Optimizing diagnostic and therapeutic strategies for patients with paraganglioma or carotid artery disease: towards improved patient care

Abstract

This dissertation addresses two major themes: optimizing diagnosis and long-term management of pheochromocytomas and paragangliomas (PPGLs) and improving risk stratification and outcomes in carotid artery stenosis. The first part focuses on PPGLs. Chapter 2 describes the development of the prospective Head and Neck Paraganglioma (HNPGL) Registry, created to systematically collect clinical, genetic, imaging and outcome data from patients with PPGLs and from asymptomatic variant carriers. Its multicenter, multinational design enables high-quality real-world data collection to answer key questions on diagnostics, surveillance and treatment, and to support future international guideline development. Chapter 3 reviews advances in genomic and transcriptomic profiling to improve metastatic risk stratification. Several emerging biomarkers are discussed, most capturing tumor-intrinsic biology, while the tumor microenvironment remains largely unexplored. A better understanding of this domain will be essential for future targeted and immunotherapeutic approaches in advanced PPGLs. The psychosocial impact of hereditary PPGL syndromes is evaluated in Chapter 4. Using five validated health-related quality-of-life questionnaires in patients and variant carriers, the study shows that catecholamine hypersecretion and hereditary disease are associated with specific concerns, particularly regarding risks for family members. Yet, overall quality-of-life scores were comparable to the general Dutch population, indicating that current multidisciplinary care generally meets patient needs, while highlighting the importance of tailored support for vulnerable subgroups. Chapter 5 compares [68Ga]Ga-DOTATOC positron emission tomography/computed tomography (PET/CT) with magnetic resonance imaging (MRI) in patients with head and neck paragangliomas. In 28% of cases, the modalities produced discordant results, with PET/CT identifying additional or clarifying lesions due to its higher sensitivity and whole-body coverage. Despite higher costs and radiation exposure, this supports its use as baseline imaging, particularly in younger patients with hereditary disease and elevated lifetime risk of multifocal or metastatic tumors. The rising incidence of PPGLs reflects improved imaging, biochemical testing and genetic diagnostics. In this rare disease, large observational cohorts often offer greater feasibility and external validity than randomized trials. The expanded HNPGL Registry is positioned to address future questions on targeted therapy, immunotherapy, PPGLs in pregnancy and standardized surveillance strategies. The second part of the dissertation addresses carotid artery stenosis. Chapter 6 presents a systematic review and meta-analysis demonstrating declining 30-day stroke and death risks after carotid endarterectomy (CEA) and carotid artery stenting (CAS) in both symptomatic and asymptomatic patients. These findings support lower contemporary risk thresholds. However, Chapter 7 shows that long-term risk remains substantial: over 9.2 years of follow-up after CEA, major adverse cardiovascular events occurred in 24% of patients, driven by age, vascular comorbidities and prior ischemic stroke, emphasizing the need for optimized secondary prevention. Chapter 8 explores ultra-high field 7T magnetic resonance imaging to assess cerebrovascular dynamics after CEA. Although only subtle, non-significant changes were observed, the approach shows promise for developing imaging biomarkers and studying brain biomechanics and cognition in carotid disease. The final discussion supports a shift from decision-making based solely on stenosis severity toward personalized strategies that integrate plaque characteristics, advanced imaging biomarkers and patient-specific risk profiles.