Nuclear relocation of STAT6 reliably predicts NAB2–STAT6 fusion for the diagnosis of solitary fibrous tumour
Christian Koelsche
Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
German Cancer Consortium (DKTK), CCU Neuropathology German Cancer Research Centre (DKFZ), Heidelberg, Germany
Search for more papers by this authorLeonille Schweizer
Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
German Cancer Consortium (DKTK), CCU Neuropathology German Cancer Research Centre (DKFZ), Heidelberg, Germany
Search for more papers by this authorMarcus Renner
Department of General Pathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorArne Warth
Department of General Pathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorDavid T W Jones
German Cancer Consortium (DKTK), Division of Paediatric Neurooncology, German Cancer Research Centre (DKFZ), Heidelberg, Germany
Search for more papers by this authorFelix Sahm
Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
German Cancer Consortium (DKTK), CCU Neuropathology German Cancer Research Centre (DKFZ), Heidelberg, Germany
Search for more papers by this authorDavid E Reuss
Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
German Cancer Consortium (DKTK), CCU Neuropathology German Cancer Research Centre (DKFZ), Heidelberg, Germany
Search for more papers by this authorDavid Capper
Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
German Cancer Consortium (DKTK), CCU Neuropathology German Cancer Research Centre (DKFZ), Heidelberg, Germany
Search for more papers by this authorThomas Knösel
Institute of Pathology, Ludwig-Maximilians-University Munich, Munich, Germany
Institute of Pathology, Friedrich-Schiller-University Jena, Jena, Germany
Search for more papers by this authorBirte Schulz
Institute of Pathology, Friedrich-Schiller-University Jena, Jena, Germany
Institute of Pathology, Hospital Lippe, Detmold, Germany
Search for more papers by this authorIver Petersen
Institute of Pathology, Friedrich-Schiller-University Jena, Jena, Germany
Search for more papers by this authorAlexis Ulrich
Department of General Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorEva Kristin Renker
Department of Orthopaedics and Traumatology, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorBurkhard Lehner
Department of Orthopaedics and Traumatology, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorStefan M Pfister
German Cancer Consortium (DKTK), Division of Paediatric Neurooncology, German Cancer Research Centre (DKFZ), Heidelberg, Germany
Department of Paediatric Oncology, Haematology and Immunology, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorPeter Schirmacher
Department of General Pathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorAndreas von Deimling
Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
German Cancer Consortium (DKTK), CCU Neuropathology German Cancer Research Centre (DKFZ), Heidelberg, Germany
Search for more papers by this authorCorresponding Author
Gunhild Mechtersheimer
Department of General Pathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
Address for correspondence: G Mechtersheimer, University Hospital Heidelberg, Department of General Pathology, Im Neuenheimer Feld 224, D-69120 Heidelberg, Germany. e-mail: [email protected]Search for more papers by this authorChristian Koelsche
Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
German Cancer Consortium (DKTK), CCU Neuropathology German Cancer Research Centre (DKFZ), Heidelberg, Germany
Search for more papers by this authorLeonille Schweizer
Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
German Cancer Consortium (DKTK), CCU Neuropathology German Cancer Research Centre (DKFZ), Heidelberg, Germany
Search for more papers by this authorMarcus Renner
Department of General Pathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorArne Warth
Department of General Pathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorDavid T W Jones
German Cancer Consortium (DKTK), Division of Paediatric Neurooncology, German Cancer Research Centre (DKFZ), Heidelberg, Germany
Search for more papers by this authorFelix Sahm
Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
German Cancer Consortium (DKTK), CCU Neuropathology German Cancer Research Centre (DKFZ), Heidelberg, Germany
Search for more papers by this authorDavid E Reuss
Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
German Cancer Consortium (DKTK), CCU Neuropathology German Cancer Research Centre (DKFZ), Heidelberg, Germany
Search for more papers by this authorDavid Capper
Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
German Cancer Consortium (DKTK), CCU Neuropathology German Cancer Research Centre (DKFZ), Heidelberg, Germany
Search for more papers by this authorThomas Knösel
Institute of Pathology, Ludwig-Maximilians-University Munich, Munich, Germany
Institute of Pathology, Friedrich-Schiller-University Jena, Jena, Germany
Search for more papers by this authorBirte Schulz
Institute of Pathology, Friedrich-Schiller-University Jena, Jena, Germany
Institute of Pathology, Hospital Lippe, Detmold, Germany
Search for more papers by this authorIver Petersen
Institute of Pathology, Friedrich-Schiller-University Jena, Jena, Germany
Search for more papers by this authorAlexis Ulrich
Department of General Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorEva Kristin Renker
Department of Orthopaedics and Traumatology, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorBurkhard Lehner
Department of Orthopaedics and Traumatology, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorStefan M Pfister
German Cancer Consortium (DKTK), Division of Paediatric Neurooncology, German Cancer Research Centre (DKFZ), Heidelberg, Germany
Department of Paediatric Oncology, Haematology and Immunology, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorPeter Schirmacher
Department of General Pathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorAndreas von Deimling
Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
German Cancer Consortium (DKTK), CCU Neuropathology German Cancer Research Centre (DKFZ), Heidelberg, Germany
Search for more papers by this authorCorresponding Author
Gunhild Mechtersheimer
Department of General Pathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
Address for correspondence: G Mechtersheimer, University Hospital Heidelberg, Department of General Pathology, Im Neuenheimer Feld 224, D-69120 Heidelberg, Germany. e-mail: [email protected]Search for more papers by this authorAbstract
Aims
Nuclear relocation of STAT6 has been shown in tumours with NAB2–STAT6 fusion, and has been proposed as an ancillary marker for the diagnosis of solitary fibrous tumours (SFTs). The aim of this study was to verify the utility of STAT6 immunohistology in diagnosing SFT.
Methods and results
A total of 689 formalin-fixed paraffin-embedded tumours comprising 35 pleural SFTs and 654 other mesenchymal tumours were investigated for STAT6 expression using immunohistochemistry. Nine dedifferentiated liposarcomas (DDLSs) and five SFTs were also examined for the presence of NAB2–STAT6 fusion at the protein level using the proximity ligation assay (PLA), and for copy number variants (CNVs) with the Illumina Infinium Human Methylation450 array. Thirty-four of 35 SFTs showed strong nuclear STAT6 expression. Furthermore, five of 68 DDLSs, two of 130 undifferentiated pleomorphic sarcomas and one of 63 cases of nodular fasciitis showed moderate to strong nuclear STAT6 expression. The PLA indicated the presence of NAB2–STAT6 fusion protein in SFTs, but signal was also detected in some DDLSs. Copy number analysis showed an overall low frequency of chromosomal imbalances in SFTs, but complex karyotypes in DDLSs, including amplification of STAT6 and MDM2 loci.
Conclusions
The detection of nuclear relocation of STAT6 with immunohistochemistry is a characteristic of SFTs, and may serve as a diagnostic marker that indicates NAB2–STAT6 fusion and helps to discriminate SFTs from histological mimics.
Supporting Information
| Filename | Description |
|---|---|
| his12431-sup-0001-FigS1.tifimage/tif, 19.7 MB | Figure S1. Copy number plots of five solitary fibrous tumours (SFTs) and nine dedifferentiated liposarcomas (DDLSs) derived from 450k array data with chromosomal gains (green) and chromosomal losses (red). |
| his12431-sup-0001-FigS3.tifimage/tif, 6.7 MB | Figure S2. Histological mimic of a solitary fibrous tumour (SFT) with absence of nuclear STAT6 expression (also depicted in Figure 1B). |
| his12431-sup-0002-FigS2.tifimage/tif, 9.8 MB | Figure S3. Solitary fibrous tumour (SFT) with strong nuclear STAT6 expression (A) and absence of MDM2 expression (B). |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F. World Health Organization classification of tumours of soft tissue and bone. Lyon: IARC Press, 2013.
- 2Louis DN, Ohgaki H, Wiestler OD et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007; 114; 97–109.
- 3Park MS, Araujo DM. New insights into the hemangiopericytoma/solitary fibrous tumor spectrum of tumors. Curr. Opin. Oncol. 2009; 21; 327–331.
- 4England DM, Hochholzer L, McCarthy MJ. Localized benign and malignant fibrous tumors of the pleura. A clinicopathologic review of 223 cases. Am. J. Surg. Pathol. 1989; 13; 640–658.
- 5Demicco EG, Park MS, Araujo DM et al. Solitary fibrous tumor: a clinicopathological study of 110 cases and proposed risk assessment model. Mod. Pathol. 2012; 25; 1298–1306.
- 6Vallat-Decouvelaere AV, Dry SM, Fletcher CD. Atypical and malignant solitary fibrous tumors in extrathoracic locations: evidence of their comparability to intra-thoracic tumors. Am. J. Surg. Pathol. 1998; 22; 1501–1511.
- 7van Houdt WJ, Westerveld CM, Vrijenhoek JE et al. Prognosis of solitary fibrous tumors: a multicenter study. Ann. Surg. Oncol. 2013; 20; 4090–4095.
- 8Wilky BA, Montgomery EA, Guzzetta AA, Ahuja N, Meyer CF. Extrathoracic location and ‘borderline’ histology are associated with recurrence of solitary fibrous tumors after surgical resection. Ann. Surg. Oncol. 2013; 20; 4080–4089.
- 9Mangham D, Kindblom L. Rarely metastasizing soft tissue tumours. Histopathology 2014; 64; 88–100.
- 10Lee JC, Fletcher CD. Malignant fat-forming solitary fibrous tumor (so-called ‘lipomatous hemangiopericytoma’): clinicopathologic analysis of 14 cases. Am. J. Surg. Pathol. 2011; 35; 1177–1185.
- 11Nielsen GP, Dickersin GR, Provenzal JM, Rosenberg AE. Lipomatous hemangiopericytoma. A histologic, ultrastructural and immunohistochemical study of a unique variant of hemangiopericytoma. Am. J. Surg. Pathol. 1995; 19; 748–756.
- 12Gengler C, Guillou L. Solitary fibrous tumour and haemangiopericytoma: evolution of a concept. Histopathology 2006; 48; 63–74.
- 13Mohajeri A, Tayebwa J, Collin A et al. Comprehensive genetic analysis identifies a pathognomonic NAB2/STAT6 fusion gene, nonrandom secondary genomic imbalances, and a characteristic gene expression profile in solitary fibrous tumor. Genes Chromosom. Cancer 2013; 52; 873–886.
- 14Chmielecki J, Crago AM, Rosenberg M et al. Whole-exome sequencing identifies a recurrent NAB2–STAT6 fusion in solitary fibrous tumors. Nat. Genet. 2013; 45; 131–132.
- 15Robinson DR, Wu YM, Kalyana-Sundaram S et al. Identification of recurrent NAB2–STAT6 gene fusions in solitary fibrous tumor by integrative sequencing. Nat. Genet. 2013; 45; 180–185.
- 16Schweizer 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. 2013; 125; 651–658.
- 17Doyle LA, Vivero M, Fletcher CD, Mertens F, Hornick JL. Nuclear expression of STAT6 distinguishes solitary fibrous tumor from histologic mimics. Mod. Pathol. 2014; 27; 390–395.
- 18Sturm D, Witt H, Hovestadt V et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 2012; 22; 425–437.
- 19Hovestadt V, Remke M, Kool M et al. 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; 913–916.
- 20Demicco EG. Sarcoma diagnosis in the age of molecular pathology. Adv. Anat. Pathol. 2013; 20; 264–274.
- 21Ambrosini-Spaltro A, Eusebi V. Meningeal hemangiopericytomas and hemangiopericytoma/solitary fibrous tumors of extracranial soft tissues: a comparison. Virchows Arch. 2010; 456; 343–354.
- 22Rieker RJ, Joos S, Bartsch C et al. Distinct chromosomal imbalances in pleomorphic and in high-grade dedifferentiated liposarcomas. Int. J. Cancer 2002; 99; 68–73.
- 23Fritz B, Schubert F, Wrobel G et al. Microarray-based copy number and expression profiling in dedifferentiated and pleomorphic liposarcoma. Cancer Res. 2002; 62; 2993–2998.
- 24Rieker RJ, Weitz J, Lehner B et al. Genomic profiling reveals subsets of dedifferentiated liposarcoma to follow separate molecular pathways. Virchows Arch. 2010; 456; 277–285.
- 25Tap WD, Eilber FC, Ginther C et al. Evaluation of well-differentiated/de-differentiated liposarcomas by high-resolution oligonucleotide array-based comparative genomic hybridization. Genes Chromosom. Cancer 2011; 50; 95–112.
- 26Doyle LA, Tao D, Marino-Enriquez A. STAT6 is amplified in a subset of dedifferentiated liposarcoma. Mod. Pathol. 2014; doi: 10.1038/modpathol.2013.247.
- 27Barretina J, Taylor BS, Banerji S et al. Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy. Nat. Genet. 2010; 42; 715–721.
- 28Mosquera JM, Fletcher CD. Expanding the spectrum of malignant progression in solitary fibrous tumors: a study of 8 cases with a discrete anaplastic component—is this dedifferentiated SFT? Am. J. Surg. Pathol. 2009; 33; 1314–1321.
- 29Meng GZ, Zhang HY, Zhang Z, Wei B, Bu H. Myofibroblastic sarcoma vs nodular fasciitis: a comparative study of chromosomal imbalances. Am. J. Clin. Pathol. 2009; 131; 701–709.
- 30Erickson-Johnson MR, Chou MM, Evers BR et al. Nodular fasciitis: a novel model of transient neoplasia induced by MYH9–USP6 gene fusion. Lab. Invest. 2011; 91; 1427–1433.
- 31Santos CI, Costa-Pereira AP. Signal transducers and activators of transcription—from cytokine signalling to cancer biology. Biochim. Biophys. Acta 2011; 1816; 38–49.
- 32Kumbrink J, Kirsch KH, Johnson JP. 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. 2010; 111; 207–217.
- 33Vivero M, Doyle LA, Fletcher CD, Mertens F, Hornick JL. GRIA2 is a novel diagnostic marker for solitary fibrous tumour identified through gene expression profiling. Histopathology 2014; 65; 71–80.
- 34Bhattacharyya S, Wei J, Melichian DS, Milbrandt J, Takehara K, Varga J. The transcriptional cofactor NAB2 is induced by TGF-beta and suppresses fibroblast activation: physiological roles and impaired expression in scleroderma. PLoS ONE 2009; 4; e7620.
Citing Literature
