Embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma, and medulloepithelioma share molecular similarity and comprise a single clinicopathological entity

Andrey Korshunov, Dominik Sturm, Marina Ryzhova, Volker Hovestadt, Marco Gessi, David T W Jones, Marc Remke, Paul Northcott, Arie Perry, Daniel Picard, Marc Rosenblum, Manila Antonelli, Eleonora Aronica, Ulrich Schüller, Martin Hasselblatt, Adelheid Woehrer, Olga Zheludkova, Ella Kumirova, Stephanie Puget, Michael D Taylor, Felice Giangaspero, V Peter Collins, Andreas von Deimling, Peter Lichter, Annie Huang, Torsten Pietsch, Stefan M Pfister, Marcel Kool, Andrey Korshunov, Dominik Sturm, Marina Ryzhova, Volker Hovestadt, Marco Gessi, David T W Jones, Marc Remke, Paul Northcott, Arie Perry, Daniel Picard, Marc Rosenblum, Manila Antonelli, Eleonora Aronica, Ulrich Schüller, Martin Hasselblatt, Adelheid Woehrer, Olga Zheludkova, Ella Kumirova, Stephanie Puget, Michael D Taylor, Felice Giangaspero, V Peter Collins, Andreas von Deimling, Peter Lichter, Annie Huang, Torsten Pietsch, Stefan M Pfister, Marcel Kool

Abstract

Three histological variants are known within the family of embryonal rosette-forming neuroepithelial brain tumors. These include embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma (EBL), and medulloepithelioma (MEPL). In this study, we performed a comprehensive clinical, pathological, and molecular analysis of 97 cases of these rare brain neoplasms, including genome-wide DNA methylation and copy number profiling of 41 tumors. We identified uniform molecular signatures in all tumors irrespective of histological patterns, indicating that ETANTR, EBL, and MEPL comprise a single biological entity. As such, future WHO classification schemes should consider lumping these variants into a single diagnostic category, such as embryonal tumor with multilayered rosettes (ETMR). We recommend combined LIN28A immunohistochemistry and FISH analysis of the 19q13.42 locus for molecular diagnosis of this tumor category. Recognition of this distinct pediatric brain tumor entity based on the fact that the three histological variants are molecularly and clinically uniform will help to distinguish ETMR from other embryonal CNS tumors and to better understand the biology of these highly aggressive and therapy-resistant pediatric CNS malignancies, possibly leading to alternate treatment strategies.

Figures

Fig. 1
Fig. 1
Microscopical appearance (a, d, g), FISH analysis of the 19q13.42 locus (b, e, h), LIN28A immunohistochemistry (c, f, i) of ETANTR (a–c), EBL (d–f) and MEPL (g–i). Amplification of 19q13.42 (b, e, h) and LIN28A immunoexpression (c, f, i) was detected in all three histological ETMR subtypes. For the FISH analysis the C19MC 19q13.42 probe (green signals) and a reference 19p13 probe were used (red signals)
Fig. 2
Fig. 2
Two examples of primary ETANTR (a, c) with further tumor transformation in either EBL (b) or MEPL (d) histology as it has been identified during analysis of the recurrence samples
Fig. 3
Fig. 3
Overall survival curves generated for ETANTR (32 cases, blue), EBL (17 cases, red), and MEPL (6 cases, green). No differences in survival time were found (log-rank, p = 0.63)
Fig. 4
Fig. 4
Cluster analyses of DNA methylation profiles of ETMR alone and compared to various other pediatric brain tumors and normal cerebellum. a Unsupervised cluster analysis of ETMR samples only shows that DNA methylation profiles of the histological variants ETANTR, EBL and MEPL are not distinct. Also, clusters outlined do not differ in terms of clinical findings, including age, gender, tumor location and outcome. b DNA methylation profiles of ETMRs are distinct from other pediatric brain tumors and normal cerebellum
Fig. 5
Fig. 5
Copy number plots generated from 450 k methylation data. Amplifications and gains are indicated in green, losses in red. a Example of an ETANTR showing amplification 19q13.42, gain of 2 and loss of 19q13.3. b Example of an EBL showing amplification 19q13.42, gain of 2, and losses of 6q and 17p. c Example of a MEPL showing amplification 19q13.42, trisomy of 2, 17 and 19. d Summarizing profiles for all 41 cases analyzed

References

    1. Adamek D, Sofowora KD, Cwiklinska M, Herman-Sucharska I, Kwiatkowski S. Embryonal tumor with abundant neuropil and true rosettes: an autopsy case-based update and review of the literature. Child Nerv Syst. 2013;29(5):849–854. doi: 10.1007/s00381-013-2037-4.
    1. Al-Hussaini M, Abuirmeileh N, Swaidan M, Al-Jumaily U, Rajjal H, Musharbash A, Hashem S, Sultan I. Embryonal tumor with abundant neuropil and true rosettes: a report of three cases of a rare tumor, with an unusual case showing rhabdomyoblastic and melanocytic differentiation. Neuropathology. 2011;31(6):620–625. doi: 10.1111/j.1440-1789.2011.01213.x.
    1. Behdad A, Perry A. Central nervous system primitive neuroectodermal tumors: a clinicopathologic and genetic study of 33 cases. Brain Pathol. 2010;20(2):441–450. doi: 10.1111/j.1750-3639.2009.00314.x.
    1. Buccoliero AM, Castiglione F, Rossi Degl’Innocenti D, Franchi A, Paglierani M, Sanzo M, Cetica V, Giunti L, Sardi I, Genitori L, Taddei GL. Embryonal tumor with abundant neuropil and true rosettes: morphological, immunohistochemical, ultrastructural and molecular study of a case showing features of medulloepithelioma and areas of mesenchymal and epithelial differentiation. Neuropathology. 2010;30(1):84–91. doi: 10.1111/j.1440-1789.2009.01040.x.
    1. Ceccom J, Bourdeaut F, Loukh N, Rigau V, Milin S, Takin R, Richer W, Uro-Coste E, Couturier J, Bertozzi AI, Delattre O, Delisle MB (2013) Embryonal tumor with multilayered rosettes: diagnostic tools update and review of the literature. Clin Neuropathol (Epub ahead of print)
    1. Eberhart CG, Brat DJ, Cohen KJ, Burger PC. Pediatric neuroblastic brain tumors containing abundant neuropil and true rosettes. Pediatr Dev Pathol. 2000;3(4):346–352. doi: 10.1007/s100249910049.
    1. Fan X, Wang Y, Kratz J, Brat DJ, Robitaille Y, Moghrabi A, Perlman EJ, Dang CV, Burger PC, Eberhart CG. hTERT gene amplification and increased mRNA expression in central nervous system embryonal tumors. Am J Pathol. 2003;162(6):1763–1769. doi: 10.1016/S0002-9440(10)64311-8.
    1. Ferri Niguez B, Martínez-Lage JF, Almagro MJ, Fuster JL, Serrano C, Torroba MA, Sola J. Embryonal tumor with abundant neuropil and true rosettes (ETANTR): a new distinctive variety of pediatric PNET: a case-based update. Childs Nerv Syst. 2010;26(8):1003–1008. doi: 10.1007/s00381-010-1179-x.
    1. Friedrich C, von Bueren AO, von Hoff K, Gerber NU, Ottensmeier H, Deinlein F, Benesch M, Kwiecien R, Pietsch T, Warmuth-Metz M, Faldum A, Kuehl J, Kortmann RD, Rutkowski S. Treatment of young children with CNS-primitive neuroectodermal tumors/pineoblastomas in the prospective multicenter trial HIT 2000 using different chemotherapy regimens and radiotherapy. Neuro Oncol. 2013;15(2):224–234. doi: 10.1093/neuonc/nos292.
    1. Fuller C, Fouladi M, Gajjar A, Dalton J, Sanford RA, Helton KJ. Chromosome 17 abnormalities in pediatric neuroblastic tumor with abundant neuropil and true rosettes. Am J Clin Pathol. 2006;126(2):277–283. doi: 10.1309/TFBX1LWQ93MXQBAW.
    1. Gessi M, Giangaspero F, Lauriola L, Gardiman M, Scheithauer BW, Halliday W, Hawkins C, Rosenblum MK, Burger PC, Eberhart CG. Embryonal tumors with abundant neuropil and true rosettes: a distinctive CNS primitive neuroectodermal tumor. Am J Surg Pathol. 2009;33(2):211–217. doi: 10.1097/PAS.0b013e318186235b.
    1. Gessi M, Zur Muehlen A, Lauriola L, Gardiman MP, Giangaspero F, Pietsch T. TP53, β-Catenin and c-myc/N-myc status in embryonal tumours with ependymoblastic rosettes. Neuropathol Appl Neurobiol. 2011;37(4):406–413. doi: 10.1111/j.1365-2990.2010.01151.x.
    1. Hovestadt V, Remke M, Kool M, Pietsch T, Northcott PA, Fischer R, Cavalli FM, Ramaswamy V, Zapatka M, Reifenberger G, Rutkowski S, Schick M, Bewerunge-Hudler M, Korshunov A, Lichter P, Taylor MD, Pfister SM, Jones DT. Robust molecular subgrouping and copy-number profiling of medulloblastoma from small amounts of archival tumour material using high-density DNA methylation arrays. Acta Neuropathol. 2013;125(6):913–916. doi: 10.1007/s00401-013-1126-5.
    1. Judkins AR, Ellison DW. Ependymoblastoma: dear, damned, distracting diagnosis, farewell! Brain Pathol. 2010;120(1):133–139. doi: 10.1111/j.1750-3639.2008.00253.x.
    1. Korshunov A, Remke M, Gessi M, Ryzhova M, Hielscher T, Witt H, Tobias V, Buccoliero AM, Sardi I, Gardiman MP, Bonnin J, Scheithauer B, Kulozik AE, Witt O, Mork S, von Deimling A, Wiestler OD, Giangaspero F, Rosenblum M, Pietsch T, Lichter P, Pfister SM. Focal genomic amplification at 19q13.42 comprises a powerful diagnostic marker for embryonal tumors with ependymoblastic rosettes. Acta Neuropathol. 2010;120(2):253–260. doi: 10.1007/s00401-010-0688-8.
    1. Korshunov A, Ryzhova M, Jones DT, Northcott PA, van Sluis P, Volckmann R, Koster J, Versteeg R, Cowdrey C, Perry A, Picard D, Rosenblum M, Giangaspero F, Aronica E, Schüller U, Hasselblatt M, Collins VP, von Deimling A, Lichter P, Huang A, Pfister SM, Kool M. LIN28A immunoreactivity is a potent diagnostic marker of embryonal tumor with multilayered rosettes (ETMR) Acta Neuropathol. 2012;124(6):875–881. doi: 10.1007/s00401-012-1068-3.
    1. Li M, Lee KF, Lu Y, Clarke I, Shih D, Eberhart C, Collins VP, Van Meter T, Picard D, Zhou L, Boutros PC, Modena P, Liang ML, Scherer SW, Bouffet E, Rutka JT, Pomeroy SL, Lau CC, Taylor MD, Gajjar A, Dirks PB, Hawkins CE, Huang A. Frequent amplification of a chr19q13.41 microRNA polycistron in aggressive primitive neuroectodermal brain tumors. Cancer Cell. 2009;16(6):533–546. doi: 10.1016/j.ccr.2009.10.025.
    1. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. WHO classification of tumors of the central nervous system. Lyon: IARC press; 2007.
    1. Manjila S, Ray A, Hu Y, Cai DX, Cohen ML, Cohen AR. Embryonal tumors with abundant neuropil and true rosettes: 2 illustrative cases and a review of the literature. Neurosurg Focus. 2011;30(1):E2. doi: 10.3171/2010.10.FOCUS10226.
    1. Northcott PA, Jones DT, Kool M, Robinson GW, Gilbertson RJ, Cho YJ, Pomeroy SL, Korshunov A, Lichter P, Taylor MD, Pfister SM. Medulloblastomics: the end of the beginning. Nat Rev Cancer. 2012;12(12):818–834. doi: 10.1038/nrc3410.
    1. Nobusawa S, Yokoo H, Hirato J, Kakita A, Takahashi H, Sugino T, Tasaki K, Itoh H, Hatori T, Shimoyama Y, Nakazawa A, Nishizawa S, Kishimoto H, Matsuoka K, Nakayama M, Okura N, Nakazato Y. Analysis of chromosome 19q13.42 amplification in embryonal brain tumors with ependymoblastic multilayered rosettes. Brain Pathol. 2012;22(5):689–697. doi: 10.1111/j.1750-3639.2012.00574.x.
    1. Paulus W, Kleihues P. Genetic profiling of CNS tumors extends histological classification. Acta Neuropathol. 2010;120(2):269–270. doi: 10.1007/s00401-010-0710-1.
    1. Picard D, Miller S, Hawkins CE, Bouffet E, Rogers HA, Chan TS, Kim SK, Ra YS, Fangusaro J, Korshunov A, Toledano H, Nakamura H, Hayden JT, Chan J, Lafay-Cousin L, Hu P, Fan X, Muraszko KM, Pomeroy SL, Lau CC, Ng HK, Jones C, Van Meter T, Clifford SC, Eberhart C, Gajjar A, Pfister SM, Grundy RG, Huang A. Markers of survival and metastatic potential in childhood CNS primitive neuro-ectodermal brain tumours: an integrative genomic analysis. Lancet Oncol. 2012;13(8):838–848. doi: 10.1016/S1470-2045(12)70257-7.
    1. Pfister S, Remke M, Castoldi M, Bai AH, Muckenthaler MU, Kulozik A, von Deimling A, Pscherer A, Lichter P, Korshunov A. Novel genomic amplification targeting the microRNA cluster at 19q13.42 in a pediatric embryonal tumor with abundant neuropil and true rosettes. Acta Neuropathol. 2009;117(4):457–464. doi: 10.1007/s00401-008-0467-y.
    1. Rickert CH, Hasselblatt M. Cytogenetic features of ependymoblastomas. Acta Neuropathol. 2006;111(6):559–562. doi: 10.1007/s00401-006-0074-8.
    1. Sturm D, Witt H, Hovestadt V, Khuong-Quang DA, Jones DT, Konermann C, Pfaff E, Tönjes M, Sill M, Bender S, Kool M, Zapatka M, Becker N, Zucknick M, Hielscher T, Liu XY, Fontebasso AM, Ryzhova M, Albrecht S, Jacob K, Wolter M, Ebinger M, Schuhmann MU, van Meter T, Frühwald MC, Hauch H, Pekrun A, Radlwimmer B, Niehues T, von Komorowski G, Dürken M, Kulozik AE, Madden J, Donson A, Foreman NK, Drissi R, Fouladi M, Scheurlen W, von Deimling A, Monoranu C, Roggendorf W, Herold-Mende C, Unterberg A, Kramm CM, Felsberg J, Hartmann C, Wiestler B, Wick W, Milde T, Witt O, Lindroth AM, Schwartzentruber J, Faury D, Fleming A, Zakrzewska M, Liberski PP, Zakrzewski K, Hauser P, Garami M, Klekner A, Bognar L, Morrissy S, Cavalli F, Taylor MD, van Sluis P, Koster J, Versteeg R, Volckmann R, Mikkelsen T, Aldape K, Reifenberger G, Collins VP, Majewski J, Korshunov A, Lichter P, Plass C, Jabado N, Pfister SM. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell. 2013;22(4):425–437. doi: 10.1016/j.ccr.2012.08.024.
    1. Wang Y, Chu SG, Xiong J, Cheng HX, Chen H, Yao XH. Embryonal tumor with abundant neuropil and true rosettes (ETANTR) with a focal amplification at chromosome 19q13.42 locus: further evidence of two new instances in China. Neuropathology. 2011;31(6):639–647. doi: 10.1111/j.1440-1789.2011.01215.x.
    1. Woehrer A, Slavc I, Peyrl A, Czech T, Dorfer C, Prayer D, Stary S, Streubel B, Ryzhova M, Korshunov A, Pfister SM, Haberler C. Embryonal tumor with abundant neuropil and true rosettes (ETANTR) with loss of morphological but retained genetic key features during progression. Acta Neuropathol. 2011;122(6):787–790. doi: 10.1007/s00401-011-0903-2.

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