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

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), 123 I-MIBG ( n = 9) scintigraphy, and multiple whole-body positron emission tomography/computed tomography (PET/CT) scans with 68 Ga-DOTATATE ( n = 10), 18 F-FDG ( n = 10), and 18 F-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 68 Ga-DOTATATE ( n = 10/10), 18 F-FDG ( n = 10/10), 18 F-FDOPA ( n = 5/6) PET/CT, and 123 I-MIBG ( n = 7/9) scintigraphy were 100, 100, 83.33, and 77.77%, respectively. Five out of 7 123 I-MIBG positive patients had minimal 123 I-MIBG avidity or detected very few lesions compared to widespread metastatic disease on 18 F-FDG PET/CT, implying that diagnosis and treatment with 123/131 I-MIBG is not a good option. 68 Ga-DOTATATE PET/CT was found to be superior or equal to 18 F-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, 131 I-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 diseas...

Emerging Treatments for Advanced/Metastatic Pheochromocytoma and Paraganglioma

“…The rate of metastasis of SDHB -related PHEOs/PGLs has been reported to be between 34% [ 22 ] and 71% [ 27 ], with a 5-year survival rate of 36% after the diagnosis of metastasis [ 28 ]. The metastatic potential attributed to mutations in the other SDH subunits has been described as 21% in SDHA , rarely malignant in SDHC , and < 10% in SDHD [ 29 ].…”

Molecular imaging and radionuclide therapy of pheochromocytoma and paraganglioma in the era of genomic characterization of disease subgroups

“…The elevated clinical value of 68 Ga-DOTATATE was also observed in the pediatric population with SDHx mutation (Jha et al 2018b). 68 Ga-DOTA-SSA PET/CT can therefore, be recommended for diagnosis, staging, and follow-up imaging of PPGL with underlying SDHx mutations (Janssen et al 2015, Jha et al 2018a,b, 2019a. Further, it is suggestive that 68 Ga-DOTA-SSA PET/CT is the most sensitive tool in the detection of HNPGLs, especially SDHD-related tumors, which may be very small in size and/or fail to sufficiently concentrate 18 F-FDOPA ( Fig.…”

“…The more intensive follow-up imaging is required in metastatic patients or patients who are at high risk to develop metastases. Such high risk-factors have been identified as SDHB, SDHA germline mutations, ATRX mutation, male sex, patient with large primary tumors (various studies have identified that from >4.5-5 cm to >10 cm), noradrenergic or dopaminergic biochemical phenotype, older age at primary tumor diagnosis (>40-50 years), and high proliferative index (Ayala-Ramirez et al 2011, King et al 2011, Schovanek et al 2014, Plouin et al 2016, Hamidi et al 2017, Jha et al 2019a, Hescot et al 2019, Mei et al 2019. These patients should be followed up indefinitely involving either whole-body CT/MRI and/or functional imaging.…”

“…As proposed in Fig. 2, when genetic status is unknown and in the absence of tumor multifocality or familial trait, 68 Ga-DOTA-SSA PET/CT should be proposed as first-line imaging modality in HNPGL, sporadic PHEO, extra-adrenal PGL, and metastatic cases (Kroiss et al 2013, Janssen et al 2016a,b, Jha et al 2018a,b, 2019a,b, Han et al 2019. For those associated with mutations in NF1/RET/MAX, 18 F-FDOPA PET/CT should be recommended first due to the optimal tumor-to-adrenal uptake ratio that facilitates their detection.…”

A Novel MAX Gene Mutation Variant in a Patient With Multiple and “Composite” Neuroendocrine–Neuroblastic Tumors

“…In recent years, growing interest in precision medicine and molecular diagnosis concerning the expanding etiology for hereditary PCCs and PGL has led to the inclusion of SDHA, TMEM127, MAX, and SDHAF2 as susceptibility genes (26)(27)(28). Genetic testing is recommended in patients at clinically high risk who are negative for the classic gene mutations (10,28).…”