Primitive Neuroectodermal Tumors of the Brainstem in Children Treated According to the HIT Trials: Clinical Findings of a Rare Disease

PEDIATRICS clinical article J Neurosurg Pediatr 15:227–235, 2015

Primitive neuroectodermal tumors of the brainstem in children treated according to the HIT trials: clinical findings of a rare disease

Carsten Friedrich, MD,1,2 Monika Warmuth-Metz, MD,3 André O. von Bueren, MD, PhD,1,4 Johannes Nowak, MD,3 Brigitte Bison, MD,3 Katja von Hoff, MD,1 Torsten Pietsch, MD,5 Rolf D. Kortmann, MD,6 and Stefan Rutkowski, MD1

1Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg; 2Division of Pediatric Oncology, Hematology and Hemostaseology, Department of Woman’s and Children’s Health, University Hospital Leipzig; 3Department of Neuroradiology, University of Wuerzburg; 4Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Medical Center Goettingen; 5Department of Neuropathology, University of Bonn; and 6Department of Radiation Oncology, University of Leipzig, Germany

Object Primitive neuroectodermal tumors of the central nervous system (CNS-PNET) arising in the brainstem are extremely rare, and knowledge about them is limited. The few existing case series report fatal outcomes. The purpose of this study was to analyze clinical characteristics of and outcome for brainstem CNS-PNET patients treated according to the consecutive, population-based HIT studies covering a 19-year time period. Methods Between September 1992 and November 2011, 6 eligible children with histologically proven brainstem CNS-PNET not otherwise specified and 2 children with brainstem ependymoblastomas (3, partial resection; 3, subtotal resection; 2, biopsy), median age 3.3 years (range 1.2–10.6 years), were treated according to consecutive multimodal HIT protocols for CNS-PNET/medulloblastoma. Postoperative treatment was according to maintenance chemotherapy protocols (3, craniospinal irradiation [CSI] followed by maintenance chemotherapy), sandwich chemotherapy protocols (2, neoadjuvant chemotherapy, CSI, maintenance chemotherapy), or a therapy protocol for children younger than 4 years (3, postoperative chemotherapy followed by CSI). Results The median duration of prediagnostic symptoms, predominantly cranial nerve deficits (n = 7), pyramidal tract signs (n = 5), or ataxia (n = 5), was 5 weeks (range 1–13 weeks). The tumors were all located in the pons. Most involved more than half of the pontine axial diameter and were sharply marginated. All patients had postoperative residual disease, including metastasis in 1 case. With 1 exception all tumors progressed early during treatment within 3.9 months (range 2.5–10.4 months), leading to a 1-year event-free survival rate (± standard error) of 13% ± 12%. After progression, patients succumbed early to their disease resulting in a 1-year overall survival rate of 25% ± 15%. The only surviving patient had a partially resected CNS-PNET, received a sandwich chemotherapy protocol, and is without disease progression 14 months after diagnosis. Conclusions CNS-PNET is a rare but important differential diagnosis in childhood brainstem tumors. So far, ef- ficient therapies are lacking. The sampling of tumor material for improved biological understanding and identification of new therapeutic targets is important. http://thejns.org/doi/abs/10.3171/2014.9.PEDS14213 KEY WORDS primitive neuroectodermal tumor; brain tumors; brainstem; children; chemotherapy; radiotherapy; oncology

ABBREVIATIONS ADC = apparent diffusion coefficient; CN = cranial nerve; CNS-PNET = central nervous system primitive neuroectodermal tumor; CSI = craniospinal irradiation; DPIG = diffuse intrinsic pontine glioma; EFS = event-free survival; GPOH = Gesellschaft für Pädiatrische Onkologie und Hämatologie (German Society for Pedi- atric Oncology and Hematology); OS = overall survival; PFS = progression-free survival. submitted April 17, 2014. accepted September 15, 2014. include when citing Published online January 2, 2015; DOI: 10.3171/2014.9.PEDS14213. DISCLOSURE The authors declare that there is no conflict of interest. The HIT 2000 trial office and the reference institutions are supported by the German Children’s Can- cer Foundation (Deutsche Kinderkrebsstiftung). The HIT ’91 trial was supported by German Cancer Aid (Deutsche Krebshilfe).

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rainstem tumors account for 14% of all CNS tu- tory. Inclusion criteria for this analysis were diagnosis of mors in the pediatric population.19 The growth pat- an intrinsic brainstem tumor, histologically confirmed di- tern is mostly diffuse pontine (80%).12 Tumors with agnosis of CNS-PNET according to the most recent WHO Bfocal growth may occur throughout the brainstem, with classification of brain tumors on central review (T.P.), or the medulla oblongata or midbrain being the predominant by the local institutional pathologist/neuropathologist.23 sites. The largest proportion of brainstem tumors are of In total, 15 patients with brainstem CNS-PNETs were glial origin (~ 90%).27 While diffuse intrinsic pontine gli- registered. We excluded 4 patients with insufficient tumor omas (DIPGs) are associated with a poor prognosis, the material for exact histological diagnosis on central review, prognosis of focal gliomas is more favorable. Histologi- and 3 patients having a large supratentorial tumor propor- cally, glial tumors need to be distinguished from other less tion or a large extension to the cervical spinal cord out- frequent tumor entities, including central nervous system side the brainstem, as previously reported.6 Eight cases primitive neuroectodermal tumors (CNS-PNETs). of CNS-PNET diagnosed between September 1992 and CNS-PNETs typically arise in the supratentorial brain 6 November 2011 from 8 different centers in Germany were but may also develop in the brainstem or spinal cord. further analyzed. All institutions participating in the HIT They are a rare tumor entity accounting for only 4.8% 19 trials had received approval from their institutional review of childhood brain tumors. CNS-PNETs are highly boards, and informed consent was obtained from all pa- malignant embryonal tumors capable of disseminating tients or their legal guardians. throughout the CNS. Morphologically, these tumors are very similar to medulloblastomas that arise in the cerebel- Treatment lum. However, there is growing evidence for a different tumorigenesis from molecular genetic studies.21,26 The The maximum possible safe resection of the primary current WHO classification hence defines CNS-PNET and tumor was recommended. The following therapy was medulloblastoma as different entities.23 Clinically, CNS- started according to the consecutive HIT ’91/HIT 2000 PNETs behave more aggressively and are associated with protocols displayed in Fig. 1. lower survival rates compared with medulloblastoma.18 In the HIT ’91 and HIT 2000 studies for CNS-PNET pa- Maintenance Chemotherapy Protocols tients older than 3–4 years, multimodal treatment consist- One patient (Case 1, Table 1 ) was treated according to ing of surgery, craniospinal irradiation (CSI) plus boosts, the HIT ’91 maintenance arm as published previously.32 and chemotherapy led to 3- to 5-year progression-free He received CSI with 35.2 Gy and a boost to the tumor re- survival (PFS) rates of 34% and 47%, respectively.14,32 In gion to 55.2 Gy, followed by maintenance chemotherapy, children younger than 3–4 years at diagnosis, intensive as shown in Fig. 1. Two patients were treated with reduced chemotherapy is often administered in an effort to delay conventional fractionated CSI of 23–24 Gy and a boost radiotherapy and avoid or reduce the associated neuropsy- to the tumor region to 54–55 Gy, as recommended in the chological sequelae. The HIT-SKK 87/92 and HIT 2000 HIT 2000 maintenance protocol for nonmetastatic medul- trials for young children with CNS-PNET resulted in loblastoma patients aged > 4 years at diagnosis.20 After 3- to 5-year PFS rates of 17% and 24%, respectively.13,33 radiotherapy, one of these 2 patients (Case 2) received 2 Ependymoblastoma is a rare malignant variant of CNS- courses of maintenance chemotherapy. PNET, histologically characterized by distinct multilay- ered rosettes with a central lumen; it is associated with a Sandwich Chemotherapy Protocols poor prognosis. Most trials on CNS-PNET include only 9,14,24,25,28,32,33 Two patients were treated according to the HIT 2000 patients with supratentorial tumor locations. sandwich chemotherapy protocol with 2 cycles of SKK Of the few small cohorts described to date—with a to- chemotherapy (Fig. 1).29,34 One patient (Case 5) subse- tal of 17 brainstem CNS-PNET patients—only 2 patients 5,10,36 quently received hyperfractionated CSI with 36.0 Gy (2 survived. Here, we report our experience caring for 8 × 1.0 Gy daily) and a boost to the tumor region up to 67.0 patients with brainstem CNS-PNET who were registered Gy, and the other patient (Case 4) was treated with 36.0 as observational patients to consecutive HIT studies in 19 Gy conventional fractionated CSI and a boost to the tumor years since 1991 (HIT ’91 and HIT 2000). region up to 60.0 Gy. The CSI was followed by up to 4 courses of maintenance chemotherapy (Fig. 1). Patients and Methods Patient Characteristics HIT 2000 Standard SKK Chemotherapy Protocol for Young Children Patients with a brainstem CNS-PNET were not included in the HIT trials HIT-SKK87, HIT-SKK92, HIT ’91, and Three patients started treatment with SKK chemother- HIT 2000 (ClinicalTrials.gov/NCT00303810) for children apy according to the HIT 2000 protocol for young chil- and adolescents conducted by the GPOH (Gesellschaft für dren with nonmetastatic CNS-PNET (Fig. 1, Table 2).13 In Pädiatrische Onkologie und Hämatologie [German So- 1 child with metastatic disease (Case 6, Table 1), an intra- ciety for Pediatric Oncology and Hematology]). Instead, ventricular access device (Omaya reservoir) was implanted they were prospectively documented as observational pa- after histological diagnosis of ependymoblastoma, and in- tients. Similar to a registry, we provided uniform recom- traventricular methotrexate was given concomitantly to the mendations for the diagnostic evaluations and the therapy SKK chemotherapy according to the guidelines described of brainstem CNS-PNET, but adherence was not manda- for nonmetastatic medulloblastoma in young children.34

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Fig. 1. Treatment schedules for patients with brainstem CNS-PNET treated according to HIT ’91/HIT 2000 with maintenance (n = 3), sandwich (n = 2), or young children (n = 3) protocols. The lightning bolt represents CSI.

Diagnostic Evaluations and Follow-Up The extent of postoperative residual tumor was calculated Staging recommendations consisted of a craniospinal as an area in order to allow better comparison to other MRI and evaluation of CSF. Central review was offered studies.16 Partial response, improvement, stable disease, for imaging and CSF analysis. If tumor cells were present and progressive disease were defined, respectively, as a in the CSF, an analysis should be obtained ≥ 14 days af- ≥ 50% decrease, 25%–50% decrease, < 25% decrease or ter surgery and before postoperative treatment. The extent increase, and ≥ 25% increase (or new metastasis) in the of surgery based on the surgical report and postoperative tumor volume on MRI.35 Imaging was to be repeated ev- MRI was defined as gross-total resection if no residual ery 3–4 months in the first 2 years after treatment, every tumor was detectable, subtotal resection if > 90% of the 6–9 months up to 5 years after treatment, and annually tumor volume was removed, partial resection if > 10%– thereafter. 90%, and biopsy if ≤ 10% was removed. Postoperative Brainstem tumors were retrospectively analyzed for imaging was performed 24–48 (–72) hours after surgery. their focality and other neuroradiological characteristics TABLE 1. Detailed patients’ tumor and treatment characteristics Case Pt Age Residual Craniospinal Time to Failure Survival No. (yrs), Sex Histology EOR Tumor* Stage Treatment Protocol RT Progression (mos) Type (mos) 1 10.6, M CNS-PNET Biopsy >1.5 cm2 M0/1 HIT ’91 mainte- SRT 8.2 Local DOD (11.3) nance 2 2.2, F CNS-PNET Partial Yes M0 HIT 2000 mainte- SRT 6.0 Local DOD (8.0) nance 3 5.5, F CNS-PNET Subtotal >1.5 cm2 M0 HIT 2000 mainte- SRT 4.0 Local DOD (5.6) nance 4 4.4, M CNS-PNET Partial >1.5 cm2 M0 HIT 2000 sandwich SRT NA NA AWD (13.6) 5 6.0, F CNS-PNET Subtotal Yes M0 HIT 2000 sandwich HFRT 10.4 Local DOD (22.7) 6 1.2, M EBL Subtotal >1.5 cm2 M1+3 Standard SKK NA 2.6 Local DOD (6.7) 7 1.8, F CNS-PNET Biopsy >1.5 cm2 n.d. Standard SKK NA 2.8 Local DOD (3.2) 8 1.9, M EBL Partial >1.5 cm2 M0 Standard SKK NA 2.5 Local DOD (4.1) AWD = alive with disease; DOD = dead of disease; EBL = ependymoblastoma; EOR = extent of resection; HFRT = hyperfractionated radiotherapy; M0 = nonmetastatic disease; M1 = tumor cells in CSF; M0/1 = no macroscopic metastasis; M2 = cranial metastasis; M3 = spinal metastasis; NA = not applicable; n.d. = not done; Pt = patient; RT = radiotherapy; SRT = standard radiotherapy. * On early postoperative MRI.

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by an experienced neuroradiologist (M.W.-M.) using the initial MRI studies. Focal brainstem tumors were considered to be limited to one anatomical brainstem segment and occupying not more than 50% of this segment as de- 2 of tumor) fined by Barkovich et al. A delineated tumor margin was

Enhancement (% not defined to be a criterion for focality, because a lot of None Focal (25–50%) None Focal (<10%) None Multifocal (0–25%) DIPGs have it in clinical praxis as well.

Statistical Analysis

T2 Data were documented and analyzed at the HIT ’91/ HIT 2000 trial center at the Children’s University Hospital

Hyper/homo Hyper/inhomo Hyper/homo Hyper/inhomo Hyper/inhomo† Hyper/inhomo† of Hamburg-Eppendorf, Germany (until 2009: Children’s University Hospital of Wuerzburg, Wuerzburg, Germany).

Signal* Radiotherapy data were collected at the Department of Radiation Oncology, University of Leipzig, Germany. Sur-

T1 vival was estimated by the Kaplan-Meier method. Overall survival (OS) was defined as date of diagnosis to death of

Hypo/homo Hypo/inhomo Hypo/homo Hypo/inhomo Hypo/homo Hypo/inhomo‡ any cause, the date of last visit specified censoring. Event- free survival (EFS) was defined as the time from the date of diagnosis to the date of first progression, relapse, oc- currence of secondary malignancy, death of any cause, or last contact–specified censoring. Analysis was performed with the SPSS software, version 18.0. MarginTumor Delineated Mostly delineated Blurred Blurred Delineated Delineated Results Patient Characteristics s

ET Tumor and treatment characteristics of the 8 patients (4 50% 50% >50% >50% >50% >50%

≤ ≤ female) with brainstem CNS-PNET are displayed in Table Segment

NS-PN 1. The median age at diagnosis (date of surgery) was 3.3

Involved Brainstem years (range 1.2–10.6 years). The median duration of time from the manifestation of the first symptoms to diagnosis

was 5 weeks (range 1–13 weeks). On baseline medical examination, pyramidal tract signs (n = 5) and ataxia (n = 5)

Moderate Marked Moderate Moderate Marked Marked were the most common neurological signs (Fig. 2). Symp- Brainstem Enlargement toms of cranial nerve (CN) lesions affected CN VII (n = 4), CN VI (n = 3), CN III (n = 1), and CN IX (n = 1) (Fig. 2). All patients had either ataxia or a pyramidal tract deficit or a cranial nerve deficit. Three of 8 patients had the triad of symptoms simultaneously. No patient had symp- lateral lateral

tomatic hydrocephalus or required a ventriculoperitoneal shunt at diagnosis. In 6 patients an open tumor resection was performed. In 3 of these patients the tumor was ac- Lateral Dorsal Ventral Dorsal, Dorsal, lateral, ventral Dorsal, Contact to the Surface cessed through the fourth ventricle, via a midline occipital craniotomy and incision of the cerebellar vermis, and in the other 3 patients through the cerebellopontine angle, via a lateral craniotomy. The neurosurgeons documented the use of neuronavigation in 3 of 6 cases and neuromoni- toring in 4 of 6 cases in their surgery reports. Surgery led

Extension to partial resection in 3 cases and subtotal resection in 3 cases. In 2 patients surgery was rated as not feasible by neurosurgeons, and stereotactic biopsies were performed.

Peduncle/mesencephalon Peduncle/mesencephalon None Peduncle Cerebellum/mesencephalon Peduncle/mesencephalon On postoperative MRI all patients had residual tumor. The extent was > 1.5 cm2 in 6 and not reasonably determin- able in 2 patients (Table 1). In the immediate postoperative period, neurological deficits remained almost unchanged spotting.

eview of cranial MRI studies obtained at diagnosis in 6 patients with brainstem C

Epicenter from those observed at initial presentation (Fig. 2). Cen-

Pons Pons Pons Pons/peduncle Pons Pons tral review of histology was obtained in 6 of 8 cases. The tumors were classified as CNS-PNET not otherwise speci- LE 2. R B 2 3 4 5 6 8

No. fied in 6 cases and ependymoblastoma in 2 cases. At diag- Case TA Homo = homogeneous; hyper = hyperintense; hypo = hypointense; inhomo = inhomogeneous; iso = isointense. * In case of inhomogeneous signal the predominant type is indicated. † Hypointense ‡ Isointense spotting. nosis 7 patients had no evidence of metastasis (5, complete

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images and a bright signal on T2-weighted images, but the signals were often inhomogeneous. Gadolinium was administered to all patients intravenously, showing a contrast uptake within the tumor in 4 of 6 patients (focal in 3, multifocal in 1).

Clinical Course After Surgery All patients treated with the maintenance chemotherapy protocols (n = 3) relapsed shortly after CSI (n = 1) or during subsequent maintenance chemotherapy (n = 2) (Fig. 4). Five patients were treated with up-front chemotherapy before the planned radiotherapy (Fig. 4). All 3 young children had disease progression after not more than 1 cycle of SKK chemotherapy. The 2 patients treated according to the HIT 2000 sandwich chemotherapy protocol (Fig. 1) received 2 cycles of SKK chemotherapy, followed by CSI and maintenance chemotherapy (Fig. 4). One of these patients had disease progression during maintenance chemotherapy, whereas the other patient is the only progression- free survivor of the whole study group, having a residual tumor at last follow-up 14 months since diagnosis as of this writing. The EFS for the 8 brainstem CNS-PNET patients was 2.5, 2.6, 2.8, 4.0, 6.0, 8.2, 10.4, and 13.6 months, leading to a 1-year EFS rate (± standard error) of 13% ± 12%. Ex- cluding the progression-free patient, the median time to progression was 3.9 months (range 2.5–10.4 months). The OS for all patients was 3.2, 4.1, 5.6, 6.7, 8.0, 11.3, 13.6, and 22.7 months, leading to a 1-year OS rate of 25% ± 15%. The Kaplan-Meier curves of EFS and OS are shown in Fig. 5. All treatment failures were local relapses. Two patients received further therapy in curative intention (1, chemo- Fig. 2. Neurological deficits of all brainstem CNS-PNET patients (n = therapy including high-dose chemotherapy; 1, chemother- 8) before (white) and immediately after (gray) surgery. Numbers in the apy) and 2 patients received palliative treatment (1, sur- boxes represent the individual cases of Table 1. gery; 1, surgery, chemotherapy, hyperthermia). In all cases of disease progression, the patients succumbed to their staging, M0; 1, craniospinal MRI but no CSF analysis, disease (median survival time 2.0 months, range 0.5–12.2 M0/1; 1, no spinal MRI or CSF staging), and 1 patient had months). macroscopic spinal metastases (M3) with tumor cells in the CSF (M1). Discussion This multiinstitutional prospective observational study Neuroradiological Characteristics is to our knowledge the largest report of CNS-PNET pri- Initial cranial MRI studies from 6 of 8 patients with marily localized in the brainstem. Eight children were reg- brainstem CNS-PNETs were available for review (Table istered in the consecutive, population-based HIT studies 2, Fig. 3). The principal part of all tumors was in the over a 19-year period, demonstrating the rareness of dis- pons—plus additionally in the peduncle in 1 patient. In 4 ease. The reported incidence of CNS-PNET among brain- of 6 patients, the tumors had an eccentric location within stem tumors is variable. In two series, 5 (17%) of 30 and 7 the pons. Four of the tumors were diffuse, because they (5%) of 146 children with brainstem tumors had the histo- involved more than half of the pontine axial diameter. logical diagnosis of a CNS-PNET.3–5,36 The vast majority They had sharp tumor margins against the adjacent tis- of these tumors were described as focal mass lesions. In 2 sue. The remaining 2 tumors were focal because they had of the 6 cases in which initial MRI studies were available a size of less than one-half of the pons. Their margins in our cohort, the tumors were defined as focal. The other were blurred. Fiber tracts were not preserved within the 4 tumors were diffuse, but unlike DIPG, the tumors did tumors. Only 1 tumor displayed exophytic expansion to not show a typical diffuse infiltrative appearance, did not the fourth ventricle. Encasement of the basilar artery was split fiber tracts, and had an eccentric location within the seen in 2 patients. Two other patients had a tumor cyst pons. Only patients with brainstem tumors that were re- or tumor necrosis with bleeding residues. No peritumoral sected or biopsied, offering the possibility for pathological edema was seen in any of the initial MRI studies. All 6 tu- diagnosis, were registered into this study. The diagnosis of mors showed a predominantly low signal on T1-weighted DIPG with a typical growth pattern is currently based on

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Fig. 3. A–C: Axial T2-weighted (A) and axial (B) and sagittal (C) contrast-enhanced T1-weighted MR images obtained in a 1.9-year-old male patient (Tables 1 and 2, Case 8) with ependymoblastoma showing the typical features of a brainstem CNS- PNET. The tumor is located eccentrically within the pons, encompassing more than half of the pontine axial diameter, with sharply marginated borders and strong T2 hyperintensity. D–F: Axial T2-weighted (D), contrast enhanced T1-weighted (E), and apparent diffusion coefficient (ADC) (F) MR images obtained in a 6.0-year-old female patient (Tables 1 and 2, Case 5) with atypical brainstem CNS-PNET, illustrating the diversity of these lesions. This tumor has a diffuse border, encompasses less than half of the pontine axial diameter, and is adjacent to a cyst (asterisk). On ADC images the tumor has low ADC values (restricted diffusion, pointing to higher cellularity, white arrow) compared with the cyst and CSF.

MRI, and biopsy at the time of diagnosis or autopsy is not The mean duration of symptoms until diagnosis was short mandatory. Diffuse infiltrative CNS-PNETs have been de- (5 weeks). 2) All patients had typical symptoms, consist- scribed in postmortem examinations of brainstem tumors ing of cranial nerve dysfunction, pyramidal tract signs, that were initially diagnosed as typical DIPGs based on and ataxia related to the pontine location of the tumor. A MRI examinations.1,31 Thus, it is possible that CNS-PNETs great portion of the patients even had all of the symptoms with such growth patterns are underdiagnosed and for this simultaneously. reason were not represented in our patient cohort. One of the 8 patients in our cohort had metastatic dis- The median age of our patients at diagnosis of brain- ease at diagnosis. In the series reported by Zagzag et al., 3 stem CNS-PNET was lower (3.3 years) than in patients of 7 patients presented with metastatic disease at diagno- with brainstem glioma (range 7–9 years).8,22 Combining sis.36 In supratentorial CNS-PNET, the incidence of meta- our data with those of the largest series published so far, static disease ranges from 13% to 27%.18 For that reason, a the median age at diagnosis of 25 children with brainstem complete initial staging—including craniospinal MRI and CNS-PNETs was 3.1 years (range 0.2–14.8 years).5,10,36 It lumbar CSF analysis—is strongly recommended, and the has been suggested before that brainstem CNS-PNETs de- radiotherapy should encompass the whole CSF space. In velop at a younger age than brainstem gliomas.36 However, contrast to CNS-PNET, metastatic disease at diagnosis is 5 of 25 patients were older than 7 years and in the age range very uncommon in brainstem glioma, although published that is considered typical for brainstem glioma. trials have not always required a complete craniospinal Clinical symptoms observed in our study resembled staging before inclusion of patients.7 the symptoms caused by DIPG or brainstem high-grade All but one of our patients with brainstem CNS-PNET glioma3,11 rather than those of focal low-grade glioma:3,11 1) developed early disease progression and succumbed to

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Fig. 4. Flow diagram of patients and response to therapy elements. Case numbers in italic refer to Table 1. NED = no evidence of progressive disease; PD = progressive disease. their disease. In two other studies the outcome was equally treatment modalities used first (chemotherapy or radio- fatal.5,36 Although conclusions are limited by small patient therapy) would result in better tumor control than the numbers, it seems to be more difficult to achieve tumor other. After treatment according to the Head Start I and II control in brainstem CNS-PNET patients compared with protocols using intensive chemotherapy (including high- medulloblastoma or supratentorial CNS-PNET patients. dose chemotherapy) and CSI, 2 of 6 brainstem CNS-PNET Our results do not suggest that one of the postoperative patients were alive without active disease.10 Although these results are promising, it needs to be proven with higher patient numbers, whether such an intensive treatment con- cept is superior to conventional chemotherapy regimens plus radiotherapy, as used in our patients. Most likely, the anatomical location contributes to the unfavorable prognosis of brainstem CNS-PNET. In prospective studies postoperative residual tumor was not a prognostic factor in supratentorial CNS-PNET patients. However, this could be related to the small patient numbers, because there was often a trend toward a worse outcome.18 In our cohort 6 of 8 patients received subtotal/partial resection without an increase in postoperative neurological deficits. However, the postoperative residual tumor was still > 1.5 cm2 in most cases. A complete resection of CNS-PNET is difficult to achieve in the brainstem without risking severe permanent neurological deficits. Therefore, the extent of resection remains to be determined on an individual basis. The tumor location of brainstem CNS-PNET adjacent Fig. 5. Survival of brainstem CNS-PNET patients (n = 8). Kaplan-Meier to the cerebellum raises the question whether its tumori- estimates for EFS and OS. genesis could be linked to that of medulloblastoma. Re-

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Unauthenticated | Downloaded 09/25/21 11:32 PM UTC C. Friedrich et al. cently, it has been shown in mouse models that certain base with a critical review of the literature. J Neurooncol histological subtypes of medulloblastoma can develop 104:279–286, 2011 from cells with brainstem origin.15,17 Recently, it has been 7. Benesch M, Wagner S, Berthold F, Wolff JE: Primary dis- semination of high-grade gliomas in children: experiences suggested that supratentorial CNS-PNETs constitute a het- from four studies of the Pediatric Oncology and Hematology erogeneous group of tumors that can largely be reclassified Society of the German Language Group (GPOH). J Neu- to other brain tumor types through the use of molecular- rooncol 72:179–183, 2005 genetic methods.30 However, gene expression analysis of 8. Berger MS, Edwards MS, LaMasters D, Davis RL, Wilson 2 diffuse pontine CNS-PNETs displayed a closer relation CB: Pediatric brain stem tumors: radiographic, pathological, to supratentorial CNS-PNET than to medulloblastoma.31 and clinical correlations. Neurosurgery 12:298–302, 1983 Thus, tissue banking and pooling of samples from large 9. Cohen BH, Zeltzer PM, Boyett JM, Geyer JR, Allen JC, study groups is important in order to gain more insights Finlay JL, et al: Prognostic factors and treatment results for in the biological properties allowing better classification supratentorial primitive neuroectodermal tumors in children using radiation and chemotherapy: a Childrens Cancer Group of these tumors and to identify targets for new treatments. randomized trial. J Clin Oncol 13:1687–1696, 1995 10. Fangusaro JR, Jubran RF, Allen J, Gardner S, Dunkel IJ, Conclusions Rosenblum M, et al: Brainstem primitive neuroectodermal tumors (bstPNET): results of treatment with intensive induc- Brainstem CNS-PNETs are associated with young tion chemotherapy followed by consolidative chemotherapy age, a short clinical history at initial presentation, and se- with autologous hematopoietic cell rescue. Pediatr Blood vere neurological symptoms. Focal brainstem masses in Cancer 50:715–717, 2008 patients with these clinical findings should be biopsied, 11. Farmer JP, Montes JL, Freeman CR, Meagher-Villemure K, whenever appropriate. Relapses occur mostly locally and Bond MC, O’Gorman AM: Brainstem gliomas. A 10-year very early during postoperative multimodal treatment, institutional review. Pediatr Neurosurg 34:206–214, 2001 leading to a dismal prognosis. It remains to be clarified, 12. Freeman CR, Farmer JP: Pediatric brain stem gliomas: a review. Int J Radiat Oncol Biol Phys 40:265–271, 1998 if patients can benefit from improved, intensive (high- 13. Friedrich C, von Bueren AO, von Hoff K, Gerber NU, Ot- dose) chemotherapy and craniospinal radiotherapy or new tensmeier H, Deinlein F, et al: Treatment of young children treatment strategies. Histological verification of diffuse with CNS-primitive neuroectodermal tumors/pineoblastomas pontine brainstem tumors in the setting of clinical trials in the prospective multicenter trial HIT 2000 using differ- or postmortem examination will allow for learning more ent chemotherapy regimens and radiotherapy. Neuro Oncol about the incidence of CNS-PNET among DIPGs diag- 15:224–234, 2013 nosed by MRI. Molecular-genetic analysis of tumor mate- 14. Gerber NU, von Hoff K, Friedrich C, von Bueren AO, rial may help to delineate the biological origin(s) of this Treulieb W, Benesch M, et al: Hyperfractionated craniospinal tumor entity in this special location as a first step toward a radiochemotherapy followed by maintenance chemotherapy in children older than 4 years with supratentorial central ner- more targeted therapy in the future. vous system primitive neuroectodermal tumor (stPNET) and pineoblastoma. Neuro Oncol 14:95, 2012 (Abstract) Acknowledgments 15. Gibson P, Tong Y, Robinson G, Thompson MC, Currle DS, We thank the participating centers for their valuable coop- Eden C, et al: Subtypes of medulloblastoma have distinct eration. Special thanks to Wiebke Treulieb and Christine Lindow developmental origins. Nature 468:1095–1099, 2010 (HIT data center) for their excellent data management and to 16. Gnekow AK: Recommendations of the Brain Tumor Sub- Katharina Petrasch for CSF reference assessments. committee for the reporting of trials. Med Pediatr Oncol 24:104–108, 1995 17. Grammel D, Warmuth-Metz M, von Bueren AO, Kool M, References Pietsch T, Kretzschmar HA, et al: Sonic hedgehog-associated 1. Angelini P, Hawkins C, Laperriere N, Bouffet E, Bartels U: medulloblastoma arising from the cochlear nuclei of the Post mortem examinations in diffuse intrinsic pontine glio- brainstem. Acta Neuropathol 123:601–614, 2012 ma: challenges and chances. J Neurooncol 101:75–81, 2011 18. Jakacki RI: Treatment strategies for high-risk medulloblas- 2. Barkovich AJ, Krischer J, Kun LE, Packer R, Zimmerman toma and supratentorial primitive neuroectodermal tumors. RA, Freeman CR, et al: Brain stem gliomas: a classification Review of the literature. J Neurosurg 102 (1 Suppl):44–52, system based on magnetic resonance imaging. Pediatr Neu- 2005 rosurg 16:73–83, 1990–1991 19. Kaatsch P, Rickert CH, Kühl J, Schüz J, Michaelis J: Popu- 3. Behnke J, Christen HJ, Brück W, Markakis E: Intra-axial lation-based epidemiologic data on brain tumors in German endophytic tumors in the pons and/or medulla oblongata. I. children. Cancer 92:3155–3164, 2001 Symptoms, neuroradiological findings, and histopathology in 20. Lannering B, Rutkowski S, Doz F, Pizer B, Gustafsson G, 30 children. Childs Nerv Syst 13:122–134, 1997 Navajas A, et al: Hyperfractionated versus conventional 4. Behnke J, Christen HJ, Mursch K, Markakis E: Intra-axial radiotherapy followed by chemotherapy in standard-risk me- endophytic tumors in the pons and/or medulla oblongata. II. dulloblastoma: results from the randomized multicenter HIT- Intraoperative findings, postoperative results, and 2-year fol- SIOP PNET 4 trial. J Clin Oncol 30:3187–3193, 2012 low up in 25 children. Childs Nerv Syst 13:135–146, 1997 21. Li MH, Bouffet E, Hawkins CE, Squire JA, Huang A: Mo- 5. Behnke J, Mursch K, Brück W, Christen HJ, Markakis E: lecular genetics of supratentorial primitive neuroectodermal Intra-axial endophytic primitive neuroectodermal tumors in tumors and pineoblastoma. Neurosurg Focus 19(5):E3, 2005 the pons: clinical, radiological, and immunohistochemical 22. Littman P, Jarrett P, Bilaniuk LT, Rorke LB, Zimmerman aspects in four children. Childs Nerv Syst 12:125–129, 1996 RA, Bruce DA, et al: Pediatric brain stem gliomas. Cancer 6. Benesch M, Sperl D, von Bueren AO, Schmid I, von Hoff 45:2787–2792, 1980 K, Warmuth-Metz M, et al: Primary central nervous system 23. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (eds): primitive neuroectodermal tumors (CNS-PNETs) of the spi- WHO Classification of Tumours of the Central Nervous nal cord in children: four cases from the German HIT data- System, ed 4. Lyon: IARC Press, 2007

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24. Marec-Berard P, Jouvet A, Thiesse P, Kalifa C, Doz F, Frap- ment of supratentorial primitive neuroectodermal tumors in paz D: Supratentorial embryonal tumors in children under 5 childhood: results of the prospective German brain tumor years of age: an SFOP study of treatment with postoperative trials HIT 88/89 and 91. J Clin Oncol 20:842–849, 2002 chemotherapy alone. Med Pediatr Oncol 38:83–90, 2002 33. Timmermann B, Kortmann RD, Kühl J, Rutkowski S, Meis- 25. Massimino M, Gandola L, Spreafico F, Luksch R, Collini P, ner C, Pietsch T, et al: Role of radiotherapy in supratentorial Giangaspero F, et al: Supratentorial primitive neuroectoder- primitive neuroectodermal tumor in young children: results mal tumors (S-PNET) in children: a prospective experience of the German HIT-SKK87 and HIT-SKK92 trials. J Clin with adjuvant intensive chemotherapy and hyperfractionated Oncol 24:1554–1560, 2006 accelerated radiotherapy. Int J Radiat Oncol Biol Phys 34. von Bueren AO, von Hoff K, Pietsch T, Gerber NU, War- 64:1031–1037, 2006 muth-Metz M, Deinlein F, et al: Treatment of young children 26. Pfister S, Remke M, Toedt G, Werft W, Benner A, Mendrzyk with localized medulloblastoma by chemotherapy alone: F, et al: Supratentorial primitive neuroectodermal tumors of results of the prospective, multicenter trial HIT 2000 con- the central nervous system frequently harbor deletions of the firming the prognostic impact of histology. Neuro Oncol CDKN2A locus and other genomic aberrations distinct from 13:669–679, 2011 medulloblastomas. Genes Chromosomes Cancer 46:839– 35. Warmuth-Metz M, Bison B, Leykamm S: Neuroradiologic 851, 2007 review in pediatric brain tumor studies. Klin Neuroradiol 27. Pierre-Kahn A, Hirsch JF, Vinchon M, Payan C, Sainte-Rose 19:263–273, 2009 C, Renier D, et al: Surgical management of brain-stem tu- 36. Zagzag D, Miller DC, Knopp E, Farmer JP, Lee M, Biria S, mors in children: results and statistical analysis of 75 cases. J et al: Primitive neuroectodermal tumors of the brainstem: Neurosurg 79:845–852, 1993 investigation of seven cases. Pediatrics 106:1045–1053, 2000 28. Pizer BL, Weston CL, Robinson KJ, Ellison DW, Ironside J, Saran F, et al: Analysis of patients with supratentorial primitive neuro-ectodermal tumours entered into the SIOP/ UKCCSG PNET 3 study. Eur J Cancer 42:1120–1128, 2006 29. Rutkowski S, Bode U, Deinlein F, Ottensmeier H, Warmuth- Author Contributions Metz M, Soerensen N, et al: Treatment of early childhood Conception and design: Rutkowski, Friedrich. Acquisition of medulloblastoma by postoperative chemotherapy alone. N data: Friedrich, Bison, Hoff, Pietsch. Analysis and interpretation Engl J Med 352:978–986, 2005 of data: Friedrich, Warmuth-Metz. Drafting the article: Friedrich, 30. Sturm D, Northcott P, Jones D, Korshunov A, Picard D, Lich- Warmuth-Metz. Critically revising the article: Rutkowski, ter P, et al: Molecular profiling of CNS-PNETs identifies re- Warmuth-Metz, von Bueren, Nowak, Hoff, Pietsch, Kortmann. current hallmark aberrations of various well-defined entities. Reviewed submitted version of manuscript: Rutkowski, Friedrich. Neuro Oncol 15:176, 2013 (Abstract) Statistical analysis: Friedrich. 31. Sufit A, Donson AM, Birks DK, Knipstein JA, Fenton LZ, Jedlicka P, et al: Diffuse intrinsic pontine tumors: a study of primitive neuroectodermal tumors versus the more com- Correspondence mon diffuse intrinsic pontine gliomas. J Neurosurg Pediatr Stefan Rutkowski, Department of Pediatric Hematology and 10:81–88, 2012 Oncology, University Medical Center Hamburg-Eppendorf, 32. Timmermann B, Kortmann RD, Kühl J, Meisner C, Dieck- Martinistr. 52, D-20246 Hamburg, Germany. email: mann K, Pietsch T, et al: Role of radiotherapy in the treat- [email protected].

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