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Case Report

Pediatr Neurosurg 2006;42:258–263 DOI: 10.1159/000092366

Atypical Teratoid-Rhabdoid Tumor Spreading along the Trigeminal Nerve

R. Beschorner a M. Mittelbronn a A. Koerbel b U. Ernemann c D.R. Thal e H.-G. Scheel-Walter d R. Meyermann a M. Tatagiba b

a Institute of Brain Research, Departments of b Neurosurgery and c Neuroradiology and d Children’s Hospital, University of Tübingen, Tübingen , and e Department of Neuropathology, University of Bonn, Bonn , Germany

Introduction

An atypical teratoid-rhabdoid tumor (ATRT) of the CNS is a rare malignant embryonic brain tumor (WHO grade IV) of unknown histogenesis that has newly been added to the WHO classifi cation of tumors of the nervous system in 1997 [1] . Histologically, an ATRT is entirely or partially composed of characteristic rhabdoid tumor cells with or without areas resembling a classical primitive neuroectodermal tumor (PNET, medulloblastoma), epi- thelial tissue or neoplastic mesenchyme [2, 3]. ATRT manifests itself almost exclusively in children and repre- sents approximately 2% of all brain tumors in childhood. There are only few reports of adults with ATRT of the CNS in the literature. Beside supratentorial (39–62%) and infratentorial (38–52%) localizations, also pineal (5%), spinal (2%) and multifocal (2%) localization has been reported [3, 4]. In contrast to classical medulloblas- toma/PNET, the prognosis of ATRT is rather poor with a median survival time of 17 months and median event- free survival of 10 months [3, 4]. However, single cases with recurrence-free survival of meanwhile 8 years at the time of their publication have been reported [4]. Further- more ATRT at any location (renal, extrarenal soft tissue, CNS) shows in about 75–90% of cases a monosomy 22 or deletion or mutation of the hSNF5/INI1 (human sucrose nonfermenting 5/integrase interactor 1) tumor suppres-

Key Words Atypical teratoid-rhabdoid tumor � Trigeminal nerve � Metastasis � Recurrence

Abstract We here describe the case of a boy with an atypical tera- toid-rhabdoid tumor (ATRT) of the 4th ventricle at 1 year of age and a local tumor recurrence at 19 months of age. Due to brainstem infi ltration, only incomplete tumor re- section was possible each time. High-dose chemothera- py, stem cell transplantation and irradiation resulted in complete tumor remission on a control MRI. At 8 years of age, another tumor appeared extending from the cer- ebellopontine angle along the right trigeminal nerve through Meckel’s cave into the cavernous sinus. The tri- geminal tumor was not in continuity with the primary ATRT but was located within the fi eld of prior irradiation, neuroradiologically mimicking a schwannoma or a me- ningioma. The origin of the trigeminal tumor as a late metastasis of the former ATRT or as a less likely irradia- tion-induced secondary ATRT and the operative ap- proach are discussed.

Received: May 10, 2005 Accepted after revision: October 2, 2005

Rudi Beschorner, MD Institute of Brain Research Calwerstrasse 3, DE–72076 Tübingen (Germany) Tel. +49 7071 29 82293, Fax +49 7071 29 4846 E-Mail [email protected]

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sor gene on chromosome 22q11.2, which is not found in medulloblastoma or PNET [2, 5–8]. It is not known whether an ATRT can be induced by radiotherapy at all or if in individuals carrying such a genetic predisposition for development of an ATRT this tumor could also be induced by irradiation.

So far, in the medical literature (according to Medline and Pubmed searches) there are neither reports on ATRTs of the CNS spreading along a cranial nerve clinically and neuroradiologically mimicking a meningioma or a schwannoma nor are data available regarding the possi- bility of an ATRT being induced by irradiation.

Case History

Seven years ago, a 14-month-old boy was admitted to hospital presenting with palsy of the left 6th and 7th cranial nerves. A cra- nial MRI showed a 2.5 ! 3 ! 2.7 cm midline posterior fossa mass compressing and infi ltrating the 4th ventricle associated with hy- drocephalus. The lesion extended from the Sylvian aqueduct to the left Luschka foramen. Spinal MRI showed no drop metastasis. The

tumor was removed via a midline suboccipital approach. Due to brainstem infi ltration, no radical tumor resection was possible. His- tology showed a tumor consisting of densely packed small to me- dium-sized tumor cells and fi elds of necrosis. Beside highly cellular fi elds resembling classic PNET, also areas exhibiting features of a malignant mesenchymal component were found ( fi g. 1 a). Further- more, some mitoses as well as typical rhabdoid tumor cells occurred in some areas ( fi g. 1 b, c). Immunohistochemistry showed expres- sion of vimentin, epithelial membrane antigen, pancytokeratin and smooth muscle actin ( fi g. 1 d). Expression of the Ki-67 antigen was found in 10% of the tumor cells. Tumor cells were negative for des- min. Thus, neuropathological fi ndings led to the diagnosis of an ATRT. A control MRI performed 2 months after the surgery dis- closed a 1.8 ! 1.6 ! 1.8 cm partially cystic residual lesion infi ltrat- ing the left paramedian pontine region. The patient underwent che- motherapy while radiotherapy was planned to be delayed until the end of the 2nd or 3rd year of life due to the inverse relationship of postradiation brain damage with the age of the patient. After 4 cycles of chemotherapy, the residual lesion decreased in size and measured 0.8 cm in diameter on radiological controls. The patient remained stable with partial improvement of the cranial nerve def- icits.

One year after primary diagnosis, the 26-month-old patient was readmitted to hospital with worsening of 6th- and 7th-nerve signs, ataxic gait and ptosis on the left side. Cranial MRI showed tumor

Fig. 1. Primary tumor. a Low magnifi cation showing areas with densely packed tumor cells (upper and right part) beside less cellular areas with spindle-shaped tumor cells (lower left) and foci of necrosis (upper left corner). b Higher magnifi cation of cellular areas with polymorphic nuclei with prominent nucleoli and few mitoses (ar- row). c In small areas, typical rhabdoid tumor cells are detected. These cells have an eccentric nucleus with a prominent nucleolus and a fi ne granular homogenous cytoplasm or contain eosinophilic cytoplasmic inclusions (arrow). d The majority of the tumor cells express ‘smooth muscle actin’ (dark-stained cells). a , b , c HE staining. d Immunohistochemistry using an anti-smooth-muscle-actin antibody. Bars = 50 � m.

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recurrence in the left cerebellar hemisphere and on the fl oor of the 4th ventricle with infi ltration of the brainstem. Cranial and spinal MRI again did not show evidence of metastases. Considering the early recurrence and the brainstem infi ltration as well as the impos- sibility of radical tumor removal, aggressive oncological treatment was planned. The patient underwent a preoperative cycle of chemo- therapy with carboplatin, etoposide and thiotepa, followed by reop- eration through a midline suboccipital approach and subtotal tumor resection. In the postoperative period (17 months after the fi rst sur- gery) 2 additional cycles of high-dose chemotherapy with carbopla- tin, thiotepa, etoposide and methotrexate were carried out followed by autogenous stem cell transplantation. Histology and immunohis- tochemistry again revealed an ATRT. Cranial MRI performed 1 month later showed complete tumor remission. Additionally, a 54- Gy dose fractioned irradiation over the fl oor of the 4th ventricle and the posterior fossa was performed 20 months after the fi rst surgery (at the age of 34 months). Cranial nerve defi cits and ataxia progres- sively improved until complete remission of symptoms.

In further follow-ups, the patient presented with a normal psy- chomotor development and visited school until the age of 8 years without neurological defi cits. Seven years (86 months) after the fi st surgery the patient was readmitted suffering from a right-sided fa- cial pain. The neurological examination demonstrated hypoesthe- sia in the dermatome of the right trigeminal nerve, while the re- maining physical and neurological examination was unremarkable. MRI did not show any signs of local tumor recurrence in the cer- ebellum but revealed a sharply demarcated, extra-axial dumbbell- shaped tumor which extended symmetrically in the right posterior and middle cerebral fossa following the cisternal and cavernous segment of the trigeminal nerve ( fi g. 2 ). Contrast enhancement on MRI was slightly inhomogeneous and computed tomography dem- onstrated small calcifi cations. No further signs of tumor spread were seen. Additionally, a cavernous hemangioma (cavernoma) which was not present on previous MRI studies was detected in the left inferior temporal gyrus ( fi g. 3 ). Based on the clinical and radio- logical features and considering the atypical tumor localization fol- lowing recurrence of the ATRT, a trigeminal schwannoma as well as a (possibly irradiation-induced) petroclival meningioma were considered as differential diagnoses.

The patient underwent a combined presigmoid supra-infraten- torial approach in the semisitting position under monitoring of somatosensory and auditory evoked potentials and electromyo- graphic tracing of the 5th and 7th cranial nerves. After dural open- ing and division of the superior petrosal sinus and tentorium, a mass involving the trigeminal nerve could be seen. Following initial partial tumor resection, marked infi ltration of the trigeminal nerve fi bers was noted. The tumor spread along the trigeminal nerve from the cerebellopontine angle to Meckel’s cave and to the interdural portion of the lateral wall of the cavernous sinus, infi ltrating some nerve fi bers. The tumor could be totally removed with preservation of the remaining neurovascular structures. Intraoperative frozen section diagnosis revealed again a malignant embryonal tumor con- sistent with an ATRT. Histology and immunohistochemistry con- fi rmed diagnosis of an ATRT with infi ltration of nerve fascicles ( fi g. 4 a–c). Both, primary tumor and trigeminal tumor lacked hSNF5/INI1 immunoreactivity, refl ecting an alteration of the hSNF5/INI1 gene [6] . Postoperatively a CT ruled out any periop- erative complications. Ten days after the operation, a control MRI was performed which confi rmed the removal of the tumor mass and showed a contrast enhancement of the trigeminal nerve which at

this point of time did not allow distinction between postsurgical barrier disruptions or rather scar tissue and residual tumor infi ltra- tion of the nerve fascicles ( fi g. 5 ). In the postoperative period, the patient experienced accentuation of the right hemifacial hypoesthe- sia without additional defi cits. He was referred to radiosurgical ir- radiation over the region of the right trigeminal nerve. At 3 months postoperatively (89 months after the fi rst surgery), he is regularly visiting school.

Fig. 2. Contrast-enhanced, T 1 -weighted MRI in the axial plane shows a dumbbell- shaped tumor extending in the right poste- rior and middle cerebral fossa following the course of the trigeminal nerve.

Fig. 3. T 2 -weighted MRI in the coronal plane shows a small, round hypointense le- sion in the left inferior temporal gyrus cor- responding to a cavernoma (arrow).

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Discussion

We here report the case of an 8-year-old boy with ATRT of the 4th ventricle at the time of the fi rst diagno- sis, who – at the time of this writing – has survived for 7 years since diagnosis. Taking into consideration the short median survival time (17 months) this is already quite a long survival for a case with ATRT of the CNS. Never- theless, even single cases with event-free survival of at least 96 months have been reported [4]. The occurrence of a second delayed tumor manifestation 7 years after initial diagnosis and 66 months after adjuvant radiother- apy along the trigeminal nerve could be either a metasta- sis or a second primary. As the trigeminal tumor at least in part developed in the area of prior irradiation, even the possibility of an irradiation-induced ATRT at this site has to be taken into consideration.

Nevertheless, the authors believe the ATRT along the trigeminal nerve to be most likely a metastasis for sev- eral reasons. First it is well known that ATRTs of the CNS frequently develop metastases through subarachnoid spread [9]. Thus, tumor dissemination from the 4th ven- tricle through Luschka foramina would not be uncom- mon. Secondly, a latency of 66 months after irradiation

Fig. 5. Contrast-enhanced, T 1 -weighted MRI in axial plane 10 days after surgery confi rms removal of the tumor mass. The enhancement of the trigeminal nerve can be attributable to either postsurgical barrier disruption or scarring or residual tumor in- fi ltration of the nerve fascicles.

Fig. 4. Trigeminal tumor. a Histology shows a highly cellular tumor (upper part) infi ltrating into a nerve fascicle (lower part). b Immunohistochemical antineurofi lament staining demonstrates residual nerve fi bers. c Smooth muscle actin is expressed at variable intensity in the majority of tumor cells. a HE staining. b , c Immunohisto- chemistry using antibodies against neurofi lament ( b ) and smooth muscle actin ( c ). Bars = 50 � m.

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is rather short or borderline as most irradiation-induced tumors develop after a longer average latency [10–13] . Furthermore, so far no case has been reported in which an irradiation-induced etiology of an ATRT was likely.

Interestingly, MR images at the age of 102 months (68 months after irradiation) additionally revealed a newly developed cavernoma in the left inferior temporal gyrus which was probably induced by radiotherapy [14–16]. Although not specifi c, ATRTs frequently show alter- ations in the hSNF5/INI1 tumor supressor gene [2, 6, 17]. Thus, even in patients with the genetic background pre- disposing to the development of an ATRT (i.e. mutations in the hSNF5/INI1 gene), irradiation-induced cell dam- age – if at all – does not inevitably cause a malignant neo- plasm.

Some tumors may localize the major portion in the posterior fossa, middle fossa or be equally distributed in both fossae, presenting a dumbbell shape. Petroclival me- ningiomas and trigeminal neuromas constitute the most common types.

The trigeminal nerve joins the brainstem about half- way between the upper and lower borders of the pons. In the posterior fossa, the nerve runs toward the petrous apex [18]. At the petrous apex, the nerve enters the mid- dle fossa in Meckel’s cave, which is located on the petrous part of the temporal bone [18]. The ophthalmic division passes forward into the interdural lower part of the lat- eral wall of the cavernous sinus to reach the superior or- bital fi ssure. Intraoperatively, one could observe the tu- mor spreading along the trigeminal nerve, infi ltrating its fi bers, from its origin into Meckel’s cave. Such a pattern of ATRT dissemination, following the course of a cranial nerve, has not been described so far. ATRTs, as other brain tumors, only exceptionally metastasize outside the CNS. So far only 1 case has been reported that developed a lung metastasis of an ATRT of the CNS [19]. Beside hematogenous metastasis of ATRTs of the CNS, contin- uous growth along a cranial nerve through openings of the cranial base is another possibility for extracranial spread/ extension of these tumors.

Various approaches have been used to remove lesions in both posterior and middle fossae, with different rates of morbity and mortality. Combined subtemporal-retro- sigmoid or subtemporal presigmoid, simple retrosigmoid route, frontotemporal with or without zygomatic resec- tion, anterior or posterior petrosectomy or a combination of them have been performed. Although the simple retro- sigmoid suboccipital approach may be used to remove some of these lesions with a good rate of success [20] , it may present some limitations in resecting some lesions

with a large middle fossa component. The retrosigmoid intradural suprameatal approach includes the standard retrosigmoid suboccipital route associated with drilling of the petrous bone above and anterior of the internal auditory meatus, with various degrees of bone resection, permitting to follow the trigeminal nerve and to reach Meckel’s cave and further the middle fossa [21] . This could have been a reasonable option in this case. How- ever, a combined approach was preferred due to the sus- picion of malignancy of the lesion and therefore the ne- cessity of radical tumor removal, including the intracav- ernous portion of the lesion, preferentially in an 1-stage surgery. By using a combined presigmoid subtemporal approach, special attention should be given to the vein of Labbé as well as to avoid opening of the semicircular ca- nal during mastoid drilling. The correct choice of the ap- proach associated with a meticulous surgical technique may allow resecting tumors located in the petroclival re- gion with minimal morbidity.

In summary, this is a unique case of an ATRT mani- festing along the trigeminal nerve, presenting both clini- cally and on neuroimages as a neoplasm consistent with a meningioma or a schwannoma. Although very rare, an ATRT should be taken into consideration in the clinical differential diagnosis of meningioma or schwannoma of cranial nerves, also in cases with no history of ATRT.

Acknowledgement

The authors whish to thank Ms. Gudrun Albrecht for photo- technical assistance.

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