Diffusion-weighted Imaging Voxelwise-matched Analyses of Lung Cancer at 3.0-T PET/MRI: Reverse Phase Encoding Approach for Echo-planar Imaging Distortion Correction.

Background PET/MRI has drawn increasing interest in thoracic oncology due to the simultaneous acquisition of PET and MRI data. Geometric distortions related to diffusion-weighted imaging (DWI) limit the evaluation of voxelwise multimodal analyses. Purpose To assess the effectiveness of reverse phase encoding in correcting DWI geometric distortion for multimodal PET/MRI voxelwise lung tumor analyses. Materials and Methods In this prospective study, reverse phase encoding method was implemented with 3.0-T PET/MRI to correct geometric distortions related to DWI. The method was validated in dedicated phantom and then applied to 12 consecutive patients (mean age, 66 years ± 13 [standard deviation]; 10 men) suspected of having lung cancer who underwent fluorodeoxyglucose PET/MRI between October 2018 and April 2019. The effects on DWI-related image matching and apparent diffusion coefficient (ADC) regional map computation were assessed. Consequences on multimodal PET/MRI voxelwise lung tumor analyses were evaluated. Spearman correlation coefficients (rs) between the standardized uptake value (SUV) and ADC data corrected for distortion were computed from optimal realigned DWI PET data, along with bootstrap confidence intervals. Results Phantom results showed that in highly distorted areas, correcting the distortion significantly reduced the mean error against the ground truth (-25% ± 10.6 to -18.4% ± 12.6; P < .001) and the number of voxels with more than 20% error (from 85.3% to 31.4%). In the 12 patients, the coregistration of multimodal PET/MRI tumor data was improved by using the reverse phase encoding method (0.4%-44%). In all tumors, voxelwise correlations (rs) between ADC and SUV revealed null or weak monotonic relationships (mean rs of 0.016 ± 0.24 with none above 0.5). Conclusion Reverse phase encoding is a simple-to-implement method for improved diffusion-weighted multimodal PET/MRI voxelwise-matched analyses in lung cancer. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Colletti in this issue.

Rapid Contour-based Segmentation for 18F-FDG PET Imaging of Lung Tumors by Using ITK-SNAP: Comparison to Expert-based Segmentation.

Purpose To assess the performance of the ITK-SNAP software for fluorodeoxyglucose (FDG) positron emission tomography (PET) segmentation of complex-shaped lung tumors compared with an optimized, expert-based manual reference standard. Materials and Methods Seventy-six FDG PET images of thoracic lesions were retrospectively segmented by using ITK-SNAP software. Each tumor was manually segmented by six raters to generate an optimized reference standard by using the simultaneous truth and performance level estimate algorithm. Four raters segmented 76 FDG PET images of lung tumors twice by using ITK-SNAP active contour algorithm. Accuracy of ITK-SNAP procedure was assessed by using Dice coefficient and Hausdorff metric. Interrater and intrarater reliability were estimated by using intraclass correlation coefficients of output volumes. Finally, the ITK-SNAP procedure was compared with currently recommended PET tumor delineation methods on the basis of thresholding at 41% volume of interest (VOI; VOI41) and 50% VOI (VOI50) of the tumor's maximal metabolism intensity. Results Accuracy estimates for the ITK-SNAP procedure indicated a Dice coefficient of 0.83 (95% confidence interval: 0.77, 0.89) and a Hausdorff distance of 12.6 mm (95% confidence interval: 9.82, 15.32). Interrater reliability was an intraclass correlation coefficient of 0.94 (95% confidence interval: 0.91, 0.96). The intrarater reliabilities were intraclass correlation coefficients above 0.97. Finally, VOI41 and VOI50 accuracy metrics were as follows: Dice coefficient, 0.48 (95% confidence interval: 0.44, 0.51) and 0.34 (95% confidence interval: 0.30, 0.38), respectively, and Hausdorff distance, 25.6 mm (95% confidence interval: 21.7, 31.4) and 31.3 mm (95% confidence interval: 26.8, 38.4), respectively. Conclusion ITK-SNAP is accurate and reliable for active-contour-based segmentation of heterogeneous thoracic PET tumors. ITK-SNAP surpassed the recommended PET methods compared with ground truth manual segmentation.

18F-FLT PET/CT in the Evaluation of Pheochromocytomas and Paragangliomas: A Pilot Study.

UNLABELLED: (18)F-FDG PET/CT has been proven to be a highly sensitive method for pheochromocytomas/paragangliomas (PHEOs/PGLs) associated with succinate dehydrogenase (SDH) mutations. This finding has been attributed to altered tumor cell metabolism resulting from these mutations and does not provide additional prognostic information to genotype. Therefore, identification of new biomarkers for aggressiveness is needed. A high Ki-67 index was proposed to be an additional prognostic factor. This pilot study aimed to evaluate 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET/CT, a PET proliferation tracer, as a potential imaging agent in a series of 12 PHEO/PGL patients with different genetic backgrounds, to compare (18)F-FLT uptake with (18)F-FDG PET/CT, and to evaluate classic factors of aggressiveness. METHODS: Twelve patients (7 metastatic and 5 nonmetastatic) were prospectively evaluated with (18)F-FDG and (18)F-FLT and followed for at least 2 y after the initial imaging work-up. Uptake was assessed at a lesion level, visually and quantitatively by maximum standardized uptake values (SUVmax) for both tracers. (18)F-FLT uptake was compared with risk factors known to be linked with a poor prognosis in PGLs (SDHB-mutated status, lesion size, dopaminergic phenotype) and with (18)F-FDG uptake. RESULTS: In 12 patients, 77 lesions were assessed. All lesions had low (18)F-FLT uptake (median SUVmax, 2.25; range, 0.7-4.5). There was no apparent superiority of (18)F-FLT uptake in progressive lesions, and most of the lesions showed a mismatch, with high (18)F-FDG uptake (median SUVmax, 10.8; range, 1.1-79.0) contrasting with low (18)F-FLT uptake. CONCLUSION: This study suggests that PHEOs/PGLs-even those that progress-do not exhibit intense (18)F-FLT uptake. It provides the first in vivo demonstration that proliferation may not be a major determinant of (18)F-FDG uptake in these tumors. These findings provide new insight into the biologic behavior of PGL and suggest that antiproliferative agents may be suboptimal for treatment of these tumors.

Superiority of [68Ga]-DOTATATE PET/CT to Other Functional Imaging Modalities in the Localization of SDHB-Associated Metastatic Pheochromocytoma and Paraganglioma.

PURPOSE: Patients with succinate dehydrogenase subunit B(SDHB) mutation-related pheochromocytoma/paraganglioma (PHEO/PGL) are at a higher risk for metastatic disease than other hereditary PHEOs/PGLs. Current therapeutic approaches are limited, but the best outcomes are based on the early and proper detection of as many lesions as possible. Because PHEOs/PGLs overexpress somatostatin receptor 2 (SSTR2), the goal of our study was to assess the clinical utility of [(68)Ga]-DOTA(0)-Tyr(3)-octreotate ([(68)Ga]-DOTATATE) positron emission tomography/computed tomography (PET/CT) and to evaluate its diagnostic utility in comparison with the currently recommended functional imaging modalities [(18)F]-fluorodopamine ([(18)F]-FDA), [(18)F]-fluorodihydroxyphenylalanine ([(18)F]-FDOPA), [(18)F]-fluoro-2-deoxy-d-glucose ([(18)F]- FDG) PET/CT as well as CT/MRI. EXPERIMENTAL DESIGN: [(68)Ga]-DOTATATE PET/CT was prospectively performed in 17 patients with SDHB-related metastatic PHEOs/PGLs. All patients also underwent [(18)F]-FDG PET/CT and CT/MRI, with 16 of the 17 patients also receiving [(18)F]-FDOPA and [(18)F]-FDA PET/CT scans. Detection rates of metastatic lesions were compared between all these functional imaging studies. A composite synthesis of all used functional and anatomical imaging studies served as the imaging comparator. RESULTS: [(68)Ga]-DOTATATE PET/CT demonstrated a lesion-based detection rate of 98.6% [95% confidence interval (CI), 96.5%-99.5%], [(18)F]-FDG, [(18)F]-FDOPA, [(18)F]-FDA PET/CT, and CT/MRI showed detection rates of 85.8% (CI, 81.3%-89.4%; P < 0.01), 61.4% (CI, 55.6%-66.9%; P < 0.01), 51.9% (CI, 46.1%-57.7%; P < 0.01), and 84.8% (CI, 80.0%-88.5%; P < 0.01), respectively. CONCLUSIONS: [(68)Ga]-DOTATATE PET/CT showed a significantly superior detection rate to all other functional and anatomical imaging modalities and may represent the preferred future imaging modality in the evaluation of SDHB-related metastatic PHEO/PGL.

18F-FDG PET/CT as a predictor of hereditary head and neck paragangliomas.

BACKGROUND: Hereditary head and neck paragangliomas (HNPGLs) account for at least 35% of all HNPGLs, most commonly due to germline mutations in SDHx susceptibility genes. Several studies about sympathetic paragangliomas have shown that (18)F-FDG PET/CT was not only able to detect and localize tumours, but also to characterize tumours ((18)F-FDG uptake being linked to SDHx mutations). However, the data concerning (18)F-FDG uptake specifically in HNPGLs have not been addressed. The aim of this study was to evaluate the relationship between (18)F-FDG uptake and the SDHx mutation status in HNPGL patients. METHODS: (18)F-FDG PET/CT from sixty HNPGL patients were evaluated. For all lesions, we measured the maximum standardized uptake values (SUVmax), and the uptake ratio defined as HNPGL-SUVmax over pulmonary artery trunk SUVmean (SUVratio). Tumour sizes were assessed on radiological studies. RESULTS: Sixty patients (53.3% with SDHx mutations) were evaluated for a total of 106 HNPGLs. HNPGLs-SUVmax and SUVratio were highly dispersed (1.2-30.5 and 1.0-17.0, respectively). The HNPGL (18)F-FDG uptake was significantly higher in SDHx versus sporadic tumours on both univariate and multivariate analysis (P = 0.002). We developed two models for calculating the probability of a germline SDHx mutation. The first one, based on a per-lesion analysis, had an accuracy of 75.5%. The second model, based on a per-patient analysis, had an accuracy of 80.0%. CONCLUSIONS: (18)F-FDG uptake in HNPGL is strongly dependent on patient genotype. Thus, the degree of (18)F-FDG uptake in these tumours can be used clinically to help identify patients in whom SDHx mutations should be suspected.

Integrated whole-body PET/MRI with 18F-FDG, 18F-FDOPA, and 18F-FDA in paragangliomas in comparison with PET/CT: NIH first clinical experience with a single-injection, dual-modality imaging protocol.

PURPOSE: Paragangliomas (PGLs) are tumors that can metastasize and recur; therefore, lifelong imaging follow-up is required. Hybrid PET/CT is an essential tool to image PGLs. Novel hybrid PET/MRI scanners are currently being studied in clinical oncology. We studied the feasibility of simultaneous whole-body PET/MRI to evaluate patients with PGLs. METHODS: Fifty-three PGLs or PGL-related lesions from 8 patients were evaluated. All patients underwent a single-injection, dual-modality imaging protocol consisting of a PET/CT and a subsequent PET/MRI scan. Four patients were evaluated with F-FDG, 2 with F-fluorodihydroxyphenylalanine, and 2 with F-fluorodopamine. PET/MRI data were acquired using a hybrid whole-body 3-tesla integrated PET/MRI scanner. PET and MRI data (Dixon sequence for attenuation correction and T2-weighted sequences for anatomic allocation) were acquired simultaneously. Imaging workflow and imaging times were documented. PET/MRI and PET/CT data were visually assessed (blindly) in regards to image quality, lesion detection, and anatomic allocation and delineation of the PET findings. RESULTS: With hybrid PET/MRI, we obtained high-quality images in an acceptable acquisition time (median, 31 minutes; range, 25-40 minutes) with good patient compliance. A total of 53 lesions, located in the head and neck area (6 lesions), mediastinum (2 lesions), abdomen and pelvis (13 lesions), lungs (2 lesions), liver (4 lesions), and bones (26 lesions), were evaluated. Fifty-one lesions were detected with PET/MRI and confirmed by PET/CT. Two bone lesions (L4 body, 8 mm, and sacrum, 6 mm) were not detectable on an F-FDA scan PET/MRI, likely because F-FDA was washed out between PET/CT and PET/MRI acquisitions. Coregistered MRI tended to be superior to coregistered CT for head and neck, abdomen, pelvis, and liver lesions for anatomic allocation and delineation. CONCLUSIONS: Clinical PGL evaluation with hybrid PET/MRI is feasible with high-quality image and can be obtained in a reasonable time. It could be particularly beneficial for the pediatric population and for precise lesion definition in the head and neck, abdomen, pelvis, and liver.

Functional characterization of nonmetastatic paraganglioma and pheochromocytoma by (18) F-FDOPA PET: focus on missed lesions.

AIMS AND METHODS: To evaluate the clinical value of (18) F-fluorodihydroxyphenylalanine ((18) F-FDOPA) PET in relation to tumour localization and the patient's genetic status in a large series of pheochromocytoma/paraganglioma (PHEO/PGL) patients and to discuss in detail false-negative results. A retrospective study of PGL patients who were investigated with (18) F-FDOPA PET or PET/CT imaging in two academic endocrine tumour centres was conducted (La Timone University Hospital, Marseilles, France and National Institutes of Health (NIH), Bethesda, MD, USA). RESULTS: One hundred sixteen patients (39·7% harbouring germline mutations in known disease susceptibility genes) were evaluated for a total of 195 PHEO/PGL foci. (18) F-FDOPA PET correctly detected 179 lesions (91·8%) in 107 patients (92·2%). Lesion-based sensitivities for parasympathetic PGLs (head, neck, or anterior/middle thoracic ones), PHEOs, and extra-adrenal sympathetic (abdominal or posterior thoracic) PGLs were 98·2% [96·5% for Timone and 100% for NIH], 93·9% [93·8 and 93·9%] and 70·3% [47·1 and 90%] respectively (P < 0·001). Sympathetic (adrenal and extra-adrenal) SDHx-related PGLs were at a higher risk for negative (18) F-FDOPA PET than non-SDHx-related PGLs (14/24 vs 0/62, respectively, P < 0·001). In contrast, the risk of negative (18) F-FDOPA PET was lower for parasympathetic PGLs regardless of the genetic background (1/90 in SDHx vs 1/19 in non-SDHx tumours, P = 0·32). (18) F-FDOPA PET failed to detect two head and neck PGLs (HNPGL), likely due to their small size, whereas most missed sympathetic PGL were larger and may have exhibited a specific (18) F-FDOPA-negative imaging phenotype. (18) F-FDG PET detected all the missed sympathetic lesions. CONCLUSIONS: (18) F-FDOPA PET appears to be a very sensitive functional imaging tool for HNPGL regardless of the genetic status of the tumours. Patients with false-negative tumours on (18) F-FDOPA PET should be tested for SDHx mutations.

Pheochromocytoma and paraganglioma: current functional and future molecular imaging.

Paragangliomas are neural crest-derived tumors, arising either from chromaffin sympathetic tissue (in adrenal, abdominal, intra-pelvic, or thoracic paraganglia) or from parasympathetic tissue (in head and neck paraganglia). They have a specific cellular metabolism, with the ability to synthesize, store, and secrete catecholamines (although most head and neck paragangliomas do not secrete any catecholamines). This disease is rare and also very heterogeneous, with various presentations (e.g., in regards to localization, multifocality, potential to metastasize, biochemical phenotype, and genetic background). With growing knowledge, notably about the pathophysiology and genetic background, guidelines are evolving rapidly. In this context, functional imaging is a challenge for the management of paragangliomas. Nuclear imaging has been used for exploring paragangliomas for the last three decades, with MIBG historically as the first-line exam. Tracers used in paragangliomas can be grouped in three different categories. Agents that specifically target catecholamine synthesis, storage, and secretion pathways include: 123 and 131I-metaiodobenzylguanidine (123/131I-MIBG), 18F-fluorodopamine (18F-FDA), and 18F-fluorodihydroxyphenylalanine (18F-FDOPA). Agents that bind somatostatin receptors include 111In-pentetreotide and 68Ga-labeled somatostatin analog peptides (68Ga-DOTA-TOC, 68Ga-DOTA-NOC, 68Ga-DOTA-TATE). The non-specific agent most commonly used in paragangliomas is 18F-fluorodeoxyglucose (18F-FDG). This review will first describe conventional scintigraphic exams that are used for imaging paragangliomas. In the second part we will emphasize the interest in new PET approaches (specific and non-specific), considering the growing knowledge about genetic background and pathophysiology, with the aim of understanding how tumors behave, and optimally adjusting imaging technique for each tumor type.