ETMR-14. TREATMENT OF EMBRYONAL TUMOURS WITH MULTILAYERED ROSETTES (ETMR) WITH CARBOPLATIN-ETOPOSIDE INDUCTION AND TANDEM HIGH-DOSE CHEMOTHERAPY WITHIN THE PROSPECTIVE HIT-TRIALS AND REGISTRIES

BACKGROUND Embryonal tumours with multilayered rosettes (ETMR) are highly aggressive tumors, mostly occurring in infants. Published clinical data refer to retrospective cohorts of inhomogeneously treated patients. Here, we describe the outcome of patients, who were prospectively treated within the P-HIT2000-trial, the subsequent HIT2000-interim-registry and earlier HIT-trials. PATIENTS AND METHODS Nineteen patients from the P-HIT2000-trial (2001–2011), 12 patients from the subsequent HIT2000-interim-registry (2012–2014) and 4 patients from earlier HIT-trials with centrally reviewed neuropathological and molecularly-confirmed diagnosis of ETMR were included. Outcome of 18 patients treated with carboplatin-etoposide-induction followed by tandem-high-dose chemotherapy (“CARBO-ETO+HDCT”) with stage-stratified radiotherapy administered in case of persistant disease, relapse or progression were compared to patients treated with HIT-SKK chemotherapy ± radiotherapy (n=9) or other regimens (n=8). RESULTS Median age at diagnosis was 2.9(1.0–5.3) years. Metastases at diagnosis were detected in 9 patients (26%). For the entire cohort of n=35, 5-year overall survival (OS) was 26.7%, and progression-free survival (PFS) was 18.5%. Five-year OS for patients with CARBO-ETO+HDCT, SKK chemotherapy or other regimens was 44.4%, 13.0% and 0%, respectively (p=0.006). Five-year PFS was 33.3%, 0% and 0%, respectively (p=0.119). Of 10 survivors, n=8 were treated with CARBO-ETO+HDCT; n=4 had craniospinal, n=2 local and n=4 no radiotherapy. Impact of initial gross-total-resection (p=0.231) and non-metastatic disease (p=0.097) was limited. CONCLUSIONS We show improved survival with carboplatin-etoposide-induction followed by tandem-high-dose chemotherapy, indicating that a cure is possible for some patients. However, despite intensive treatment, outcome is unsatisfactory and innovative therapies urgently need to be included in an upfront setting.

Trends in paediatric central nervous system tumour incidence by global region from 1988 to 2012

Background Central nervous system (CNS) tumours comprise 20% of childhood cancers worldwide. Whether childhood CNS tumour incidence has increased over time across geographic regions remains to be explored. Methods We identified CNS cancers in the Cancer in Five Continents (CI5) data and estimated age standardized incidence rates (ASRs; cases/million children) and 95% confidence intervals (95% CI), male-to-female incidence rate ratios (IRR; 95% CI) and average annual percent change in incidence (AAPC; 95% CI) by geographic region for children aged 0–19 years where data were available using Poisson regression and generalized estimating equations (GEE). Cancers included: astrocytic tumours, medulloblastoma, ependymal, oligodendroglial and mixed glioma, glioma of uncertain origin, and other embryonal tumours. Geographic regions were defined using the United Nations geoscheme. Results There were 56 468 CNS cancers included in the study. ASRs were highest for astrocytic tumours globally in 2012 (ASR: 5.83; 95% CI: 5.68–5.99). Globally, all cancers exhibited a male excess in incidence. Regionally, only medulloblastoma had a consistently elevated male-to-female IRR at 1.4–2.2. Globally, incidence decreased for astrocytic tumours in GEE models (AAPC: −1.66; 95% CI: −3.04 to −0.26) and increased for medulloblastoma (AAPC 0.66; 95% CI: 0.19–1.14), ependymal tumours (AAPC: 1.49; 95% CI: 1.49; 95%: 0.69–2.30), glioma of uncertain origin (AAPC: 4.76; 95% CI: 1.17–1.14) and other embryonal tumours (AAPC: 3.58; 95% CI: 2.03–5.15). Regional variation in incidence trends was observed. Countries moving from lower to higher Human Development Index (HDI) over time did not appear to drive observed incidence trends. Conclusions Epidemiologic and molecular studies on underlying mechanisms for changes in the global incidence of CNS tumours are necessary.

Central nervous system

Chapter 6 discusses brain tumours, the commonest solid neoplasms of children and young people, which account for about one-quarter of all malignancies in this age group. There are many different varieties: medulloblastomas and other embryonal tumours, and low- and high-grade gliomas, form the commonest categories. Craniopharyngiomas, ependymomas, intracranial germ cell tumours, and other rare types are less frequently encountered. Most brain and spinal tumours are treated with a multimodality schedule comprising surgery, chemotherapy, and radiotherapy. The place of radiotherapy in the management of central nervous system tumours is described in detail.

Extracranial solid tumours

Chapter 7 discusses paediatric extracranial solid tumours. Paediatric extracranial solid tumours are very diverse. They include soft tissue and bone sarcomas, embryonal tumours such as neuroblastoma and Wilms tumour, and carcinomas. The prognosis of each type varies considerably depending on stage, tumour biology, and other factors. Careful risk stratification is necessary to determine the best approach to treatment. This is often multimodal, usually including chemotherapy and surgery, and sometimes radiotherapy. It is often possible to avoid radiotherapy in the better-prognosis risk groups, reserving this treatment, and the associated late effects, for those with the worst outlook. A strong evidence base has developed for the most common tumour types, but further clinical trials are required to optimize the role of radiotherapy.

Embryonal Tumours

Paediatric embryonal tumours are highly heterogeneous entities which account for 15–20% of all childhood tumours of the central nervous system (CNS). Although historically considered one entity, integrated genomic analysis has unveiled this is no longer the case, and in fact CNS-PNET (primitive neuroectodermal tumour) has been removed from the World Health Organization (WHO) classification of CNS tumours. Patients are risk-stratified based on residual disease after surgery, metastatic dissemination, and, with the medulloblastoma subgroup, specific molecular features. In patients with medulloblastoma, 60–70% of patients over three years old are classified as standard-risk cases, while high-risk patients include those with disseminated and/or residual disease, large-cell and/or anaplastic histotypes, and MYC gene amplification in some protocols. Atypical teratoid rhabdoid tumours (ATRTs) are risk-stratified in a similar manner; however, recently integrated genomics has revealed the presence of three distinct molecular variants which seem to have distinct clinical features and outcomes. Clinical trials already underway or currently being planned will (1) examine the feasibility of reducing the dose of craniospinal irradiation and the volume of posterior fossa radiotherapy (RT) for patients generally considered at low biological risk (i.e. those with the WNT subgroup of medulloblastomas; (2) ascertain whether intensifying chemotherapy or RT can improve outcomes in high-risk patients; and (3) seek therapeutic targets that will enable tailored therapies, especially for relapsing patients and those at higher biological risk.

Paediatric Embryonal Tumours in Multilayered Rosettes Presenting as a Low Grade Glioma- An Unusual Case Report

Paediatric Embryonal Tumours in Multilayered Rosettes (ETMR) are rare aggressive tumours with poor survival statistics, defined in 2016 by World Health Organisation (WHO) classification of brain tumours. The tumours have a characteristic radiological appearance on Magnetic Resonance Imaging (MRI) of the brain, which is easily decipherable. This combined with a clinical picture of raised intracranial pressure symptoms, seizures and rapidly progressive new onset neurological deficits make the diagnosis fairly obvious. The final confirmation of the diagnosis is done by immunohistochemical analysis of the C19Myc gene alteration. Rarely, certain radiological presentations are uncharacteristic and resemble other more benign pathologies with overlapping clinical presentations. This can be misleading, as ETMRs require aggressive surgery followed by adjuvant chemotherapy and radiation to ensure best possible survival. We present such a case report of what appeared to be a low-grade glioma in the frontal lobe. This tumour presented with one episode of generalised tonic clonic seizures not unusual as a presenting complaint in low-grade gliomas per se. Surgical debulking under ultrasonic guidance was done and the specimen was sent to histopathological analysis. The histopathological analysis showed a surprise ETMR diagnosis which was sent for confirmation to two other centers. This case report highlights the need to keep ETMRs as a rare differential diagnosis for even low-grade gliomas of the brain, thereby allowing accurate prognostication only after histopathological and immunohistochemical assessment. We present a brief literature review on unusual presentations of ETMRs reported in literature to further illustrate the chimeric nature of this rare disease.

A Cerebellar High-Grade Neuroepithelial Tumour with BCOR Alteration in a five-year-old Child: A case report

ABSTRACT: New groups of high-grade neuroepithelial tumours (HGNET) have emerged from the reclassification of central nervous system (CNS) embryonal tumours that have recognised CNS HGNET with BCOR alteration (CNS HGNET-BCOR). We report a two-year, nine-month-old Omani boy who presented to the Royal Hospital, Muscat, Oman, in 2015 with subacute head tilting and neck pain. A well-defined cerebellar lesion was found and he was treated with standard chemoradiotherapy. After a relapse at the age of five years, molecular testing revealed a BCOR alteration. He was treated with further surgery and high-dose chemotherapy; unfortunately, he relapsed and died three years after he was diagnosed.Keywords: Neuroepithelial Tumor; Glioblastoma; Human BCOR Protein; Embryonal Tumors; Case Report; Oman.

Medulloblastoma

Under the term embryonal tumours, we examine the malignant neoplasms medulloblastomas, CNS-PNETs, AT/RTs, and ETANTRs. The common histological link between them is the small, round, blue cells which appear on H&E stains. They are considered highly malignant tumours (WHO Grade IV), although significant variation of prognosis exists between the different subtypes. Current classification is based on their histopathological features. Advances on understanding of the molecular biology and behaviour of their cellular lines, has dramatically changed their stratification and scientific approach. Combination of surgical treatment with new schemes of adjuvant chemo- and radiotherapy offers improved survival rates but comes with a high cost on neurocognitive, endocrine, and overall functional status. New therapies with molecular targets will hopefully improve outcomes with minimal side effects and collateral damage.

Spinal cord compression and bone marrow suppression

Childhood cancer in adults outlines the uncommon challenge presented by the occurrence of these pathologies in young adults, and the need for shared expertise in their successful management. The embryonal tumours, medulloblastoma, retinoblastoma, neuroblastoma, and Wilms’ tumour are considered first, emphasising similarities and differences in the pathology and management of each when adults are compared with children. The soft tissue sarcoma, rhabdomyosarcoma, is frequently best managed with chemotherapy and surgery. The important role of specialist cytogenetics in all these tumours is emphasised.