|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2008.19.1551 on October 14 2008 © 2008 American Society of Clinical Oncology.
In Reply:
Department of Pathology and Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands The key message of Kauhanen et al1 in their letter in response to our article is that carbidopa may mask visualization of insulinoma and pancreatic β-cell hyperplasia by means of 6-[18F]fluoro-3,4-dihydroxy-L-phenylalanine (18F-DOPA). In our study, we analyzed 24 patients with carcinoid and 23 patients with islet cell tumor with 18F-DOPA and [11C]-5-hydroxy-tryptophan (11C-5-HTP) positron emission tomography (PET).2 All patients received carbidopa 2 mg/kg orally 1 hour before tracer injection to increase tracer availability for uptake in tumor cells. The reason to include carbidopa was that the literature (see also1) indicated that carbidopa can increase accumulation of both tracers by neuroendocrine tumor cells. Carbidopa is a competitive inhibitor of aromatic L-amino acid decarboxylase (AADC, EC 4.1.1.28 [EC] ), which does not cross the blood-brain barrier. Outside the brain, AADC activity is present in many organs, notably the liver and kidneys.3 Coadministration of carbidopa with 18F-DOPA and 11C-5-HTP results in higher tracer availability for tumor uptake, as a result of inhibiton of renal decarboxylation and subsequent clearance of the decarboxylated tracers. In patients with islet cell tumors, per-patient analysis showed sensitivities for 18F-DOPA PET and 11C-5-HTP PET of 89% and 100%, respectively; per-lesion analysis showed 41% and 67%, respectively.2 None of our patients with islet cell tumor had an insulinoma. In addition, we performed a study in animals with a xenograft of the islet cell tumor BON.4 Here we showed that, indeed, the administration of carbidopa before the 18F-DOPA and 11C-5-HTP tracer injection did increase islet cell tumor uptake. Kauhanen et al1 and previously Ribeiro et al5 show convincingly that carbidopa masked the uptake of 18F-DOPA in total in two of three patients with hyperinsulinism and in one out of two patients with insulinoma. It should be noted that these patients probably represent a group with diseases that can be considered as nonmalignant. Insulinomas are mostly classified as well-differentiated endocrine tumors of benign or uncertain behavior at the time of diagnosis, in contrast to the other islet cell tumors that are in general well-differentiated endocrine carcinomas with low-grade malignant behavior. Given this information, we would like to discuss 18F-DOPA and 11C-5-HTP tracer handling by the tumor cells and to propose an explanation for current observations, as well as suggestions on how to implement this knowledge for future scanning of islet cell tumor patients with these tracers. In the cellular accumulation of labeled amines from amine-precursor tracers in neuroendocrine tumors, several essential steps play a role (Fig 1). 18F-DOPA and 11C-5-HTP are transported into the cell by the L-type amino acid transporter and subsequently become decarboxylated by AADC, resulting in the formation of 18F-dopamine and 11C-serotonin. These biogenic amine tracers are then transported into the cellular granules by vesicular monoamine transporter and thus are protected from enzymatic degradation by intracellular enzymes such as monoamine oxidase and catechol-O-methyl transferase. 18F-dopamine and 11C-serotonin formed by decarboxylation in other cells/organs, theoretically can enter the cell via the dopamine and serotonin transporters and thereafter become stored in granules as described above.
AADC is obviously a key enzyme to aid in our understanding of the role of cardidopa. Its activity varies widely between tissues and is highly dependent on factors such as availability of its cofactor pyridoxal phosphate (active form of vitamin B6).6 Moreover, the affinity of this enzyme for DOPA is approximately two-fold lower than for 5-HTP in rat pancreatic acinar cells.7 Our explanation for the carbidopa effect on visualization of insulinoma by 18F-DOPA is based on variation in AADC activity in tumors. AADC is in general upregulated in neuroendocrine tumors, which exhibit the capacity to produce biogenic amines. It is highly expressed in pheochromocytomas8 and carcinoids,9 and lower levels are present in islet cell tumors.9 The observation that more than half of the islet cell tumors could be visualized in our study with carbidopa and 18F-DOPA2 supports the fact that there are islet cell tumors with AADC activity. Carbidopa diffuses to a variable extent into different normal tissue types and always at least slightly suppresses AADC, including in the pancreas.10,11 When AADC activity is already low, further reduction prohibits visualization with 18F-DOPA. In the pancreas, dopamine handling is especially complex, as both endocrine and exocrine cells contain markers associated with dopamine synthesis, notably tyrosine hydroxylase, AADC, dopamine transporter, and vesicular monoamine transporter, but are differently regulated. After 18F-DOPA administration without carbidopa pretreatment, some diffuse accumulation of the radioactive tracer throughout the pancreas can be seen. Pancreatic dopamine is especially produced in the exocrine cells and is considered to be involved in protection of the intestinal mucosa.12 Visualization of the pancreas diminishes after carbidopa administration, perhaps specifically by affecting the conversion to 18F-dopamine in the exocrine cells. Because exocrine cells form the majority of the pancreas, carbidopa results in reduction of background activity, potentially increasing the tumor-to-background ratio. Whether the islet cell tumor, when still in situ, shows up is dependent on the tumor AADC activity. In case of the likely rare situation of an intrinsic total absence of AADC activity in the tumor, as can occur in neurendocrine tumors,9 no dopamine will be produced intracellularly after 18F-DOPA injection, and only pheripheral decarboxylation of the tracer can result in 18F-dopamine tumor uptake by the dopamine transporter (Fig 1). This rescue would be blocked by carbidopa. That AADC affinity for 5-HTP is likely higher than for DOPA and therefore converts 5-HTP to serotonin at a lower level than for DOPA to dopamine may explain that the results of the 11C-5-HTP scan are less, or even not, hampered by carbidopa administration. Earlier, we indicated that we think that 11C-5-HTP PET is superior in islet cell tumors, whereas 18F-DOPA PET performs best in carcinoids. The inferior performance of 11C-5-HTP PET in carcinoids is likely due to the fact that in carcinoids, in contrast to islet cell tumors, the serotonin pathway is highly active, saturating the granules and leaving less storage capacity for 11C-serotonin.2 We consider the main reason for the finding of variable results found after carbidopa with 18F-DOPA PET scan in islet cell tumors to be the dependency of this effect on AADC activity. This would mean that in islet cells tumors with significant AADC activity, carbidopa pretreatment results in a better (or in case of low/absent AADC, a worse) tumor visualization with 18F-DOPA PET scan. For carcinoids and pheochromocytomas, it was shown that these tumors have higher activity than surrounding normal endocrine tissue.8,9 Whether this also holds true for the generally benign insulinomas versus other malignant islet cell tumors remains to be investigated. Currently, 11C-5-HTP with carbidopa pretreatment is the superior tracer for islet cell tumor patients. However, given the limited availability of this tracer because of its laborious production process, it is worthwhile to study in which islet cell tumor patients 18F-DOPA PET scan might perform best with or without carbidopa pretreatment and correlate the findings with tumor AADC levels. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
NOTES published online ahead of print atwww.jco.org on October 13, 2008 REFERENCES 2. Koopmans KP, Neels OC, Kema IP, et al: Improved staging of patients with carcinoid and islet cell tumors with 18F-dihydroxy-phenyl-alanine and 11C-5-hydroxy-tryptophan positron emission tomography. J Clin Oncol 26:1489-1495, 2008 3. Nagatsu T: Biochemistry of catecholamines. University Park Press Baltimore, MD 1973, pp 153-208 4. Neels OC, Koopmans KP, Jager PL, et al: Manipulation of [11C]-5-hydroxytryptophan and 6-[18F]fluoro-3,4-dihydroxy-L-phenylalanine accumulation in neuroendocrine tumor cells. Cancer Res 68:7183-7190, 2008 5. Ribeiro MJ, Boddaert N, Bellanné-Chantelot C, et al: The added value of [18F]fluoro-L-DOPA PET in the diagnosis of hyperinsulinism of infancy: A retrospective study involving 49 children. Eur J Nucl Med Mol Imaging 34:2120-2128, 2007[CrossRef][Medline] 6. Hartvig P, Lindner KJ, Bjurling P, et al: Pyridoxine effect on synthesis rate of serotonin in the monkey brain measured with positron emission tomography. J Neural Transm Gen Sect 94:127-135, 1993[CrossRef][Medline] 7. Yu EW, Stern L, Tenenhouse A: Decarboxylation of L-dopa and 5-hydroxytryptophan in dispersed rat pancreas acinar cells. Pharmacology 29:185-192, 1984[CrossRef][Medline] 8. Isobe K, Nakai T, Yukimasa N, et al: Expression of mRNA coding for four catecholamine-synthesizing enzymes in human adrenal pheochromocytomas. Eur J Endocrinol 138:383-387, 1998[Abstract] 9. Uccella S, Cerutti R, Vigetti D, et al: Histidine decarboxylase, DOPA decarboxylase, and vesicular monoamine transporter 2 expression in neuroendocrine tumors: Immunohistochemical study and gene expression analysis. J Histochem Cytochem 54:863-875, 2006 10. Durso R, Evans JE, Josephs E, et al: Variable absorption of carbidopa affects both peripheral and central levodopa metabolism. J Clin Pharmacol 40;854-860, 2000[Abstract] 11. Vickers S, Stuart EK, Bianchinine JR, et al: Metabolism of carbidopa [L-(-)- 12. Mezey E, Eisenhofer G, Harta G, et al: A novel nonneuronal catecholaminergic system: Exocrine pancreas synthesizes and releases dopamine. Proc Natl Acad Sci USA 93:10377-10382, 1996
Related Correspondence
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
-hydrazino3,4-dihydroxy-
