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Abstract
Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine tumors. PGLs can further be divided into sympathetic (sPGLs) and head-and-neck (HN-PGLs). There are virtually no treatment options, and no cure, for metastatic PCCs and PGLs (PPGLs). Here, we composed a tissue microarray (TMA) consisting of 149 PPGLs, reflecting clinical features, presenting as a useful resource. Mutations in the pseudohypoxic marker HIF-2α correlate to an aggressive tumor phenotype. We show that HIF-2α localized to the cytoplasm in PPGLs. This subcompartmentalized protein expression differed between tumor subtypes, and strongly correlated to proliferation. Half of all sPGLs were metastatic at time of diagnosis. Cytoplasmic HIF-2α was strongly expressed in metastatic sPGLs and predicted poor outcome in this subgroup. We propose that higher cytoplasmic HIF-2α expression could serve as a useful clinical marker to differentiate paragangliomas from pheochromocytomas, and may help predict outcome in sPGL patients.
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1 Lund University, Division of Pediatrics, Department of Clinical Sciences, Lund, Sweden (GRID:grid.4514.4) (ISNI:0000 0001 0930 2361); Lund University, Lund Stem Cell Center, Lund, Sweden (GRID:grid.4514.4) (ISNI:0000 0001 0930 2361); Lund University, Lund University Cancer Center, Lund, Sweden (GRID:grid.4514.4) (ISNI:0000 0001 0930 2361)
2 Sahlgrenska University Hospital, Department of Surgery, Gothenburg, Sweden (GRID:grid.1649.a) (ISNI:000000009445082X); University of Gothenburg, Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, Gothenburg, Sweden (GRID:grid.8761.8) (ISNI:0000 0000 9919 9582)
3 Spanish National Cancer Research Centre (CNIO), Hereditary Endocrine Cancer Group, Madrid, Spain (GRID:grid.7719.8) (ISNI:0000 0000 8700 1153)
4 University of Gothenburg, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, Gothenburg, Sweden (GRID:grid.8761.8) (ISNI:0000 0000 9919 9582)
5 Sahlgrenska University Hospital, Department of Clinical Genetics and Genomics, Gothenburg, Sweden (GRID:grid.1649.a) (ISNI:000000009445082X); Sahlgrenska Academy, Gothenburg University, Department of Laboratory Medicine, Institute of Biomedicine, Gothenburg, Sweden (GRID:grid.8761.8) (ISNI:0000 0000 9919 9582)
6 Lund University, Lund University Cancer Center, Lund, Sweden (GRID:grid.4514.4) (ISNI:0000 0001 0930 2361); Lund University, Translational Cancer Research, Department of Laboratory Medicine, Lund, Sweden (GRID:grid.4514.4) (ISNI:0000 0001 0930 2361)