Surveillance of succinate dehydrogenase gene mutation carriers: Insights from a nationwide cohort

Abstract

ObjectiveMutations in the genes coding for succinate dehydrogenase (SDHx) are the most frequent germline alterations in pheochromocytomas and paragangliomas. Evidence for the advantages associated with presymptomatic screening for SDHx mutation carriers is scarce. This study describes a nationwide cohort of these mutation carriers and aims to compare patients with clinical manifestations of the disease and those diagnosed through genetic screening. DESIGN: Cross‐sectional study.PatientsSDHx mutation carriers (n = 118) followed through the Portuguese Oncology referral centres: 41 probands and 77 nonprobands.MeasurementsAll participants were subjected to biochemical and body imaging examinations for a complete assessment of the extent and spread of disease. Clinical data obtained this way were further analysed.ResultsThe mean age of this cohort was 44.5 ± 17.4 years, and more than half carried the same founder SDHB mutation. About 50.8% of the mutation carriers developed pheochromocytomas or paragangliomas. Compared to patients diagnosed through genetic screening, those diagnosed clinically were characterized by larger tumours (P < .001), more frequent metastases (P = .024), were more frequently subjected to surgery (P = .011) and radiotherapy (P = .013), and had worse outcomes, such as macroscopic positive margins (P = .034). Persistent and/or unresectable disease and disease‐related mortality were also more frequent in symptomatic patients compared to those diagnosed through genetic screening (P = .014).ConclusionsIn this nationwide cohort study, a large proportion of mutation carriers were found to develop SDHx‐related neoplasia. Genetic testing and subsequent follow‐up resulted in the diagnosis of smaller and nonmetastatic tumours, fewer treatment procedures, fewer complications and greater number of disease‐free patients.

Surveillance Improves Outcomes for Carriers of SDHB Pathogenic Variants: A Multicenter Study

“…In total, 14.5% of patients with disease died in this study. In other studies mortality of SDHB PV carriers with disease was between 2.1% and 13.0% ( 3 , 8 , 9 , 28 , 33-36 ). In studies that only examined patients with metastatic PPGL, mortality rates were understandably higher from 18.5% to 60.9% ( 2 , 32 , 37 , 38 ).…”

Tumor detection rates in screening of individuals with SDHx-related hereditary paraganglioma–pheochromocytoma syndrome

“…Given the risk of PGL/PCC as well as RCC and GIST, expert consensus guidelines recommend standard screening protocols for individuals with SDHx PVs 17 , 18 . A combination of serial imaging from the skull base to pelvis with annual biochemical testing (metanephrines, catecholamines) has been suggested to identify presymptomatic tumors in this at-risk population, and results in better outcomes 19 – 22 . Therefore, a consensus working group from the American Association of Cancer Researchers recommends whole-body MRI every two years starting at age 6–8 with annual biochemical testing for individuals with known SDHx PVs 17 .…”

Genetic and clinical aspects of paediatric pheochromocytomas and paragangliomas

“…Therefore, all paediatric cases must undergo a very rigorous annual investigation for recurrence and metastases. Indeed, genetic diagnosis and surveillance have been demonstrated to have a positive impact on clinical outcomes for patients with germline SDHx or VHL pathogenic variants 26,27 . Moreover, Wong et al 28 recommended that the approach to surveillance should be tailored to the SDHx gene affected in a meta‐analysis including asymptomatic SDHx carriers and index cases.…”

“…Indeed, genetic diagnosis and surveillance have been demonstrated to have a positive impact on clinical outcomes for patients with germline SDHx or VHL pathogenic variants. 26,27 Moreover, Wong et al 28 recommended that the approach to surveillance should be tailored to the SDHx gene affected in a meta-analysis including asymptomatic SDHx carriers and index cases. Clinical and biochemical screening should generally commence at 5 years old for individuals carrying SDHB pathogenic variants and at 10 years old for those carrying SDHA, SDHC or SDHD pathogenic variants.…”