Literature Review Paper

CASE REPORT

Atypical teratoid rhabdoid tumor: long-term survival after chemoradiotherapy

Vivek Verma1 & Catrina P. Johnson2 & Nathan R. Bennion1 & Abhijeet R. Bhirud1 & Sicong Li1 & Rodney D. McComb3 & Chi Lin1

Received: 24 March 2015 /Accepted: 20 April 2015 /Published online: 5 May 2015 # Springer-Verlag Berlin Heidelberg 2015

Abstract Purpose Atypical teratoid rhabdoid tumors (ATRTs) arise from the central nervous system largely in the pediatric pop- ulation. They portend a very poor prognosis with few long- term survivors. We describe a series of five cases at our institution. Methods We conducted a retrospective chart review and clin- ical follow-up. Results Three patients underwent chemoradiation after surgi- cal resection; the two patients whose caretakers declined this therapy passed away soon after diagnosis. Chemoradiation included intravenous and intrathecal chemotherapy as well

as intensity-modulated radiotherapy after resection. Of the pa- tients receiving chemoradiation, two patients had infratentorial tumors, two had gross residual tumor after re- section, and two were under the age of 3 years. The three patients receiving trimodality therapy remain clinically and symptomatically disease-free with follow-up times of 44, 46, and 55 months. Two of the patients have mild neuropsychiat- ric sequelae after therapy. Conclusions Long-term, high-volume trials of ATRT are cur- rently not published. We offer experience in successful long- term survival of this tumor treated with chemoradiotherapy.

Keywords Atypical teratoid rhabdoid tumor . Pediatric brain tumors . Radiotherapy . Chemotherapy

Introduction

Atypical teratoid/rhabdoid tumors (ATRTs) are rare primary central nervous system tumors with the peak incidence from birth to the second year of life [1]. Anatomically, the majority of tumors are infratentorial, most commonly in the cerebellum or cerebellopontine angle; histologically, the majority of ATRTs have epithelial, mesenchymal, or primitive neuroectodermal tumor elements [2]. Relatively larger volume epidemiological studies have shown that the median overall survival of ATRTs is around 10 months [3], but with chemo- therapy [4, 5], radiotherapy [6], or both [7, 8], survival has been shown to be 14–18 months or longer.

Though cases with long-term survival have been reported [9], the lack of such not only indicates that large-scale clinical trials are needed to define optimal management but also sug- gests that until these trials are published, individual experi- ences remain important in identifying factors that contribute to high survival in patients with this aggressive malignancy.

* Chi Lin [email protected]

Vivek Verma [email protected]

Catrina P. Johnson [email protected]

Nathan R. Bennion [email protected]

Abhijeet R. Bhirud [email protected]

Sicong Li [email protected]

Rodney D. McComb [email protected]

1 Department of Radiation Oncology, University of Nebraska Medical Center, 987521 Nebraska Medical Center, Omaha, NE, USA

2 Department of Anesthesiology, University of Nebraska Medical Center, Omaha, NE, USA

3 Department of Pathology, University of Nebraska Medical Center, Omaha, NE, USA

Childs Nerv Syst (2015) 31:1393–1399 DOI 10.1007/s00381-015-2723-5

We present five cases of ATRT from our institution with sub- sequent management. We furthermore analyze and discuss improved outcomes of the children that received chemoradia- tion when compared to those who did not.

Case reports

Case 1

A 15-year-old male experienced nausea and vomiting for 1- month duration with an accompanying right frontal headache. Computed tomography (CT) scan and subsequent magnetic resonance imaging (MRI) revealed a 2 cm mass centered with- in the frontal horn of the right lateral ventricle (Fig. 1). There was no midline shift. He underwent right craniotomy, tumor resection, and placement of external intraventricular drain. Pathology revealed ATRT with a mixture of small cells and rhabdoid cells (Fig. 2). Immunostaining for INI1 (BAF47) was negative in tumor cells and positive in vascular cells. FISH cytogenetic studies were positive for loss of the BCL2L13 (22q11.21) and SMARCB1/INI1 (22q11.23) gene regions. Postoperative MRI demonstrated residual tumor ad- jacent to the inferior right frontal horn. He started a course of chemotherapy per the Dana-Farber protocol [8] with vincris- tine, cisplatin, doxorubicin, and cyclophosphamide in addi- tion to intrathecal cytarabine, methotrexate, and hydrocorti- sone totaling 51 weeks (radiotherapy administered between 7 and 12 weeks of treatment). At time of radiation oncology consultation, physical examination was unremarkable. He underwent a course of postoperative intensity-modulated ra- diation therapy (IMRT) to the surgical bed and residual dis- ease to 5404 cGy in 28 daily fractions (Fig. 3). With a follow- up of 55 months, he remains clinically and symptomatically disease-free. Though he has short-term memory deficits, he is highly functioning and is enrolled as a full-time university student.

Case 2

A 2-year-old female with history of Pierre-Robin syn- drome and cleft palate status post repair presented with a 2-week history of headaches, progressive vomiting, and postural instability. Further imaging demonstrated a mass in the posterior cranial fossa with metastatic lesions in the pituitary infundibulum and foramen of Monro (Fig. 4). Thereafter, the tumor was resected with postoperative imaging suggestive of residual tumor at the rim of the resection cavity, near the left lateral ven- tricle, caudate nucleus, corpus callosum, and suprasellar/ hypothalamic region. Pathology revealed ATRT. Immunostaining for INI1 (BAF47) was negative in tu- mor cells and positive in vascular cells. FISH

cytogenetic studies were positive for loss of BCR (22q11.2) and EWSR1 (22q12) gene regions, which flank the SMARCB1/INI1 region. Three subsequent lumbar punctures failed to identify any malignant cells. She received chemotherapy per the Dana-Farber proto- col [8] with vincristine, cisplatin, doxorubicin, and cy- clophosphamide in conjunction with intrathecal cytarabine, methotrexate, and hydrocortisone. During her chemotherapy, she went on to complete a course

Fig. 1 T1-weighted with contrast MRI pre-surgical images of case 1 (a axial; b coronal; c sagittal)

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of IMRT, with a total of 5400 cGy in 30 fractions administered (Fig. 5). At 46 months after initial com- pletion of therapy, she remains clinically without evi- dence of disease. She developed behavioral health issues including adjustment disorder.

Case 3

An otherwise normal 8-year-old female experienced 2 weeks of nausea, vomiting, diplopia, and generalized headaches. Head CT and subsequent MRI were remarkable for a 2 cm mass within the third ventricle obstructing the foramen of Monro and cerebral aqueduct, causing hydrocephalus (preop- erative images not available). She was taken to the operating room for left frontal craniotomy and transcallosal removal of the tumor along with third ventriculostomy. Pathology showed ATRT. Immunostaining for INI1 (BAF47) was nega- tive in tumor cells and positive in vascular cells. FISH cyto- genetic studies were positive for loss of the BCR (22q11.2) region, but there was no deletion of the TUPLE-1 region at 22q11.2. Postoperative course included near-complete resolu- tion in the aforementioned symptoms. She began chemother- apy per the Dana-Farber protocol [8] with intrathecal metho- trexate, cytarabine, and hydrocortisone; this was followed by cisplatin, doxorubicin, etoposide, and leucovorin. During che- motherapy, she presented in consultation for radiotherapy, during which she was having severe nausea and vomiting as well as failure to thrive from chemotherapy. Though a treatment plan for prescription dose of 5400 cGy in 28 fractions to the tumor bed was made, her mother elected to discontinue chemotherapy after 4 weeks due to se- vere side effects and forwent radiotherapy. A follow-up brain MRI 2 months after consultation indicated a

0.5 cm nodular area at the inferior left basal ganglia area which was interpreted as postoperative change ver- sus recurrent tumor, with recommendations to repeat imaging in 2 months. This MRI revealed that the size had increased from 0.5 to 1.8 cm, which also protruded into the foramen of Monro. The mother insisted on

Fig. 2 Representative hematoxylin and eosin staining of tumor in all five cases. The neoplasm is composed of rhabdoid cells with large nuclei and abundant eosinophilic cytoplasm. Other areas of this tumor are composed of small cells. Bar=50 μm

Fig. 3 Radiotherapy treatment plan of case 1 (a axial; b coronal; c sagittal). Yellow volume indicates clinical target volume (CTV) and turquoise volume the planning target volume (PTV); isodose lines provided on scale at right

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discontinuing any form of therapy and the patient passed away 7 months after consultation, 11 months after initial symptoms.

Case 4

The patient, an 11-day-old male, was born at 39 weeks gesta- tion to a 19-year-old G0P0 mother with an uncomplicated vaginal delivery. MRI of the brain was performed due to in- ability to move bilateral lower extremities at birth. It showed a

Fig. 5 Radiotherapy treatment plan of case 2 (a axial; b coronal; c sagittal). Red volume indicates CTV and green volume the PTV; isodose lines provided on scale at right

Fig. 4 T1-weighted with contrast MRI pre-surgical images of case 2 (a axial; b coronal; c sagittal)

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right cerebellopontine angle mass with a severely enlarged mid- and distal spinal cord due to a second mass starting at T5-6 extending to the lower thoracic and lumbar regions with a third area of enhancing tissue in the sacral canal (Fig. 6). Biopsy demonstrated ATRT; immunostaining for INI1 (BAF47) was negative in tumor cells and positive in vascular cells. Physical examination at the time of radiotherapy consul- tation confirmed lack of movement in spite of stimulation to bilateral lower extremities. The tumor was deemed inoperable, and after consultation, it was also decided that he was not a candidate for radiotherapy at that time because of his age and need for initial chemotherapy. After an extensive discussion

with the family regarding chemotherapy, the mother wished not to pursue further treatment and elected to concentrate on comfort care. The patient passed away 20 days after initial evaluation and workup.

Case 5

A young girl of 21 months developed new-onset nausea, vomiting, and gait ataxia over 1–2 weeks. An MRI subse- quently demonstrated a large mass in the posterior fossa (Fig. 7) for which gross total resection was accomplished. Histopathologically, the tumor was an ATRT; immunostaining for INI1 (BAF47) was negative in tumor cells and positive in vascular cells. Though there was no residual tumor on subse- quent imaging, her postoperative course was complicated by subdural effusion (nonmalignant) and cerebrospinal fluid leak. She began with vincristine, dactinomycin, cyclophosphamide, cisplatin, doxorubicin, and temozolomide, as well as intrathe- cal methotrexate, cytarabine, and hydrocortisone. Radiation therapy was prescribed to 5400 cGy in 30 fractions to the posterior fossa tumor bed (Fig. 8), which she tolerated well with improving functionality as time progressed. At last follow-up of 48 months, she continues to do well without significant sequelae.

Discussion

We report five cases from our institution of the rare but highly aggressive ATRT, with excellent survival after combined che- moradiation. Of the three patients that underwent trimodality therapy, there was no evidence of disease recurrence at 44, 46, and 55 months. Due to the nature of this tumor, reports of long-term survival of these patients are rare. This experience lends data supporting the use of combined chemoradiotherapy for this tumor ahead of large-volume clinical trial results.

The three patients in this series (cases 1, 2, and 5) had several reasons to have a poor prognosis. Two of the patients (cases 1 and 2) had residual tumor after resection, and one patient (case 2) had multiple areas of residual tumor for which radiotherapy had to cover a large volume, including the left lateral ventricle and caudate nucleus, corpus callosum, and suprasellar/hypothalamic region. Furthermore, two patients (cases 2 and 5) were less than 3 years of age and also had infratentorial tumors, both of which are known poor prognos- tic factors in ATRTs [10]. Hence, the long-term survival shown in these patients with multiple factors associated with worse outcomes is important to define for future treatment regimens.

We agree with previous reports emphasizing the impor- tance of multimodality management [11]. Higher powered studies may likely affirm that long-term overall survival can be reached in these patients with the use of intensive

Fig. 6 T1-weighted with contrast MRI images of case 4 (a axial; b coronal; c sagittal)

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chemoradiotherapy after surgical debulking [12]. However, even in the face of aggressive treatment, it has already been reported in some cases that these tumors can recur up to 20 years from initial therapy [13]. Thus, we advocate these patients to have regular and frequent long-term follow-up with imaging, especially in the absence of defined criteria for sur- veillance in these patients.

Due to the relative rarity of these tumors, little is known about modifying treatment regimens based on both tumor and

patient characteristics, let alone optimal sequencing and timing of adjuvant therapy. Our results support the work of Pai Pananiker et al. [14] who noted that children with a 1 month or longer delay in the start of radiotherapy after sur- gical resection were more likely to have local and distant failure. In our series, all patients that received radiotherapy completed it within 1 month of diagnosis.

In the three patients that underwent chemoradiation, two patients developed neuropsychiatric conditions. Though im- pairments did not affect daily functioning, radiation may be incompletely associated with sequelae. This raises the ques- tion that though most clinical trials for this tumor have used photon beam radiotherapy [8, 12], the growth of radiotherapy technology necessitates questions of whether other radiation

Fig. 8 Radiotherapy treatment plan of case 5 (a axial; b coronal; c sagittal). Pink volume indicates CTV and red-orange volume the PTV; isodose lines provided on scale at right

Fig. 7 T1-weighted with contrast (a axial; c sagittal) and T2 (b coronal) MRI pre-surgical images of case 5

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modalities are superior. A case report from Scandinavia has described long-term survival with trimodality therapy using Gamma Knife radiosurgery with a dose of 18 Gy in one frac- tion (biologically equal to 50. 4 Gy fractionated) [15]. Another trial of ten patients has shown favorable initial outcomes with proton therapy (doses to 50.4 Gy to the tumor or 23.4 Gy craniospinal with tumor boost to total 55.8 Gy), with de- creased doses to several surrounding intracranial structures including the cochlea and whole cerebrum [16]. Though initial findings are encouraging, these results will need to be corrob- orated with longer follow-up, larger volume, and eventually phase III data.

Today, the outcomes for ATRT are generally poor. However, we report long-term survival in a series of patients treated with trimodality therapy at our institution despite mul- tiple poor prognostic factors. As our understanding of this disease increases, we anticipate the elucidation of more effec- tive patient selection, treatment administration, and more ro- bust reports of treatment outcomes to contribute to improved outcomes in these patients.

Acknowledgments None

Ethical approval For this type of study, formal consent is not required. This article does not contain any studies with human participants or an- imals performed by any of the authors.

Conflict of interest The authors all declare that conflicts of interest do not exist.

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