Background: Pheochromocytoma and paraganglioma (PHEO/PGL) are rare neuroendocrine tumors which may cause potentially life-threatening complications, with about a third of cases found to harbor specific gene mutations. Thus, early diagnosis, treatment, and meticulous monitoring are of utmost importance. Because of low incidence of succinate dehydrogenase complex subunit A (SDHA)-related metastatic PHEO/PGL, currently there exists insufficient clinical information, especially with regards to its diagnostic and treatment characteristics. Methods: Ten patients with SDHA-related metastatic PHEO/PGL were followed-up prospectively and/or retrospectively between January 2010-July 2018. They underwent biochemical tests (n = 10), 123I-MIBG (n = 9) scintigraphy, and multiple whole-body positron emission tomography/computed tomography (PET/CT) scans with 68Ga-DOTATATE (n = 10), 18F-FDG (n = 10), and 18F-FDOPA (n = 6). Results: Our findings suggest that these tumors can occur early and at extra-adrenal locations, behave aggressively, and have a tendency to develop metastatic disease within a short period of time. None of our patients had a family history of PHEO/PGL, making them appear sporadic. Nine out of 10 patients showed abnormal PHEO/PGL-specific biochemical markers with predominantly noradrenergic and/or dopaminergic phenotype, suggesting their utility in diagnosing and monitoring the disease. Per patient detection rates of 68Ga-DOTATATE (n = 10/10), 18F-FDG (n = 10/10), 18F-FDOPA (n = 5/6) PET/CT, and 123I-MIBG (n = 7/9) scintigraphy were 100, 100, 83.33, and 77.77%, respectively. Five out of 7 123I-MIBG positive patients had minimal 123I-MIBG avidity or detected very few lesions compared to widespread metastatic disease on 18F-FDG PET/CT, implying that diagnosis and treatment with 123/131I-MIBG is not a good option. 68Ga-DOTATATE PET/CT was found to be superior or equal to 18F-FDG PET/CT in 7 out of 10 patients and hence, is recommended for evaluation and follow-up of these patients. All 7 out of 7 patients who received conventional therapies (chemotherapy, somatostatin analog therapy, radiation therapy, 131I-MIBG, peptide receptor radionuclide therapy) in addition to surgery showed disease progression. Conclusion: In our cohort of patients, SDHA-related metastatic PHEO/PGL followed a disease-course similar to that of SDHB-related metastatic PHEO/PGL, showing highly aggressive behavior, similar imaging and biochemical phenotypes, and suboptimal response to conventional therapies. Therefore, we recommend careful surveillance of the affected patients and a search for effective therapies.

Clinical Endocrine Section National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health Bethesda MD United States

Department of Nuclear Medicine La Timone University Hospital Aix Marseille University Marseille France

Department of Pediatrics RJ and LA Carver College of Medicine University of Iowa Iowa City IA United States

Division of Cancer Treatment and Diagnosis National Cancer Institute National Institutes of Health Bethesda MD United States

Endocrine Oncology Branch Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda MD United States

Mitochondria Apoptosis and Cancer Research Group School of Medical Science Menzies Health Institute Queensland Griffith University Southport QLD Australia

Molecular Therapy Group Institute of Biotechnology Czech Academy of Sciences Prague Czechia

Neuroendocrine Tumor Program Division of Endocrinology and Metabolism Department of Medicine Holden Comprehensive Cancer Center The University of Iowa Iowa City IA United States

Nuclear Medicine Division Radiology and Imaging Sciences Warren Grant Magnuson Clinical Center National Institutes of Health Bethesda MD United States

Nuclear Medicine Radiology and Radiological Science Johns Hopkins Medicine Baltimore MD United States

Positron Emission Tomography Department Warren Grant Magnuson Clinical Center National Institutes of Health Bethesda MD United States

Radiology and Imaging Sciences Warren Grant Magnuson Clinical Center National Institutes of Health Bethesda MD United States

Section of Diabetes Endocrinology and Metabolism Department of Medicine University of Santo Tomas Hospital Manila Philippines

Section on Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health Bethesda MD United States

Section on Medical Neuroendocrinology Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health Bethesda MD United States

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Should Methoxytyramine Routinely Be Included in the Guidelines for Biochemical Assessment of Pheochromocytomas and Paragangliomas?