[¹⁸F]FDOPA PET/CT is superior to [⁶⁸Ga]DOTATOC PET/CT in diagnostic imaging of pheochromocytoma

The study included all patients referred for PPGL functional imaging from the Department of Endocrinology and Internal Medicine to the Department of Nuclear Medicine and PET Centre, Aarhus University Hospital in the period January 10, 2018, to May 3, 2022. All patients were referred on a clinical and biochemical suspicion of PPGL (i.e., with elevated metanephrines on consecutive measurements and either an adrenal incidentaloma or a relevant clinical genetic predisposition). Five patients only had measurements of methoxynoradrenalin. Elevated metanephrines were calculated as an index according to the upper normal limit [9], i.e., a value of 2.01 and an upper limit of 0.45 give a calculated index of 3.47. All patients with normal metanephrines were given a basic value of 1.

We also included patients referred on the suspicion of PPGL recurrence (local recurrence, new PPGL, or metastases). These patients were analyzed separately.

Each patient underwent both a DOTATOC and a FDOPA scan for diagnostic purposes. The PET scans were on average performed within a span of 9 days (minimum 1 day in between).

The institutional review board at Aarhus University Hospital granted access to patient files. According to Danish legislation, individual patients’ consent was waived due to the retrospective nature of the study. All methods were carried out in accordance with relevant guidelines and regulations.

FDOPA was produced using a 16.8-MeV PETtrace cyclotron (GE Medical Systems, Uppsala, Sweden) and according to a standard procedure [10].

DOTATOC was produced by standard procedures using a registered product (edotreotide, SomaKIT TOC), as described by Manoharan et al. [11].

The subjects were scanned on three scanner models: (1) A Siemens Biograph Truepoint TrueV (2018–2019) (N = 18), (2) Siemens Biograph Vision 600 (2019–2022) (N = 63) and (3) GE Healthcare Discovery MI scanner (2019–2022) (N = 32). All scanners were cross-calibrated using an ¹⁸FDG phantom.

Truepoint emission data were corrected for attenuation, based on a low-dose CT (CARE Dose 4D, 50 mAs, 120 kV). PET reconstruction parameters were TrueX, 4 iterations, 21 subsets, 336 matrix, 3-mm Gaussian postfilter, voxel size 2.0³ mm³ and a central spatial resolution around 5-mm FWHM.

Vision emission data were corrected for attenuation based on a low-dose CT (CARE Dose 4D, 25 mAs, 120 kV, CARE kV). PET reconstruction parameters were TrueX + TOF, 4 iterations, 5 subsets, 440 matrix, 2-mm Gaussian postfilter, voxel size 1.65³ mm³ and a central spatial resolution around 3.5-mm FWHM.

Discovery emission data were corrected for attenuation based on a low-dose CT (Smart mA, Noise index 43, 100 kV). PET reconstruction parameters were VPFX-S, 3 iterations, 16 subsets, 384 matrix, 3-mm Gaussian postfilter, voxel size 1.8 × 1.8 × 2.8 mm³ and a central spatial resolution around 3.9-mm FWHM.

A low-dose CT without contrast was performed for attenuation and coregistration purposes. However, if a diagnostic CT scan had not been performed within 1 month before the first PET scan, a contrast-enhanced CT scan (arterial phase of thorax, abdomen and pelvis and a portal phase of upper abdomen) was performed according to local procedures for neuroendocrine tumor-imaging.

All the scans were re-evaluated by two experienced nuclear medicine specialists blinded to the clinical outcome, with access to the same information as present at the time of the scans (e.g., previous PPGL, result of previous CT scans, and if metastatic disease was suspected). The two scans were evaluated consecutively in the same session in random order.

The results of PET scans were recorded for both adrenal and extraadrenal locations. The findings in the adrenals were registered whether there was a PCC present and if so, the side location was noted to do a lesion-based comparison to the clinical diagnosis. The extraadrenal lesions were recorded with location and number and assessed as single, multiple, or metastatic PGL.

The subjects were told not to take drugs or food for 4 h before the scan but were free to drink water. No patients were premedicated with carbidopa. Sixty minutes after intravenous injection of 400 MBq [¹⁸F]FDOPA patients were placed in a supine position and scanned from top of the skull to mid-thigh.

The co-registered FDOPA PET/low-dose CT images were displayed together with a contrast-enhanced CT. FDOPA uptake in the adrenal glands was considered pathological if there was asymmetric uptake correlated to a focal lesion. If there were no focal lesions in any of the glands, symmetrical uptake was considered pathological if noticeably more intense than the liver. FDOPA uptake outside the adrenal glands was considered pathological if there was any uptake beyond the surrounding tissue in a non-physiologic distribution. Maximum standardized uptake value (SUV_max) was measured for each lesion.

The were no special preparations for the subjects before the scan. Ninety minutes after injection of [⁶⁸Ga]DOTATOC, 2.5 MBq/kg, a minimum of 100 MBq and a maximum of 250 MBq, patients were placed in a supine position and scanned from skull to mid-thigh.

When interpreting DOTATOC PET, two conditions were considered, namely the absolute uptake in an adrenal lesion and, because the physiological uptake is high in the adrenals, also the difference in uptake between the two adrenals (ie the healthy one and the diseased). If there were lesions in both adrenal glands, we only looked at the absolute uptake. The absolute uptake had to be above liver level, i.e., at least Krenning 3 (modified Krenning scale: 0 = no lesions, 1 = weak uptake, considerable uptake below liver level; 2 = moderate uptake, less than or equal to the liver; 3 = intense uptake above the liver and below the spleen; and 4 = excessive uptake above the spleen). Outside the adrenal glands, any focal lesions with increased DOTATOC uptake were considered pathologic if assessed as Krenning 2 or higher. We defined negative DOTATOC scans as Krenning 2 scores or below, without difference in uptake in the two adrenal glands.

The accuracy of the patient- and lesion-based PET diagnoses was analyzed using the final clinical diagnosis as gold standard. The final clinical diagnosis was primarily based on pathological examinations. In the few instances where no pathological examination was available (eg. if patients did not undergo surgery), the clinical diagnosis was based on an overall clinical assessment consisting of a combination of the available imaging, laboratory tests, and (when applicable) the follow-up data.

We used a nonparametric test (Mann–Whitney, two-tailed) to compare differences between groups of patients, with probability values of less than 0.05 as the threshold of statistical significance. A nonparametric test was used to test correlation between XY-pairs (Spearman r test with computation of nonparametric Spearman correlations, two-tailed, confidence interval 95%).

To compare the two scanning modalities for sensitivity and specificity, a McNemar’s test was used.

In total, 113 patients were included in the study of whom 97 were referred on the suspicion of primary PPGL and 16 on suspicion of recurrence. After diagnostic workup, 57 (59%) of 97 newly referred patients were diagnosed with PPGL. Age, sex, genetic status, and PPGL types are summarized in Table 1. Eleven (69%) of the 16 with previous PPGL were confirmed to have PPGL.

FDOPA had higher sensitivity for detection of PCC compared to DOTATOC (patient-based: 100 vs. 49%, p < 0.001; lesion-based: 100 vs. 49% p < 0.001), whereas the specificity was similar for the two modalities (patient-based 95 vs. 98% p = 1.00; lesion-based: 98 vs. 99%, p = 0.62) (Table 2). In addition, FDOPA had a higher negative predictive value and diagnostic accuracy compared to DOTATOC (both p < 0.001).

Mean FDOPA SUV_max differed between patients with PCC (unilateral and bilateral) and patients without PCC (p < 0.001). FDOPA SUV_max was 4.0 ± 2.3 (mean ± SD) (range 1.3 to 12.6) in adrenal glands in patients without PCC, 15.6 ± 7.3 (range 3.5 to 28.8) in adrenal lesions in patients with unilateral PCC, and 17.8 ± 8.9 (range 9.2 to 33.4) in adrenal lesions in patients with bilateral PCC (Fig. 1).

A receiver operating characteristic (ROC) analysis was used to evaluate sensitivity and specificity based on FDOPA SUV_max values (AUC: 0.96, p < 0.001) (Fig. 2). The optimal cutoff of SUV_max was resulting in 93% sensitivity and 91% specificity for diagnosing pheochromocytoma.

No difference was observed in FDOPA SUV_max in adrenals of PCC patients with or without a pathogenic genetic variant (14.8 ± 8.4 vs. 16.1 ± 6.8, p = 0.42) (Fig. 3).

In patients with PCC, adrenal FDOPA SUV_max showed no correlation to the plasma level of methoxyadrenaline or methoxynoradrenaline (including calculated pathologic values above 1) (Fig. 4).

Figure 5 shows a clinical case of a patient suspected of primary PPGL. This case illustrates the advantage of using FDOPA for detecting small structures in the adrenal glands due to the low physiological uptake in the normal adrenal glands as opposed to the high physiological uptake with DOTATOC.

Figure 6 shows three clinical cases of patients suspected of primary PPGL. These cases illustrate the advantage of using FDOPA, not only in patients with small structures in the adrenal glands, but also in patients with large size PC. All cases show FDOPA-positive lesions with no correlating DOTATOC uptake (below physiological uptake in the adherent and contralateral adrenal gland).

Six patients had paragangliomas, 5 single PGL, and 1 metastatic PGL. All were detected by FDOPA, whereas DOTATOC failed to detect three paragangliomas.

Of the 16 patients referred for suspected recurrent disease, 2 had local recurrence, 4 had single PGL, and 5 had metastatic PCC. In 5 patients, the diagnosis was refuted (Table 3).

All 11 patients with recurrent disease were detected by DOPA, while 5 patients had no detectable disease on DOTATOC. In two patients with metastatic PCC, the number of lesions was different; in one patient, there were more lesions on DOPA, in the other there were more lesions on DOTATOC.