Case Series: ATRX Variants in Four Patients with Metastatic Pheochromocytoma

Few reports have highlighted the rare presence of somatic <i>ATRX</i> variants in clinically aggressive, metastatic pheochromocytoma/paraganglioma (PCC/PGL); however, none have addressed detailed clinical presentation (including biochemistry and imaging) and management of these patients. Here, we address these clinical features and management based on four PCC patients with somatic <i>ATRX</i> variants from our National Institutes of Health PCC/PGL cohort. A total of 192 patients underwent exome sequencing (germline, somatic, or both), and four males were found to have somatic <i>ATRX</i> variants (with additional somatic <i>VHL</i> and <i>FH</i> oncogenic variants in patients 2 and 4, respectively). Per-lesion and per-patient comparisons were performed among functional imaging scans performed at the NIH. Biochemical phenotype and response to systemic treatment were evaluated. This mini-series supports prior studies showing aggressive/metastatic PCC in patients with somatic <i>ATRX</i> variants, as all developed widespread metastatic disease. All four PCC patients presented with noradrenergic biochemical phenotype, and some with significant elevation in 3-methoxytyramine. ¹⁸F-FDOPA PET/CT was found to be the superior functional imaging modality, with 100% lesion detection rate when compared to that of ⁶⁸Ga-DOTATATE, ¹⁸F-FDG, ¹⁸F-FDA, and ¹²³I-MIBG scans. While patients did not respond to chemotherapy or tyrosine kinase inhibitors, they responded to targeted radiotherapy using high-specific-activity ¹³¹I-MIBG (Azedra^®) or ¹⁷⁷Lu-DOTATATE (Lutathera^®).