Diagnostic performance of [68Ga]DOTATATE PET/CT, [18F]FDG PET/CT, MRI of the spine, and whole-body diagnostic CT and MRI in the detection of spinal bone metastases associated with pheochromocytoma and paraganglioma

Objective To compare the diagnostic performance of [68Ga]DOTATATE PET/CT, [18F]FDG PET/CT, MRI of the spine, and whole-body CT and MRI for the detection of pheochromocytoma/paraganglioma (PPGL)–related spinal bone metastases. Materials and methods Between 2014 and 2020, PPGL participants with spinal bone metastases prospectively underwent [68Ga]DOTATATE PET/CT, [18F]FDG PET/CT, MRI of the cervical-thoracolumbar spine (MRIspine), contrast-enhanced MRI of the neck and thoraco-abdominopelvic regions (MRIWB), and contrast-enhanced CT of the neck and thoraco-abdominopelvic regions (CTWB). Per-patient and per-lesion detection rates were calculated. Counting of spinal bone metastases was limited to a maximum of one lesion per vertebrae. A composite of all functional and anatomic imaging served as an imaging comparator. The McNemar test compared detection rates between the scans. Two-sided p values were reported. Results Forty-three consecutive participants (mean age, 41.7 ± 15.7 years; females, 22) with MRIspine were included who also underwent [68Ga]DOTATATE PET/CT (n = 43), [18F]FDG PET/CT (n = 43), MRIWB (n = 24), and CTWB (n = 33). Forty-one of 43 participants were positive for spinal bone metastases, with 382 lesions on the imaging comparator. [68Ga]DOTATATE PET/CT demonstrated a per-lesion detection rate of 377/382 (98.7%) which was superior compared to [18F]FDG (72.0%, 275/382, p < 0.001), MRIspine (80.6%, 308/382, p < 0.001), MRIWB (55.3%, 136/246, p < 0.001), and CTWB (44.8%, 132/295, p < 0.001). The per-patient detection rate of [68Ga]DOTATATE PET/CT was 41/41 (100%) which was higher compared to [18F]FDG PET/CT (90.2%, 37/41, p = 0.13), MRIspine (97.6%, 40/41, p = 1.00), MRIWB (95.7%, 22/23, p = 1.00), and CTWB (81.8%, 27/33, p = 0.03). Conclusions [68Ga]DOTATATE PET/CT should be the modality of choice in PPGL-related spinal bone metastases due to its superior detection rate. Clinical relevance statement In a prospective study of 43 pheochromocytoma/paraganglioma participants with spinal bone metastases, [68Ga]DOTATATE PET/CT had a superior per-lesion detection rate of 98.7% (377/382), compared to [18F]FDG PET/CT (p < 0.001), MRI of the spine (p < 0.001), whole-body CT (p < 0.001), and whole-body MRI (p < 0.001). Graphical abstract Key Points • Data regarding head-to-head comparison between functional and anatomic imaging modalities to detect spinal bone metastases in pheochromocytoma/paraganglioma are limited. • [68Ga]DOTATATE PET/CT had a superior per-lesion detection rate of 98.7% in the detection of spinal bone metastases associated with pheochromocytoma/paraganglioma compared to other imaging modalities: [18]F-FDG PET/CT, MRI of the spine, whole-body CT, and whole-body MRI. • [68Ga]DOTATATE PET/CT should be the modality of choice in the evaluation of spinal bone metastases associated with pheochromocytoma/paraganglioma.


Introduction
Pheochromocytomas and paragangliomas (PPGLs) are rare catecholamine-producing neuroendocrine tumors that cause life-threatening complications [1][2][3].Bone metastases are frequently observed in patients with solid tumors and are observed in up to 71% (91/137) of metastatic PPGL patients [4][5][6].Further, 20% (26/128) of metastatic PPGL patients have exclusively bony metastases, with the spine being the most common location of bone metastasis (81%, 74/91) [4].Bone metastases weaken and destroy skeletal tissue and predispose cancer patients to acute and chronic skeletal-related events (SREs) such as bone pain, spinal cord compression, pathological fractures, and/or hypercalcemia [7,8].SREs can be the first manifestation of metastatic disease in 31% (15/48) of PPGL patients who develop SREs [4] and spinal cord compression may occur in 20% (5/25) of PPGL patients [9].The majority of SREs in solid tumors occur within 1 month of diagnosis of bone metastasis [7].In metastatic PPGL, the median duration between diagnosis of bone metastases and development of the first SRE was 4.3 months, and interval development of a second SRE took a median duration of 9.8 months [4].SREs not only affect the quality of life, but also increase medical costs, health resource utilization, morbidity, and mortality [7,10].Furthermore, vertebral destruction by spinal tumors leads to bony instability and spinal cord compression, with consequent intractable pain, impaired ambulation, neurologic dysfunction, and resultant paralysis [11].Therefore, prompt diagnosis and intervention are critical in mitigating complications related to bone metastases.
Additionally, [ 68 Ga]DOTATATE PET/CT was found to be superior to other functional imaging modalities and contrast-enhanced computed tomography (CT) and/or magnetic resonance imaging (MRI) in the detection of patients harboring pathogenic variants in genes encoding succinate dehydrogenase (SDH) enzyme subunit B (SDHB)-related, subunit A (SDHA)-related, pediatric SDHx-related, and apparently sporadic metastatic PPGL including bone metastases [24][25][26][27].However, thus far, head-to-head comparison between these radiopharmaceuticals and MRI of the spine to detect spinal bone metastases has not been performed.Accordingly, this study aims to evaluate and compare the diagnostic performance of [ 68 Ga]DOTATATE PET/CT to [ 18 F]FDG PET/CT, MRI of the cervical-thoracolumbar spine (MRI spine ), whole-body diagnostic MRI of the neck and thoraco-abdominopelvic regions (MRI WB ), and whole-body diagnostic CT of the neck and thoraco-abdominopelvic regions (CT WB ) for the detection of spinal bone metastases in PPGL.

Materials and methods
The study protocol was approved by the Institutional Review Board of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (ClinicalTrials.govIdentifier: NCT00004847).Participants were prospectively enrolled between January 2014 and March 2020.Written informed consent from adult participants, or parents along with informed assent from pediatric participants, was obtained for all clinical, genetic, biochemical, and imaging studies.Our institution complies with all applicable laws, regulations, and policies concerning privacy and confidentiality.

Eligibility criteria
The inclusion criteria were (1) age ≥ 10 years, (2) confirmed histopathologic diagnosis of PPGL with presence/suspicion of spinal bone metastases, (3) MRI spine and functional imaging with [ 68 Ga]DOTATATE PET/CT and [ 18 F]FDG PET/ CT, all performed at our institution and within 6 months of each other, and (4) whole-body imaging with either CT WB or MRI WB .Participants were excluded if pregnant or breastfeeding, or found to have a tumor type other than PPGL.

Study design
This was a prospective, open-label single-center study.

Imaging studies and techniques
[ 68 Ga]DOTATATE was manufactured under an investigational new drug application.PET/CT scans from the upper thighs to the skull were performed 60. 4   F]FDG PET/CT images were reconstructed on a 256 × 256 with 3-mm thickness, using an iterative reconstruction algorithm provided by the manufacturer, utilizing time of flight.Low-dose CT without oral or intravenous contrast was performed for attenuation correction and anatomic co-registration.
MRI spine of the cervical-thoracolumbar spine was performed using a 3.0-Tesla whole-body MRI scanner (Achieva, Philips Healthcare).The acquisition protocol consisted of sagittal T1-weighted, sagittal short tau inversion time inversion recovery (STIR) images, and axial T2-weighted images of the spine, and contrast was not administered.Slice thickness was 3 mm for all studies.
MRI WB of the neck and thoraco-abdominopelvic regions were obtained with 1.5-and 3-Tesla scanners (Achieva, Philips Medical Systems; Aera 1.5 Tesla or Siemens Verio 3 Tesla, Siemens Medical Solutions).Imaging protocols varied by body part.The neck included axial STIR and/ or T2-weighted images as well as axial T1-weighted or Dixon and sagittal Dixon pre-and post-contrast images.Chest studies included axial T2-weighted, STIR or fatsaturated T2 images, axial fat-saturated T1 pre-contrast and multiphase post-contrast, and coronal fat-saturated T1 post-contrast images.Coronal pre-contrast T2, axial diffusion-weighted imaging (DWI), and non-breath-hold axial T2* were each sometimes included.Abdominal studies also included axial DWI, axial T2-weighted images with and without fat saturation, axial T1 in and out of phase, and multiphase, multiplanar T1-weighted images before and after contrast injection.Pelvic studies included axial T2-weighted or STIR, axial DWI and T1-weighted, and sagittal fat-saturated T2-weighted images prior to and multiplanar fat-saturated T1-weighted images following contrast injection.Slice thickness was no greater than 5 mm for all neck studies, and no greater than 6 mm for all thoraco-abdominopelvic scans.Post-gadolinium contrast images as thin as 1 mm in the neck and 3 mm for other body parts were obtained for most scans.Pelvic imaging was typically performed contemporaneously with abdominal imaging, sharing a single contrast injection.Similarly, chest and neck imaging were typically performed contemporaneously, and shared a single contrast injection.Each contrast injection consisted of 0.1 mmol/kg of a gadolinium-based contrast agent.
CT WB of the neck and thoraco-abdominopelvic regions were all performed using Siemens Somatom Force or Siemens Definition Flash (Siemens Medical Solutions) or Toshiba Aquilion One scanners (Canon Medical Systems).Slice thickness was 2 mm for all studies.All studies were performed with rapid intravenous infusion (injection rate 2 mL/s) of a nonionic low osmolality water-soluble contrast agent (Isovue 300, Bracco Diagnostics).

Analysis of data
All PET/CT studies were interpreted by an experienced nuclear medicine physician (J.A.C., 36 years of experience), all whole-body diagnostic CT WB and MRI WB studies were interpreted by an experienced radiologist (A.L., 36 years of experience), and all MRI spine were interpreted by an experienced neuroradiologist (R.S., 21 years of experience).Moreover, they had 22, 16, and 5 years of experience, respectively, in interpreting PPGL imaging and were blinded to all other imaging and clinical data except for the suspected diagnosis, sex, and age of the patient.
[ 68 Ga]DOTATATE and [ 18 F]FDG PET/CT images were all reviewed using MIM software (version 7.0.7).Orthogonal views as well as maximum intensity projection (MIP) images were reviewed from each modality.Typically, [ 68 Ga]DOTATATE PET/CT images of the spine were reviewed first followed by review of [ 18 F]FDG PET/CT.

Standard of reference
Histologic proof of all spinal bone metastases was not feasible.Therefore, a composite of all the imaging studies served as an imaging comparator or reference standard for the calculation of detection rates [24,25,27].A "positive" result on both functional PET/CT imaging ([ 68 Ga]DOTATATE and [ 18 F]FDG) or at least on one functional PET/CT ([ 68 Ga] DOTATATE or [ 18 F]FDG) imaging and on one of the anatomic imaging modalities (MRI spine or MRI WB or CT WB ) was considered as true disease.A positive lesion found only on one imaging modality while negative on all other imaging modalities was considered a false-positive imaging result.

Statistical analysis
Results are given as means with 95% confidence intervals (CIs) unless stated otherwise.Per-patient and per-lesion detection rates of [ 68 Ga]DOTATATE PET/CT, [ 18 F]FDG PET/CT, MRI spine , MRI WB , and CT WB were calculated.A participant was considered abnormal or "positive" regardless of the number of positive lesions present; counting of spinal bone metastases was limited to a maximum of one lesion per vertebrae.Cochran's Q test was used to perform a global comparison of detection rates across the imaging modalities.Since MRI WB and CT WB were not performed in all participants, Cochran's Q test was performed with and without MRI WB and CT WB .The McNemar test was used to compare detection rates between [ 68 Ga]DOTA-TATE PET/CT and the other imaging modalities.Twosided p values were reported.Statistical analyses (A.J. and N.S.) were performed using SPSS v29.0 (IBM Corp.), SAS v9.4 (SAS Institute), and StatXact (Cytel Inc.).

Results
Of the 58 consecutive participants undergoing MRI spine for the evaluation of spinal bone metastases, 15 participants were excluded (Fig. 1).One participant each was excluded for having scans more than 6 months apart and not undergoing [ 68 Ga]DOTATATE PET/CT.Two of 15 participants underwent scans (one participant each with [ 68 Ga]DOTA-TATE and [ 18 F]FDG PET/CT) at outside institutions and therefore were excluded.Ten of 16 participants were excluded due to incomplete MRI spine (one did not complete the scan due to bone pain; T1-weighted and STIR images were not obtained in one and eight participants, respectively).Finally, one participant did not have any biochemical or imaging evidence of PPGL.Further, eight vertebral bodies in three participants were excluded from analysis due to the presence of artifacts on anatomic imaging caused by spinal hardware.One participant did not undergo either MRI WB or CT WB as they had an outside CT WB .
A  Values in the table are detection rates expressed in ratios, defined as the number of lesions or participants detected by the imaging modality compared to the total number of lesions or participants evaluated by that modality.In parentheses are the percentages along with 95% confidence intervals
To note, DWI and contrast-enhanced imaging were not part of the MRI spine protocol.MRI spine in our institution is a clinically indicated study and does not include these sequences for detection of spinal bone metastases.Moreover, these sequences were included for the abdominopelvic region of MRI WB and did not improve the detection of spinal bone metastases.
There are some limitations of this study.First, the study cohort is modest in size although relatively large considering the rarity of spinal bone metastatic PPGLs.Second, there may be selection bias as only participants with known or suspicious spinal metastases underwent accrual, thereby excluding asymptomatic patients with spinal metastases.However, it was not feasible to perform MRI spine on all the participants getting enrolled in our protocol.Lastly, even though the chosen imaging comparator likely provides a close approximation of "truth, " falsepositive and false-negative findings could not be excluded [27].Histological proof was neither feasible nor ethical for the confirmation of metastatic lesions [29].

Conclusions and future directions
[ 68 Ga]DOTATATE PET/CT demonstrated superiority in the detection of spinal bone metastases compared to [ 18 F]FDG PET/CT, MRI spine , MRI WB , and CT WB indicating that it should be the imaging modality of choice when looking for metastatic spine disease associated with PPGL.Not only is it more sensitive than the other modalities, but it is also useful in the detection of primaries, soft tissue metastases, and the treatment planning and response assessment of targeted radionuclide therapy (Radium-223 dichloride, Lutetitium-177/Yttrium-90/ Actinium-225/Lead-212-DOTA-analogs) in patients with bone-only metastatic PPGL in whom response evaluation using anatomic imaging is challenging.Future studies may include diffusion-weighted and post-contrast images in the MRI spine protocol and determine its performance against [ 68 Ga]DOTATATE PET/CT.

Fig. 1
Fig. 1 Schematic diagram representing enrollment of participants in the study.The diagram of flow of participants' inclusion and exclusion

Fig. 3
Fig. 3 Multimodality imaging in a spinal bone metastatic pheochromocytoma/paraganglioma participant with spinal hardware.The images of sagittal short tau inversion recovery (STIR, a) MRI, contrast-enhanced CT (b sagittal), fused sagittal 68 Ga-DOTA(0)-Tyr(3)-octreotate ([ 68 Ga] DOTATATE; c, d images at two different sagittal planes) PET/CT, and fused sagittal 18 F-fluoro-2-deoxy-d-glucose ([ 18 F]FDG PET/CT; e, f images at the same two sagittal planes as [ 68 Ga]DOTATATE PET/CT) focused on thoracic spine of a 48-year-old woman with negative germline testing in pheochromocytoma and paraganglioma susceptibility genes are shown.This participant had spinal hardware placed at the T5-T9 vertebrae which therefore were excluded from the analysis due to the associated artifacts on MRI and CT.However, PET/CT imaging clearly is advantageous in the evaluation of patients with spinal bone hardware as demonstrated by the spinal bone metastases at T7-T9 on [ 68 Ga]DOTATATE PET/CT (arrows) and at T7 and T9 on [ 18 F]FDG PET/CT (arrows), where spinal hardware is placed.The uptake on [ 18 F]FDG PET/CT is comparatively much fainter compared to [ 68 Ga]DOTATATE PET/CT.This participant did not undergo whole-body MRI

Table 2
Per-lesion and per-patient detection rate (%) of spinal bone metastases utilizing [ 68 Ga]DOTATATE PET/CT, [ 18 F]FDG PET/CT, MRI of the spine, whole-body MRI, and whole-body CT in pheochromocytoma/paraganglioma participants
Values in the table are expressed in ratios, defined as the number of participants of [ 68 Ga]DOTATATE PET/CT detecting greater, equal, lesser, and greater or equal number of lesions per participant compared to [ 18 F]FDG PET/CT, MRI of the spine, contrast-enhanced whole-body MRI, and contrast-enhanced CT.In parentheses are the percentages along with 95% confidence intervals 18