Diagnosis, Pathophysiology And Molecular Biology of Pheochromocytoma and Paraganglioma

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

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Abstract

The Section is conducting patient-oriented research about the etiology, epidemiology, pathophysiology, genetics, diagnosis, and treatment of pheochromocytoma and paraganglioma (PPGL). Projects include not only translational research-applying basic science knowledge to clinical diagnosis, pathophysiology, and treatment-but also reverse translation research where appreciation of clinical findings leads to new concepts that basic researchers can pursue in the laboratory. In order to achieve our goals, the strategy of the Section is based on the multidisciplinary collaborations among NIH investigators and outside medical centers/institutions. Our Section links together a patient-oriented component with two bench-level components. The patient-oriented component (Medical Neuroendocrinology) is currently the main driving force for our hypotheses and discoveries. The two bench-level components (Tumor Pathogenesis, Genetics, Chemistry & Biomarkers and Experimental Immunotherapies) emphasize first, technologies of basic research tailored for pathway and target discovery and second, the development of the discoveries into clinical applications. Clinical and genetic aspects of PPGLs We publihsed a summary of the plenary lecture presented by Jared Rosenblum MD that was awarded the Manger Prize at the 6th International Symposium on Pheochromocytoma/paraganglioma held on October 22-25, 2022 in Prague, Czech Republic. Herein, review our initial identification of a new syndrome of multiple paragangliomas, somatostatinomas, and polycythemia caused by early post-zygotic mosaic mutations in EPAS1, encoding hypoxia-inducible factor-2 (HIF-2), and our continued exploration of new disease phenotypes in this syndrome, including vascular malformations and neural tube defects. Continued recruitment and close monitoring of patients with this syndrome as well as the generation and study of a corresponding disease mouse model as afforded by the pheochromocytoma/paraganglioma translational program at the National Institutes of Health has provided new insights into the natural history of these developmental anomalies and the pathophysiologic role of HIF-2. Further, these studies have highlighted the importance of the timing of genetic defects in the development of related disease phenotypes. The recent discovery and continued study of this syndrome has not only rapidly evolved our understanding of pheochromocytoma and paraganglioma but also deepened our understanding of other developmental tumor syndromes, heritable syndromes, and sporadic diseases In this machine learning modeling study, we used cross-sectional cohort data from the PMT trial, based in Germany, Poland, and the Netherlands, to prospectively examine the utility of methoxytyramine to predict metastatic disease in 267 patients with pheochromocytoma or paraganglioma and positive biochemical test results at initial screening. Another retrospective dataset of 493 patients with these tumors enrolled under our clinical protocols at NIH and the Netherlands (PRESCRIPT trial) was used to train and validate machine learning models according to selections of additional features. The best performing machine learning models were then externally validated using data for all patients in the PMT trial. For comparison, 12 specialists provided predictions of metastatic disease using data from the training and external validation datasets. Prospective predictions indicated that plasma methoxytyramine could identify metastatic disease at sensitivities of 52% and specificities of 85%. The best performing machine learning model was based on an ensemble tree classifier algorithm that used nine features: plasma methoxytyramine, metanephrine, normetanephrine, age, sex, previous history of pheochromocytoma or paraganglioma, location and size of primary tumors, and presence of multifocal disease. This model had an area under the receiver operating characteristic curve of 0942 (95% CI 0894-0969) that was larger (p<00001) than that of the best performing specialist before (0815, 0778-0853) and after (0812, 0781-0854) provision of SDHB variant data. Sensitivity for prediction of metastatic disease in the external validation cohort reached 83% at a specificity of 92%. Patients with germline SDHD pathogenic variants (encoding succinate dehydrogenase subunit D; ie, paraganglioma 1 syndrome) are predominantly affected by head and neck paragangliomas, which, in almost 20% of patients, might coexist with paragangliomas arising from other locations (eg, adrenal medulla, para-aortic, cardiac or thoracic, and pelvic). Given the higher risk of tumour multifocality and bilaterality for phaeochromocytomas and paragangliomas (PPGLs) because of SDHD pathogenic variants than for their sporadic and other genotypic counterparts, the management of patients with SDHD PPGLs is clinically complex in terms of imaging, treatment, and management options. Furthermore, locally aggressive disease can be discovered at a young age or late in the disease course, which presents challenges in balancing surgical intervention with various medical and radiotherapeutic approaches. The axiom-first, do no harm-should always be considered and an initial period of observation (ie, watchful waiting) is often appropriate to characterise tumour behaviour in patients with these pathogenic variants. These patients should be referred to specialised high-volume medical centres. This consensus guideline aimed to help physicians with the clinical decision-making process when caring for patients with SDHD PPGLs. PPGLs 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 PPGLs 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 PPGL 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 PPGL and identify biomarkers of potential clinical significance Imaging aspects of PPGLs The study identifies the importance of PET and anatomic imaging modalities and their individual performances in detecting SDHA-related metastatic PPGL. The detection rates of PET modalities-68Ga-DOTATATE, 18F-FDG, and 18F-FDOPA-along with the combination of computed tomography (CT) and magnetic resonance imaging (MRI) are compared in a cohort of 11 patients with metastatic PPGL in the setting of a germline SDHA mutation. The imaging detection performances were evaluated at three levels: overall lesions, anatomic regions, and a patient-by-patient basis. 68Ga-DOTATATE PET demonstrated a lesion-based detection rate of 88.6% 95% confidence interval (CI), 84.3-92.5%, while 18F-FDG, 18F-FDOPA, and CT/MRI showed detection rates of 82.9% (CI, 78.0-87.1%), 39.8% (CI, 30.2-50.2%), and 58.2% (CI, 52.0-64.1%), respectively. The study found that 68Ga-DOTATATE best detects lesions in a subset of patients with SDHA-related metastatic PPGL. However, 18F-FDG did detect more lesions in the liver, mediastinum, and abdomen/pelvis anatomic regions, showing the importance of a combined approach using both modalities.