Meningeal hemangiopericytoma and solitary fibrous tumors carry the NAB2-STAT6 fusion and can be diagnosed by nuclear expression of STAT6 protein

Abstract

Non-central nervous system hemangiopericytoma (HPC) and solitary fibrous tumor (SFT) are considered by pathologists as two variants of a single tumor entity now subsumed under the entity SFT. Recent detection of frequent NAB2-STAT6 fusions in both, HPC and SFT, provided additional support for this view. On the other hand, current neuropathological practice still distinguishes between HPC and SFT. The present study set out to identify genes involved in the formation of meningeal HPC. We performed exome sequencing and detected the NAB2-STAT6 fusion in DNA of 8/10 meningeal HPC thereby providing evidence of close relationship of these tumors with peripheral SFT. Due to the considerable effort required for exome sequencing, we sought to explore surrogate markers for the NAB2-STAT6 fusion protein. We adopted the Duolink proximity ligation assay and demonstrated the presence of NAB2-STAT6 fusion protein in 17/17 HPC and the absence in 15/15 meningiomas. More practical, presence of the NAB2-STAT6 fusion protein resulted in a strong nuclear signal in STAT6 immunohistochemistry. The nuclear reallocation of STAT6 was detected in 35/37 meningeal HPC and 25/25 meningeal SFT but not in 87 meningiomas representing the most important differential diagnosis. Tissues not harboring the NAB2-STAT6 fusion protein presented with nuclear expression of NAB2 and cytoplasmic expression of STAT6 proteins. In conclusion, we provide strong evidence for meningeal HPC and SFT to constitute variants of a single entity which is defined by NAB2-STAT6 fusion. In addition, we demonstrate that this fusion can be rapidly detected by STAT6 immunohistochemistry which shows a consistent nuclear reallocation. This immunohistochemical assay may prove valuable for the differentiation of HPC and SFT from other mesenchymal neoplasms.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ (1990) Basic local alignment search tool. J Mol Biol 215:403–410

    PubMed  CAS  Google Scholar 

  2. 2.

    Bouvier C, Metellus P, de Paula AM, Vasiljevic A, Jouvet A, Guyotat J, Mokhtari K, Varlet P, Dufour H, Figarella-Branger D (2012) Solitary fibrous tumors and hemangiopericytomas of the meninges: overlapping pathological features and common prognostic factors suggest the same spectrum of tumors. Brain Pathol 22:511–521

    PubMed  Article  Google Scholar 

  3. 3.

    Chmielecki J, Crago AM, Rosenberg M, O’Connor R, Walker SR, Ambrogio L, Auclair D, McKenna A, Heinrich MC, Frank DA, Meyerson M (2013) Whole-exome sequencing identifies a recurrent NAB2-STAT6 fusion in solitary fibrous tumors. Nat Genet 45:131–132

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Fletcher C, Bridge J, Hogendoorn P, Mertens F (2013) WHO classification of tumours of soft tissue and bone. IARC Press, Lyon

  5. 5.

    Fredriksson S, Gullberg M, Jarvius J, Olsson C, Pietras K, Gustafsdottir SM, Ostman A, Landegren U (2002) Protein detection using proximity-dependent DNA ligation assays. Nat Biotechnol 20:473–477

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Hasegawa T, Matsuno Y, Shimoda T, Hasegawa F, Sano T, Hirohashi S (1999) Extrathoracic solitary fibrous tumors: their histological variability and potentially aggressive behavior. Hum Pathol 30:1464–1473

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Henn W, Wullich B, Thonnes M, Steudel WI, Feiden W, Zang KD (1993) Recurrent t(12;19)(q13;q13.3) in intracranial and extracranial hemangiopericytoma. Cancer Genet Cytogenet 71:151–154

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Herath SE, Stalboerger PG, Dahl RJ, Parisi JE, Jenkins RB (1994) Cytogenetic studies of four hemangiopericytomas. Cancer Genet Cytogenet 72:137–140

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Insabato L, Siano M, Somma A, Gentile R, Santangelo M, Pettinato G (2009) Extrapleural solitary fibrous tumor: a clinicopathologic study of 19 cases. Int J Surg Pathol 17:250–254

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Jones D, Jäger N, Kool M, Zichner T, Hutter B, Sultan M, Cho Y-J, Pugh T, Hovestadt V, Stütz A, Rausch T, Warnatz H-J, Ryzhova M, Bender S, Sturm D, Pleier S, Cin H, Pfaff E, Sieber L, Wittmann A, Remke M, Witt H, Hutter S, Tzaridis T, Weischenfeldt J, Raeder B, Avci M, Amstislavskiy V, Zapatka M, Weber U, Wang Q, Lasitschka B, Bartholomae C, Schmidt M, von Kalle C, Ast V, Lawerenz C, Eils J, Kabbe R, Benes V, van Sluis P, Koster J, Volckmann R, Shih D, Betts M, Russell R, Coco S, Tonini G, Schüller U, Hans V, Graf N, Kim Y-J, Monoranu C, Roggendorf W, Unterberg A, Herold-Mende C, Milde T, Kulozik A, von Deimling A, Witt O, Maass E, Rössler J, Ebinger M, Schuhmann M, Frühwald M, Hasselblatt M, Jabado N, Rutkowski S, von Bueren A, Williamson D, Clifford S, McCabe M, Collins V, Wolf S, Wiemann S, Lehrach H, Brors B, Scheurlen W, Felsberg J, Reifenberger G, Northcott P, Taylor M, Meyerson M, Pomeroy S, Yaspo M-L, Korbel J, Korshunov A, Eils R, Pfister S, Lichter P (2012) Dissecting the genomic complexity underlying medulloblastoma. Nature 488:100–105

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Kleihues P, Cavenee WK (2000) Pathology and genetics of tumours of the nervous system. IARC Press, Lyon

  12. 12.

    Kumbrink J, Kirsch KH, Johnson JP (2010) EGR1, EGR2, and EGR3 activate the expression of their coregulator NAB2 establishing a negative feedback loop in cells of neuroectodermal and epithelial origin. J Cell Biochem 111:207–217

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Louis D, Ohgaki H, Wiestler O, Cavenee W (2007) World Health Organization Classification of tumours of the central nervous system. In: Bosman F, Jaffe E, Lakhani S, Ohgaki H (eds) World Health Organization Classification of tumours, 4th edn. IARC Press, Lyon

  14. 14.

    Mandahl N, Orndal C, Heim S, Willen H, Rydholm A, Bauer HC, Mitelman F (1993) Aberrations of chromosome segment 12q13-15 characterize a subgroup of hemangiopericytomas. Cancer 71:3009–3013

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Mena H, Ribas JL, Pezeshkpour GH, Cowan DN, Parisi JE (1991) Hemangiopericytoma of the central nervous system: a review of 94 cases. Hum Pathol 22:84–91

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Mullings RE, Wilson SJ, Puddicombe SM, Lordan JL, Bucchieri F, Djukanovic R, Howarth PH, Harper S, Holgate ST, Davies DE (2001) Signal transducer and activator of transcription 6 (STAT-6) expression and function in asthmatic bronchial epithelium. J Allergy Clin Immunol 108:832–838

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Nishio H, Matsui K, Tsuji H, Tamura A, Suzuki K (2001) Immunolocalisation of the Janus kinases (JAK)–signal transducers and activators of transcription (STAT) pathway in human epidermis. J Anat 198:581–589

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Perry A, Scheithauer BW, Nascimento AG (1997) The immunophenotypic spectrum of meningeal hemangiopericytoma: a comparison with fibrous meningioma and solitary fibrous tumor of meninges. Am J Surg Pathol 21:1354–1360

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Rajaram V, Brat DJ, Perry A (2004) Anaplastic meningioma versus meningeal hemangiopericytoma: immunohistochemical and genetic markers. Hum Pathol 35:1413–1418

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Reuss D, Piro R, Jones D, Simon M, Ketter R, Kool M, Becker A, Sahm F, Pusch S, Meyer J, Hagenlocher C, Schweizer L, Capper D, Kickingereder P, Mucha J, Koelsche C, Jäger N, Santarius T, Tarpey P, Stephens P, Futreal P, Wellenreuther R, Kraus J, Lenartz D, Herold-Mende C, Hartmann C, Mawrin C, Giese N, Eils R, Collins V, König R, Wiestler O, Pfister S, von Deimling A (2013) Secretory meningiomas are defined by combined KLF4 K409Q and TRAF7 mutations. Acta Neuropathol 125:351–358

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    Robinson DR, Wu YM, Kalyana-Sundaram S, Cao X, Lonigro RJ, Sung YS, Chen CL, Zhang L, Wang R, Su F, Iyer MK, Roychowdhury S, Siddiqui J, Pienta KJ, Kunju LP, Talpaz M, Mosquera JM, Singer S, Schuetze SM, Antonescu CR, Chinnaiyan AM (2013) Identification of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing. Nat Genet 45:180–185

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Scheithauer BW, Fuller GN, VandenBerg SR (2008) The 2007 WHO classification of tumors of the nervous system: controversies in surgical neuropathology. Brain Pathol 18:307–316

    PubMed  Article  Google Scholar 

  23. 23.

    Soderberg O, Gullberg M, Jarvius M, Ridderstrale K, Leuchowius KJ, Jarvius J, Wester K, Hydbring P, Bahram F, Larsson LG, Landegren U (2006) Direct observation of individual endogenous protein complexes in situ by proximity ligation. Nat Methods 3:995–1000

    PubMed  Article  Google Scholar 

  24. 24.

    Svaren J, Apel ED, Simburger KS, Jenkins NA, Gilbert DJ, Copeland NA, Milbrandt J (1997) The Nab2 and Stat6 genes share a common transcription termination region. Genomics 41:33–39

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Svaren J, Sevetson BR, Apel ED, Zimonjic DB, Popescu NC, Milbrandt J (1996) NAB2, a corepressor of NGFI-A (Egr-1) and Krox20, is induced by proliferative and differentiative stimuli. Mol Cell Biol 16:3545–3553

    PubMed  CAS  Google Scholar 

  26. 26.

    Tihan T, Viglione M, Rosenblum MK, Olivi A, Burger PC (2003) Solitary fibrous tumors in the central nervous system. A clinicopathologic review of 18 cases and comparison to meningeal hemangiopericytomas. Arch Pathol Lab Med 127:432–439

    PubMed  Google Scholar 

  27. 27.

    Vallat-Decouvelaere AV, Dry SM, Fletcher CD (1998) Atypical and malignant solitary fibrous tumors in extrathoracic locations: evidence of their comparability to intra-thoracic tumors. Am J Surg Pathol 22:1501–1511

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Wang J, Mullighan CG, Easton J, Roberts S, Heatley SL, Ma J, Rusch MC, Chen K, Harris CC, Ding L, Holmfeldt L, Payne-Turner D, Fan X, Wei L, Zhao D, Obenauer JC, Naeve C, Mardis ER, Wilson RK, Downing JR, Zhang J (2011) CREST maps somatic structural variation in cancer genomes with base-pair resolution. Nat Methods 8:652–654

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgments

We wish to thank Kerstin Lindenberg, Katja Böhmer, Diana Rieker, Margot Werner, Claudia Decker, Juliane Bissel and Victoria Zeller for skillful technical assistance.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Andreas von Deimling.

Additional information

L. Schweizer, C. Koelsche, F. Sahm and R. M. Piro contributed equally.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Schweizer, L., Koelsche, C., Sahm, F. et al. Meningeal hemangiopericytoma and solitary fibrous tumors carry the NAB2-STAT6 fusion and can be diagnosed by nuclear expression of STAT6 protein. Acta Neuropathol 125, 651–658 (2013). https://doi.org/10.1007/s00401-013-1117-6

Download citation

Keywords

  • Solitary fibrous tumor
  • SFT
  • Hemangiopericytoma
  • NAB2
  • STAT6
  • Fusion protein
  • Meningioma
  • Immunohistochemistry
  • Proximity ligation