Literature Review Paper

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Central nervous system atypical teratoid rhabdoid tumours: The Canadian Paediatric Brain Tumour Consortium experience

L. Lafay-Cousin a,*, C. Hawkins b, A.S. Carret c, D. Johnston d, S. Zelcer e, B. Wilson f, N. Jabado g, K. Scheinemann h, D. Eisenstat i, C. Fryer j, A. Fleming j, C. Mpofu k, V. Larouche l, D. Strother a, E. Bouffet m, A. Huang m

a Division of Pediatric Hematology Oncology and Bone Marrow Transplantation, Alberta Children’s Hospital, Calgary, Alberta, Canada b Department of Pediatric Pathology, Hospital for Sick Children, Toronto, Ontario, Canada c Division of Pediatric Hematology Oncology, Hospital Sainte Justine, Montreal, Quebec, Canada d Division of Pediatric Hematology Oncology, Children Hospital of Eastern Ontario, Ontario, Canada e Division of Pediatric Hematology Oncology, Children Hospital of Western Ontario, London, Ontario, Canada f Division of Pediatric Hematology Oncology, Strollery Children’s Hospital, Edmonton, Alberta, Canada g Division of Pediatric Hematology Oncology, Montreal Children’s Hospital, McGill University, Montreal, Quebec, Canada h Division of Pediatric Hematology Oncology, McMaster University, Hamilton, Ontario, Canada i Division of Pediatric Hematology Oncology, Cancer Care Manitoba, Winnipeg, Manitoba, Canada j Division of Pediatric Hematology Oncology, Children and Women British Columbia’s Hospital, Vancouver, British Columbia, Canada k Division of Pediatric Hematology Oncology, Saskatoon Cancer Center, Saskatoon, Saskatchewan, Canada l Division of Pediatric Hematology Oncology, Hospital Universitaire de Quebec, Quebec City, Quebec, Canada m Pediatric Brain Tumor Program, Hospital for Sick Children, Toronto, Ontario, Canada

A R T I C L E I N F O

Article history:

Received 12 May 2011

Received in revised form 2 August

2011

Accepted 12 September 2011

Available online 22 October 2011

Keywords:

Atypical teratoid rhabdoid tumor

CNS

Paediatric

Population based study

High dose chemotherapy

Radiation therapy

0959-8049/$ - see front matter � 2011 Elsevi doi:10.1016/j.ejca.2011.09.005

* Corresponding author: Address: Division o Hospital, 2888 Shaganappi trail NW, Calgary,

E-mail address: lucie.lafay-cousin@albert

A B S T R A C T

Background: Atypical teratoid rhabdoid tumours (ATRT) are aggressive brain tumours

mostly occurring in early childhood. Largest published series arise from registries and insti-

tutional experiences (1–4). The aim of this report is to provide population-based data to fur-

ther characterise this rare entity and to delineate prognostic factors.

Patients and methods: A national retrospective study of children 618 years diagnosed with a

central nervous system (CNS) ATRT between 1995 and 2007 was undertaken. All cases

underwent central pathology review.

Results: There were 50 patients (31 males; median age at diagnosis of 16.7 months). Twelve

patients were >36 months. Infratentorial location accounted for 52% of all cases. Nineteen

patients (38%) had metastatic disease. Fifteen (30%) underwent gross total resection (GTR).

Ten patients (20%) underwent palliation. Among the 40 remaining patients, 22 received

conventional chemotherapy and 18 received high dose chemotherapy regimens (HDC); nine

received intrathecal chemotherapy and 15 received adjuvant radiation.

Thirty of the 40 treated patients relapsed/progressed at a median time of 5.5 months (0–32).

The median survival time of the entire cohort was 13.5 months (1–117.5 months).

er Ltd. All rights reserved.

f Pediatric Hematology Oncology and Bone Marrow Transplantation, Alberta Children’s Alberta, Canada. Tel.: +1 403 955 2554; fax: +1 403 955 2645.

shealthservices.ca (L. Lafay-Cousin).

354 E U R O P E A N J O U R N A L O F C A N C E R 4 8 ( 2 0 1 2 ) 3 5 3 – 3 5 9

Age, tumour location and metastatic status were not prognostic. Patients with GTR had a

better survival (2 years overall survival (OS): 60% ± 12.6 versus 21.7% ± 8.5, p = 0.03). HDC

conferred better outcome (2 years OS 47.9% ± 12.1 versus 27.3% ± 9.5, p = 0.036). Upfront

radiation did not provide survival benefit. Six of the 12 survivors (50%) did not receive

radiation.

Conclusion: The outcome of CNS ATRT remains poor. However, the use of HDC provides

encouraging results. GTR is a significant prognostic factor. The role of adjuvant radiation

remains unclear.

� 2011 Elsevier Ltd. All rights reserved.

1. Introduction positively charged microscope slides. INI1 (BAF47, BD Biosci-

Since their first description in the mid 1980s, atypical teratoid

rhabdoid tumours (ATRT) of the central nervous system (CNS)

are increasingly recognised and are now routinely diagnosed

despite their rarity.5–7 These brain tumours that mostly affect

infants and young children have historically been character-

ised by an aggressive behaviour and a grim prognosis with a

median survival ranging from 6 to 11 months.3,8,9 Given the

rarity of the disease, our current knowledge is mostly based

on small series with a limited number of patients. No defini-

tive guidelines have been established that reflect optimal

treatment. Most recent treatment strategies recommend

maximal surgical resection followed by intensive chemother-

apy with or without intrathecal chemotherapy and focal or

craniospinal radiation. Although early results of pilot studies

have shown encouraging results, the respective contribution

of each modality in improved outcome is unclear. In the past

5 years treatment approaches in Canada have been relatively

homogeneous and based on the use of high dose chemother-

apy. The use of adjuvant radiation from centre with an even

distribution of children subjected or not to radiation. With

this large centrally reviewed national cohort, our aim was to

provide population-based data on this entity to better define

prognostic factors and highlight new trend in outcome.

2. Patients and methods

2.1. Patients

This retrospective study was conducted through the Canadian

Paediatric Brain Tumour Consortium (CPBTC), a network of 17

Canadian Paediatric centres collaborating in paediatric neu-

ro-oncology research. After approval from their respective

institutional review board, each participating centre was asked

to provide anonymised clinical data and pathology tumour

slides on patients, aged between 0 and 18 years, and locally

diagnosed with CNS ATRT between 1995 and 2007. Data collec-

tion forms inquired about demographics, pathology and cyto-

genetic reports, surgical procedures, post operative

management and outcome.

2.2. Central pathology review

All cases underwent central pathology review (CH) including

immunostaining for INI1/BAF47 to confirm the diagnosis of

AT/RT. For immunohistochemistry representative four micro-

metre sections were cut from each case and mounted on

ences, Mississauga, Canada) immunohistochemistry at a dilu-

tion of 1:100 was performed on the Ventana Benchmark XT

autoimmunostainer (Ventana Medical Systems, Tucson, AZ),

with a closed avidin–biotin complex method system using the

Ultraview reagent kit (Ventana Medical Systems, Tucson, AZ).

Neuroblastoma was used as a positive control. Further, for a tu-

mour to be considered true negative on-slide endothelial cells

must have been immunopositive. Parallel slides omitting the

primary antibody were run as a negative control in all cases.

Data capture was completed in May 2010 and central

pathology review in September 2010.

2.3. Statistical analysis

The statistical analysis was performed using SPSP15. For

descriptive statistics, continuous data were compared using

Student’s t-test. Non-continuous data were compared using

Chi-square. For both tests p < 0.05 was considered significant.

Estimation of event-free survival and overall survival was per-

formed using the Kaplan–Meier analysis and significance

testing (a = 0.05) based on the log-rank test. Overall survival

was calculated from the date of diagnosis to the date of last

follow-up or date of death from any cause. Event-free survival

was calculated from the date of initial diagnosis to the date of

earliest radiologic disease progression. The level of signifi-

cance was p = 0.05.

3. Results

Among the 17 institutions of the CPBTC, 6 had no patients eli-

gible for the study. Data were obtained from 10 out 11 remain-

ing centres.

3.1. Patients description

Clinical information was obtained on 55 patients with an insti-

tutional diagnosis of CNS ATRT. Samples for pathology review

were available for 53 patients. Seven samples previously re-

viewed in the context of a retrospective institutional study

were not revaluated for the purpose of the current report.10

Following central review, five patients were excluded from

the initial cohort as the diagnosis of AT/RT was not confirmed.

The two patients without sample available for central review

were kept in the final cohort after careful review of the

institutional pathology and cytogenetic reports describing

morphological characteristics, cytogenetic alterations and

immunohistochemical profiles in keeping with ATRT. Results

Table 1 – Patient characteristics.

N = 50

Sex ratio 31 M/19 F

Median age at diagnosis 16.7 months (1–187.9) <12 months 17 (34%) >36 months 12 (24%)

Metastatic status at diagnosis 19 (38%) M1 5 M2 3 M3 4 M2/M3 4 M4, M4/MRT 3

Extent of resection GTR 15 30%) STR 18 (36%) PR 14 (28%) Biopsy 3 (6%)

Palliative care 10 (20%) Conventional chemotherapy 22 (55%) HDC 18 (45%) IT chemotherapy 9 (22.5%)

Radiation 21 (52%) CSI 11 Focal 9 Cranial 1

Adjuvant RT 15 (37.5%)

M, male; F, female; MRT, multiple rhabdoid tumours; GTR, gross

total resection; STR, subtotal resection; PR, partial resection; HDC,

high dose chemotherapy; IT, intrathecal chemotherapy; RT, radio-

therapy; CSI, craniospinal irradiation.

E U R O P E A N J O U R N A L O F C A N C E R 4 8 ( 2 0 1 2 ) 3 5 3 – 3 5 9 355

are therefore reported on a cohort of 50 patients (Table 1).

Amongst these, 31 were males (62%). The median age at

diagnosis was 16.7 months (range 1 day–15.6 years). Twelve

patients (24%) were older than 36 months. The median dura-

tion of presenting symptoms was 3 weeks (range 0–20 weeks).

Most frequent presenting symptoms were signs related to in-

creased intracranial pressure, followed by change in behaviour

(irritability, regression of milestones) as well as localising signs

like motor deficit, cranial nerve deficit and seizure. Complete

staging consisting of magnetic resonance imaging (MRI) of

the spine and brain and cerebrospinal fluid (CSF) cytology from

lumbar puncture, was available for 39 patients (78%). Nineteen

patients had metastatic disease at diagnosis (Table 1). Three

patients presented with metastasis or lesion outside of the

CNS; one had positive uptake on the vault on bone scan, and

a positive submandibular lymph node on biopsy. Two others

presented with synchronous rhabdoid lesions (brain + kidney

and brain + skin, lung, bone) in keeping with multiple rhabdoid

tumours syndrome (MRT); nine patients (18%) underwent ge-

netic testing and three were found to carry germline mutation

for INI1.

Twenty-six (52%) tumours were infratentorial, 22 were

supratentorial (44%) and two were intraspinal (4%). Initial

maximal surgical resection was attempted in all but three pa-

tients who only had biopsy. Two patients underwent second-

look surgery that resulted in gross total resection (GTR) and

subtotal resection (STR), respectively. Overall, gross total

resection was achieved in 15 patients (30%).

Following surgical resection, ten patients (20%) received no

further anti-tumour therapy. These patients who underwent

palliative care immediately after diagnosis were younger

(median 7.6 months [range 1.5–21.4] compared to 19.5 months

[range 0–188] for patients who received active postoperative

treatment). However, both groups had similar metastatic dis-

tribution (40% versus 37.5%) (See Table 2).

3.2. Survival and prognostic factors

Survival data are given for the 40 patients who received active

post-operative treatment.

Thirty patients either relapsed or progressed at a median

time of 5.5 months from diagnosis (range 0–32 months). Only

three patients relapsed beyond 12 months from diagnosis.

None of the relapse occurred outside of the Collin’s Law per-

iod. The median survival time was 14 months with a pro-

jected 2-years overall survival of 36.4% ± 7.7. At the

completion of survey, 12 patients were alive at a median fol-

low up of 43 months (range 10–117.3 months).

3.3. Age and demographics

Median survival time according to age was, respectively,

9.6 months for patients <12 months of age (n = 9), 17.4 months

for patients 12–36 months (n = 19) and 19.1 months for those

>36 months (n = 12). There was a trend towards a poorer out-

come for children younger than 12 months, however this did

not reach statistical significance (p = 0.06) (Fig. 1a).

Sex (p = 0.67), metastatic status at diagnosis (p = 0.24) and

tumour location (p = 0.49) were not associated with significant

difference in outcome.

3.4. Extent of surgery

Twelve patients (30%) had a gross total surgical resection. Pa-

tient who achieved a GTR had a better survival with a 2y OS of

60% ± 12.6 compared to 21.7% ± 8.5 for patients who under-

went less than GTR (p = 0.03) (Fig. 1b).

3.5. Chemotherapy

Twenty-two patients (55%) received conventional chemother-

apy and 18 (45%) received a protocol that included high dose

chemotherapy and autologous stem cell rescue (HDC and

SCR). Various regimens of conventional chemotherapy were

used, essentially ‘baby brain protocols’11 IRS III like12 and

ICE regimens13. Only nine patients received anthracycline

based chemotherapy regimens.

Three major high dose chemotherapy regimens were used:

the Headstart regimen14 (methotrexate based induction fol-

lowed by one cycle of high dose Carboplatin Thiotepa, VP16)

in four patients, three sequential cycle of high dose Carbo-

platin and Thiotepa in seven patients whilst seven patients

received a methotrexate based induction followed by three

sequential high dose Carboplatin and Thiotepa.

Nine of the 18 patients who received HDC regimens were

alive at a median follow up time of 40.8 months (10–90) from

diagnosis. HDC was associated with a significant survival

Table 2 – Characteristics and treatment of the survivors.

No Sex/age at diagnosis

Tumour location

Metastatic status

Surgery Conventional CT only

CT regimen including high dose chemotherapy (HDC)

Intrathecal chemotherapy (IT)

RT field and dose

RT indication Relapse or progression

FU from diagnosis (months)

1 F/19.1 Supra tentorial

M2/M3 GTR VCR, VP16, CB, IFOS

– – 45 Gy cranial/780 focal

Relapse + 117.3

2 M/12.5 Supra tentorial

M0 GTR – MTX, CDDP, CPM, VCR, VP16, (CB, Thiotepa) · 3

– – – 33.5

3 F/131.5 Supra tentorial

M0 GTR VCR CCNU PRED

– – 59 Gy focal Primary – 84.0

4 F/17 Infra tentorial

M0 GTR – CDDP, CPM, VCR, VP16, (CB, Thiotepa) · 3

– – – 96.0

5 M/15.2 Infra tentorial

M0 STR – CDDP, CPM, VCR, TMD VP16 (CB Thiotepa VP16) · 1

– – – 55.5

6 M/60.7 Infra tentorial

M1 PR – MTX, CDDP, CPM, VCR, VP16, (CB, Thiotepa) · 3

– 36 Gy CSI/18 Gy focal boost

Primary – 10.0

7 F/19.8 Supra tentorial

M0 GTR – MTX, CDDP, CPM, VCR, VP16, (CB, Thiotepa) · 3

– 55.8 Gy Focal Primary – 40.8

8 M/180.4 Supra tentorial

M0 GTR IFOS, CB, VP16

– – 36 Gy CSI/18 Gy focal boost

Primary – 114.8

9 F/11.2 Infra tentorial

M2 STR – CDDP, CPM, VCR, VP16, (CB, Thiotepa) · 3

TIT · 2 – – 42.7

10 M/31 Infra tentorial

M0 GTR – CDDP, CPM, VCR, VP16, (CB, Thiotepa) · 3

TIT · 2 54 Gy focal Primary – 43.4

11 M/43.3 Supra tentorial

M0 GTR – CDDP, CPM, VCR, VP16, (CB, Thiotepa) · 3

TIT · 3 – – 29.2

12 M/28.2 Supra tentorial

M2 STR – CDDP, CPM, VCR, VP16, (CB, Thiotepa) · 3

TIT · 3 – Persistent CSF+a 23.5

F, female; M, male; GTR, gross total resection; STR, subtotal resection; PR, partial resection; VCR, vincristine; CCNU, Lomustine; CB, carboplatin; CDDP, cisplatinum; CPM, cyclophosphamide; TMD,

temozolomide; VP16, etoposide; TIT, triple intrathecal (aracytine, hydrocortisone, methotrexate); CSI, craniospinal irradiation; Gy, Gray; IFOS, ifosfamide; PRED, prednisone; RT, radiation therapy;

MTX, methotrexate.

a Treated with tamoxifen and Cis retinoic acid.

3 5

6 E

U R

O P

E A

N J

O U

R N

A L

O F

C A

N C

E R

4 8

( 2

0 1

2 )

3 5

3 –

3 5

9

Fig. 1 – Analysis of overall survival (Kaplan–Meier method) according to: (a) age at diagnosis; (b) the extent of resection; (c) the

use of high dose chemotherapy; (d) the use of adjuvant radiation.

E U R O P E A N J O U R N A L O F C A N C E R 4 8 ( 2 0 1 2 ) 3 5 3 – 3 5 9 357

benefit with a 2 years OS of 47.9% ± 12.1 versus 27.3% ± 9.5 for

the conventional chemotherapy group (p = 0.036) (Fig. 1c).

In addition to systemic therapy, nine patients (22.5%) re-

ceived intrathecal chemotherapy (IT). Among them, six were

treated with systemic HDC. The most commonly used IT

drugs were the triple combination of cytosine arabinoside,

hydrocortisone and methotrexate (seven patients) or single

agent Thiotepa (two patients) with a median of 3 IT adminis-

trations [range 1–10] per patients during therapy. The used of

IT chemotherapy was not associated with a significant prog-

nostic value (median survival of 17.8 months versus

13.1 months (p = 0.32).

3.6. Radiation

Twenty-one (52.5%) patients received radiation therapy during

therapy (11 craniospinal radiation with focal boost, nine focal

radiation, one cranial radiation). The dose of craniospinal radi-

ation ranged from 12 to 45 Gy (median 36 Gy) with the boost

dose to the primary tumour ranged from 11 to 33 Gy. For the pa-

tient who received focal radiation, the dose of focal radiation

ranged from 45 to 59 Gy (median 54 Gy). Radiation therapy

was delivered in an adjuvant setting in 15 children and at the

time of relapse or progression in the six remaining children.

The median age at diagnosis of patients who received RT was

34 months (6.3–187.9) as compared to 14 months (0–43.3) for

those who did not. Whether radiation was given in an adjuvant

setting or at any time during therapy, did not appear to signif-

icantly influence survival. Patient who received radiation in an

adjuvant setting had a median survival of 17.8 months as com-

pared to 14 months for those who did not (p = 0.64) (Fig. 1d).

Eleven of the 18 patients treated with HDC (39%) did not re-

ceive adjuvant radiation. Median survival time has not been

reached yet for these 11 patients: at the completion of the sur-

vey, six were alive at a median follow up of 38.1 months

(range 23.5–96). Three of the seven children who received RT

with HDC were alive (10, 40.8, 43.4 months). In total six of

the 12 survivors (50%) did not receive radiation.

Among the 12 survivors, 10 were alive in first complete

remission whilst two were in second complete remission.

4. Discussion

This national registry represents one of the largest popula-

tion-based series of CNS ATRT reported to date. The central

pathology review ensured the homogeneity of this retrospec-

tive series. Although we collected cases from 1995 onwards, a

period during which this entity was better recognised, it is

likely that our survey underestimated the total number of

Canadian CNS ATRT, since the central pathology review did

not include all embryonal tumours diagnosed during the

study.2,10

358 E U R O P E A N J O U R N A L O F C A N C E R 4 8 ( 2 0 1 2 ) 3 5 3 – 3 5 9

Unlike voluntary based registry1 or series from clinical tri-

als, this population-based registry provides unbiased data

with regard to demographic characteristics and post opera-

tive management. The median age at diagnosis (16.7 months)

of our population appears to be younger than what was re-

ported in the United States of America (USA) CNS ATRT regis-

try or in recent clinical trials1,3,4 but more in keeping with the

ATRT population from the recently reported Austrian regis-

try.2 In our series, 20% of the patients did not receive further

therapy beyond surgery. This is in keeping with the initial

descriptions from Rorke et al.15 where 14% of the patients

did not receive any postoperative treatment. Children who

underwent post operative palliative care tended to be younger

at presentation. The inclusion of untreated younger patients

may contribute to explain the lower median age at diagnosis.

Although the number of CNS ATRT cases per year continu-

ously increased from 1995 to 2007, the proportion of un-

treated patients remained constant throughout the study

period. This information is important and suggests that regis-

tries are an important complement of prospective protocols

as they allow incorporating these missing patients.

In our study, we confirmed a rate of metastatic disease in

the range of 30–40% and we did not find a prognostic signifi-

cance of dissemination at diagnosis. In contrast with previous

reports, we did not find a survival advantage in children older

than 3 years.1,4

Despite the known prognostic value of complete resection,

that was confirmed in our experience, only two children

underwent second look surgery to attempt gross total resec-

tion.1,3,4 It should be reinforced that second look surgery

should be strongly considered as recommended in most cur-

rent ATRT protocols.

The management of CNS ATRT with conventional chemo-

therapy has been consistently associated with dismal out-

come and most series have supported the benefit of

aggressive multimodal therapy.16 Chi et al.3 recently reported

on 20 patients a 2 years progression free and overall survival

of 53% ± 13 and 70% ± 10, respectively, with a protocol using

intensive rhabdomyosarcoma-based chemotherapy, intrathe-

cal therapy and age-based radiotherapy. Similarly from the 19

patients in the Austrian registry, all eight long term survivors

received combined multimodality therapy, with high dose

chemotherapy in seven patients, intrathecal therapy in 6

and all received focal radiation.2

The respective role of each treatment modality, namely

high dose chemotherapy, intrathecal chemotherapy and

radiation, remains difficult to delineate.17 Our series provide

further evidence that high dose chemotherapy is associated

with survival benefit when compared to conventional ther-

apy with a 2 years OS of 47.9% ± 12.1 versus 27.3% ± 9.5

(p = 0.036).18,19 Whether IT chemotherapy contributes to im-

proved outcome or can replace craniospinal radiation still

remains to be confirmed. In their meta-analysis Athale

et al. suggested patients who received IT therapy had a sur-

vival advantage with a 2 years OS of 64% versus 17.3% for

those who did not (p < 0.0001).20 In our series, the use of IT

was only described in most recent patients but in only nine

patients, limiting our ability to draw meaningful conclusion.

Similarly, based on the initial experience of IRS III type

therapy in rhabdoid tumour,12 some authors have suggested

a role for anthracyclines in CNS ATRT.21–23,3 In our experience

nine patients received an anthracycline based regimen but

none of them are long term survivors.

The potential contribution of radiation in this subtype of

tumour is even more a matter of debate since 2/3 of the pa-

tients diagnosed with ATRT are younger than three at the time

of diagnosis and therefore more vulnerable to radiation in-

duced neurocognitive impairment. Several reports have sug-

gested a survival benefit with radiotherapy.24,25 Although in

the ATRT registry, the median age of 13 patients who received

upfront radiation was higher (47 months) compared to the en-

tire cohort (24 months),1 it is possible that confounding fac-

tors such as age or the addition of multimodal therapies

contributed to that figure. Based on these findings and those

from the NCI ATRT workshop,8 radiation has been recom-

mended and integrated into current ATRT protocols.

We did not find any prognostic value for radiation neither

when used in an upfront setting nor when delivered at any

given time during the course of the disease. The absence of

significant value may be due to the limited small size of our

cohort. However six out of the 11 long term survivors in our

experience were treated with HDC without radiation (median

follow up of 38.1 months (range 23.5–96). In total six of 12 sur-

vivors (50%) did not receive radiation. These encouraging re-

sults suggest that some patients with ATRT may be spared

from radiation. Amongst these six patients, two had meta-

static disease at diagnosis and two had a subtotal resection

of their mass. Further identification of molecular markers

may help to better delineate the subgroup of patients that

can be cured without radiation.

5. Conclusion

Despite the well recognised dismal prognosis associated with

CNS ATRT, a trend to improved outcome is emerging with the

use of multimodalities strategies and the data from our na-

tional cohort to support that trend. Furthermore our series

highlights the encouraging results associated with the use

of high dose chemotherapy and describe a proportion of long

term survivors (50%) who did not receive radiation.

Conflict of interest statement

None declared.

Acknowledgements

This work has been supported by a research grant from

B.R.A.I.N. Child (Brain Tumor Research Assistance and infor-

mation Network).

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