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Vol. 27. Num. 2.March - April 2016Pages 51-102
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Vol. 27. Num. 2.March - April 2016Pages 51-102
Case Report
DOI: 10.1016/j.neucir.2015.01.003
Prognosis of atypical teratoid rhabdoid tumors (AT/RT) treated with multimodal therapy protocols. Report of our series
Pronóstico de los tumores teratoides rabdoides atípicos (TT/RA) tratados con protocolos de terapia multimodal. Descripción de nuestra serie
Alfonso Valencia-Moyaa, Laura González-Garcíab,
Corresponding author

Corresponding author.
, Bienvenido Ros-Lópezb, Tomás Acha-Garcíac, Bernardo Weil-Larad, Pablo Obando-Pachecoc, Miguel Ángel Arráez-Sánchezb
a Neurosurgery Department, Gómez Ulla Hospital, Madrid, Spain
b Neurosurgery Department, Carlos Haya University Hospital, Málaga, Spain
c Oncology Department, Carlos Haya University Hospital, Málaga, Spain
d Pathology Department, Carlos Haya University Hospital, Málaga, Spain
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Tables (1)
Table 1. Review of the literature.

Atypical teratoid rhabdoid tumors (AT/RT) of the central nervous system are rare, very aggressive embryological tumors, typically diagnosed in young patients and having a low survival rate after diagnosis. The aim of this study was to emphasize, based on the latest results in the literature, the need for protocols for multidisciplinary treatment in these patients.

Material and methods

We report our series of 3 cases treated, diagnosed and followed up between 2009 and 2014. They were treated with multimodal therapy protocols (Rhabdoid SIOP-2007 and European Rhabdoid Registry EU-RHAB-2010). In addition, we carried out a literature review.


Two of our 3 cases (supratentorial and spinal tumors) did not show any progression of the disease after long follow-up, in contrast with most of the cases available in the literature. The second patient had a shorter survival.


Patient age at the time of diagnosis, supratentorial location of the mass and fewer complications with adjuvant treatments seem to be factors yielding good prognosis for AT/RT tumors. In agreement with the latest international protocols, multidisciplinary treatment is the ideal treatment, consisting of radiotherapy and chemotherapy after complete tumor resection.

Atypical teratoid rhabdoid tumor
Brain tumor
Pediatric patients
Multidisciplinary treatment

Los tumores teratoides rabdoides atípicos (TT/RA) del sistema nervioso central son tumores embrionarios muy agresivos, de baja incidencia, típicamente diagnosticados en pacientes jóvenes, con una baja supervivencia tras el diagnóstico. El objetivo de este estudio es resaltar la necesidad del tratamiento multidisciplinar protocolizado de estos pacientes sobre la base de los resultados más actuales de la literatura.

Material y métodos

Presentamos nuestra serie de 3 casos de TT/RA diagnosticados, tratados y seguidos entre 2009 y 2014. Nuestros pacientes se trataron siguiendo los protocolos de terapia multimodal (Rhabdoid SIOP-2007, European Rhabdoid Registry EU-RHAB-2010). De forma adicional, se realizó una revisión de la literatura.


Dos de nuestros pacientes (lesiones supratentorial y espinal) no presentaron progresión de la enfermedad años tras el diagnóstico, en comparación con lo descrito en la literatura. Por otra parte, el segundo paciente presentó una supervivencia menor.


Pueden considerarse factores de buen pronóstico: la edad del paciente en el momento del diagnóstico, las lesiones supratentoriales, y las escasas complicaciones de los tratamientos adyuvantes. El consenso actual en cuanto al tratamiento idóneo consiste en cirugía, seguida de quimioterapia y radioterapia.

Palabras clave:
Tumor teratoide rabdoide atípico
Tumor cerebral
Pacientes pediátricos
Tratamiento multidisciplinar
Full Text

Atypical teratoid rhabdoid tumors (AT/RT) of the central nervous system are very aggressive embryological tumors, with their own radiological and histological features. They comprise a group of central nervous system embryonal tumors that should be taken into account when diagnosing neoplasms in children under the age of three. Genetically, they are characterized by inactivating mutations of the INI1/SMARCB1 gene located at chromosome 22q11. The original cell is still unknown. Their estimated incidence is also unknown, with a male-female ratio of 2:1.1 Most cases are infratentorial (52%) or supratentorial (44%), only a 4% have a spinal location. Disseminated forms occur in 20–30% of the cases.2 Survival 1 year after diagnosis is 39.7%3; age and metastasis have been described as prognostic factors, with younger patients, particularly <2 years faring worse.4 Multimodal therapies including surgery, radiotherapy and chemotherapy seem to improve survival rates in children.8

Material and methods

We report our series of three cases of AT/RT which have been diagnosed, treated and followed up in our institution between 2009 and 2014. Those patients were all female, and the tumors were found in different locations, two intracranial and the third one in the lumbar spine.

A thorough search of the literature was performed and articles published in the last 20 years were selected. Among them, the ones with cases of cranial and spinal locations of AT/RT were detailed. Different reported treatment protocols were included as well.

Case 1

A 20-month-old female was referred to our center due to a space occupying lesion detected on a computed tomography, performed on account of nausea and vomiting. The magnetic resonance image (MRI) showed a left parietal, well-circumscribed mass with heterogeneous enhancement, with a great cystic component (Fig. 1). Cerebrospinal fluid seeding was not identified at the time of diagnosis. After parietal craniotomy, a total resection of the tumor was performed as showed on postoperative controls (Fig. 1C). A peripheral area of brain tissue, gliosis and infiltration of the leptomeningeal neoplasia was observed after complete resection.

Fig. 1.

Case 1: MRI. (A) Axial T2-weighted MRI showed a polycystic fronto-parietal lesion and associated edema. (B) Sagittal T1-weighted MRI demonstrated heterogeneous contrast enhancement. (C) Postoperative gadolinium enhanced T1 showed no contrast uptake and no tumor remnants.

Histopathological examination showed macroscopically a solid tumor (4.2cm), with areas of hemorrhage and necrosis, and a 3cm cystic area (Fig. 2). A detailed exam of paraffin embedded tissue showed a neoplasm mostly made up of cells with oval nucleus, prominent central nucleolus and large cytoplasm, with globular eosinophilic inclusions (Fig. 3A). Frequent mitotic figures were present, and cytological pleomorphism with multinucleated rhabdoid cells was observed. Rhabdoid cells were present, as large epitheloid cells with papillary growth pattern distributed in diffuse sheets, occasionally separated by fibrous tracts (fascicles of spindle shaped mesenchymal cells). The sections contained cystic and hemorrhagic spaces, and extensive areas of necrosis with occasional calcifications. Within the area of epithelial neoplasia, stromal hyalinization and mucinous microcysts were observed (Fig. 3B and C); and in few sections of the tumor, cells were organized in bundles of mesenchymal sarcomatous appearance (Fig. 3D). On immunohistochemical stain, the tumor showed positivity for vimentin, EMA (epithelial membrane antigen), cytokeratin AE1–AE3, GFAP (glial fibrillary acidic protein), neurofilaments and SMA (smooth muscle actin). GFAP and neurofilaments positivity was low and dispersed, in contrast with the intense and uniform one for the other markers. Synaptophysin, chromogranin, S100 and desmin were negative. Ki67 was 80%. The characteristic loss of INI1 was also detected. Atypical rhabdoid/teratoid tumor AT/RT (WHO grade IV) was the final pathologic diagnosis. Chemotherapy consisted of nine induction cycles (5 VCD, 4 ICE), with 4 intrathecal doses, and 8 maintenance cycles (4 temozolomide, trophosfamide and oral etoposide). Radiotherapy (54Gy) was administrated in 30 doses after the chemotherapy following the Rhabdoid-SIOP-2007 Protocol. In the clinical and imaging follow-up the patient presents a slight attention-deficit and a mild hemiparesis as the only consequences of the treatment. The last MRI, performed at the age of 7 (61 months follow-up), showed no recurrences of the tumor.

Fig. 2.

Case 1: Macroscopic tumor.

Fig. 3.

Histopathologic exam. (A) Microscopic appearance of rhabdoid cells. Note the large globular eosinophilic cytoplasm which rejects the core to the periphery. The cells were distributed in sheets. It was the predominant histologic pattern. Hematoxylin–Eosin (HE). (B) Focus of epithelial appearance. HE. (C) Mucinous microcystic focus. Alcian Blue-PAS. (D) Sarcomatous appearance area. HE.

Case 2

A 31-month-old female with headache and vomiting was admitted to our institution to rule out an intracranial mass lesion. The neurological examination showed a setting sun sign with no other neurological deficits. A 1.8cm solid mass located in the pineal region was identified in the MRI, and it showed contrast enhancement and low apparent diffusion coefficient; dilation of the III ventricle and transependymal edema were observed as well (Fig. 4). Endoscopic third ventriculostomy and biopsy were performed in the same endoscopic procedure, improving the patient clinical findings. The pathology was negative for this biopsy, and a posterior infratentorial supracerebellar approach to the pineal region was performed for subtotal resection. The postoperative MRI showed an ischemic injury in the knee of the corpus callosum, and remaining tumor attached to the roof of the third ventricle. The resected lesion was informed as an AT/RT, positive for EMA, cytokeratin AE1–AE3, GFAP, neurofilaments, synaptophysin, S-100, and loss of INI-1 tumor-suppressor gene. Ki67 was 70%. The patient was discharged with a mild left hemiparesis and affected ocular motility. Adjuvant chemotherapy consisted of four cycles (2 DOX, 1 ICE and 1 VCA), with 4 intraventricular doses following the European Rhabdoid Registry EU-RHAB-2010. Follow-up, three months after surgery, revealed complete blindness and cognitive deficit. Radiotherapy could not be performed due to the decease of the patient at the age of 37 months (6 months after diagnosis).

Fig. 4.

Case 2: 4-year-old girl. (A) Sagittal T2-weighted MRI showing a solid mass in the pineal region. (B) Axial T1-weighted and contrast enhanced MRI showing contrast uptake of the mass and a dilated right lateral ventricle. (C) Sagittal T1-weighted and contrast enhanced MRI showing contrast uptake of the mass.

Case 3

A 35-month-old female was referred to our center with the diagnosis of an intra-axial lesion in the conus medullaris detected by MRI. The patient presented urinary incontinence, postural instability, and an intense bilateral leg pain. Craniospinal MRI showed a well-defined 3cm×1cm×2cm solid mass located at L2, with heterogeneous contrast enhancement (Fig. 5). Macroscopically total resection was performed. In the immediate postoperative period leg pain disappeared without any complications. The resected specimen was described as an AT/RT, positive for vimentin, EMA and cytokeratin; loss of INI1 was detected as well. Adjuvant treatment included chemotherapy (3 DOX courses, 3 ICE and 3 VCA plus intrathecal methotrexate) and radiotherapy (54Gy) following the European Rhabdoid Registry EU-RHAB-2010. Twenty months after surgery, urine incontinence persists, without further symptoms, and the last MRI control was negative for recurrences.

Fig. 5.

(A) STIR sequence. Sagittal view showing an intradural intramedullary mass lesion from D12 to L2. (B) Postoperative T1 with gadolinium, laminectomy D12-L2 without intra or extradural collections. Fatty infiltration replacing bone marrow can be appreciated after radiotherapy.


Described for the first time in 1981 and recognized as an entity in 1990,5 AT/RT comprises one of the most lethal central nervous system tumors in children, with a median survival time of 16.75 months.6 The incidence of AT/RT is unknown; however, derived from institutional reviews and from the data of institutional cancer registries it is suggested that AT/RT constitutes 50% of all malignant brain neoplasms in children less than one year of age.7 Given the rarity of these tumors, we need international protocols for the management such as the one we have followed in our cases (European Rhabdoid Registry, EU-RHAB 2010).8


Young age is an important risk factor for event free survival and overall survival has been most likely related with the use of radiotherapy.9 Children with familiar AT/RT compared to children with sporadic AT/RT are younger at diagnosis and are more likely to die from tumor progression.10

Location of the tumor

The relation between supratentorial and intratentorial tumors is 1.2:1, and they constitute the vast majority of the cases; unusually they appear in the spine.11–15 Cranial AT/RTs are mainly located in the cerebral or cerebellar hemispheres. They can also occur anywhere along the spinal axis and may be intramedullary or intradural extramedullary in origin. Myxopapillary ependymoma, malignant nerve sheath tumor, PNET, ependymoma, astrocytoma, and ganglioglioma are in the differential diagnosis depending on its intra- or extramedullary location.12 Metastases are more common tumors and can be found in about 20% of the cases at diagnosis.13


MRI is the method of choice for imaging patients with AT/RT. It reveals a well-circumscribed mass with homogeneous or heterogeneous contrast enhancement, high signal on diffusion-weighted imaging and low apparent diffusion coefficient.16 Calcifications within AT/RT have been described in 50% of cases.17

The typical histopathological finding is the presence of rhabdoid cells with cytoplasmic inclusions. Mesenchymal, epithelial, and/or neuronal components may be presented within the tumor. On immunohistochemical stain, the tumor showed positivity for vimentin, EMA and cytokeratin. The loss of INI1 gene expression resulting from hSNF5/SMARCB1 mutations (a member of the SWI/SNF chromatin remodeling complex located on chromosome 22q11.2) can be demonstrated using immunohistochemistry18; it could be considered diagnostic for AT/RT in almost all cases.19 No other recurrent genomic alterations have been identified.20 High level expression of epidermal growth factor receptor (EGFR) protein has been found within these tumors.21 However, differential diagnosis of AT/RT remains very difficult based on histopathology, especially from other central nervous system tumors, such as primitive neuroectodermal tumor (PNET), choroid plexus carcinoma, and medulloblastoma.4,18


Disease related death usually occurs within 2–20 months from diagnosis in the majority of published cases.14 Long term survival rates have been reported before,15 and they have a strong relation with the supratentorial location of the mass and lower complications of the treatments.9 Our series include three different locations with a diverse survival rate, varying from 6 months to at least 5 years (last follow up in surviving patients), case number 2 being the most complicated in terms of surgical approach and consequent morbidity, and also the one with the lowest EFS. None of our patients had metastases during the follow up.

Multimodal treatment protocols

All the patients were enrolled in their respective protocols (Rhabdoid SIOP-2007 and European Rhabdoid Registry EU-RHAB-2010), which were the most up-dated evidence for the AT/RT at the time of diagnosis. The pathology was centralized and reviewed in Münster (Germany), and presented the distinctive features and immunostaining characteristics of these tumors. Although the best treatment remains unclear, surgery followed by chemotherapy and radiotherapy is the most approved one. The treatment of choice for the reported cases number 1 and 3 was surgery followed by chemotherapy and focal radiotherapy, with a long survival. In the second case, radiotherapy could not be administrated because of the death of the patient. The third case deserves special attention, as it is one of the few reported cases of spinal AT/RT. From those tumors reported in the literature, ours is presented in an older patient and has a better outcome than the average survival rate, which appears to be close to the survival observed on intracranial ones. Table 1 shows a review of the most complete and recent studies in pediatric patients and identifies those that distinguish age of the patient, localization of the tumor, grade of resection, adjuvant therapy and outcomes.

Table 1.

Review of the literature.

  Patients (N=Age (months)  Localization of the tumor  Surgery (resection)  Adjuvant therapy  Survival (months) 
Lafay-Cousin (2012)a1219  Supratentorial  Complete  RT+CT  117 
12  Supratentorial  Complete  CT  33 
131  Supratentorial  Complete  RT+CT  84 
17  PF  Complete  CT  96 
15  PF  Incomplete  CT  55 
60  PF  Incomplete  RT+CT  10 
19  Supratentorial  Complete  RT+CT  40 
180  Supratentorial  Complete  RT+CT  114 
11  PF  Incomplete  CT  42 
31  PF  Complete  RT+CT  43 
43  Supratentorial  Complete  CT  29 
28  Supratentorial  Incomplete  CT  23 
Park (2012)9PF  Complete  CT  15 (dead) 
Spinal  Incomplete  RT+CT  7 (dead) 
PF  Incomplete  RT+CT  16 
11  PF  Complete  RT+CT  50 
12  PF  Complete  RT+CT  70 
13  Supratentorial  Complete  CT  2 (dead) 
15  PF  Complete  RT+CT  19 
16  Supratentorial  Incomplete  CT 
28  Supratentorial  Incomplete  RT+CT  20 
De Amorim (2013)1051  Supratentorial  Complete  RT+CT  100 
Supratentorial  Incomplete  RT+CT  49 
0.5  PF  Complete  RT+CT  38 
14  PF  Complete  RT+CT  29 
20  Supratentorial  Complete  RT+CT  27 
Supratentorial  Incomplete  RT+CT  26 
20  PF  Incomplete  RT+CT  14 (dead) 
231  Supratentorial  Incomplete  RT+CT  17 
32  Supratentorial  Incomplete  RT+CT  12 
185  Brachial P  Incomplete  RT+CT 
Zaky (2013)1927  PF  Incomplete  HDCT  79 
PF  Complete  HDCT  44 (dead) 
18  Supratentorial  Complete  HDCT  4 (dead) 
PF  Complete  HDCT  0.5 (dead) 
10  Supratentorial  Incomplete  HDCT  2 (dead) 
Supratentorial  Complete  HDCT  5 (dead) 
10  PF  Complete  HDCT  0.3 (dead) 
10  Supratentorial  Incomplete  HDCT  13 (dead) 
PF  Incomplete  HDCT  14 (dead) 
19  PF  Incomplete  HDCT  0.6 (dead) 
PF  N.I.  HDCT  1 (dead) 
32  PF  Complete  RT+CT  47 
17  PF  Incomplete  HDCT  8 (dead) 
21  Supratentorial  Complete  HDCT  12 (dead) 
13  PF  Incomplete  HDCT  6 (dead) 
27  PF  Complete  HDCT  40 (dead) 
PF  Incomplete  HDCT  5 (dead) 
13  PF  Incomplete  HDCT  42 
15  PF  Complete  HDCT  3 (dead) 
Present study (2014)320  Supratentorial  Complete  RT+CT  61 
31  Pineal  Subtotal  CT  6 (dead) 
35  Spine  Complete  RT+CT  20 

PF, posterior fossa; CT, chemotherapy; RT, radiotherapy; HDCT, high-dose-CT.


Death on follow up is not specified per case.

Nevertheless, the inconsistence comes when dealing with children under the age of three. High dose chemotherapy with stem cell rescue has been proposed as the adjuvant treatment of choice in this group, being superior to supportive care measures only10; and avoiding irradiation of healthy tissues. Some studies have reported an improved survival rate in these patients, deferring radiotherapy; nevertheless, other studies have failed to reproduce those results and therefore suggest an early application of radiotherapy, at least focal and prior to high dose chemotherapy,22 even for disease recurrence,23 rendering radiotherapy an indispensable treatment.10 Favorable results with proton therapy have also been reported,24 which could turn out as an alternative to the classic radiotherapy in very young patients; and a second look surgery has to be strongly considered as recommended in the current AT/RT protocols.11


Age of the patient at the time of diagnosis, supratentorial location of the mass and lower complications of the applied treatments seem to be good prognosis factors for AT/RT tumors. Two of our three cases (suprantentorial and spine tumors) did not show any progression of the disease after few years of follow up. In agreement with the available international protocols, a multidisciplinary treatment has to be performed including radiotherapy and chemotherapy in addition to complete resection of the tumor.

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Copyright © 2014. Sociedad Española de Neurocirugía
Neurocirugía (English edition)

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