Case Series: ATRX Variants in Four Patients with Metastatic Pheochromocytoma

Abstract

Few reports have highlighted the rare presence of somatic ATRX 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 ATRX 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 ATRX variants (with additional somatic VHL and FH 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 ATRX 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^®).

Keywords: ATRX; case report; imaging; pheochromocytoma; prognosis.

Figure 1

The anterior maximum intensity projection images of ¹⁸F-FDOPA positron emission tomography/computed tomography (PET/CT) (A), ⁶⁸Ga-DOTATATE PET/CT (B), ¹⁸F-FDG PET/CT (C), and ¹²³I-MIBG single photon emission computed tomography/computed tomography (SPECT/CT) (D) of a 67-year-old male (patient 3) with a likely oncogenic somatic ATRX variant (c.2018dup, p.Thr674fs) with a history of a previously resected 8.7 cm right pheochromocytoma demonstrates metastatic lesions in lungs, liver, and bones. ¹⁸F-FDOPA PET/CT shows superiority in detection of metastatic lesions compared to ⁶⁸Ga-DOTATATE PET/CT, ¹⁸F-FDG PET/CT, and ¹²³I-MIBG SPECT/CT. Liver lesions are detected by ¹⁸F-FDOPA PET/CT and ¹²³I-MIBG SPECT/CT and are not seen on ⁶⁸Ga-DOTATATE PET/CT and ¹⁸F-FDG PET/CT. Furthermore, ¹⁸F-FDOPA PET/CT detects more bone and lung lesions compared to ⁶⁸Ga-DOTATATE PET/CT, ¹⁸F-FDG PET/CT, and ¹²³I-MIBG SPECT scintigraphy. Based on widespread avidity of metastatic lesions on ¹²³I-MIBG scintigraphy compared to ⁶⁸Ga-DOTATATE PET/CT, the patient was recommended for high-specific-activity ¹³¹I-MIBG (Azedra^®) targeted radiotherapy. Additionally, ¹⁸F-FDG PET/CT demonstrates diffuse increased uptake in the colon, likely physiologic and not suggestive of malignancy. The ¹⁸F-FDA PET/CT, unfortunately, was not performed in this patient. To note, contrast recovery, sensitivity, and spatial resolution of PET/CT imaging is superior to SPECT/CT imaging, and therefore, smaller lesions on PET/CT scans may not be visible on SPECT/CT scans despite adequate uptake.

Figure 2

H&E stain (20x) of the periaortic lymph node metastatic lesion in patient 4 (A). Immunohistochemistry stain (40x) showing retained ATRX protein (brown staining) in internal control of endothelial and stromal cells of vessels (blue arrows) and loss of protein in tumor cells (orange arrows) (B).