Abstract
Embryonal tumor with multilayered rosettes (ETMR) is a rare, aggressive embryonal central nervous system tumor characterized by LIN28A expression and alterations in the C19MC locus. ETMRs predominantly occur in young children, have a dismal prognosis, and no definitive treatment guidelines have been established. We report on nine consecutive patients and review the role of initiation/timing of radiotherapy on survival. Between 2006 and 2018, nine patients were diagnosed with ETMR. Diagnosis was confirmed histopathologically, immunohistochemically and molecularly. Median age was 25 months (5–38). Location was supratentorial in five, pineal in three, and brainstem in one. Seven patients had a gross total resection, one a partial resection and one a biopsy at initial diagnosis. Chemotherapy augmented with intrathecal therapy started a median of 10 days (7–20) after surgery. Only two patients who after gross total resection received radiotherapy very early on (six weeks after diagnosis) are alive and in complete remission 56 and 50 months after diagnosis. All remaining patients for whom radiotherapy was deferred until the end of chemotherapy recurred, albeit none with leptomeningeal disease. A literature research identified 228 patients with ETMR. Including our patients only 26 (11%) of 237 patients survived >36 months with no evidence of disease at last follow-up. All but two long-term (>36 months) survivors received radiotherapy, ten of whom early on following gross total resection (GTR). GTR followed by early focal radiotherapy and intrathecal therapy to prevent leptomeningeal disease are potentially important to improve survival of ETMR in the absence of effective targeted therapies.
Highlights
Embryonal tumors with multilayered rosettes (ETMR) are rare and highly aggressive embryonal brain tumors primarily affecting infants and young children under the age of four years
Reassessment of all highly malignant embryonal brain tumors formerly classified as ETANTR, medulloepithelioma, ependymoblastoma, or central nervous system (CNS) Primitive neuroectodermal tumor (PNET) with regard to LIN28A expression and amplification of the C19MC microRNA cluster disclosed nine patients treated at the Medical University of Vienna (MUV) since 2006
Because of the median age of 37 months at presentation treatment typically consists of surgery followed by chemotherapy and delayed or no radiotherapy
Summary
Embryonal tumors with multilayered rosettes (ETMR) are rare and highly aggressive embryonal brain tumors primarily affecting infants and young children under the age of four years. Broad bands of well-differentiated neuropil islands, ependymoblastic rosettes, or medulloepitheliomatous rosettes may be present [3] They are typically characterized by a focal amplification spanning the C19MC microRNA cluster at 19q13.42 and high expression of the stem cell marker LIN28A [4]. Due to Abbreviations: ETMR, Embryonal tumors with multilayered rosettes; ETANTR, Embryonal tumor with abundant neuropil and true rosettes; CNS, Central nervous system; PNET, Primitive neuroectodermal tumor; WHO, World Health Organisation; NOS, Not otherwise specified; HDCT, High dose chemotherapy; MUV, Medical University of Vienna; GTR, Gross total resection; STR, Subtotal resection; PR, Partial resection; RANO, Response assessment in neuro-oncology; IHC, Immunohistochemical; iFISH, Interphase fluorescence in situ hybridization; FFPE, Formalin-fixed paraffin-embedded tissue; ATRT, Atypical teratoid rhabdoid tumor; IP-CZD, Polish infant protocol; Depocyte, Liposomal cytarabine; 3D, Three dimensional; GTV, Gross tumor volume; CTV, Clinical target volume; PTV, Planning target volume; VMAT, Volume mediated radiotherapy; MEMMAT, (MEMMAT;ClinicalTrials.gov Identifier: NCT01356290); BID, Bis in die (two times per day); PNET-HR protocol, Primitive neuroectodermal tumor high-risk protocol; HRQoL, Healthrelated quality of life; MRI, Magnetic resonance imaging; CNV, Copy number variations; OS, Overall survival; CSI, Craniospinal irradiation; SNV, Single nucleotide variants; TOP1, Topoisomerase 1; PARP, Poly (ADPribose) polymerase
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