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Desmoplastic myxoid tumor, SMARCB1-mutant: clinical, histopathological and molecular characterization of a pineal region tumor encountered in adolescents and adults

  • Christian Thomas
  • Annika Wefers
  • Susanne Bens
  • Karolina Nemes
  • Abbas Agaimy
  • Florian Oyen
  • Silke Vogelgesang
  • Fausto J. Rodriguez
  • Francesca M. Brett
  • Roger McLendon
  • Istvan Bodi
  • Fanny Burel-Vandenbos
  • Kathy Keyvani
  • Stefan Tippelt
  • Frantz R. Poulsen
  • Eric S. Lipp
  • Caterina Giannini
  • Guido Reifenberger
  • Klaus Kuchelmeister
  • Torsten Pietsch
  • Uwe Kordes
  • Reiner Siebert
  • Michael C. Frühwald
  • Pascal D. Johann
  • Martin Sill
  • Marcel Kool
  • Andreas von Deimling
  • Werner Paulus
  • Martin HasselblattEmail author
Original Paper

Abstract

Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly occurring in infants. Mutations of the SMARCB1 gene are the characteristic genetic lesion. SMARCB1-mutant tumors in adolescents and adults are rare and may show uncommon histopathological and clinical features. Here we report seven SMARCB1-deficient intracranial tumors sharing distinct clinical, histopathological and molecular features. Median age of the four females and three males was 40 years (range 15–61 years). All tumors were located in the pineal region. Histopathologically, these tumors displayed spindled and epithelioid cells embedded in a desmoplastic stroma alternating with a variable extent of a loose myxoid matrix. All cases showed loss of nuclear SMARCB1/INI1 protein expression, expression of EMA and CD34 was frequent and the Ki67/MIB1 proliferation index was low in the majority of cases (median 3%). Three cases displayed heterozygous SMARCB1 deletions and two cases a homozygous SMARCB1 deletion. On sequencing, one tumor showed a 2 bp deletion in exon 4 (c.369_370del) and one a short duplication in exon 3 (c.237_276dup) both resulting in frameshift mutations. Most DNA methylation profiles were not classifiable using the Heidelberg Brain Tumor Classifier (version v11b4). By unsupervised t-SNE analysis and hierarchical clustering analysis, however, all tumors grouped closely together and showed similarities with ATRT-MYC. After a median observation period of 48 months, three patients were alive with stable disease, whereas one patient experienced tumor progression and three patients had succumbed to disease. In conclusion, our series represents an entity with distinct clinical, histopathological and molecular features showing epigenetic similarities with ATRT-MYC. We propose the designation desmoplastic myxoid tumor (DMT), SMARCB1-mutant, for these tumors.

Notes

Acknowledgements

We thank patients and their families for their support of the study. MH and CT are supported by DFG (HA 3060/8-1 and TH 2345/1-1).

Supplementary material

401_2019_2094_MOESM1_ESM.docx (21 kb)
Supplementary file1 (DOCX 20 kb)
401_2019_2094_MOESM2_ESM.pdf (5.1 mb)
Supplementary file2 (PDF 5202 kb)
401_2019_2094_MOESM3_ESM.pdf (139 kb)
Supplementary file3 (PDF 139 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Christian Thomas
    • 1
  • Annika Wefers
    • 2
    • 3
  • Susanne Bens
    • 4
  • Karolina Nemes
    • 5
  • Abbas Agaimy
    • 6
  • Florian Oyen
    • 7
  • Silke Vogelgesang
    • 8
  • Fausto J. Rodriguez
    • 9
  • Francesca M. Brett
    • 10
  • Roger McLendon
    • 11
  • Istvan Bodi
    • 12
  • Fanny Burel-Vandenbos
    • 13
  • Kathy Keyvani
    • 14
  • Stefan Tippelt
    • 15
  • Frantz R. Poulsen
    • 16
  • Eric S. Lipp
    • 17
  • Caterina Giannini
    • 18
  • Guido Reifenberger
    • 19
    • 20
  • Klaus Kuchelmeister
    • 21
  • Torsten Pietsch
    • 21
  • Uwe Kordes
    • 7
  • Reiner Siebert
    • 4
  • Michael C. Frühwald
    • 5
  • Pascal D. Johann
    • 22
    • 23
  • Martin Sill
    • 22
    • 23
  • Marcel Kool
    • 22
    • 23
  • Andreas von Deimling
    • 2
    • 3
  • Werner Paulus
    • 1
  • Martin Hasselblatt
    • 1
    Email author
  1. 1.Institute of NeuropathologyUniversity Hospital MünsterMünsterGermany
  2. 2.Clinical Cooperation Unit NeuropathologyGerman Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)HeidelbergGermany
  3. 3.Department of Neuropathology, Institute of PathologyUniversity Hospital HeidelbergHeidelbergGermany
  4. 4.Institute of Human GeneticsUniversity of Ulm and Ulm University HospitalUlmGermany
  5. 5.Swabian Childrens’ Cancer CenterUniversity Childrens’ Hospital Augsburg and EU-RHAB RegistryAugsburgGermany
  6. 6.Institute of PathologyUniversity of ErlangenErlangenGermany
  7. 7.Department of Pediatric Hematology and OncologyUniversity Medical Center Hamburg-EppendorfHamburgGermany
  8. 8.Institute of Pathology, Department of NeuropathologyUniversity Medicine GreifswaldGreifswaldGermany
  9. 9.Department of PathologyJohns HopkinsBaltimoreUSA
  10. 10.Department of NeuropathologyBeaumont HospitalDublinIreland
  11. 11.Department of PathologyDuke UniversityDurhamUSA
  12. 12.Department of Clinical NeuropathologyKing’s College Hospital NHS Foundation TrustLondonUK
  13. 13.Central Laboratory of PathologyNice University Hospital, Hôpital PasteurNiceFrance
  14. 14.Institute of NeuropathologyUniversity of Duisburg-EssenEssenGermany
  15. 15.Department of Pediatric Oncology and Hematology, Pediatrics IIIUniversity Hospital EssenEssenGermany
  16. 16.Department of NeurosurgeryOdense University HospitalOdenseDenmark
  17. 17.Preston Robert Tisch Brain Tumor CenterDuke UniversityDurhamUSA
  18. 18.Department of Laboratory Medicine and PathologyMayo ClinicRochesterUSA
  19. 19.Department of NeuropathologyHeinrich Heine UniversityDüsseldorfGermany
  20. 20.German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, German Cancer Research Center (DKFZ)DüsseldorfGermany
  21. 21.Institute of Neuropathology and DGNN Brain Tumor Reference CentreUniversity of BonnBonnGermany
  22. 22.Hopp-Children’s Cancer Center (KiTZ)HeidelbergGermany
  23. 23.Division of Pediatric NeurooncologyGerman Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)HeidelbergGermany

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