Literature Review Paper

Korab-Chrzanowska E • Radiotherapy in atypical teratoid rhabdoid tumour

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The importance of radiotherapy in paediatric atypical teratoid rhabdoid tumour of the brain Elżbieta KORAB CHRZANOWSKA1, Joanna BARTOSZEWSKA2, Monika DROGOSIEWICZ3, Stanisław KWIATKOWSKI4, Anna SKOWROŃSKA-GARDAS5

SUMMARY

BACKGROUND: Atypical teratoid rhabdoid tumours (ATRT) are very rare children’s cancers. Approxi- mately 200 cases of ATRT located in the central nervous system have been described in the literature up till now.

AIM: The aim of this report was to analyze the results of treatment of 8 children with these very rare neoplasms of the central nervous system, who were treated according to the Polish Paediatric Brain Tumour Group protocol.

MATERIAL AND METHODS: Eight children aged from 4 months to 22 years, 5 girls, 3 boys with ATRT of the central nervous system are presented. All children have been operated on and received multidrug chemotherapy; 5 children received radiotherapy as well. In all craniospinal irradiation was applied, in doses of 35 Gy to the whole axis and 55 Gy to tumour boost.

RESULTS: Five patients died and 3 children are still alive. The progression-free survival of all 8 patients was 3 to 73 months. The overall survival was 5 to 73 months. All living children received radiotherapy. Two of them had total surgical resection and one partial.

CONCLUSIONS: We conclude that radiotherapy prolonged survival in ATRT and should be incorporated in all treatment protocols for patients with this diagnosis.

KEY WORDS: atypical teratoid rhabdoid tumour, children, radiotherapy

Received: 20.01.2009 Accepted: 28.04.2009 Subject: original paper

1, 2Department of Radiotherapy University Children’s Hospital of Cracow 265 Wielicka St.

3Department of Paediatric Haemato-Oncology Child Health Centre-Memorial Hospital in Warsaw 20 Dzieci Polskich Ave

4Department of Paediatric Neurosurgery, University Children’s Hospital of Cracow 265 Wielicka St.

5Department of Radiotherapy Maria Sklodowska-Curie Memorial Cancer Centre Warsaw, 11 Wawelska St.

Address for correspondence: Elżbieta Korab Chrzanowska Department of Radiotherapy University Children’s Hospital of Cracow 30-663 Cracow 265 Wielicka St, Poland tel: +48126573715 fax: +48126573715 e-mail: [email protected]

BACKGROUND Atypical teratoid rhabdoid tumours (ATRT) are very rare children’s cancers. They were described by Beckwith in 1978 as malignant rhabdoid tumours located in the kidney [1]. Cerebral location was acknowledged in the late 1980s. To date, approximately 200 cases of atypical teratoid/rhabdoid tumours of the central nervous system have been described in the literature [2]. Although ATRT accounts for less than 5% of all paediatric CNS tumours, up to 20% of malignant brain tumours diagnosed in patients less than 3 years old are ATRTs. In adults this tumour was reported anecdot- ally [3,4]. The cerebral form of ATRT has been mistaken for PNET/medulloblastoma tumours.

There are many publications about diagnostic diffi culties, especially for pathologists, when differentiating between PNET/medulloblas- toma and ATRT [5, 6, 7]. These tumours have also been mistaken for ependymomas. Despite immunohistochemical and genetic testing it is very diffi cult to fi nd differences between ATRT and PNET, especially in infratentorial location [8, 9, 10, 11, 12, 13]. This distinction is important, because survival times in ATRT are much shorter than those obtained for medullo- blastoma/PNETs, and a signifi cant portion of patients die as a result of local or craniospinal recurrence despite aggressive surgery and che- motherapy. There are no treatment standards

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for ATRT because of their rarity, but there is some evidence that long-term survival can oc- cur with the use of adjuvant radiation therapy [2, 14, 15].

AIM The aim of our study is to present clinical sta- tus and treatment approaches in 8 patients with ATRT, treated according to the Polish Paediatric Brain Tumours Group protocol.

MATERIALS AND METHODS Between 2000 and 2008, 8 children with ATRT aged from 4 months to 22 years were treated according to the Polish Paediatric Brain Tu- mours Group protocol [16, 17]. There were 5 girls and 3 boys. In 8 patients fi nal histopatho- logical diagnosis of ATRT was confi rmed.

Diagnostic diffi culties concerning histo- pathology were confi rmed in 3 patients. In 2 children the tumour samples had histological features similar to PNET. However, results were uncertain and further examinations of the tumour tissue were performed, which fi nally confi rmed ATRT. One child had a tu- mour with a pathological tissue image typi- cal for medulloblastoma. He was reoperated again because of disease progression during chemotherapy. The tissue specimen obtained during the surgery was typical for ATRT. In these patients immunohistochemical data for INI-1 were not obtained.

In 2 children tumours were located in the posterior fossa region and 6 patients had su- pratentorial location. All children received radical treatment including surgery: 3 patients underwent total surgery, 3 subtotal and 2 par- tial resection. Multidrug chemotherapy was introduced as part of their treatment for all 8 patients. Three children received multidrug chemotherapy according to the Polish proto- col for children below 3 years old (vincristine, etoposide, cisplatin, cyclophosphamide). In 5 patients chemotherapy was given according to the standard Polish protocol for medulloblas- toma/PNET (vincristine, etoposide, carbopla- tin, ifosfamide, cisplatin).

Five children received radiotherapy; in all craniospinal irradiation was applied, in doses of 35 Gy to the whole axis and 55 Gy to tumour boost. This method was similar to that applied to medulloblastoma patients [18].

Three patients did not receive radiotherapy at all. In two cases progression during chemo- therapy was observed, and one child was too young for radiotherapy.

RESULTS Five patients died and three are still alive, with no evidence of disease. There are two girls and one boy in the group of living chil- dren. One of them is suffering due to second cancer (myeloblastic leukaemia). Four deaths were caused by local progression, and one pa- tient died because of local progression accom- panied by massive dissemination to the brain and spinal cord. This patient passed away before planned radiotherapy. The overall sur- vival of all 8 patients was 5 to 73 months. The progression-free survival of all 8 patients was 3 to 73 months. All living patients received radiotherapy as part of their treatment. Two of them had total resection of the tumour and one partial. Treatment results are presented in table 1.

DISCUSSION ATRT of the cerebral region are among tu- mours with the worst prognosis. Despite worldwide multiple research concerning these types of tumours, obtained treatment results are still poor. Diagnostic and therapeutic dif- fi culties are related to the rarity of these tu- mours. Hence, the possibility of randomized multicentre trials assessing treatment effi - ciency is limited. So far, genetic and immuno- histochemical research in the fi eld of ATRT have not resulted in any signifi cant progress in therapeutic and diagnostic procedures in- cluding differentiation between ATRT and PNET/medulloblastoma.

There are publications describing long-arm deletion of chromosome 22q and gene INI1 mutation [9, 12, 19, 20]. From the immunohis- tochemical point of view the following staining methods seem to be signifi cant when differen- tiating ATRT from PNET: E-cadherin, N-cad- herin, beta-catenin immunoreactions [21]. In Rorke’s report diagnostic diffi culties with dis- tinction between ATRT and PNET/medulloblas- toma did not improve treatment results. 13% of ATRT were composed purely of rhabdoid cells, 31% of ATRT had malignant mesenchymal com- ponents, 67% were PNET/ATRT [22].

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Korab-Chrzanowska E • Radiotherapy in atypical teratoid rhabdoid tumour

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Numerous publications inform about mis- diagnosed tumours, especially in the in- fratentorial location, where they resemble medulloblastoma tumours and are frequently mistaken for them [3, 5, 6, 7, 8, 11, 12]. Accord- ing to the Koral report on preoperative MRI examinations of 36 patients with medulloblas- toma and 19 with ATRT, conventional MRI showed similar characteristics between ATRT and medulloblastoma. Cerebellopontine angle involvement and intratumoural haemorrhage are more common in atypical teratoid rhab- doid tumour [23]. In our patients, diagnostic diffi culties were noted in two cases. One pa- tient (a boy, 4 months old) had a tumour with location and histology typical for medulloblas- toma. Because of the patient’s young age, only chemotherapy according to the protocol for children below 3 years old was administered. Unfortunately, disease progression was ob-

served during chemotherapy and additionally ATRT was detected in the patient’s kidney. In the case of a second child histological diffi cul- ties concerning tumour distinction between PNET, carcinoma plexus chorioidei and ATRT were noted. However, fi nal confi rmation of the ATRT diagnosis was achieved after specimen consultations and histochemical examinations (but not with immuno-histochemical data).

So far, published treatment results have not been satisfactory. Long-term survivals are very rare. Many authors have observed that older age and female gender predicted better prognosis [1, 2, 4, 13, 15, 24, 25, 26, 27]. In our study group, only one child below 3 years old and 2 older children are alive. So far no stan- dard methods for the most effective therapy have been developed, but a review of published materials showed that high-dose chemotherapy together with radiotherapy improved survival

Pt Age

years Sex Histopathology Location Treatment

Type of surgery

Radiotherapy PFS

months OS

months Result

FF 4/12 M Medulloblas- toma/ATRT

Inf S+CHT PR No 6 10 DOD

CD 4 F ATRT Sup S+CHT SR No 3 5 DOD

AG 2.5 F ATRT Inf S+CHT SR No 7 10 DOD

IM 2 F ATRT Sup S+CHT+RT PR CSI 35Gy+boost 55Gy

73 73 NED

EN 5 F ATRT Sup S+CHT+RT TR CSI 35Gy+boost 55Gy

72 72 NED second cancer

AG 11 M PNET/ca.plexus chorioidei/ATRT

Sup S+CHT+RT TR CSI 35Gy+boost 55Gy

7 9 DOD

WN 6 F ATRT/PNET Sup S+CHT+RT+CHT SR CSI 35Gy+boost 55Gy

13 25 DOD

MG 22 M ATRT Sup S+CHT+RT+CHT TR CSI 35Gy+boost 54Gy

28 28 NED

Legend: Sup – supratentorial, Inf – infratentorial S – surgery, CHT – chemotherapy, RT – radiotherapy PR – partial resection, SR – subtotal resection, TR – total resection PFS – progression-free survival OS – overall survival NED – no evidence of disease, DOD – dead of disease, LWD – living with disease

Table 1. Results of treatment

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rate in ATRT [15]. We observed a similar ef- fect in our study group. All living children have undergone high dose radiotherapy to the tumour bed and to the craniospinal axis as well. In St. Jude Hospital’s report, concerning 31 children treated during 19 years, 2-year overall survival was 17%±8% and 89%±11% for the group of children below 3 years old and older children, respectively. There is no doubt that patient’s age and the presence of radiotherapy treatment prolonged survival in the described groups of patients. In the group of younger children disease progression dur- ing chemotherapy was observed in 82% of pa- tients and second-line chemotherapy failed. After rescue radiotherapy long-term remis- sion was found in 2 children. There is no clear answer regarding the area of radiotherapy. However, in most cases relapses occur in the tumour bed [15]. This was also confi rmed in our material; only one patient had local pro- gression together with dissemination before planned radiotherapy.

Recently, CD133, a 5-transmembrane gly- coprotein, was identifi ed as an important marker. Chou reported that the amount of CD 133(+) in ATRT correlated positively with the degree of resistance to radiation therapy [28].

According to a multicentre register of ATRT where information about 42 chil- dren was gathered, disease-free survival longer than 2 years was achieved in 24% of patients. All living patients underwent ag- gressive treatment including total surgery, radiotherapy and/or intrathecal or high dose chemotherapy with stem cell graft [29]. Chen et al., in their report of 17 patients, found im- portant prognostic factors using multivari- ate analysis. Those factors included: clinical status of patients, radiotherapy dose, and time between surgery and radiation therapy. Eighty percent of patients suffered from dis- seminated disease despite the fact that all of them received CSI. In the authors’ opinion, radiotherapy is a key method of ATRT treat- ment. They recommend radiotherapy direct- ly after surgical therapy [16]. Also, Mexican authors who observed 10 patients established that radiotherapy beside surgery comprised the major method of paediatric ATRT treat- ment [30].

CONCLUSIONS We conclude that radiotherapy with a higher dose (i.e. over 50 Gy) prolonged survival in ATRT and should be incorporated in all treat- ment protocols for patients with this diagno- sis. It is diffi cult to estimate the role of whole craniospinal axis radiotherapy because of dif- ferent relapse character.

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