Metastatic Pheochromocytoma and Paraganglioma: Somatostatin Receptor 2 Expression, Genetics, and Therapeutic Responses

Author:

Fischer Alessa1,Kloos Simon1,Maccio Umberto2,Friemel Juliane2,Remde Hanna3,Fassnacht Martin3,Pamporaki Christina4,Eisenhofer Graeme4,Timmers Henri J L M5,Robledo Mercedes67,Fliedner Stephanie M J8,Wang Katharina9,Maurer Julian9,Reul Astrid1,Zitzmann Kathrin9,Bechmann Nicole10,Žygienė Gintarė10,Richter Susan10,Hantel Constanze14,Vetter Diana11,Lehmann Kuno11,Mohr Hermine12,Pellegata Natalia S1213,Ullrich Martin14,Pietzsch Jens1415,Ziegler Christian G34,Bornstein Stefan R14,Kroiss Matthias9,Reincke Martin9,Pacak Karel16,Grossman Ashley B1718,Beuschlein Felix19,Nölting Svenja19ORCID

Affiliation:

1. Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ), and University of Zurich (UZH) , CH-8091 Zurich , Switzerland

2. Department of Pathology and Molecular Pathology, University Hospital Zurich , CH-8091 Zurich , Switzerland

3. Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg , 97080 Würzburg , Germany

4. Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden , 01307 Dresden , Germany

5. Division of Endocrinology, Department of Internal Medicine, Radboud University Medical Center , 6525 GA Nijmegen , Netherlands

6. Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center (CNIO) , Madrid , Spain

7. Centro de Investigación Biomédica en Red de Enfermedades Raras , Madrid , Spain

8. First Department of Medicine, University Medical Center Schleswig-Holstein , 23538 Lübeck , Germany

9. Department of Medicine IV, University Hospital, Ludwig-Maximilians-University Munich , 80336 Munich , Germany

10. Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse , 01307 Dresden , Germany

11. Department of Visceral and Transplantation Surgery, University Hospital , 8091 Zürich , Switzerland

12. Institute for Diabetes and Cancer, Helmholtz Zentrum München , 85764 Neuherberg , Germany

13. Department of Biology and Biotechnology, University of Pavia , 27100 Pavia , Italy

14. Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR) , Dresden , Germany

15. Faculty of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden , Dresden , Germany

16. Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Rockville, MD 20847 , USA

17. Green Templeton College, University of Oxford , Oxford , UK

18. NET Unit, ENETS Centre of Excellence, Royal Free Hospital , London , UK

Abstract

Abstract Context Pheochromocytomas and paragangliomas (PPGLs) with pathogenic mutations in the succinate dehydrogenase subunit B (SDHB) are associated with a high metastatic risk. Somatostatin receptor 2 (SSTR2)–dependent imaging is the most sensitive imaging modality for SDHB-related PPGLs, suggesting that SSTR2 expression is a significant cell surface therapeutic biomarker of such tumors. Objective Exploration of the relationship between SSTR2 immunoreactivity and SDHB immunoreactivity, mutational status, and clinical behavior of PPGLs. Evaluation of SSTR-based therapies in metastatic PPGLs. Methods Retrospective analysis of a multicenter cohort of PPGLs at 6 specialized Endocrine Tumor Centers in Germany, The Netherlands, and Switzerland. Patients with PPGLs participating in the ENSAT registry were included. Clinical data were extracted from medical records, and immunohistochemistry (IHC) for SDHB and SSTR2 was performed in patients with available tumor tissue. Immunoreactivity of SSTR2 was investigated using Volante scores. The main outcome measure was the association of SSTR2 IHC positivity with genetic and clinical–pathological features of PPGLs. Results Of 202 patients with PPGLs, 50% were SSTR2 positive. SSTR2 positivity was significantly associated with SDHB- and SDHx-related PPGLs, with the strongest SSTR2 staining intensity in SDHB-related PPGLs (P = .01). Moreover, SSTR2 expression was significantly associated with metastatic disease independent of SDHB/SDHx mutation status (P < .001). In metastatic PPGLs, the disease control rate with first-line SSTR-based radionuclide therapy was 67% (n = 22, n = 11 SDHx), and with first-line “cold” somatostatin analogs 100% (n = 6, n = 3 SDHx). Conclusion SSTR2 expression was independently associated with SDHB/SDHx mutations and metastatic disease. We confirm a high disease control rate of somatostatin receptor–based therapies in metastatic PPGLs.

Funder

German Research Foundation

University Medicine Zurich

Publisher

The Endocrine Society

Subject

Biochemistry (medical),Clinical Biochemistry,Endocrinology,Biochemistry,Endocrinology, Diabetes and Metabolism

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