Metastatic pheochromocytomas and paragangliomas: proceedings of the MEN2019 workshop

Pheochromocytomas and paragangliomas (PPGLs) are adrenal or extra-adrenal autonomous nervous system-derived tumors. Most PPGLs are benign, but approximately 15% progress with metastases (mPPGLs). mPPGLs are more likely to occur in patients with large pheochromocytomas, sympathetic paragangliomas, and norepinephrinesecreting tumors. Older subjects, those with larger tumors and synchronous metastases, advance more rapidly. Germline mutations of SDHB, FH, and possibly SLC25A11, or somatic MAML3 disruptions relate to a higher risk for metastatic disease. Ho wever, it is unclear whether these mutations predict outcome. Once diagnosed, there are no well-established predictors of outcome in mPPGLs, and aggressive tumors have few therapeutic options and limited response. High-specific activity (HSA) metaiodine-benzyl-guanidine (MIBG) is the first FDA approved treatment and shows clinical effectiveness for MIBG- avid mPPGLs. Ongoing and future investigations should involve validation of emerging candidate outcome biomarkers, including somatic ATRX, TERT, and microRNA disruptions and identification of novel prognostic indicators. Long- term effect of HSA-MIBG and the role of other radiopharmaceuticals should be investigated. Novel trials targeting molecular events prevalent in SDHB/FH mutant tumors, such as activated hypoxia inducible factor 2 (HIF2), angiogenesis, or other mitochondrial defects that might confer unique vulnerability to these tumors should be developed and initiated. As therapeutic options are anticipated to expand, multi-institutional collaborations and well-defined clinical and molecular endpoints will be critical to achieve higher success rates in improving care for patients with mPPGLs.