18F-FDOPA PET/CT Imaging of MAX-Related Pheochromocytoma

Abstract

Context: MYC-associated factor X (MAX) has been recently described as a new susceptibility pheochromocytoma (PHEO) gene with a total of ~40 reported cases. At present, no study has specifically described the functional imaging phenotype of MAX-related PHEO.

Objective, patients, and design: The objective of the present study was to present our experience with contrast-enhanced computed tomography (CT) and 18F-fluorodihydroxyphenylalanine (18F-FDOPA) positron emission tomography (PET)/CT in six consecutive patients (four at the initial diagnosis and two at the follow-up evaluation) with rare, but clinically important, MAX-related PHEOs. In five patients, 18F-FDOPA was also compared with other radiopharmaceutical agents.

Results: The patients had five different mutations in the MAX gene that caused disruption of Max/Myc interaction and/or abolished interaction with DNA based on in silico analyses. All but one patient developed bilateral PHEOs during their lifetime. In all cases, 18F-FDOPA PET/CT accurately visualized PHEOs that were often multiple within the same gland or bilaterally and detected more adrenal and extra-adrenal lesions than did CT (per-lesion sensitivity, 90.9% vs 52.4% for CT/magnetic resonance imaging). The two PHEOs missed on 18F-FDOPA PET/CT were <1 cm, corresponding to nodular adrenomedullary hyperplasia. 68Ga-DOTA,Tyr3-octreotate PET/CT detected fewer lesions than did 18F-FDOPA PET/CT in one of three patients, and 18F-fluorodeoxyglucose PET/CT was only faintly positive in two of four patients with underestimation of extra-adrenal lesions in one patient.

Conclusions: MAX-related PHEOs exhibit a marked 18F-FDOPA uptake, a finding that illustrates the common well-differentiated chromaffin pattern of PHEOs associated with activation of kinase signaling pathways. 18F-FDOPA PET/CT should be considered as the first-line functional imaging modality for diagnostic or follow-up evaluations for these patients.

Trial registration: ClinicalTrials.gov NCT00004847.

Figures

Figure 1.

Schematic cartoon representation of the sequence and 3D structures of Myc-Max heterodimer complexes bound to their DNA target. (A) Schematic representation of Max protein and its variants. Max protein sequence contains 160 amino acids (shown as light pink box). (B–F) Schematic representation of the 3D structures of Myc-Max heterodimer complexes bound to their DNA target. Myc and Max proteins are shown in pale green and light pink, respectively. The in silico modeling demonstrates that mutations found in the patients caused disruption of Max/Myc interactions and/or abolished interaction with DNA. The figure was generated using pymol (available at: http://www.pymol.org/). WT, wild type.

Figure 2.

18F-FDOPA PET/CT findings at initial diagnosis for three patients withMAX-related PHEOs (patients 1 to 3). All the patients exhibited bilateral PHEOs with multiple uptake foci within the two adrenal glands (arrows). Axial attenuation-corrected (A, C, E, G, I, and K) 18F-FDOPA PET and (B, D, F, H, J, and L) 18F-FDOPA PET/CT images. Pt. no., patient number.

Figure 3.

Head to head comparison between 18F-FDOPA, 68Ga-DOTATATE, and 18F-FDG PET/CT with MAX-related PHEOs in two patients: (A–F) patient (Pt. no.) 5 and (G–L) patient 6. Both patients exhibited unilateral PHEOs in the left adrenal gland (arrows). Axial attenuation-corrected (A and G) 18F-FDOPA PET, (D and J) 18F-FDOPA PET/CT, (B and H) 68Ga-DOTATATE PET, (E and K) 68Ga-DOTATATE PET/CT, (C and I) 18F-FDG PET, and (F and L) 18F-FDG PET/CT images. In patient 4, peripheral uptake with central photopenia was observed in all 18F-FDOPA, 68Ga-DOTATATE, and 18F-FDG PET/CT images. In patient 5, because of the very low uptake pattern on 18F-FDG PET, the findings were read as negative for PHEO in the left adrenal gland.

Figure 4.

Anterior maximum-intensity projection PET images of (A) 18F-FDOPA, (B) 68Ga-DOTATATE, and (C) 18F-FDG PET/CT of patient (Pt. no.) 6 for the evaluation of residual and/or recurrent disease. 18F-FDOPA was superior to 68Ga-DOTATATE and 18F-FDG PET/CT by identifying a total of five lesions (arrows) located in the medial to anterior aspect of the right kidney (identified by all three radiotracers), aortocaval region (also identified on 68Ga-DOTATATE apart from 18F-FDOPA PET/CT), adjacent to the right crus, aortocaval region, and left side of midline anterior to descending aorta at the level of L1; the last three were only identified by 18F-FDOPA PET/CT.