tumor, and inhibiting EZH2 strongly impairs tumor cell growth (01). The Children’s Oncology Group is currently conducting a phase 2 study of the EZH2 inhibitor, tazemetostat, through the NCI-Pediatric MATCH (molecular analysis for therapy choice). Patients with recurrent atypical teratoid/rhabdoid tumor or other SMARCB1 deficient are eligible for the study. Future trials in newly diagnosed patients will likely incorporate a targeted therapy into the ACNS0333 backbone.
Alyssa Reddy MD
Dr. Reddy of the University of California San Francisco has received honorariums from Astra Zeneca as an advisory board memberSee Profile
Roger J Packer MD
Dr. Packer of George Washington University and Children’s National Health System received honorariums from AstraZeneca and Novartis as an advisory board member.See Profile
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