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rhabdoid tumors of the central nervous system: imaging and clinical findings in 16 children
Clinical Radiology (2009) 64, 256e264
Atypical teratoid/rhabdoid tumors of the central nervous system: imaging and clinical findings in 16 children I.H. Leea, S.-Y. Yooa,*, J.H. Kima, H. Eoa, O.H. Kimb, I.-O. Kimc, J.-E. Cheonc, A.Y. Jungc, B.J. Yoonc a
Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, bDepartment of Radiology, Ajou University Hospital, and c Department of Radiology, Seoul National University Hospital, Seoul, Republic of Korea Received 23 May 2008; received in revised form 30 August 2008; accepted 2 September 2008
AIM: To investigate the imaging and clinical findings of central nervous system (CNS) atypical teratoid/rhabdoid tumours (AT/RTs) in children. MATERIALS AND METHODS: The computed tomography (CT) and magnetic resonance imaging (MRI) findings and clinical records of 16 children with CNS AT/RTs were retrospectively reviewed. Tumour location, size, composition, enhancement pattern, peritumoural oedema, signal intensity (SI) on MRI and CT attenuation were evaluated. RESULTS: A total of 17 lesions from 16 patients (median age 2.3 years, age range 0.7e15 years) were included in the evaluation. Tumour location was infratentorial for 11 lesions and supratentorial for six lesions. The mean diameter of the largest dimension for a tumour was 4 cm. The tumour was mainly solid in 65% of cases, and solid and cystic or cystic and solid in 35% of cases. The solid component of the tumours had a homogeneous iso SI (n ¼ 15) on T2-weighted MRI images and iso SI (n ¼ 14) on T1-weighted images. Moderate to strong enhancement of the solid component was noted in most cases. In spite of a large tumour size, peritumoural oedema was minimal or mild except in four cases. Rapid growth of the tumour was demonstrated in three cases. Seven patients died from tumour progression, with a mean survival time of 8.4 months (range 2e12 months). CONCLUSION: Although the AT/RTs had non-specific imaging findings, the tumours tended to be large in size, have iso SI on T1 and T2-weighted MR images with prominent enhancement, and relatively mild peritumoural oedema. Rapid growth of the tumour was seen during the follow-up period. ª 2008 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction An atypical teratoid/rhabdoid tumour (AT/RT) is a rare and highly malignant central nervous system (CNS) tumour, usually affecting young children under the age of 3 years. AT/RTs are reported to occur with a rate of 3% among childhood CNS malignancies. To date, approximately 220 cases of CNS AT/RTs have been described in the literature * Guarantor and correspondent: S.-Y. Yoo, Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Gangnam-Gu, Seoul 135-710, Republic of Korea. Tel.: þ822-3410-0511; fax: þ822-3410-2559. E-mail address: [email protected] (S.-Y. Yoo).
since the disease was first described by Lefkowits et al. in 1987.1 The lesion was termed an ‘‘AT/RT’’ as the tumour consisted of rhabdoid cells, as well as varying portions of neuroepithelial, peripheral epithelial, and mesenchymal elements without divergent tissue development characteristic of a malignant teratoma. The incidence of AT/RTs has been underestimated and AT/RTs have frequently been misdiagnosed in the past as a primitive neuroectodermal tumours/medulloblastomas (PNETs/MBs) because of histological and radiological similarities. Definitive diagnosis depends on the result of an immunohistochemical evaluation.2,3 As AT/RTs have a dismal prognosis, even with the use of current multimodality therapy, differentiation of this tumour from a PNET/MB is crucial and,
0009-9260/$ - see front matter ª 2008 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.crad.2008.09.007
Atypical teratoid/rhabdoid
moreover, still remains a diagnostic challenge to the radiologist.4 To the authors’ knowledge, there are only limited studies describing the imaging features of this entity. The objective of this study was to investigate the computed tomography (CT) and magnetic resonance imaging (MRI) features of CNS AT/RTs in 16 children and to identify the clinical characteristics.
Materials and methods Approval from the institutional review board was obtained to review clinical records and radiological images for this study. The clinical records of 16 children (male:female 7:9; age range 0.7e15 years; median age 2.3 years) with histopathologically proven CNS AT/RTs were collected from three medical centres (Samsung Medical Centre, Seoul National University Hospital, Ajou University Hospital) in South Korea between 1998 and 2007. At the time of diagnosis, 10 patients (63%) were 3 years of age or younger. Unenhanced (n ¼ 11) and contrast-enhanced CT (n ¼ 8) examinations were performed using 5 mm axial sections. For MRI examinations, 1, 1.5, or 3 T units, produced by various manufacturers (Siemens, Erlangen, Germany; GE Medical Systems, Milwaukee, WI USA), were used. Imaging protocols included at least non-enhanced axial and sagittal T1-weighted images (WI), axial and coronal T2-WI, axial fluid-attenuated inversion recovery (FLAIR), and contrast-enhanced axial, sagittal, and coronal imaging. The section thickness used was usually 5 mm. Eleven patients also underwent spinal MRI at initial diagnosis and/or during follow-up period. The neuroimaging findings were analysed in terms of the location, size, internal content, enhancement pattern, peritumoural oedema, MRI signal intensity, and CT attenuation of the tumours by two observers in consensus. Tumour location was categorized as supratentorial/infratentorial and intra-axial/extra-axial. If the lesion involved two or more regions, the location was designated according to the centre of the mass. The size of a tumour was determined according to its greatest dimension. The SI of the tumours was compared with that of the grey matter for each imaging sequence. A tumour was considered to have a cystic component if it contained an area of typical fluid-like attenuation or SI on CT or MRI images and had rim-like enhancement after contrast medium administration. If areas of high SI were noted on non-enhanced T1-WI with no demonstrable calcification on the corresponding area on a unenhanced CT image, intratumoural
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haemorrhage was considered as present. Peritumoural oedema was categorized as absent, minimal (affecting an area of less than 10% of a tumour), mild (affecting an area greater than 10% and less than 50% of a tumour), moderate (affecting an area greater than 50% and less than 100% of a tumour), and severe (affecting an area greater than 100% of a tumour). The enhancement pattern of the solid component of a tumour was classified subjectively as absent, mild, moderate, and strong by consensus of two observers. Clinical features were reviewed with respect to the presenting symptoms and signs, treatment, and outcome.
Results Imaging analysis Of the 17 lesions in 16 patients, 11 tumours (65%) were infratentorial (six vermis, three brain stem, and two cerebellopontine angle cistern) and six tumours (35%) were supratentorial (three frontal lobe, one temporal lobe, one parieto-occipital lobe, and one lateral ventricle locations). Fifteen tumours were intra-axial, whereas two tumours were extraaxial in the cerebellopontine angle cistern. The sizes of tumours were 1e7 cm in the greatest dimension (mean size 4 cm). On unenhanced CT (n ¼ 11), the attenuation of tumours was most often slightly hyperattenuated (n ¼ 4) or iso-attenuated (n ¼ 4) as compared with the adjacent brain parenchyma. Calcification was noted in two lesions. The most common MRI feature of the tumour was a strong, enhancing, solid mass with an iso-SI seen on T1-WI and T2-WI. In six AT/RTs, a cystic component larger than 1 cm was seen. Peritumoural oedema was most often minimal (n ¼ 5) or mild (n ¼ 5). Less frequently, moderate (n ¼ 1) or severe (n ¼ 3) oedema was noted. In one case, peritumoural oedema was initially absent, but as the tumour grew rapidly, mild peritumoural oedema developed. Enhancement of the solid component was strong (n ¼ 12), moderate (n ¼ 3), mild (n ¼ 1), and absent (n ¼ 1). Areas of low SI seen on T2-WI were noted in four tumours secondary to calcification (n ¼ 1), or haemorrhage (n ¼ 3). Rapid growth of a tumour was demonstrated in three cases as seen on follow-up imaging preoperatively (n ¼ 1) and postoperatively (n ¼ 2). In one of the patients, a 1 cm-sized mass in the left cerebellopontine angle grew up to 3.7 cm in the greatest dimension after 2 weeks with a volume doubling time of 3.9 days (Fig. 1). In another patient who underwent only a biopsy, a 4.7 cm
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mass grew up to 6.2 cm on postoperative day 10 (Fig. 2). In another patient who underwent total tumour removal, a recurrent mass was observed on postoperative day 9.
Clinical findings Symptoms were variable depending on tumour location and age (Table 1). Fourteen patients initially underwent surgical treatment, consisting of gross total removal (n ¼ 11), partial removal
I.H. Lee et al.
(n ¼ 1), and subtotal resection (n ¼ 1). In three patients, only a biopsy was performed without surgical removal. Postoperative chemotherapy was administered in 12 patients with additional radiation therapy in seven patients. Peripheral blood stem cell transplantation was performed in two patients. Leptomeningeal seeding was noted in seven patients on MRI or cerebrospinal fluid study (Fig. 3). Seven patients, including five patients who underwent intensive therapy, died from
Figure 1 Patient 8 presented with a left facial palsy. (aeb) A solid mass (arrow) measuring up to 1 cm is seen in the left cerebellopontine angle. The mass has iso SI on a T1-WI (a). Strong enhancement with small cystic foci (arrowhead) is seen after gadolinium administration (b).(c) After 12 days the mass (arrow) in the left cerebellopontine angle increased in size, measuring up to 3 cm, without haemorrhage. (d) After 2 days from the time of (c), the mass (arrow) appeared larger, measuring up to 3.7 cm on an unenhanced CT image.
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Figure 2 Patient 13 presented with poor oral intake and right side weakness. (aeb) A 4.7 cm mass with a lobulated contour and iso SI on a T1-WI and T2-WI is seen in the left cerebellopontine angle cistern, cerebellum, and brain stem. The mass with mild peritumoural oedema displaces the adjacent midbrain and invades into the parenchyma. (c) The mass (arrow) shows strong enhancement following gadolinium administration. (d) After postoperative day 10 from a biopsy, the mass increased in size, measuring up to 6.2 cm with some haemorrhage.
tumour progression with a mean survival time of 8.4 months (range 2e12 months). Follow-up in six patients was lost. The survival time of the remaining three patients ranged from 11 to 39 months (mean survival 24 months). Tumour recurrence after surgery or chemotherapy developed in five patients. In the present study, two patients underwent nephrectomy due to rhabdoid tumour. In one patient, an AT/RT was detected by brain ultrasonography 1 year after the nephrectomy due to a malignant rhabdoid tumour. In another patient, an AT/RT in the brain and a rhabdoid tumour in the kidney were detected at the same time. In one patient, bone metastasis of an AT/RT was
noted. The clinical and imaging features of the AT/RTs are summarized in Tables 1 and 2.
Discussion An AT/RT, which is classified as grade IV by the WHO, is a rare and aggressive malignant CNS tumour seen in early childhood. It has been reported that the radiological features of an AT/ RT are similar to those of a PNET/MB, which often leads to the preoperative misdiagnosis of a PNET/ MB.3,5e7 One of the differential characteristics between a PNET/MB and AT/RT is the patient age;
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Table 1
Clinical findings
Patient No
Age (y) / Sex
Symptoms/ signs
CSF seeding
Treatment
Outcome (Survival time)
Remark
1 2
3/F 1.3/M
þ
Op (Partial) þ C þ R Op (GTR)
Died (12 months) NA
Recur Rhabdoid tumor of kidney
3 4
0.8/M 0.7/F
þ þ
Bx þ C Op (GTR) þ C
Died (9 months) NA (5 months)
5
3.5/M
þ
Op (GTR) þ C
Died (9 months)
6
6.5/M
þ
Bx only
F/U loss
7 8
9.8/F 1.7/F
þ
Op (GTR) þ C þ R Op (GTR) þ C
Alive (39 months) Died (3 months)
9
2.5/M
Op (Subtotal)
F/U loss
10
2/F
þ
Op (GTR) þ C
Died (12 months)
Rapid growth Recur
11
15/F
Op (GTR) þ C þ R
Died (12 months)
Recur
12
15/M
Op (GTR) þ C þ R
F/U loss (7 months)
Recur, Bone metastasis
13
0.9/F
Bx only
Died (2 months)
Rapid growth
14
14/F
Op (GTR) þ C þ R
Alive (11 months)
15
1/M
Vomiting, seizure Detected at screening brain ultrasonography Left ptosis Irritability, enlarged head circumference Gait disturbance, vomiting, headache Lethargy, ptosis, right side weakness Left L/E weakness Left facial palsy, nausea, vomiting Gait disturbance, vomiting Vomiting, lethargy, seizure Headache, vomiting, nausea Right temporal hemianopsia, headache Poor oral intake Right side weakness Right side weakness, headache, nausea Vomiting
Op (GTR) þ C þ R
F/U loss
16
1/F
Vomiting, head tilting
Op (GTR) þ C þ R
Alive (23 months)
Rapid growth
Rhabdoid tumor of kidney Recur
GTR (gross tumor removal), C (chemotherapy), R (radiation therapy), F/U loss (follow-up loss), Bx (biopsy), NA (not available).
PNET/MB tumours are usually found at approximately 5e7 years of age in contrast to the younger age of presentation for AT/RTs.2,7e9 In the present series, at the time of diagnosis, 10 patients (63%) were 3 years of age or younger. The prognosis for patients with an AT/RT is known to be very poor, especially in the patients younger than 3 years or patients that present with a disseminated tumour at diagnosis/staging and later.2,8,10e13 In the present study, five (50%) of 10 patients aged 3 years or below had died, whereas two (33%) of six patients above 3 years had died at the time the study was undertaken. Although a statistical comparison was not made between these two groups of children, it seems that the prognosis for younger children is worse than for older children. AT/RT should be considered in the differential diagnosis of a posterior fossa tumour having a similar neuroimaging appearance to PNET/MB in any child under the age of 3 years. In the present study, leptomeningeal dissemination occurred in seven (44%) patients from initial diagnosis to 1 year after diagnosis. A similar or lower frequency of leptomeningeal dissemination
was reported in 15e35% of patients with AT/RTs in previous studies.2,8,10,11,14 Another disparity between an AT/RT and PNET/ MB is the location of the tumour. Whereas 80% of classic PNET/MBs arise in the cerebellum,15 AT/RTs occur in the posterior fossa in 47e52%.4,7,14 In the present study, 65% of the AT/RTs were infratentorial with 35% of the tumours occurring in the cerebellum. Among the infratentorial tumours, only 55% occurred in the cerebellum (six out of 11 cases). Rorke et al. 2 reported the cerebellopontine angle cistern as the preferential location (15%) for an AT/RT. Koral et al.9 reported that cerebellopontine angle involvement (8/11, 72.7%) was more frequent; two cases (12%) of AT/RTs occurred in the cerebellopontine angle cistern in the present study. As more common posterior fossa tumours in children, cerebellar astrocytoma and ependymoma should be differentiated from AT/ RT. They also frequently extend to the cerebellopontine angle, but they are more commonly seen in older children. Cerebellar astrocytoma tends to be predominantly cystic and usually hypodense relative to normal brain parenchyma on
Atypical teratoid/rhabdoid
261
Figure 3 Patient 4 presented with irritability and an enlarged head circumference. (a) A well-demarcated mass is seen in the midline of the posterior fossa representing a cerebellar vermis origin mass. The mass demonstrates iso SI with high signal intensity foci representing haemorrhage on a T1-WI. (b) The mass demonstrates iso SI with mild peritumoural oedema on a T2-WI. (c) The mass shows strong enhancement in the main solid portion following gadolinium administration. (d) Five months after gross total tumour removal and the administration of chemotherapy, an MRI image shows multiple nodular and linear enhancing lesions along the ependyma and leptomeninges, representing cerebrospinal fluid seeding.
unenhanced CT. Ependymoma shows frequent calcifications and can extend through the foramina of Magendie and the foramen magnum with insinuation around blood vessels and nerves, often surrounding and engulfing structures. It is known that some renal rhabdoid tumours are associated with synchronous intracranial neoplasms; pineoblastomas, medulloblastomas, or primitive neuroectodermal tumours have been reported.12,16e18 In the present study, one patient had a previous history of nephrectomy due to a malignant rhabdoid tumour and another patient had
a rhabdoid tumour of the kidney at the time of diagnosis of the CNS AT/RT. There are close correlations between clinical presentation of an AT/RT and the age of onset and the location of the tumour. Increased intracranial pressure or localizing signs, such as cranial nerve palsies, headache, and hemiplegia, are common in older children, whereas non-specific symptoms and signs, such as vomiting, lethargy, irritability, loss of weight, macrocephaly, and failure to thrive are common in children younger than 3 years of age.2,5,19,20 In the present study, patients younger
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Table 2
Imaging features
Patient No
Location/ Size
Composition
CT attenuation of solid component
T2 SI
T1 SI
Enhancement
Edema
1 2-1 2-2 3 4 5 6
Vermis/3.2 cm LV/2.3 cm Tectum/1.8 cm Midbrain/1.6 cm Vermis/5.8 cm Vermis/4.4 cm Midbrain and Pons/ 4 cm Frontal lobe/5.4 cm CPA cistern/1-> 3.7 cm Vermis/5.1 cm Frontal lobe/7 cm Temporal lobe/3.5 cm Parieto-occipital lobe/ 5.6cm CPA, brain stem and cerebellum/4.7 cm Frontal lobe/4.7 cm Vermis/4.2 cm Vermis/3 cm
Solid Solid Solid Solid Solid Solid Solid and cystic
NA NA NA NA Low with focal high Slightly high Low
Iso Iso Iso Iso Iso Iso High
Iso Iso Iso Iso Iso Iso Low
Strong No Strong Strong Moderate Strong Strong
Severe Absent Absent Minimal Mild Mild Minimal
Cystic and solid, Caþþ Solid Solid Cystic and solid Solid Solid, Caþþ
Slightly high Iso Iso NA Iso Slightly high
Iso Iso Iso Iso Iso Low
Iso Iso Low Iso Iso High
Strong Strong Mild Strong Strong Moderate
Mild Absent-> mild Absent Mild Severe Severe
Solid
Slightly high
Iso
Iso
Strong
Mild
Cystic and solid Cystic and solid Solid and cystic
Iso NA NA
Iso Iso Iso
Iso Iso Iso
Moderate Strong Strong
Moderate Absent Minimal
7 8 9 10 11 12 13 14 15 16
LV (lateral ventriclel), CPA (cerebellopontine angle), Caþþ (calcification), NA (not available).
than 3 years of age presented with non-specific symptoms; however, some patients under 3 years presented with left facial palsy or right side weakness due to the location of the tumour. On MRI, iso SI seen on T1-WI and T2-WI was noted in more than 70% of the patients and after administration of gadolinium, moderate to strong enhancement was seen in most tumours. However, previous studies have reported various patterns of enhancement in AT/RTs, as well as in PNET/ MBs.14,21,22
In a previous study by Parmar et al.,7 AT/RTs were shown to have moderate to marked surrounding oedema. However, in the present study, moderate or severe peritumoural oedema was noted in only four cases. The frequent presence of cysts associated with AT/RTs has also been reported,8,23e26 and a cystic component, including a small cystic portion, was a common finding in the present study (Fig. 4). Rapid tumour growth was noted during a relatively short interval (range 9e14 days) in three
Figure 4 Patient 14 presented with right side weakness, headache, and nausea. (a) A T2-WI shows a large cystic and solid mass with moderate peritumoural oedema in the left frontal lobe. (b) A contrast-enhanced image demonstrates moderate enhancement of the solid component with a large cystic portion after gadolinium administration.
Atypical teratoid/rhabdoid
cases preoperatively (n ¼ 1) and postoperatively (n ¼ 2) in the present study. All three patients died (mean survival time 5.7 months). The volume doubling time was estimated from patient who underwent sequential MRI examinations preoperatively. With initial and follow-up MRI images on a 2048 1536 picture archiving and communication systems (PACS) monitor (Totoku Electric, Tokyo, Japan), the volume of each tumour was measured by adding the measured cross-sectional areas and multiplying by the section thickness. The measurement of the cross-sectional area in each tumour was performed by drawing the perimeter of the tumour using the area measurement tool of the PACS. As in previous studies, the tumour volume was calculated.27e29 However, some inevitable errors might have occurred due to manual measurement [calculated with the formula: Td ¼ t log2/(log (Vt/Vo)), where Td ¼ volume doubling time, t ¼ the interval between MRI examinations, Vt ¼ tumour volume at the second MRI examination, Vo ¼ tumour volume at the initial MRI examination]. To the authors’ knowledge, there are no available data on the volume doubling time of AT/RTs. There have been a few reports describing the volume doubling time of medulloblastomas or malignant gliomas, with reported volume doubling times in the range of 6.84 days to 24 days.30e32 In the present study, the volume doubling time was 3.9 days in patient 8. The volume doubling time of an AT/RT was relatively shorter than that of a medulloblastoma or malignant glioma. Although the number of cases was very small, the short volume doubling time, indicating a markedly high growth rate, may reflect the aggressiveness of AT/RTs. More cases are needed to evaluate the relation between the aggressiveness of an AT/ RT and the volume doubling time. In conclusion, although AT/RTs have non-specific imaging findings, the tumours tend to be relatively large in size, have iso SI in T1-WI and T2WI with prominent enhancement, and relatively mild peritumoural oedema. Rapid tumour growth can be seen during the follow-up period, and this rapid growth with a short volume doubling time may reflect the aggressiveness of AT/RTs.
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3. Fenton LZ, Foreman NK. Atypical teratoid/rhabdoid tumor of the central nervous system in children: an atypical series and review. Pediatr Radiol 2003;33:554e8. 4. Dang T, Vassilyadi M, Michaud J, et al. Atypical teratoid/ rhabdoid tumors. Childs Nerv Syst 2003;19:244e8. 5. Chung YN, Wang KC, Shin SH, et al. Primary intracranial atypical teratoid/rhabdoid tumor in a child: a case report. J Korean Med Sci 2002;17:723e6. 6. Lee YK, Choi CG, Lee JH. Atypical teratoid/rhabdoid tumor of the cerebellum: report of two infantile cases. AJNR Am J Neuroradiol 2004;25:481e3. 7. Parmar H, Hawkins C, Bouffet E, et al. Imaging findings in primary intracranial atypical teratoid/rhabdoid tumors. Pediatr Radiol 2006;36:126e32. 8. Packer RJ, Biegel JA, Blaney S, et al. Atypical teratoid/ rhabdoid tumor of the central nervous system: report on workshop. J Pediatr Hematol Oncol 2002;24:337e42. 9. Koral K, Gargan L, Bowers DC, et al. Imaging characteristics of atypical teratoiderhabdoid tumor in children compared with medulloblastoma. AJR Am J Roentgenol 2008;190:809e14. 10. Hilden JM, Meerbaum S, Burger P, et al. Central nervous system atypical teratoid/rhabdoid tumor: results of therapy in children enrolled in a registry. J Clin Oncol 2004;22: 2877e84. 11. Tekautz TM, Fuller CE, Blaney S, et al. Atypical teratoid/ rhabdoid tumors (ATRT): improved survival in children 3 years of age and older with radiation therapy and high-dose alkylator-based chemotherapy. J Clin Oncol 2005;23:1491e9. 12. Burger PC, Yu IT, Tihan T, et al. Atypical teratoid/rhabdoid tumor of the central nervous system: a highly malignant tumor of infancy and childhood frequently mistaken for medulloblastoma: a Pediatric Oncology Group study. Am J Surg Pathol 1998;22:1083e92. 13. Bruch LA, Hill DA, Cai DX, et al. A role for fluorescence in situ hybridization detection of chromosome 22q dosage in distinguishing atypical teratoid/rhabdoid tumors from medulloblastoma/central primitive neuroectodermal tumors. Hum Pathol 2001;32:156e62. 14. Meyers SP, Khademian ZP, Biegel JA, et al. Primary intracranial atypical teratoid/rhabdoid tumors of infancy and childhood: MRI features and patient outcomes. AJNR Am J Neuroradiol 2006;27:962e71. 15. Lee MC, Park SK, Lim JS, et al. Atypical teratoid/rhabdoid tumor of the central nervous system: clinico-pathological study. Neuropathology 2002;22:252e60. 16. Bonnin JM, Rubinstein LJ, Palmer NF, et al. The association of embryonal tumors originating in the kidney and in the brain. A report of seven cases. Cancer 1984;54: 2137e46. 17. Howat AJ, Gonzales MF, Waters KD, et al. Primitive neuroectodermal tumour of the central nervous system associated with malignant rhabdoid tumour of the kidney: report of a case. Histopathology 1986;10:643e50. 18. Sotelo-Avila C, Gonzalez-Crussi F, deMello D, et al. Renal and extrarenal rhabdoid tumors in children: a clinicopathologic study of 14 patients. Semin Diagn Pathol 1986;3:151e63. 19. Munoz A, Carrasco A, Munoz MJ, et al. Cranial rhabdoid tumor with marginal tumor cystic component and extraaxial extension. AJNR Am J Neuroradiol 1995;16:1727e8. 20. Rorke LB, Packer R, Biegel J. Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood. J Neurooncol 1995;24:21e8. 21. Meyers SP, Kemp SS, Tarr RW. MR imaging features of medulloblastomas. AJR Am J Roentgenol 1992;158:859e65. 22. Koeller KK, Rushing EJ. From the archives of the AFIP: medulloblastoma: a comprehensive review with radiologicepathologic correlation. RadioGraphics 2003;23:1613e37.
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Atypical teratoid/rhabdoid tumors of the central nervous system: imaging and clinical findings in 16 children I.H. Leea, S.-Y. Yooa,*, J.H. Kima, H. Eoa, O.H. Kimb, I.-O. Kimc, J.-E. Cheonc, A.Y. Jungc, B.J. Yoonc a
Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, bDepartment of Radiology, Ajou University Hospital, and c Department of Radiology, Seoul National University Hospital, Seoul, Republic of Korea Received 23 May 2008; received in revised form 30 August 2008; accepted 2 September 2008
AIM: To investigate the imaging and clinical findings of central nervous system (CNS) atypical teratoid/rhabdoid tumours (AT/RTs) in children. MATERIALS AND METHODS: The computed tomography (CT) and magnetic resonance imaging (MRI) findings and clinical records of 16 children with CNS AT/RTs were retrospectively reviewed. Tumour location, size, composition, enhancement pattern, peritumoural oedema, signal intensity (SI) on MRI and CT attenuation were evaluated. RESULTS: A total of 17 lesions from 16 patients (median age 2.3 years, age range 0.7e15 years) were included in the evaluation. Tumour location was infratentorial for 11 lesions and supratentorial for six lesions. The mean diameter of the largest dimension for a tumour was 4 cm. The tumour was mainly solid in 65% of cases, and solid and cystic or cystic and solid in 35% of cases. The solid component of the tumours had a homogeneous iso SI (n ¼ 15) on T2-weighted MRI images and iso SI (n ¼ 14) on T1-weighted images. Moderate to strong enhancement of the solid component was noted in most cases. In spite of a large tumour size, peritumoural oedema was minimal or mild except in four cases. Rapid growth of the tumour was demonstrated in three cases. Seven patients died from tumour progression, with a mean survival time of 8.4 months (range 2e12 months). CONCLUSION: Although the AT/RTs had non-specific imaging findings, the tumours tended to be large in size, have iso SI on T1 and T2-weighted MR images with prominent enhancement, and relatively mild peritumoural oedema. Rapid growth of the tumour was seen during the follow-up period. ª 2008 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction An atypical teratoid/rhabdoid tumour (AT/RT) is a rare and highly malignant central nervous system (CNS) tumour, usually affecting young children under the age of 3 years. AT/RTs are reported to occur with a rate of 3% among childhood CNS malignancies. To date, approximately 220 cases of CNS AT/RTs have been described in the literature * Guarantor and correspondent: S.-Y. Yoo, Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Gangnam-Gu, Seoul 135-710, Republic of Korea. Tel.: þ822-3410-0511; fax: þ822-3410-2559. E-mail address: [email protected] (S.-Y. Yoo).
since the disease was first described by Lefkowits et al. in 1987.1 The lesion was termed an ‘‘AT/RT’’ as the tumour consisted of rhabdoid cells, as well as varying portions of neuroepithelial, peripheral epithelial, and mesenchymal elements without divergent tissue development characteristic of a malignant teratoma. The incidence of AT/RTs has been underestimated and AT/RTs have frequently been misdiagnosed in the past as a primitive neuroectodermal tumours/medulloblastomas (PNETs/MBs) because of histological and radiological similarities. Definitive diagnosis depends on the result of an immunohistochemical evaluation.2,3 As AT/RTs have a dismal prognosis, even with the use of current multimodality therapy, differentiation of this tumour from a PNET/MB is crucial and,
0009-9260/$ - see front matter ª 2008 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.crad.2008.09.007
Atypical teratoid/rhabdoid
moreover, still remains a diagnostic challenge to the radiologist.4 To the authors’ knowledge, there are only limited studies describing the imaging features of this entity. The objective of this study was to investigate the computed tomography (CT) and magnetic resonance imaging (MRI) features of CNS AT/RTs in 16 children and to identify the clinical characteristics.
Materials and methods Approval from the institutional review board was obtained to review clinical records and radiological images for this study. The clinical records of 16 children (male:female 7:9; age range 0.7e15 years; median age 2.3 years) with histopathologically proven CNS AT/RTs were collected from three medical centres (Samsung Medical Centre, Seoul National University Hospital, Ajou University Hospital) in South Korea between 1998 and 2007. At the time of diagnosis, 10 patients (63%) were 3 years of age or younger. Unenhanced (n ¼ 11) and contrast-enhanced CT (n ¼ 8) examinations were performed using 5 mm axial sections. For MRI examinations, 1, 1.5, or 3 T units, produced by various manufacturers (Siemens, Erlangen, Germany; GE Medical Systems, Milwaukee, WI USA), were used. Imaging protocols included at least non-enhanced axial and sagittal T1-weighted images (WI), axial and coronal T2-WI, axial fluid-attenuated inversion recovery (FLAIR), and contrast-enhanced axial, sagittal, and coronal imaging. The section thickness used was usually 5 mm. Eleven patients also underwent spinal MRI at initial diagnosis and/or during follow-up period. The neuroimaging findings were analysed in terms of the location, size, internal content, enhancement pattern, peritumoural oedema, MRI signal intensity, and CT attenuation of the tumours by two observers in consensus. Tumour location was categorized as supratentorial/infratentorial and intra-axial/extra-axial. If the lesion involved two or more regions, the location was designated according to the centre of the mass. The size of a tumour was determined according to its greatest dimension. The SI of the tumours was compared with that of the grey matter for each imaging sequence. A tumour was considered to have a cystic component if it contained an area of typical fluid-like attenuation or SI on CT or MRI images and had rim-like enhancement after contrast medium administration. If areas of high SI were noted on non-enhanced T1-WI with no demonstrable calcification on the corresponding area on a unenhanced CT image, intratumoural
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haemorrhage was considered as present. Peritumoural oedema was categorized as absent, minimal (affecting an area of less than 10% of a tumour), mild (affecting an area greater than 10% and less than 50% of a tumour), moderate (affecting an area greater than 50% and less than 100% of a tumour), and severe (affecting an area greater than 100% of a tumour). The enhancement pattern of the solid component of a tumour was classified subjectively as absent, mild, moderate, and strong by consensus of two observers. Clinical features were reviewed with respect to the presenting symptoms and signs, treatment, and outcome.
Results Imaging analysis Of the 17 lesions in 16 patients, 11 tumours (65%) were infratentorial (six vermis, three brain stem, and two cerebellopontine angle cistern) and six tumours (35%) were supratentorial (three frontal lobe, one temporal lobe, one parieto-occipital lobe, and one lateral ventricle locations). Fifteen tumours were intra-axial, whereas two tumours were extraaxial in the cerebellopontine angle cistern. The sizes of tumours were 1e7 cm in the greatest dimension (mean size 4 cm). On unenhanced CT (n ¼ 11), the attenuation of tumours was most often slightly hyperattenuated (n ¼ 4) or iso-attenuated (n ¼ 4) as compared with the adjacent brain parenchyma. Calcification was noted in two lesions. The most common MRI feature of the tumour was a strong, enhancing, solid mass with an iso-SI seen on T1-WI and T2-WI. In six AT/RTs, a cystic component larger than 1 cm was seen. Peritumoural oedema was most often minimal (n ¼ 5) or mild (n ¼ 5). Less frequently, moderate (n ¼ 1) or severe (n ¼ 3) oedema was noted. In one case, peritumoural oedema was initially absent, but as the tumour grew rapidly, mild peritumoural oedema developed. Enhancement of the solid component was strong (n ¼ 12), moderate (n ¼ 3), mild (n ¼ 1), and absent (n ¼ 1). Areas of low SI seen on T2-WI were noted in four tumours secondary to calcification (n ¼ 1), or haemorrhage (n ¼ 3). Rapid growth of a tumour was demonstrated in three cases as seen on follow-up imaging preoperatively (n ¼ 1) and postoperatively (n ¼ 2). In one of the patients, a 1 cm-sized mass in the left cerebellopontine angle grew up to 3.7 cm in the greatest dimension after 2 weeks with a volume doubling time of 3.9 days (Fig. 1). In another patient who underwent only a biopsy, a 4.7 cm
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mass grew up to 6.2 cm on postoperative day 10 (Fig. 2). In another patient who underwent total tumour removal, a recurrent mass was observed on postoperative day 9.
Clinical findings Symptoms were variable depending on tumour location and age (Table 1). Fourteen patients initially underwent surgical treatment, consisting of gross total removal (n ¼ 11), partial removal
I.H. Lee et al.
(n ¼ 1), and subtotal resection (n ¼ 1). In three patients, only a biopsy was performed without surgical removal. Postoperative chemotherapy was administered in 12 patients with additional radiation therapy in seven patients. Peripheral blood stem cell transplantation was performed in two patients. Leptomeningeal seeding was noted in seven patients on MRI or cerebrospinal fluid study (Fig. 3). Seven patients, including five patients who underwent intensive therapy, died from
Figure 1 Patient 8 presented with a left facial palsy. (aeb) A solid mass (arrow) measuring up to 1 cm is seen in the left cerebellopontine angle. The mass has iso SI on a T1-WI (a). Strong enhancement with small cystic foci (arrowhead) is seen after gadolinium administration (b).(c) After 12 days the mass (arrow) in the left cerebellopontine angle increased in size, measuring up to 3 cm, without haemorrhage. (d) After 2 days from the time of (c), the mass (arrow) appeared larger, measuring up to 3.7 cm on an unenhanced CT image.
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Figure 2 Patient 13 presented with poor oral intake and right side weakness. (aeb) A 4.7 cm mass with a lobulated contour and iso SI on a T1-WI and T2-WI is seen in the left cerebellopontine angle cistern, cerebellum, and brain stem. The mass with mild peritumoural oedema displaces the adjacent midbrain and invades into the parenchyma. (c) The mass (arrow) shows strong enhancement following gadolinium administration. (d) After postoperative day 10 from a biopsy, the mass increased in size, measuring up to 6.2 cm with some haemorrhage.
tumour progression with a mean survival time of 8.4 months (range 2e12 months). Follow-up in six patients was lost. The survival time of the remaining three patients ranged from 11 to 39 months (mean survival 24 months). Tumour recurrence after surgery or chemotherapy developed in five patients. In the present study, two patients underwent nephrectomy due to rhabdoid tumour. In one patient, an AT/RT was detected by brain ultrasonography 1 year after the nephrectomy due to a malignant rhabdoid tumour. In another patient, an AT/RT in the brain and a rhabdoid tumour in the kidney were detected at the same time. In one patient, bone metastasis of an AT/RT was
noted. The clinical and imaging features of the AT/RTs are summarized in Tables 1 and 2.
Discussion An AT/RT, which is classified as grade IV by the WHO, is a rare and aggressive malignant CNS tumour seen in early childhood. It has been reported that the radiological features of an AT/ RT are similar to those of a PNET/MB, which often leads to the preoperative misdiagnosis of a PNET/ MB.3,5e7 One of the differential characteristics between a PNET/MB and AT/RT is the patient age;
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Table 1
Clinical findings
Patient No
Age (y) / Sex
Symptoms/ signs
CSF seeding
Treatment
Outcome (Survival time)
Remark
1 2
3/F 1.3/M
þ
Op (Partial) þ C þ R Op (GTR)
Died (12 months) NA
Recur Rhabdoid tumor of kidney
3 4
0.8/M 0.7/F
þ þ
Bx þ C Op (GTR) þ C
Died (9 months) NA (5 months)
5
3.5/M
þ
Op (GTR) þ C
Died (9 months)
6
6.5/M
þ
Bx only
F/U loss
7 8
9.8/F 1.7/F
þ
Op (GTR) þ C þ R Op (GTR) þ C
Alive (39 months) Died (3 months)
9
2.5/M
Op (Subtotal)
F/U loss
10
2/F
þ
Op (GTR) þ C
Died (12 months)
Rapid growth Recur
11
15/F
Op (GTR) þ C þ R
Died (12 months)
Recur
12
15/M
Op (GTR) þ C þ R
F/U loss (7 months)
Recur, Bone metastasis
13
0.9/F
Bx only
Died (2 months)
Rapid growth
14
14/F
Op (GTR) þ C þ R
Alive (11 months)
15
1/M
Vomiting, seizure Detected at screening brain ultrasonography Left ptosis Irritability, enlarged head circumference Gait disturbance, vomiting, headache Lethargy, ptosis, right side weakness Left L/E weakness Left facial palsy, nausea, vomiting Gait disturbance, vomiting Vomiting, lethargy, seizure Headache, vomiting, nausea Right temporal hemianopsia, headache Poor oral intake Right side weakness Right side weakness, headache, nausea Vomiting
Op (GTR) þ C þ R
F/U loss
16
1/F
Vomiting, head tilting
Op (GTR) þ C þ R
Alive (23 months)
Rapid growth
Rhabdoid tumor of kidney Recur
GTR (gross tumor removal), C (chemotherapy), R (radiation therapy), F/U loss (follow-up loss), Bx (biopsy), NA (not available).
PNET/MB tumours are usually found at approximately 5e7 years of age in contrast to the younger age of presentation for AT/RTs.2,7e9 In the present series, at the time of diagnosis, 10 patients (63%) were 3 years of age or younger. The prognosis for patients with an AT/RT is known to be very poor, especially in the patients younger than 3 years or patients that present with a disseminated tumour at diagnosis/staging and later.2,8,10e13 In the present study, five (50%) of 10 patients aged 3 years or below had died, whereas two (33%) of six patients above 3 years had died at the time the study was undertaken. Although a statistical comparison was not made between these two groups of children, it seems that the prognosis for younger children is worse than for older children. AT/RT should be considered in the differential diagnosis of a posterior fossa tumour having a similar neuroimaging appearance to PNET/MB in any child under the age of 3 years. In the present study, leptomeningeal dissemination occurred in seven (44%) patients from initial diagnosis to 1 year after diagnosis. A similar or lower frequency of leptomeningeal dissemination
was reported in 15e35% of patients with AT/RTs in previous studies.2,8,10,11,14 Another disparity between an AT/RT and PNET/ MB is the location of the tumour. Whereas 80% of classic PNET/MBs arise in the cerebellum,15 AT/RTs occur in the posterior fossa in 47e52%.4,7,14 In the present study, 65% of the AT/RTs were infratentorial with 35% of the tumours occurring in the cerebellum. Among the infratentorial tumours, only 55% occurred in the cerebellum (six out of 11 cases). Rorke et al. 2 reported the cerebellopontine angle cistern as the preferential location (15%) for an AT/RT. Koral et al.9 reported that cerebellopontine angle involvement (8/11, 72.7%) was more frequent; two cases (12%) of AT/RTs occurred in the cerebellopontine angle cistern in the present study. As more common posterior fossa tumours in children, cerebellar astrocytoma and ependymoma should be differentiated from AT/ RT. They also frequently extend to the cerebellopontine angle, but they are more commonly seen in older children. Cerebellar astrocytoma tends to be predominantly cystic and usually hypodense relative to normal brain parenchyma on
Atypical teratoid/rhabdoid
261
Figure 3 Patient 4 presented with irritability and an enlarged head circumference. (a) A well-demarcated mass is seen in the midline of the posterior fossa representing a cerebellar vermis origin mass. The mass demonstrates iso SI with high signal intensity foci representing haemorrhage on a T1-WI. (b) The mass demonstrates iso SI with mild peritumoural oedema on a T2-WI. (c) The mass shows strong enhancement in the main solid portion following gadolinium administration. (d) Five months after gross total tumour removal and the administration of chemotherapy, an MRI image shows multiple nodular and linear enhancing lesions along the ependyma and leptomeninges, representing cerebrospinal fluid seeding.
unenhanced CT. Ependymoma shows frequent calcifications and can extend through the foramina of Magendie and the foramen magnum with insinuation around blood vessels and nerves, often surrounding and engulfing structures. It is known that some renal rhabdoid tumours are associated with synchronous intracranial neoplasms; pineoblastomas, medulloblastomas, or primitive neuroectodermal tumours have been reported.12,16e18 In the present study, one patient had a previous history of nephrectomy due to a malignant rhabdoid tumour and another patient had
a rhabdoid tumour of the kidney at the time of diagnosis of the CNS AT/RT. There are close correlations between clinical presentation of an AT/RT and the age of onset and the location of the tumour. Increased intracranial pressure or localizing signs, such as cranial nerve palsies, headache, and hemiplegia, are common in older children, whereas non-specific symptoms and signs, such as vomiting, lethargy, irritability, loss of weight, macrocephaly, and failure to thrive are common in children younger than 3 years of age.2,5,19,20 In the present study, patients younger
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Table 2
Imaging features
Patient No
Location/ Size
Composition
CT attenuation of solid component
T2 SI
T1 SI
Enhancement
Edema
1 2-1 2-2 3 4 5 6
Vermis/3.2 cm LV/2.3 cm Tectum/1.8 cm Midbrain/1.6 cm Vermis/5.8 cm Vermis/4.4 cm Midbrain and Pons/ 4 cm Frontal lobe/5.4 cm CPA cistern/1-> 3.7 cm Vermis/5.1 cm Frontal lobe/7 cm Temporal lobe/3.5 cm Parieto-occipital lobe/ 5.6cm CPA, brain stem and cerebellum/4.7 cm Frontal lobe/4.7 cm Vermis/4.2 cm Vermis/3 cm
Solid Solid Solid Solid Solid Solid Solid and cystic
NA NA NA NA Low with focal high Slightly high Low
Iso Iso Iso Iso Iso Iso High
Iso Iso Iso Iso Iso Iso Low
Strong No Strong Strong Moderate Strong Strong
Severe Absent Absent Minimal Mild Mild Minimal
Cystic and solid, Caþþ Solid Solid Cystic and solid Solid Solid, Caþþ
Slightly high Iso Iso NA Iso Slightly high
Iso Iso Iso Iso Iso Low
Iso Iso Low Iso Iso High
Strong Strong Mild Strong Strong Moderate
Mild Absent-> mild Absent Mild Severe Severe
Solid
Slightly high
Iso
Iso
Strong
Mild
Cystic and solid Cystic and solid Solid and cystic
Iso NA NA
Iso Iso Iso
Iso Iso Iso
Moderate Strong Strong
Moderate Absent Minimal
7 8 9 10 11 12 13 14 15 16
LV (lateral ventriclel), CPA (cerebellopontine angle), Caþþ (calcification), NA (not available).
than 3 years of age presented with non-specific symptoms; however, some patients under 3 years presented with left facial palsy or right side weakness due to the location of the tumour. On MRI, iso SI seen on T1-WI and T2-WI was noted in more than 70% of the patients and after administration of gadolinium, moderate to strong enhancement was seen in most tumours. However, previous studies have reported various patterns of enhancement in AT/RTs, as well as in PNET/ MBs.14,21,22
In a previous study by Parmar et al.,7 AT/RTs were shown to have moderate to marked surrounding oedema. However, in the present study, moderate or severe peritumoural oedema was noted in only four cases. The frequent presence of cysts associated with AT/RTs has also been reported,8,23e26 and a cystic component, including a small cystic portion, was a common finding in the present study (Fig. 4). Rapid tumour growth was noted during a relatively short interval (range 9e14 days) in three
Figure 4 Patient 14 presented with right side weakness, headache, and nausea. (a) A T2-WI shows a large cystic and solid mass with moderate peritumoural oedema in the left frontal lobe. (b) A contrast-enhanced image demonstrates moderate enhancement of the solid component with a large cystic portion after gadolinium administration.
Atypical teratoid/rhabdoid
cases preoperatively (n ¼ 1) and postoperatively (n ¼ 2) in the present study. All three patients died (mean survival time 5.7 months). The volume doubling time was estimated from patient who underwent sequential MRI examinations preoperatively. With initial and follow-up MRI images on a 2048 1536 picture archiving and communication systems (PACS) monitor (Totoku Electric, Tokyo, Japan), the volume of each tumour was measured by adding the measured cross-sectional areas and multiplying by the section thickness. The measurement of the cross-sectional area in each tumour was performed by drawing the perimeter of the tumour using the area measurement tool of the PACS. As in previous studies, the tumour volume was calculated.27e29 However, some inevitable errors might have occurred due to manual measurement [calculated with the formula: Td ¼ t log2/(log (Vt/Vo)), where Td ¼ volume doubling time, t ¼ the interval between MRI examinations, Vt ¼ tumour volume at the second MRI examination, Vo ¼ tumour volume at the initial MRI examination]. To the authors’ knowledge, there are no available data on the volume doubling time of AT/RTs. There have been a few reports describing the volume doubling time of medulloblastomas or malignant gliomas, with reported volume doubling times in the range of 6.84 days to 24 days.30e32 In the present study, the volume doubling time was 3.9 days in patient 8. The volume doubling time of an AT/RT was relatively shorter than that of a medulloblastoma or malignant glioma. Although the number of cases was very small, the short volume doubling time, indicating a markedly high growth rate, may reflect the aggressiveness of AT/RTs. More cases are needed to evaluate the relation between the aggressiveness of an AT/ RT and the volume doubling time. In conclusion, although AT/RTs have non-specific imaging findings, the tumours tend to be relatively large in size, have iso SI in T1-WI and T2WI with prominent enhancement, and relatively mild peritumoural oedema. Rapid tumour growth can be seen during the follow-up period, and this rapid growth with a short volume doubling time may reflect the aggressiveness of AT/RTs.
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