Evaluation of somatostatin, CXCR4 chemokine and endothelin A receptor expression in a large set of paragangliomas

// Daniel Kaemmerer 1 , Jörg Sänger 2 , Ruza Arsenic 3 , Jan G. D’Haese 4 , Jens Neumann 5 , Annette Schmitt-Graeff 6 , Ralph Markus Wirtz 7 , Stefan Schulz 8 and Amelie Lupp 8 1 Department of General and Visceral Surgery, Zentralklinik Bad Berka, Bad Berka, Germany 2 Laboratory of Pathology and Cytology Bad Berka, Bad Berka, Germany 3 Institute of Pathology, Charité University Hospital Berlin, Berlin, Germany 4 Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the University of Munich, Munich, Germany 5 Department of Pathology, Ludwig-Maximilians-University Munich, Munich, Germany 6 Department of Pathology, Albert-Ludwigs-University of Freiburg, Freiburg, Germany 7 STRATIFYER Molecular Pathology GmbH, Köln, Germany 8 Institute of Pharmacology and Toxicology, Jena University Hospital, Jena, Germany Correspondence to: Amelie Lupp, email: Amelie.Lupp@med.uni-jena.de Keywords: somatostatin receptors, CXCR4, endothelin receptor A, immunohistochemistry, paraganglioma Abbreviations: Ct, cycle threshold; ETA, endothelin receptor A; IHC, immunohistochemistry; SST, somatostatin receptor Received: June 07, 2017 Accepted: August 17, 2017 Published: September 23, 2017 ABSTRACT Paragangliomas are predominantly benign tumors, but in some cases invasive growth and also metastasis are observed. Given the limited number of nonsurgical treatment options, novel target structures for diagnostics and therapy of this tumor entity are urgently needed. In the present study, expression of all five somatostatin receptor (SST) subtypes, chemokine receptor CXCR4 and endothelin receptor type A (ETA) was assessed by means of immunohistochemistry in a total of 66 paraffin-embedded paraganglioma samples from 55 patients. The stainings were rated by means of the Immunoreactive Score and correlated to clinical data and to succinate dehydrogenase subunit B (SDHB) expression. SST2A was by far the most prominent receptor in the paragangliomas investigated. It was present in 89% of the tumors at a high intensity, followed by SST5, SST3, SST1 and SST4, which were detected in 47%, 35%, 35% and 13% of the samples, respectively. SDHB positive tumors exhibited significantly higher SST2A and SST3 expression as compared to SDHB negative cases. There was no correlation between SST and Ki-67 expression or grading of the tumors and no difference in SST expression between primary tumors and metastases. Cell surface expression of CXCR4 and ETA was detected only in few samples. On tumor capillaries, however, exceptionally strong staining for these two receptors was noticed in the vast majority of the tumors. In conclusion, paragangliomas are well suited for SST2A-based diagnostics and treatment modalities. An indirect targeting of these highly vascularized tumors via CXCR4 or ETA may also represent a promising future strategy.