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Paragangliomas (PGL) of the adrenal (also known as pheochromocytomas) or extra-adrenal neural crest-derived cells are highly heritable tumors, usually driven by single pathogenic variants that occur mutually exclusively in genes involved in multiple cellular processes, including the response to hypoxia, MAPK/ERK signaling, and WNT signaling. The discovery of driver mutations has led to active clinical surveillance with outcome implications in familial PGL. The spectrum of mutations continues to grow and reveal unique mechanisms of tumorigenesis that inform tumor biology and provide the rationale for targeted therapy. Here we review recent progress in the genetics and molecular pathogenesis of PGLs and discuss new prospects for advancing research with new disease models and ongoing clinical trials presented at the recent International Symposium of Pheochromocytomas and Paragangliomas (ISP2022) held in October 2022 in Prague.

Pheochromocytomas (PC) and paragangliomas (PG) are rare neuroendocrine tumors associated with autonomic nerves. Here we use single-nuclei RNA-seq and bulk-tissue gene-expression data to characterize the cellular composition of PCPG and normal adrenal tissues, refine tumor gene-expression subtypes and make clinical and genotypic associations. We confirm seven PCPG gene-expression subtypes with significant genotype and clinical associations. Tumors with mutations in VHL, SDH-encoding genes (SDHx) or MAML3-fusions are characterized by hypoxia-inducible factor signaling and neoangiogenesis. PCPG have few infiltrating lymphocytes but abundant macrophages. While neoplastic cells transcriptionally resemble mature chromaffin cells, early chromaffin and neuroblast markers are also features of some PCPG subtypes. The gene-expression profile of metastatic SDHx-related PCPG indicates these tumors have elevated cellular proliferation and a lower number of non-neoplastic Schwann-cell-like cells, while GPR139 is a potential theranostic target. Our findings therefore clarify the diverse transcriptional programs and cellular composition of PCPG and identify biomarkers of potential clinical significance., (© 2022. The Author(s).)

Abstract: This manuscript is the result of the North American Neuroendocrine Tumor Society consensus conference on the medical management and surveillance of metastatic and unresectable pheochromocytoma and paraganglioma held on October 2 and 3, 2019. The panelists consisted of endocrinologists, medical oncologists, surgeons, radiologists/nuclear medicine physicians, nephrologists, pathologists, and radiation oncologists. The panelists performed a literature review on a series of questions regarding the medical management of metastatic and unresectable pheochromocytoma and paraganglioma as well as questions regarding surveillance after resection. The panelists voted on controversial topics, and final recommendations were sent to all panel members for final approval., Competing Interests: T.E. discloses consulting on an advisory board for HRA Pharma and Corcept Therapeutics, and participates in institutional contracted clinical study for Merck and Co, Inc, Corcept Therapeutics, and Strongbridge Biopharma. J.R.H. discloses National Institutes of Health grant funding unrelated to this project and royalties for a book on endocrine surgery unrelated to this project. S.L.A. discloses board membership for Leica Biosystems, consults for PathAI, and has received speaker payment from Med Learning Group. P.L.M.D. discloses support to travel to North American Neuroendocrine Tumor Society, is a full-time faculty member at the University of Texas Health San Antonio, and received grant funding for other projects from the National Institutes of Health and Alex's Lemonade Stand Foundation. T.A.H. discloses consulting for Ipsen and pending grant from Advanced Accelerator Applications. P.L.K. discloses consulting for Advanced Accelerator Applications and Ipsen and has grants from Advanced Accelerator Applications, Ipsen, Brahms (Thermo Fisher Scientific), Lexicon Pharmaceuticals, and Xencor. K.P. discloses serving one time on an advisory board panel for Celgene and Eisai, both unrelated to this manuscript. D.A.P. discloses consulting honoraria from Siemens, Progenics, Bayer, Ipsen, Fusion, 511 Pharma, and Actinium, and receiving research funding from Siemens, Fusion, Nordic Nanovector, 511 Pharma, and Progenics. A.R.S. discloses being part owner of a start-up called Sanguine Diagnostics and Therapeutics and also lecturing for Novartis pending. M.C.S. discloses consulting fees from Guerbet LLC, Genentech, and Instylla, and grant funding from Guerbet LLC and Boston Scientific. The other authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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 norepinephrine-secreting 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. However, 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.

Context: Mutations in genes encoding for the succinate dehydrogenase (SDH) complex are linked to hereditary paraganglioma syndromes. Paraganglioma syndrome 3 is associated with mutations in SDHC and typically manifests as benign, nonfunctional head and neck paragangliomas., Design: We describe a case of a 51-year-old woman who initially presented with diarrhea and hypertension and was found to have a retroperitoneal mass, which was resected with a pathology consistent with paraganglioma. Five years later, her symptoms recurred, and she was found to have new retroperitoneal lymphadenopathy and lytic lesions in the first lumbar vertebral body and the right iliac crest, which were visualized on CT scan and octreoscan but not on iodine-123-meta-iodobenzylguanidine (123I-MIBG) and bone scans. She had significantly elevated 24-hour urine norepinephrine and dopamine. The patient received external beam radiation and a series of different antineoplastic agents. Her disease progressed, and she eventually expired within 2 years. Genetic testing revealed a heterozygous SDHC c.43C>T, p.Arg15X mutation, which was also detected in her daughter and her grandson, both of whom have no biochemical or imaging evidence of paraganglioma syndrome yet., Conclusion: We report a unique case of functional, metastatic abdominal paraganglioma associated with SDHC germline mutation. Our case exemplifies that SDHC germline mutation has variable penetrance, which may manifest with an aggressive biology that could be missed by a 123I-MIBG scan.