Klaas Pieter Koopmans

Improved Staging of Patients With Carcinoid and Islet Cell Tumors With 18F-Dihydroxy-Phenyl-Alanine and 11C-5-Hydroxy-Tryptophan Positron Emission Tomography

PURPOSE To evaluate and compare diagnostic sensitivity of positron emission tomography (PET) scanning in carcinoid and islet cell tumor patients with a serotonin and a catecholamine precursor as tracers. PATIENTS AND METHODS Carcinoid (n = 24) or pancreatic islet cell tumor (n = 23) patients with at least one lesion on conventional imaging including somatostatin receptor scintigraphy (SRS) and computed tomography (CT) scan underwent (11)C-5-hydroxytryptophan ((11)C-5-HTP) PET and 6-[F-18]fluoro-L-dihydroxy-phenylalanine ((18)F-DOPA) PET. PET findings were compared with a composite reference standard derived from all available imaging along with clinical and cytologic/histologic information. RESULTS In carcinoid tumor patients, per-patient analysis showed sensitivities for (11)C-5-HTP PET, (18)F-DOPA PET, SRS, and CT of 100%, 96%, 86%, 96%, respectively, and in islet cell tumors of 100%, 89%, 78%, 87%, respectively. In carcinoid patients, per-lesion analysis revealed sensitivities for (11)C-5-HTP PET, (11)C-5-HTP PET/CT, (18)F-DOPA PET, (18)F-DOPA PET/CT, SRS, SRS/CT, and CT alone of, respectively, 78%, 89%, 87%, 98%, 49%, 73%, and 63% and in islet cell tumors of 67%, 96%, 41%, 80%, 46%, 77%, and 68%, respectively. In all carcinoid patients (18)F-DOPA PET and (11)C-5-HTP PET detected more lesions than SRS (P < .001). (11)C-5-HTP PET was superior to (18)F-DOPA PET in islet cell tumors (P < .0001). In all cases, CT improved the sensitivity of the nuclear scans. CONCLUSION (18)F-DOPA PET/CT is the optimal imaging modality for staging in carcinoid patients and (11)C-5-HTP PET/CT in islet cell tumor patients.

6-L-18F-fluorodihydroxyphenylalanine PET in neuroendocrine tumors: basic aspects and emerging clinical applications.

In recent years, 6-l-18F-fluorodihydroxyphenylalanine (18F-DOPA) PET has emerged as a new diagnostic tool for the imaging of neuroendocrine tumors. This application is based on the unique property of neuroendocrine tumors to produce and secrete various substances, a process that requires the uptake of metabolic precursors, which leads to the uptake of 18F-DOPA. This nonsystematic review first describes basic aspects of 18F-DOPA imaging, including radiosynthesis, factors involved in tracer uptake, and various aspects of metabolism and imaging. Subsequently, this review provides an overview of current clinical applications in neuroendocrine tumors, including carcinoid tumors, pancreatic islet cell tumors, pheochromocytoma, paraganglioma, medullary thyroid cancer, hyperinsulinism, and various other clinical entities. The application of PET/CT in carcinoid tumors has unsurpassed sensitivity. In medullary thyroid cancer, pheochromocytoma, and hyperinsulinism, results are also excellent and contribute significantly to clinical management. In the remaining conditions, the initial experience with 18F-DOPA PET indicates that it seems to be less valuable, but further study is required.

18F-dihydroxyphenylalanine PET in patients with biochemical evidence of medullary thyroid cancer: relation to tumor differentiation.

Curative treatment for recurrent medullary thyroid cancer (MTC), diagnosed by rising serum calcitonin, is surgery, but tumor localization is difficult. Therefore, the value of 18F-dihydroxyphenylanaline PET (18F-DOPA PET), 18F-FDG PET, 99mTc-V-di-mercaptosulfuricacid (DMSA-V) scintigraphy, and MRI or CT was studied. Methods: Twenty-one patients with biochemical recurrent or residual MTC underwent 18F-DOPA PET, 18F-FDG PET, DMSA-V scintigraphy, and MRI or CT. Patient- and lesion-based sensitivities were calculated using a composite reference consisting of all imaging modalities. Results: In 76% of all patients with MTC, one or more imaging modalities was positive for MTC lesions. In 6 of 8 patients with a calcitonin level of <500 ng/L, imaging results were negative. In 15 patients with positive imaging results, 18F-DOPA PET detected 13 (sensitivity, 62%; with 4.6 lesions per patient [lpp]). Morphologic imaging (n = 19) was positive in 7 (sensitivity, 37%; 4.7 lpp), DMSA-V (n = 18) in 5 (sensitivity, 28%; 1.1 lpp), and 18F-FDG PET (n = 17) in 4 (sensitivity, 24%; 1.6 lpp). In a lesion-based analysis, 18F-DOPA PET detected 95 of 134 lesions (sensitivity, 71%), morphologic imaging detected 80 of 126 (sensitivity, 64%), DMSA-V detected 20 of 108 (sensitivity, 19%), and 18F-FDG PET detected 48 of 102 (sensitivity, 30%). In 2 of 3 patients with a calcitonin/carcinoembryonic antigen (CEA) doubling time of ≤12 mo, 18F-FDG PET performed better than 18FDOPA PET; in the third patient, 18F-FDG PET was not performed. Conclusion: MTC lesions are best detectable when serum calcitonin was >500 ng/L. 18F-DOPA PET is superior to 18F-FDG PET, DMSA-V, and morphologic imaging. With short calcitonin doubling times (≤12 mo), 18F-FDG PET may be superior.

111In-Octreotide Is Superior to 123I-Metaiodobenzylguanidine for Scintigraphic Detection of Head and Neck Paragangliomas

In this study, we evaluated the diagnostic yield of somatostatin receptor scintigraphy (SRS), I-metaiodobenzylguanidine (MIBG) scintigraphy, and morphologic imaging (CT or MRI) in patients with head and neck paragangliomas. Methods: In a university hospital setting, patients considered to have head and neck paraganglioma were referred to the outpatient endocrinology department and underwent CT or MRI, SRS, and MIBG imaging. For validation, we used a composite reference standard consisting of clinical and histologic data and CT or MRI, with which SRS and MIBG imaging were compared. Urinary metanephrine and normetanephrine measurements were also obtained. Results: Twenty-nine consecutively referred patients (17 women and 12 men) were included and were found to have paraganglioma. Both morphologic and SRS were positive in 27 patients (sensitivity, 93%, and 95% confidence interval [CI], 77%–98%, compared with the composite reference standard), whereas MIBG was positive in only 13 patients (44%; 95% CI, 23%–61%) (P < 0.001, compared with SRS). On a lesion-based analysis, morphologic imaging detected 31 lesions (sensitivity, 82%; 95% CI, 65%–92%), SRS detected 34 (89%; 95% CI, 75%–97%), and MIBG detected 15 (42%; 95% CI, 26%–59%). SRS was superior to MIBG (P = 0.001). With SRS, a previously unknown carcinoid tumor was detected in 1 patient, and a carcinoid was suspected in another patient. MIBG detected an additional adrenal pheochromocytoma in 1 patient. Urinary metanephrine or normetanephrine excretion was elevated in 6 patients. The number of lesions on SRS and MIBG per patient correlated with the levels of abnormal metanephrine or normetanephrine excretion (P = 0.005 and P = 0.02, respectively). Conclusion: SRS was superior to MIBG in patients with highly suspected head and neck paraganglioma.

Clinical Relevance of 18F-FDG PET and 18F-DOPA PET in Recurrent Medullary Thyroid Carcinoma

The transition from stable to progressive disease is unpredictable in patients with biochemical evidence of medullary thyroid carcinoma (MTC). Calcitonin and carcinoembryonic antigen (CEA) doubling times are currently the most reliable markers for progression, but for accurate determination, serial measurements, which need time, are required. We compared 18F-FDG PET and 18F-dihydroxyphenylanaline (18F-DOPA) PET with biochemical parameters and survival to assess whether these imaging modalities could be of value in detecting progressive disease. Methods: We evaluated the outcome of 18F-FDG PET or 18F-DOPA PET with calcitonin and CEA doubling times in 47 MTC patients. A subgroup of patients was included in the whole metabolic burden (WBMTB) analysis, with determination of standardized uptake values and number of lesions. WBMTB of 18F-DOPA PET and 18F-FDG PET was compared with biochemical parameters. Furthermore, survival was compared with 18F-DOPA PET or 18F-FDG PET positivity. Results: Doubling times were available for 38 of 40 patients undergoing 18F-FDG PET. There was a significant correlation with 18F-FDG PET positivity. Doubling times were less than 24 mo in 77% (n = 10/13) of 18F-FDG PET–positive patients, whereas 88% (n = 22/25) of 18F-FDG PET–negative patients had doubling times greater than 24 mo (P < 0.001). Between doubling times and 18F-DOPA PET positivity, no significant correlation existed. 18F-DOPA PET detected significantly more lesions (75%, 56/75) than did 18F-FDG PET (47%, 35/75) in the 21 patients included in WBMTB analysis (P = 0.009). Calcitonin and CEA levels correlated significantly with WBMTB on 18F-DOPA PET, but doubling times did not. 18F-FDG PET positivity was a more important indicator for poor survival in patients for whom both scans were obtained. Conclusion: 18F-FDG PET is superior in detecting patients with biochemical progressive disease and identifying patients with poor survival. Although 18F-DOPA PET has less prognostic value, it can more accurately assess the extent of the disease in patients with residual MTC. Hence, both scans are informative about tumor localization and behavior. On the basis of these results, we designed a clinical flow diagram for general practice in detecting recurrent MTC.

Molecular imaging: what can be used today

Biochemical cellular targets and more general metabolic processes in cancer cells can be visualised. Extensive data are available on molecular imaging in preclinical models. However, innovative tracers move slowly to the clinic. This review provides information on the currently available methods of metabolic imaging, especially using PET in humans. The uptake mechanisms of tracer methods and a brief discussion of the more ‘molecular’ targeted methods are presented. The main focus is on the different classes of tracers and their application in various types of cancer within each class of tracers, based on the current literature and our own experience. Studies with [18F]FDG (energy metabolism), radiolabelled amino acids (protein metabolism), [18F]FLT (DNA metabolism), [11C]choline (cell membrane metabolism) as general metabolic tracer methods and [18F]DOPA (biogenic amine metabolism) as a more specific tracer method are discussed. As an example, molecular imaging methods that target the HER2 receptor and somatostatin receptor are described.

Manipulation of [11C]-5-Hydroxytryptophan and 6-[18F]Fluoro-3,4-Dihydroxy-L-Phenylalanine Accumulation in Neuroendocrine Tumor Cells

[(11)C]-5-Hydroxytryptophan ([(11)C]HTP) and 6-[(18)F]fluoro-3,4-dihydroxy-l-phenylalanine ([(18)F]FDOPA) are used to image neuroendocrine tumors with positron emission tomography. The precise mechanism by which these tracers accumulate in tumor cells is unknown. We aimed to study tracer uptake via large amino acid transporters, peripheral decarboxylation (inhibited by carbidopa), and intracellular breakdown by monoamine oxidase (MAO). [(11)C]HTP and [(18)F]FDOPA tracer accumulation was assessed in a human neuroendocrine tumor cell line, BON. The carbidopa experiments were done in a tumor-bearing mouse model. Intracellular [(11)C]HTP accumulation was 2-fold higher than that of [(18)F]FDOPA. Cellular transport of both tracers was inhibited by amino-2-norbornanecarboxylic acid. The MAO inhibitors clorgyline and pargyline increased tracer accumulation in vitro. Carbidopa did not influence tracer accumulation in vitro but improved tumor imaging in vivo. Despite lower accumulation in vitro, visualization of [(18)F]FDOPA is superior to [(11)C]HTP in the neuroendocrine pancreatic tumor xenograft model. This could be a consequence of the serotonin saturation of BON cells in the in vivo model.

Total 18F-dopa PET tumour uptake reflects metabolic endocrine tumour activity in patients with a carcinoid tumour

PurposePositron emission tomography (PET) using 6-[18F]fluoro-L-dihydroxyphenylalanine (18F-dopa) has an excellent sensitivity to detect carcinoid tumour lesions. 18F-dopa tumour uptake and the levels of biochemical tumour markers are mediated by tumour endocrine metabolic activity. We evaluated whether total 18F-dopa tumour uptake on PET, defined as whole-body metabolic tumour burden (WBMTB), reflects tumour load per patient, as measured with tumour markers.MethodsSeventy-seven consecutive carcinoid patients who underwent an 18F-dopa PET scan in two previously published studies were analysed. For all tumour lesions mean standardised uptake values (SUVs) at 40% of the maximal SUV and tumour volume on 18F-dopa PET were determined and multiplied to calculate a metabolic burden per lesion. WBMTB was the sum of the metabolic burden of all individual lesions per patient. The 24-h urinary serotonin, urine and plasma 5-hydroxindoleacetic acid (5-HIAA), catecholamines (nor)epinephrine, dopamine and their metabolites, measured in urine and plasma, and serum chromogranin A served as tumour markers.ResultsAll but 1 were evaluable for WBMTB; 74 patients had metastatic disease. 18F-dopa PET detected 979 lesions. SUVmax on 18F-dopa PET varied up to 29-fold between individual lesions within the same patients. WBMTB correlated with urinary serotonin (r = 0.51) and urinary and plasma 5-HIAA (r = 0.78 and 0.66). WBMTB also correlated with urinary norepinephrine, epinephrine, dopamine and plasma dopamine, but not with serum chromogranin A.ConclusionTumour load per patient measured with 18F-dopa PET correlates with tumour markers of the serotonin and catecholamine pathway in urine and plasma in carcinoid patients, reflecting metabolic tumour activity.

Combining 6-fluoro-[18F]l-dihydroxyphenylalanine and [18F]fluoro-2-deoxy-d-glucose positron emission tomography for distinction of non-carcinoid malignancies in carcinoid patients.

AIM Carcinoid patients frequently develop a second primary malignancy (SPM), which can deserve full treatment. Distinguishing a SPM from carcinoid lesions is therefore important. Differentiation can be achieved using the difference in uptake between different positron emission tomography (PET) tracers. METHODS AND RESULTS Between January 2005 and August 2008, 105 carcinoid patients were seen at the Department of Medical Oncology for treatment and follow-up. We identified 3 patients who presented with a new SPM in whom differentiation between carcinoid lesions and the SPM was guided by functional imaging of the catecholamine pathway with 6-fluoro-[(18)F]l-dihydroxyphenylalanine ((18)F-DOPA) PET and [(18)F]fluoro-2-deoxy-d-glucose ((18)F-FDG) PET as radiotracer for the glucose metabolism. All 3 patients had metastatic carcinoid disease and localised adenocarcinoma based on the PET-scans. For the adenocarcinoma they received curative treatment. CONCLUSION The difference in uptake between these PET techniques can be used for decision making when a primary or metastatic SPM is suspected.

Potential value of EUS in pancreatic surveillance of VHL patients

BACKGROUND Patients with von Hippel-Lindau (VHL) disease are prone to develop pancreatic neuroendocrine tumors (pNETs). However, the best imaging technique for early detection of pNETs in VHL is currently unknown. In a head-to-head comparison, we evaluated endoscopic ultrasound (EUS) and (11)C-5-hydroxytryptophan positron emission tomography ((11)C-5-HTP PET) compared with conventional screening techniques for early detection of pancreatic solid lesions in VHL patients. METHODS We conducted a cross-sectional, prospective study in 22 patients at a tertiary care university medical center. Patients with VHL mutation or with one VHL manifestation and a mutation carrier as first-degree family member, with recent screening by abdominal computed tomography (CT) or magnetic resonance imaging (MRI) and somatostatin receptor scintigraphy (SRS), were eligible. Patients underwent EUS by linear Pentax echoendoscope and Hitachi EUB-525, and (11)C-5-HTP PET. Patient-based and lesion-based positivity for pancreatic solid lesions were calculated for all imaging techniques with a composite reference standard. RESULTS In 10 of the 22 patients, 20 pancreatic solid lesions were detected: 17 with EUS (P < 0.05 vs CT/MRI+ SRS), 3 with (11)C-5-HTP PET, 3 with SRS, 9 with CT/MRI, and 9 with CT/MRI + SRS. EUS evaluations showed solid lesions with a median size of 9.7 mm (range 2.9-55 mm) and most of them were homogeneous, hypoechoic, isoelastic, and hypervascular. Moreover, EUS detected multiple pancreatic cysts in 18 patients with a median of 4 cysts (range 1-30). CONCLUSIONS EUS is superior to CT/MRI + SRS for detecting pancreatic solid lesions in VHL disease.(11)C-5-HTP PET has no value as a screening method in this setting. EUS performs well in early detection of pNETs, but its role in VHL surveillance is unclear.