Clinical, Diagnostic, and Treatment Characteristics of SDHA-Related Metastatic Pheochromocytoma and Paraganglioma

Abhishek Jha; Kristine de Luna; Charlene Ann Balili; Corina Millo; Cecilia Angela Paraiso; Alexander Ling; Melissa K Gonzales; Bruna Viana; Rami Alrezk; Karen T Adams; Isabel Tena; Alice Chen; Jiri Neuzil; Margarita Raygada; Electron Kebebew; David Taieb; M Sue O'Dorisio; Thomas O'Dorisio; Ali Cahid Civelek; Constantine A Stratakis; Leilani Mercado-Asis; Karel Pacak

doi:10.3389/fonc.2019.00053

Clinical, Diagnostic, and Treatment Characteristics of SDHA-Related Metastatic Pheochromocytoma and Paraganglioma

Front Oncol. 2019 Feb 22:9:53. doi: 10.3389/fonc.2019.00053. eCollection 2019.

Authors

Abhishek Jha¹, Kristine de Luna^{1

2}, Charlene Ann Balili^{1

2}, Corina Millo³, Cecilia Angela Paraiso^{1

2}, Alexander Ling⁴, Melissa K Gonzales¹, Bruna Viana¹, Rami Alrezk⁵, Karen T Adams¹, Isabel Tena¹, Alice Chen⁶, Jiri Neuzil^{7

8}, Margarita Raygada⁹, Electron Kebebew¹⁰, David Taieb¹¹, M Sue O'Dorisio¹², Thomas O'Dorisio¹³, Ali Cahid Civelek^{14

15}, Constantine A Stratakis⁹, Leilani Mercado-Asis², Karel Pacak¹

Affiliations

¹ Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States.
² Section of Diabetes, Endocrinology and Metabolism, Department of Medicine, University of Santo Tomas Hospital, Manila, Philippines.
³ Positron Emission Tomography Department, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, MD, United States.
⁴ Radiology and Imaging Sciences, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, MD, United States.
⁵ Clinical Endocrine Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States.
⁶ Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
⁷ Mitochondria, Apoptosis and Cancer Research Group, School of Medical Science, Menzies Health Institute Queensland, Griffith University, Southport, QLD, Australia.
⁸ Molecular Therapy Group, Institute of Biotechnology, Czech Academy of Sciences, Prague, Czechia.
⁹ Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States.
¹⁰ Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
¹¹ Department of Nuclear Medicine, La Timone University Hospital, Aix-Marseille University, Marseille, France.
¹² Department of Pediatrics, RJ and LA Carver College of Medicine, University of Iowa, Iowa City, IA, United States.
¹³ Neuroendocrine Tumor Program, Division of Endocrinology and Metabolism, Department of Medicine, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA, United States.
¹⁴ Nuclear Medicine Division, Radiology and Imaging Sciences, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, MD, United States.
¹⁵ Nuclear Medicine, Radiology and Radiological Science, Johns Hopkins Medicine, Baltimore, MD, United States.

Abstract

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.

Keywords: 123I-MIBG; 18F-FDG; 18F-FDOPA; 68Ga-DOTATATE; PET/CT; SDHA; paraganglioma; pheochromocytoma.

Abstract

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