With the radionuclide tracers available today, 50-90 per cent of neuroendocrine tumours of the gastro-intestinal tract can be visualised with PET (positron-emission tomography). PET also enables the effect of tumour treatment to be monitored in terms of biochemical and functional variables, which is not possible with other radiological techniques. Owing to the very good tumour resolution possible with PET, it serves as a complement to other routine methods such as computed tomography and ultrasonography, and can be used to screen the chest and abdomen for small primary tumours that can not be detected with other methods. In several pre-operative trials PET has been shown to demonstrate more changes in the pancreas and liver than was possible with other methods. In the near future it will be possible to demonstrate the presence of and quantify growth factor receptors, hormones, enzymes, DNA synthesis, mRNA synthesis and protein synthesis. Access to these tumour biological data will be of crucial importance to the individualisation of treatment.

Positron emission tomography (PET) supplies a range of labeled compounds to be used for the characterization of tumor biochemistry. Some of these have proved to be of value for clinical diagnosis, treatment follow up, and clinical research. The first routinely used PET tracer in oncology, ¹⁸F-labeled deoxyglucose (FDG), was successfully used for diagnosis of cancer, reflecting increased expression of glucose transporter in cancerous tissue. This tracer, however, usually does not show sufficient uptake in well-differentiated tumors such as neuroendocrine tumors. We developed a tracer more specific to neuroendocrine tumors—the serotonin precursor 5-hydroxytryptophan (5-HTP) labeled with ¹¹C—and demonstrated increased uptake and irreversible trapping of this tracer in carcinoid tumors. The uptake was so selective and the resolution was so high that we could detect more liver and lymph node metastases with PET than with CT or octreotide scintigraphy. To further improve the method, especially to reduce the high renal excretion of the tracer producing streaky artifacts in the area of interest, we introduced premedication by the decarboxylase inhibitor carbidopa, leading to a six-fold decreased renal excretion while the tumor uptake increased three-fold, hence improving the visualization of the tumors.

¹¹C-labeled l-DOPA was evaluated as an alternative tracer, especially for endocrine pancreatic tumors, which usually do not demonstrate enhanced urinary serotonin metabolites. However, only half of the EPTs, mainly functioning tumors, could be detected with l-DOPA. Instead 5-HTP seems to be a universal tracer for EPT and foregut carcinoids. With new, more sensitive PET cameras, larger field of view and procedures for whole-body coverage, the PET examination with 5-HTP is now routinely performed as reduced whole-body PET examinations with coverage of the thorax and abdomen. With this method we have been able to visualize small neuroendocrine lesions in the pancreas and thorax (e.g., ACTH-producing bronchial carcinoids) not detectable by any other method, including octreotide scintigraphy, MRI, and CT. Another tracer, the 11β-hydroxylase inhibitor, metomidate labeled with ¹¹C, was developed to simplify diagnosis and follow-up of patients with incidentalomas. A large series of patients with incidentally found adrenal masses have been investigated and so far all lesions of adrenocortical origin have been easily identified because of exceedingly high uptake of ¹¹C-metomidate, whereas noncortical lesions showed very low uptake. In addition, adrenocortical cancer shows high uptake, suggesting that this PET tracer can be used for staging purposes.

Positron emission tomography (PET) performed with various radiolabelled compounds facilitates the study of tumor biochemistry. If the tumor uptake of an administered tracer is greater than that of surrounding normal tissue, it is also possible to localize the tumor. In initial studies, 18F-labeled deoxyglucose (FDG) was attempted to visualize the tumors, since this tracer had been successfully used in oncology, reflecting increased glucose metabolism in cancerous tissue. However, this tracer was not to any significant degree taken up by the neuroendocrine tumors. Instead, the serotonin precursor 5-hydroxytryptophan (5-HTP) labeled with 11C was used and showed an increased uptake and irreversible trapping of this tracer in carcinoid tumors. The uptake was selective and the resolution so high that we could detect more liver and lymph node metastases with PET than with CT or octreotide scintigraphy. One problem was, however, the high renal excretion of the tracer producing streaky artifacts in the area of interest. Using the decarboxylase inhibitor carbidopa, given as peroral premedication, the renal excretion decreased 6-fold and at the same time the tumor uptake increased 3-fold, hence improving the visualization of the tumors. When patients were followed during treatment with PET using 5-HTP as a tracer, a > 95% correlation between changes in urinary 5-hydroxyindoleacetic acid (U-5-HIAA) and changes in the transport rate constant for 5-HTP was observed. Thus, PET can be used to monitor treatment effects. Elevation of U-5-HIAA is considered to be uncommon in endocrine pancreatic tumors (EPTs). Initially, 11C-labeled L-DOPA was attempted as another amine important in the APUD system. With L-DOPA about half of the EPTs, mainly functioning tumors, could be detected. Recently, 5-HTP was explored as a universal tracer also for EPT and foregut carcinoids, extending the PET-examination to both thorax and abdomen (whole-body PET-examination). With this method we were able to visualize small lesions in the pancreas and thorax (e.g. ACTH-producing bronchial carcinoids) not detectable by any other method including octreotide scintigraphy, MRI and CT. Several other tracers have been investigated, e.g. the monoamineoxidase (MAO-A) inhibitor harmine with promising results in non-functioning EPTs. We are currently exploring a wide range of biochemical systems, including enzymes and receptors, both for neurotransmitters and for peptides and proteins in in vitro assays with the potential to use some of the developed tracers for in vivo visualization and tumor biological studies. In conclusion, PET is a valuable tool in the diagnosis of neuroendocrine tumors. It can detect small lesions in the thorax and abdomen not detected by other methods, which has been of great value preoperatively in several cases. It detects more lesions in the liver and lymph nodes than other methods and furthermore, it can be used to monitor treatment effects.

Positron emission tomography is an in vivo tracer and imaging technique that utilizes short-lived positron emitting radionuclides (11C, 15O, 13N, 18F) with half-lives ranging between 2 min and 2 hours. These radionuclides are interesting from the labelling viewpoint since they are natural constituents of most biologically active compounds. The short half-life is an advantage with regard to the irradiation dose to the patient but it is also a limitation since it requires the production of these radionuclides in close vicinity to the positron emission tomography camera.

Positron emission tomography (PET) supplies a range of labelled compounds to be used for the characterization of tumour biochemistry. Some of these have proved to be of value for clinical diagnosis, treatment follow-up, and clinical research. ¹⁸F-fluorodeoxyglucose PET scanning is now a widely accepted imaging approach in clinical oncology, reflecting increased expression of glucose transporters in cancerous tissue. This tracer, however, does not show sufficient uptake in well-differentiated tumours such as neuroendocrine tumours. Endocrine tumours have the unique characteristics of taking up and decarboxylating amine precursors. These so-called APUD characteristics offer highly specific targets for PET tracers. Using this approach, radiopharmaceuticals such as [¹¹C]-5-hydroxytryptophan and [¹¹C]-l-dihydroxyphenylalanine for localization of carcinoid and endocrine pancreatic tumours, 6-[¹⁸F]-fluorodopamine and [¹¹C]-hydroxyephedrine for phaeochromocytomas, and [¹¹C]-metomidate for adrenal cortical tumours have been developed. Functional imaging with PET using these compounds is now being employed to complement rather than replace other imaging modalities. Development of new PET radiopharmaceuticals may in the future allow in vivo detection of tumour biological properties, such as malignant potential and responsiveness to treatment.

In a substantial proportion of cases with endocrine malignant disease the primary lesion cannot be localised and the pathologist hesitates upon the origin of the tumour. Well differentiated neuroendocrine carcinomas of the small bowel can usually be identified by the strong serotonin immunoreactivity, but foregut carcinoids may also stain positive for serotonin and the differential diagnosis between the various foregut tumours may be difficult. We examined if immunostaining for gastrin-releasing-peptide (GRP) may aid in establishing the origin of an unknown neuroendocrine tumour. Tumour tissue from 79 patients (27 lung carcinoids, 4 thymic carcinoids, 4 gastric neuroendocrine tumours, 17 pancreatic well differentiated neuroendocrine carcinomas, 1 duodenal well differentiated neuroendocrine tumour and 26 well differentiated neuroendocrine carcinomas of the small bowel) were immunostained with antibodies against GRP and serotonin. Positive staining for GRP was found in 12/27 lung carcinoids. All other tumour types were consistently GRP-negative (p?<?0.0001). We conclude that immunostaining for GRP may aid in defining the origin of the tumour, and that GRP-immunoreactivity increases the suspicion of a lung carcinoid.

For general oncological imaging, positron emission tomography (PET) using [18F]fluoro-deoxy-glucose (FDG) has evolved as a powerful functional imaging modality. Unfortunately, FDG-PET has not been as advantageous for imaging gastropancreatic neuroendocrine tumors, and only tumors with high proliferative activity and low differentiation have shown an increased FDG uptake. Therefore, the 11C-labeled amine precursors L-dihydroxyphenylalanine and 5-hydroxy-L-tryptophan (5-HTP) were developed for PET imaging of these tumors. Because of the higher tumor uptake of the latter tracer in a study of patients with endocrine pancreatic tumors, 11C-5-HTP was chosen for further evaluation. In comparative studies of patients with carcinoids and endocrine pancreatic tumors, 5-HTP-PET proved better than CT and somatostatin receptor scintigraphy for tumor visualization, and many small, previously overlooked lesions were diagnosed by 11C-5-HTP-PET. The strong correlation found during medical treatment between the changes in the transport rate constant at repeated PET and those of U-HIAA indicates the possible use of 11C-5-HTP-PET also for therapy monitoring. By premedication of patients with Carbidopa orally before PET examination, in order to block the aromatic amino acid decarboxylase enzyme, the decarboxylation rate of 11C-5-HTP was decreased, leading to a higher tumor uptake and a considerably lower urinary radioactivity concentration.

Positron emission tomography (PET) with ¹¹C-labeled 5-hydroxytryptophane (5-HTP) is a sensitive technique to visualize neuroendocrine tumours (NETs), due to high intracellular uptake of amine-precursors like L-dihydroxyphenylalanine (L-DOPA) and 5-HTP. NETs are often small and difficult to localize in spite of overt clinical symptoms due to hormonal excess. In our study, 38 consecutive NET patients underwent ¹¹C-5-HTP-PET and morphological imaging by CT within 12 weeks prior to surgery. Surgical, histopathological and 5-HTP PET findings were correlated. ¹¹C-5-HTP-PET corresponded to the surgical findings in 31 cases, was false negative in six, and true negative in one case resulting in 83.8% sensitivity and 100% specificity. Positive predicted value was 100%. In 11 patients ¹¹C-5-HTP-PET was the only imaging method applied to localize the tumour. Thus, we could demonstrate that functional imaging by ¹¹C-5-HTP-PET in many cases adds vital preoperative diagnostic information and in more than every fourth patient was the only imaging method that will guide the surgeon in finding the NET-lesion. Although the present results demonstrates that ¹¹C-5-HTP may be used as an universal NET tracer, the sensitivity to visualize benign insulinomas and non functioning pancreatic NETs was lower.

PURPOSE: Positron emission tomography (PET) with 11C-5-hydroxytryptophan (5-HTP) as tracer is a promising imaging instrument in the management of patients with neuroendocrine tumours (NETs). However, high radioactivity concentrations in the urinary collecting system sometimes produce image reconstruction artefacts that can make detection of small NETs difficult. As a means to decrease urinary excretion of radioactivity and thereby improve image quality, we examined the effect of pretreatment with carbidopa (CD), a peripheral inhibitor of aromatic amino acid decarboxylase (AADC), which converts 5-HTP to serotonin (5-hydroxytryptamine, 5-HT). METHODS: Six patients with midgut carcinoid metastases were examined with 11C-5-HTP PET before and 1 h after oral administration of 100 or 200 mg of CD. RESULTS: There was a fourfold significant reduction of tracer uptake in the urinary collecting system after CD administration (p=0.0277, n=6), with a mean standard uptake value (SUV) of 155+/-195 before CD and 39+/-14 after CD. In tumour lesions there was a significant increase in SUV after CD administration (p<0. 0001, n=18), with a mean SUV of 11+/-3 before CD and 14+/-3 after CD. There was no difference between the doses (100 and 200 mg) of CD in this respect. In all patients, image interpretation and tumour detection were markedly improved after CD administration. CONCLUSION: We conclude that CD premedication improves 11C-5-HTP PET image quality and facilitates detection of NET lesions. Because of the similarity of metabolic pathways, this method could probably be applied to improve PET imaging using other tracers like 18F-DOPA and 11C-DOPA.