Increased expression of Nrf2 and elevated glucose uptake in pheochromocytoma and paraganglioma with SDHB gene mutation

Abstract

Background Pheochromocytomas (PCC) and paragangliomas (PGL) are catecholamine-producing neuroendocrine tumors. According to the World Health Organization Classification 2017, all PCC/PGL are considered to have malignant potential. There is growing evidence that PCC/PGL represent a metabolic disease that leads to aerobic glycolysis. Cellular energy metabolism involves both transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and succinate dehydrogenase (SDH) subtypes, but the association of these substances with PCC/PGL is largely unknown. Methods We investigated SDHB gene mutation and protein expressions for SDHB and Nrf2 in surgical specimens from 29 PCC/PGL. We also assessed preoperative maximum standard glucose uptake (SUVmax) on [18F]fluorodeoxy-glucose positron emission tomography and mRNA levels for Nrf2. Results Among 5 PCC/PGL with a PASS Score ≥ 4 or with a moderately to poorly differentiated type in the GAPP Score, 4 were metastatic and found to be SDHB mutants with homogeneous deletion of SDHB protein. SDHB mutants showed a higher expression of Nrf2 protein and a higher preoperative SUVmax than non-SDHB mutants with a PASS < 4 or a well-differentiated GAPP type. Furthermore, protein expression of Nrf2 was positively associated with preoperative SUVmax. The Nrf2 mRNA level positively correlated with malignant phenotype, higher expression for Nrf2 protein and SDHB gene mutant, but negatively correlated with expression for SDHB protein. There was also a positive correlation between Nrf2 mRNA level and SUVmax. Conclusion These results suggest that activation of Nrf2 and elevated metabolism play roles in PCC/PGL with malignant potential that have SDHB gene mutation and SDHB deficiency.

A rare case report of multifocal para-aortic and para-vesical paragangliomas

“…The pathology mechanism of PGLs varies. One such mechanism is that the Nfr2 activation and the elevated glucose uptake contribute to PGL malignancy with SDHB gene mutation ( 16 ). VHL and MEN-2 have a low malignancy risk of PGLs.…”

Case report: Intraoperative frozen section analysis of Thyroid paraganglioma

“…Additionally, thyroid PGL is significantly correlated with mutations in succinate dehydrogenase ( 3 ), and a large percentage of hereditary PGL is a result of susceptible gene mutations in the succinate dehydrogenase complex ( SDH x; including SDHA , SDHB , SDHC , SDHD ), TMEM127 , or MAX ( 4 ). SDHB mutations are important because these are strongly associated with the malignant behavior of PGL ( 5 , 6 ).…”