False-positive findings on 6-[18F]fluor-l-3,4-dihydroxyphenylalanine PET (18F-FDOPA-PET) performed for imaging of neuroendocrine tumors

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  • 1 Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
  • | 2 Department of Pathology, Erasmus University Medical Center, Rotterdam and Reinier de Graaf Hospital, Delft, The Netherlands
  • | 3 Departments of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
  • | 4 Departments of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
  • | 5 Departments of Surgical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
  • | 6 Departments of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

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Background/aim

PET with 6-[18F]fluor-l-3,4-dihydroxyphenylalanine (18F-FDOPA) has been shown to be a useful imaging tool with a high sensitivity for the visualization of neuroendocrine tumors (NETs). 18F-FDOPA uptake in tumors other than NETs has been suggested previously, but data on this phenomenon are limited. We therefore studied the non-physiological, false-positive uptake of 18F-FDOPA in a large population of patients with a NET or with a high clinical suspicion of harboring a NET.

Patients and methods

Retrospective single-center study among adult patients in whom 18F-FDOPA PET scintigraphy was performed between January 2004 and December 2014. The original scan report was compared with the original pathology report corresponding with the 18F-FDOPA PET-positive lesion. In case this was inconsistent with the diagnosis of a NET, both the scan and the pathology slides were reassessed. Specimens of these non-NET tissues were immunohistochemically stained for AADC.

Results

1070 18F-FDOPA PET scans from 705 patients were evaluated. Focal or multiple 18F-FDOPA-avid lesions were described in 709 18F-FDOPA PET scans (66%). Histology of these 18F-FDOPA PET-positive lesions was present in 508 (72%) cases. In seven cases, the histopathology was not compatible with NET but showed squamous cell carcinoma of the cervix, multiple myeloma (two cases), hepatocellular carcinoma, Schwannoma, adrenocortical carcinoma and a skeletal myxoid chondrosarcoma, with positive immunohistochemical staining for AADC in 67%.

Conclusions

Pathological uptake of 18F-FDOPA does not always indicate the presence of a NET. The possibility of 18F-FDOPA uptake by tumor types other than NETs, although rare, should be considered.

Abstract

Background/aim

PET with 6-[18F]fluor-l-3,4-dihydroxyphenylalanine (18F-FDOPA) has been shown to be a useful imaging tool with a high sensitivity for the visualization of neuroendocrine tumors (NETs). 18F-FDOPA uptake in tumors other than NETs has been suggested previously, but data on this phenomenon are limited. We therefore studied the non-physiological, false-positive uptake of 18F-FDOPA in a large population of patients with a NET or with a high clinical suspicion of harboring a NET.

Patients and methods

Retrospective single-center study among adult patients in whom 18F-FDOPA PET scintigraphy was performed between January 2004 and December 2014. The original scan report was compared with the original pathology report corresponding with the 18F-FDOPA PET-positive lesion. In case this was inconsistent with the diagnosis of a NET, both the scan and the pathology slides were reassessed. Specimens of these non-NET tissues were immunohistochemically stained for AADC.

Results

1070 18F-FDOPA PET scans from 705 patients were evaluated. Focal or multiple 18F-FDOPA-avid lesions were described in 709 18F-FDOPA PET scans (66%). Histology of these 18F-FDOPA PET-positive lesions was present in 508 (72%) cases. In seven cases, the histopathology was not compatible with NET but showed squamous cell carcinoma of the cervix, multiple myeloma (two cases), hepatocellular carcinoma, Schwannoma, adrenocortical carcinoma and a skeletal myxoid chondrosarcoma, with positive immunohistochemical staining for AADC in 67%.

Conclusions

Pathological uptake of 18F-FDOPA does not always indicate the presence of a NET. The possibility of 18F-FDOPA uptake by tumor types other than NETs, although rare, should be considered.

Introduction

Neuroendocrine tumors (NETs) are rare tumors arising from neuroendocrine cells throughout the body, such as medullary thyroid carcinomas (MTCs), pheochromocytomas (PCCs), paragangliomas (PGLs) and gastro-entero-pancreatic (GEP) NETs. Establishing hormonal overproduction and functional nuclear imaging are important diagnostic tools, used for both the initial work-up and the follow-up of NETs. PET scanning with 6-[18F]fluoro-l-3,4-dihydroxyphenylalanine (18F-FDOPA) has been shown to be a valuable technique for the imaging of NETs (1, 2, 3, 4, 5, 6, 7, 8, 9). Recently, a guideline was published in order to assist nuclear medicine physicians in reporting and interpreting the results of 18F-FDOPA PET scans in this heterogeneous group of tumors (9). 18F-FDOPA is transported into the cell by type 1 L-type amino acid transporter (LAT-1). This membrane-bound transporter is responsible for the uptake of amino acids such as tyrosine and tryptophan, the precursors of dopamine and serotonin respectively (3, 10). 18F-FDOPA is subsequently decarboxylated by aromatic-l-amino acid decarboxylase (AADC) to 18F-fluorodopamine, which is transported into storage vesicles by the vesicular monoamine transporters (VMATs). This pathway is active in various NETs and an overexpression of the enzymes involved has been demonstrated in these tumors (3).

The sensitivity of 18F-FDOPA PET varies from 74% for metastatic PGLs up to 100% for benign PCC and metastatic GEP NETs (2, 4, 11, 12). While the sensitivity of 18F-FDOPA PET has been assessed in several studies, information about its specificity is scarce. Recently, Chondrogiannis et al. and Calabria et al. described the normal bio distribution pattern and physiologic variants of 18F-FDOPA PET imaging (13, 14). Studies systematically describing false-positive results other than physiological variants are virtually lacking, besides the series of Calabria et al. with 54 patients who underwent whole-body 18F-DOPA PET (14). Therefore, the primary aim of this study was to examine a large series of 18F-FDOPA PET scans in order to assess the occurrence of false-positive test results, i.e. uptake in benign or malignant non-NET lesions that cannot be attributed to physiological variants. Furthermore, we aimed to examine whether false-positive test results are associated with the expression of AADC as measured by immunohistochemical staining of the histologically proven non-NET lesions.

Patients and methods

Patients

Patients, aged 18 years or older, in whom a 18F-FDOPA PET scan was performed for the purpose of imaging of either the primary location of a NET or NET metastases (PCC, PGL, MTC, GEP-NET, ACTH-producing tumor, lung carcinoid), were eligible for this study. This single-center study was conducted at the University Medical Center Groningen (UMCG). All 18F-FDOPA PET scans performed between January 2004 (introduction of this scan for NET indication at the UMCG) and December 2014 were evaluated. Clinical data were obtained from medical charts. A lesion was considered positive (i.e. pathological) if not compatible with the normal bio distribution pattern and physiologic variants of 18F-FDOPA PET uptake (13, 14). The original 18F-FDOPA PET scan report was compared to the original pathology report (when histology was present) of an 18F-FDOPA PET-positive lesion, resulting in a direct lesion-to-lesion comparison. In case the pathologic examination of a 18F-FDOPA PET-positive lesion did not reveal the presence of a NET, the 18F-FDOPA PET scan and the pathology slides were reassessed by a nuclear medicine physician (AHB) and two dedicated NET pathologists (GKU, RdK) respectively. If reassessment confirmed these discrepancies, the uptake was classified as false positive, i.e. uptake in a tumor other than a NET. Patients gave written informed consent for reassessment of histology. Because of the retrospective nature of this study and the use of clinical data, no further institutional review board approval was required, according to the Dutch Medical Research Involving Human Subjects Act.

18F-FDOPA PET

The 18F-FDOPA was produced in the radiochemical laboratory of our hospital as described previously (2). Patients fasted for 6 h before the examination and were allowed to continue their medication. The whole-body PET images were acquired 60 min after the intravenous injection of 200 MBq 18F-FDOPA. Carbidopa (2 mg/kg, max 150 mg) was given 60 min prior to the 18F-FDOPA injection. In case of a pancreatic NET, no Carbidopa was given (9). Patients were scanned from upper thigh to head in up to eight consecutive bed positions. During the study period, two different cameras were used, a Siemens ECAT HR+ (high-resolution) PET-only camera (from January 2004 until September 2009) and the Siemens Biograph mCT (64 slice) PET-CT camera (from September 2009 onwards). Camera scanning time per bed position was 8 min (5 min emission and 3 min transmission for attenuation correction) for the PET-only and 1–3 min (depending on body weight) for the PET/CT camera. For the PET/CT camera, a non-enhanced low-dose CT scan was performed for attenuation and scatter correction. Standardized uptake values (SUVs) for measurement of the uptake in a tumor normalized on the basis of a distribution volume was calculated in accordance with the EARL (European Association of Nuclear Medicine Research Ltd.) version 1 (15) for patients scanned on the PET/CT camera.

Immunohistochemistry

Immunohistochemical staining for chromogranin A and synaptophysin was performed for all but one of the 18F-FDOPA PET-positive lesions other than a NET before the reassessment of the dedicated NET pathologists. Furthermore, AADC immunohistochemistry was performed using the Envision Detection Systems Peroxidase/DAB, Rabbit/Mouse kit (No. K4065; Dako), as previously described (Chemicon/Millipore AB136; 1:100 dilution) (16). Synaptophysin and chromogranin A immunohistochemistry were performed in a routine diagnostic setting using the Ventana automated stainer (details available upon request).

Statistics

All data are descriptive and performed using SPSS statistics (version 22.0; IBM Corp., Armonk, NY, USA).

Results

Patients

Between January 2004 and December 2014, 1070 18F-FDOPA PET scans were performed at the UMCG. Overall, 566 (53%) of these scans were performed before September 2009. The 18F-FDOPA PET scan was ordered in case of a high index of clinical suspicion or evaluation of the following NETs: GEP-NET (n = 683), PCC (n = 198), MTC (n = 81), PGL (n = 66), ACTH-producing tumor (n = 26), lung carcinoids (n = 9) and a group of various other NETs consisting of thymus carcinoids, pituitary adenoma, primitive NET of the sellar region, aryepiglottic NET, FGF23-producing NET and NETs of unknown origin (n = 7).

A total of 1070 18F-FDOPA PET scans were performed in 705 patients. The majority, i.e. 505 patients (72%), underwent a single 18F-FDOPA PET scan, whereas 116 (16%) and 84 (12%) of the patients underwent two or at least three scans, respectively.

18F-FDOPA PET scans

According to the original report, focal or multiple 18F-FDOPA avid lesions were described in 709 18F-FDOPA PET scans (66%). Only physiological uptake was described in the remaining 361 18F-FDOPA PET scans (34%) (Fig. 1). In 507 out of 709 (72%) scans, histology of an 18F-FDOPA PET-positive lesion was present after lesion-to-lesion comparison. The original pathology report was not compatible with a NET in 7 of these 507 (1.4%) scans. These seven 18F-FDOPA PET scans were performed in seven different individuals with a mean age of 54 (±13) years. Four of the seven 18F-FDOPA PET scans were performed before September 2009 (PET-only camera).

Figure 1
Figure 1

Flowchart of re-evaluation of the 6-[18F]fluor-l-3,4-dihydroxyphenylalanine PET (18F-FDOPA PET) scan reports.

Citation: European Journal of Endocrinology 179, 2; 10.1530/EJE-18-0321

The pathological uptake in these seven 18F-FDOPA scans was attributable to histologically proven squamous cell carcinoma of the cervix (n = 1), multiple myeloma (n = 2), hepatocellular carcinoma (n = 1), Schwannoma (n = 1), adrenocortical carcinoma (n = 1) and a skeletal myxoid chondrosarcoma (n = 1) (Figs 2, 3 and Table 1). Except for one, all false-positive lesions had a mild-to-moderate 18F-FDOPA tracer uptake. SUVmax values for the three cases scanned on the PET/CT were 1.82 (patient 3), 9.26 (patient 6) and 2.11 (patient 7) (Table 1).

Figure 2
Figure 2

6-[18F]fluor-l-3,4-dihydroxyphenylalanine (18F-FDOPA) uptake in a histologically proven squamous cell carcinoma of the cervix. Transverse reconstruction of the pelvic area of (A) low-dose CT, (B) fused 18F-FDOPA PET (PET)/CT, (C) 18F-FDOPA PET only images, and (D) sagittal maximum intensity projection of the whole body 18F-FDOPA PET.

Citation: European Journal of Endocrinology 179, 2; 10.1530/EJE-18-0321

Figure 3
Figure 3

6-[18F]fluor-l-3,4-dihydroxyphenylalanine (18F-FDOPA) uptake in a histologically proven hepatocellular carcinoma of the liver. Maximum intensity projection of the whole body 18F-FDOPA PET.

Citation: European Journal of Endocrinology 179, 2; 10.1530/EJE-18-0321

Table 1

Results of 6-[18F]fluor-l-3,4-dihydroxyphenylalanine (18F-FDOPA) uptake and immunohistochemical staining in non-neuroendocrine tumors.

Gender and age (years)Clinical pictureIndication 18F-FDOPA PET scan: suspicion ofUptake in*Final pathologyImmunohistochemical staining for AADC
1F, 60New-onset diabetes, pancreas lesion*, elevated CgAGEP-NETIliac bone, right humerusMultiple myelomaNegative
2F, 67Malaise, liver lesion*, elevated CgAGEP-NETLiverHepatocellular carcinomaPositive
3M, 47Tumor of carotid body* deafness, peripheral facialis paresisParagangliomaCarotid bodyMultiple myelomaPositive
4F, 34Neck mass, elevated MNParagangliomaNeckSchwannomaNA
5F, 41Tumor of skull base*, elevated MNParagangliomaSkull baseSkeletal myxoid chondrosarcomaNegative
6F, 64Hypertension, elevated MNPheochromocytomaPelvic regionSquamous cell carcinoma cervixPositive
7M, 62Flank pain, nausea, flushes, retroperitoneal mass*PheochromocytomaLeft adrenal gland and liver lesionsAdrenocortical carcinomaPositive

*Confirmed by anatomical imaging CT/MRI − lesion-to-lesion comparison.

18F-FDOPA PET, l-6-fluor-3,4-dihydroxyphenylalanine-position emission tomography; CgA, chromogranin A; F, female; GEP-NET, gastro-entero-pancreatic neuroendocrine tumor; M, male; MN, metanephrines; NA, not assessed.

Immunohistochemical findings

Six out of the seven 18F-FDOPA PET-positive lesions other than a NET were available for immunohistochemical staining for AADC, chromogranin A and synaptophysin. Besides a positive staining for synaptophysin in the case of adrenocortical carcinoma (Fig. 3, panel D), no other tumor tissue specimen stained positive for chromogranin A and synaptophysin. Notably, positive immunostaining for synaptophysin has been well described in adrenocortical carcinoma (17). Four of the six tumor tissue specimens (67%) stained positive for AADC (Fig. 4 and Table 1).

Figure 4
Figure 4

Histology and immunohistochemical staining pattern of selected lesions: (A, B, C and D) adrenocortical carcinoma with: (A) Hematoxylin and eosin staining. (B) Positive immunohistochemical staining for aromatic-l-amino acid decarboxylase (AADC). (C) Negative staining for Chromogranin A. (D) Positive staining for synaptophysin. (E and F) Squamous cell carcinoma of the larynx with: (E) Hematoxylin and eosin staining. (F) Negative staining for AADC.

Citation: European Journal of Endocrinology 179, 2; 10.1530/EJE-18-0321

Discussion

In the present study, we show that pathological uptake of the PET tracer 18F-FDOPA is not always synonymous with the presence of a NET. In this large series, false-positive test results due to 18F-FDOPA uptake in a tumor other than a NET were observed in various neoplasms such as carcinoma, multiple myeloma, chondrosarcoma and benign Schwannoma.

According to the recently published guideline for 18F-FDOPA PET/CT imaging of NETs, our findings emphasize the importance to be a priori aware of what is expected to ‘be seen’ (i.e. physiological tracer uptake and variants), what is ‘looked for’ (i.e. clinical suspicion) and the common and uncommon pitfalls related to pathology (i.e. non-physiological false-positive tracer uptake) (9).

Even if the 18F-FDOPA PET scan is performed in a patient with a high index of clinical suspicion of harboring a NET, one should be aware of false-positive tracer uptake due to the presence of a non-NET. One should even consider the possibility of a concurrent second primary malignancy, since patients with a NET are at increased risk to develop other neoplasms, especially those older than 70 years of age (18).

Chondrogiannis et al. and Calabria et al. recently described the physiological bio distribution, normal variants and common pitfalls of the 18F-FDOPA PET scan, such as uptake in excretory organs like gallbladder, pancreas and urinary tract (13, 14). Uptake of 18F-FDOPA in tumors other than NETs is only been described earlier in a few patient reports including the following diagnoses: epiglottic squamous cell carcinoma (19), Hürthle cell neoplasm (20), solid pseudopapillary pancreatic tumor (21) and a poorly differentiated metastatic adenocarcinoma of unknown primary (22). In addition, it has been described in vitro in squamous cell carcinoma cell lines and in corresponding mouse tumor xenograft models (23, 24).

To the best of our knowledge, there has been only one study so far in which non-physiological and false-positive 18F-FDOPA PET uptake was systematically examined in a relative large group of patients (14). In this study by Calabria et al. of 54 patients who underwent whole-body 18F-DOPA PET, several cases were described with false-positive 18F-DOPA uptake, predominantly in inflammatory tissue and some benign tumors as well (14). In that study, however, the suggested false-positive 18F-FDOPA uptake was not firmly established as data on the clinical follow-up were often incomplete and histological proof of the lesions was lacking. In our study, we report for the first time 18F-FDOPA uptake in various malignant tumors and demonstrate an association between this uptake and the presence of AADC in the corresponding tissues.

The catecholamine precursor 18F-FDOPA is transported into the cell by the membrane-bound LAT-1, where it is subsequently decarboxylated by AADC to 18F-fluorodopamine (3, 10). After its decarboxylation, 18F-fluorodopamine is transported from the cytosol into storage vesicles, preferentially by VMAT1 (25). This pathway is active in various NETs, which explains the high sensitivity of 18F-FDOPA PET for detecting these tumors. Our study suggests, however, that this pathway is not entirely specific for NETs, but might also be active in other tumor tissues as illustrated by our finding of positive immunohistochemical staining for AADC. The negative immunostaining for synaptophysin and chromogranin A shows that the tumors in our series should not be considered as neuroendocrine differentiated.

The pathophysiological role of DOPA uptake and decarboxylation in non-NET tumors is yet to be established. AADC primarily catalyzes the conversion of l-DOPA toward dopamine. Several studies have shown that dopamine exerts inhibitory effects on cell proliferation and angiogenesis (26, 27). The uptake of DOPA and the expression of AADC might therefore be viewed as a favorable sign, but this remains speculative and further studies are warranted to determine whether 18F-FDOPA uptake by tumors other than NET has any prognostic significance. The enzymatic activity and expression of the AADC enzyme has been demonstrated previously in a subset of adenocarcinomas, (head and neck) squamous cell carcinomas, osteosarcomas, melanomas, neuroblastomas and carcinomas of prostate and lung (28, 29, 30, 31, 32, 33, 34).

Another element of this pathway, which has recently received specific attention is LAT-1 and its potential function in human tumors. LAT-1 is physiologically expressed in a few organs, i.e. brain, spleen, thymus and testes (10, 35). It has been suggested that upregulation of this transporter stimulates tumorigenesis by increasing the uptake of several amino acids, thereby enhancing protein synthesis. In addition, one of the major LAT substrates is leucine, which has been implicated in human carcinogenesis by activating mTORC 1 (mammalian target of rapamycin complex 1) (10, 35, 36, 37, 38). LAT-1 expression has been documented previously in various neoplasms such as squamous cell carcinomas, adenocarcinomas of the gastrointestinal tract, multiple myeloma, renal cell carcinoma, hepatocellular carcinoma, prostate carcinoma, pancreatic carcinoma, gliomas, non-small-cell lung cancer and mesotheliomas (10, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51). LAT1 belongs to the family of L-type neutral amino acid transporters, which consists of four members. LAT1 and LAT 2 are bound to a cell-surface glycoprotein CD98 heavy chain, thereby forming a heterodimer exchanger with a high affinity. The other two members, i.e. LAT3 and LAT4, do not associate with CD98 heavy chain and have a low affinity for neutral amino acids. In contrast to LAT1, however, the potential role of the other LAT subtypes in carcinogenesis has been less well documented (24, 52, 53). It is currently unknown whether tumors other than NETs also express other components of the DOPA uptake and conversion pathway such as VMATs.

It is usually considered that 18F-FDOPA PET scintigraphy results in few false-positive findings, based on the paradigm that only neuroendocrine cells are able to take up, decarboxylate and store amino acids and their amines. Our study, however, suggests that this pathway is not entirely specific for NET, and that it might also be active in other tumor tissues not classified as NET. There could be differences in the metabolic activity of this pathway, since uptake characteristics in the demonstrated non-NET tumors seemed less intense when compared to NET.

A limitation of this study was that histological confirmation was not available for all 18F-FDOPA-positive lesions. Therefore, we cannot draw any firm conclusions about the specificity of 18F-FDOPA PET imaging for detection of a NET, but this was also not the aim of our study. The chance that 18F-FDOPA PET is taken up by a non-NET tumor seems to be relatively low as only 7 of 507 (1.4%) pathological proven lesions were not compatible with a NET. However, this is likely to represent an underestimation of the true incidence since 18F-FDOPA PET scans were only performed during the diagnostic work-up of a suspected NET. The absence of positive immunohistochemical staining for AADC in two tissue specimens despite the presence of 18F-FDOPA PET positivity could also reflect a tissue sampling error. Alternatively, this could be explained by ‘overfixation’ of the samples, which might have influenced the binding of the specific antibodies.

In conclusion, in case of demonstration of 18F-FDOPA PET-avid lesions, the presence of a non-NET tumor should also be considered. This phenomenon seems at least in part to be related to the expression of AADC in these tumors.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this study.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Author contribution statement

Study design: A M A Berends, J W Bolt, M N Kerstens, T P Links, A H Brouwers, A N A v d Horst-Schrivers. Data collection: A M A Berends, J W Bolt, E Korpershoek, R R de Krijger, A M E Walenkamp, W Noordzij, B van Etten, G Kats-Ugurlu. Data analysis: A M A Berends, J W Bolt, A H Brouwers, M N Kerstens, A N A v d Horst-Schrivers. Preparation of the manuscript: A M A Berends, A H Brouwers, M N Kerstens, A N A v d Horst-Schrivers. Editing and final approval of the manuscript: All authors.

References

  • 1

    Hoegerle S, Ghanem N, Altehoefer C, Schipper J, Brink I, Moser E & Neumann HP. 18F-DOPA positron emission tomography for the detection of glomus tumours. European Journal of Nuclear Medicine and Molecular Imaging 2003 30 689694. (https://doi.org/10.1007/s00259-003-1115-3)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Koopmans KP, de Vries EGE, Kema IP, Elsinga PH, Neels OC, Sluiter WJ, van der Horst-Schrivers ANA & Jager PL. Staging of carcinoid tumours with 18F-DOPA PET: a prospective, diagnostic accuracy study. Lancet Oncology 2006 7 728734. (https://doi.org/10.1016/S1470-2045(06)70801-4)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3

    Koopmans KP, Neels ON, Kema IP, Elsinga PH, Links TP, de Vries EGE & Jager PL. Molecular imaging in neuroendocrine tumours: molecular uptake mechanisms and clinical results. Critical Reviews in Oncology/Hematology 2009 71 199213. (https://doi.org/10.1016/j.critrevonc.2009.02.009)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Fiebrich HB, Brouwers AH, Kerstens MN, Pijl ME, Kema IP, de Jong JR, Jager PL, Elsinga PH, Dierckx RA & van der Wal JE et al. 6-[F-18]Fluoro-l-dihydroxyphenylalanine positron emission tomography is superior to conventional imaging with (123)I-metaiodobenzylguanidine scintigraphy, computed tomography, and magnetic resonance imaging in localizing tumours causing catecholamine excess. Journal of Clinical Endocrinology and Metabolism 2009 94 39223930. (https://doi.org/10.1210/jc.2009-1054)

    • Search Google Scholar
    • Export Citation
  • 5

    Treglia G, Cocciolillo F, Di, Nardo F, Poscia A, de, Waure C, Giordano A & Rufini V. Detection rate of recurrent medullary thyroid carcinoma using fluorine-18 dihydroxyphenylalanine positron emission tomography: a meta-analysis. Academic Radiology 2012 19 12901299. (https://doi.org/10.1016/j.acra.2012.05.008)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Kauhanen S, Schalin-Jäntti C, Seppänen M, Kajander S, Virtanen S, Schildt J, Lisinen I, Ahonen A, Heiskanen I & Väisänen M et al. Complementary roles of 18F-DOPA PET/CT and 18F-FDG PET/CT in medullary thyroid cancer. Journal of Nuclear Medicine 2011 52 18551863. (https://doi.org/10.2967/jnumed.111.094771)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    Janssen I, Taieb D, Patronas NJ, Millo CM, Adams K, Nambuba J, Chen CC, Herscovitch P, Sadowski SM & Fojo AT et al. 68Ga-DOTATATE PET/CT in the localization of head and neck paragangliomas compared with other functional imaging modalities and CT/MRI. Journal of Nuclear Medicine 2016 57 186191. (https://doi.org/10.2967/jnumed.115.161018)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8

    Imani F, Agopian VG, Auerbach MS, Walter MA, Imani F, Benz MR, Dumont RA, Lai CK, Czernin JG & Yeh MW. 18F-FDOPA PET and PET/CT accurately localize pheochromocytomas. Journal of Nuclear Medicine 2009 50 513519. (https://doi.org/10.2967/jnumed.108.058396)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9

    Bozkurt MF, Virgolini I, Balogova S, Beheshti M, Rubello D, Decristoforo C, Ambrosini V, Kjaer A, Delgado-Bolton R & Kunikowska J et al. Guideline for PET/CT imaging of neuroendocrine neoplasms with 68Ga-DOTA-conjugated somatostatin receptor targeting peptides and 18F-DOPA. European Journal of Nuclear Medicine and Molecular Imaging 2017 44 15881601. (https://doi.org/10.1007/s00259-017-3728-y)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Zhao Y, Wang L & Pan J. The role of L-type amino acid transporter 1 in human tumours. Intractable and Rare Diseases Research 2015 4 165169. (https://doi.org/10.5582/irdr.2015.01024)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Timmers HJLM, Chen CC, Carrasquillo JA, Whatley M, Ling A, Havekes B, Eisenhofer G, Martiniova L, Adams KT & Pacak K. Comparison of 18F-fluoro-l-DOPA, 18F-fluoro-deoxyglucose, and 18F-fluorodopamine PET and 123I-MIBG scintigraphy in the localization of pheochromocytoma and paraganglioma. Journal of Clinical Endocrinology and Metabolism 2009 94 47574767 (https://doi.org/10.1210/jc.2009-1248)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12

    Treglia G, Cocciolillo F, de Waure C, Di Nardo F, Gualano MR, Castaldi P, Rufini V & Giordano A. Diagnostic performance of 18F-dihydroxyphenylalanine positron emission tomography in patients with paraganglioma: a meta-analysis. European Journal of Nuclear Medicine and Molecular Imaging 2012 39 11441153. (https://doi.org/10.1007/s00259-012-2087-y)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Chondrogiannis S, Marzola MC, Al-Nahhas A, Venkatanarayana TD, Mazza A, Opocher G & Rubello D. Normal biodistribution pattern and physiologic variants of 18F-DOPA PET imaging. Nuclear Medicine Communications 2013 34 11411149. (https://doi.org/10.1097/MNM.0000000000000008)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Calabria FF, Chiaravalloti A, Jaffrain-Rea ML, Zinzi M, Sannino P, Minniti G, Rubello D & Schillaci O. 18F-DOPA PET/CT Physiological distribution and pitfalls: experience in 215 patients. Clinical Nuclear Medicine 2016 41 753760. (https://doi.org/10.1097/RLU.0000000000001318)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Boellaard R, O’Doherty MJ, Weber WA, Mottaghy FM, Lonsdale MN, Stroobants SG, Oyen WJG, Kotzerke J, Hoekstra OS & Pruim J et al. FDG PET and PET/CT: EANM procedure guidelines for tumour PET imaging: version 1.0. European Journal of Nuclear Medicine and Molecular Imaging 2010 37 181200. (https://doi.org/10.1007/s00259-009-1297-4)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Osinga TE, Korpershoek E, de Krijger RR, Kerstens MN, Dullaart RPF, Kema IP, van der Laan BF, van der Horst-Schrivers AN & Links TP. Catecholamine-synthesizing enzymes are expressed in parasympathetic head and neck paraganglioma tissue. Neuroendocrinology 2015 101 289295. (https://doi.org/10.1159/000377703)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Weissferdt A, Phan A, Suster S & Moran CA. Adrenocortical carcinoma: a comprehensive immunohistochemical study of 40 cases. Applied Immunohistochemistry and Molecular Morphology 2014 22 2430. (https://doi.org/10.1097/PAI.0b013e31828a96cf)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18

    Clift AK, Drymousis P, Al-Nahhas A, Wasan H, Martin J, Holm S & Frilling A. Incidence of second primary malignancies in patients with neuroendocrine tumours. Neuroendocrinology 2015 102 2632. (https://doi.org/10.1159/000381716)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Dietemann S, Debry C, Onea A, Namer IJ & Imperiale A. Epiglottic squamous cell carcinoma showing unexpected 18F-FDOPA uptake on PET/CT investigation. Clinical Nuclear Medicine 2015 40 370371. (https://doi.org/10.1097/RLU.0000000000000818)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20

    Pauleau G, Palazzo FF, Essamet W, Sebag F & Taïeb D. Hürthle cell neoplasma: a new differential diagnosis for 18F-FDOPA-avid thyroid nodules? Journal of Clinical Endocrinology and Metabolism 2013 98 865866. (https://doi.org/10.1210/jc.2012-3687)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21

    Imperiale A, Addeo F, Averous G, Namer IJ & Bachellier P. Solid-pseudopapillary pancreatic tumour mimicking a neuroendocrine neoplasm on 18F-FDOPA PET/CT. Journal of Clinical Endocrinology and Metabolism 2013 98 26432644. (https://doi.org/10.1210/jc.2013-1942)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    Heimburger C, Averous G, Charlin E, Lang H, Kurtz JE & Imperiale A. Adrenal metastasis of a poorly differentiated adenocarcinoma mimicking a pheochromocytoma on 18F-FDOPA PET/CT. Clinical Nuclear Medicine 2016 41 691692. (https://doi.org/10.1097/RLU.0000000000001299)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Bergmann R, Pietzsch J, Fuechtner F, Pawelke B, Beuthien-Baumann B, Johannsen B & Kotzerke J. 3-O-methyl-6-18F-fluoro-l-dopa, a new tumour imaging agent: investigation of transport mechanism in vitro. Journal of Nuclear Medicine 2004 45 21162122.

    • Search Google Scholar
    • Export Citation
  • 24

    Haase C, Bergmann R, Fuechtner F, Hoepping A & Pietzsch J. L-type amino acid transporters LAT1 and LAT4 in cancer: uptake of 3-0-Methyl-6-18F-fluoro-l-dopa in human adenocarcinoma and squamous cell carcinoma in vitro and in vivo. Journal of Nuclear Medicine 2007 48 20632071. (https://doi.org/10.2967/jnumed.107.043620)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25

    Wimalasena K. Vesicular monoamine transporters: structure-function, pharmacology, and medicinal chemistry. Medicinal Research Reviews 2011 31 483519. (https://doi.org/10.1002/med.20187)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Rubi B, Maechler P. Minireview: new roles for peripheral dopamine on metabolic control and tumour growth: let’s seek the balance. Endocrinology 2010 151 55705581. (https://doi.org/10.1210/en.2010-0745)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Osinga TE, Links TP, Dullaart RPF, Pacak K, van der Horst-Schrivers ANA, Kerstens MN & Kema IP. Emerging role of dopamine in neovascularization of pheochromocytoma and paraganglioma. FASEB Journal 2017 31 22262240. (https://doi.org/10.1096/fj.201601131R)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28

    Vachtenheim J & Novotna H. Expression of the aromatic L-amino acid decarboxylase mRNA in human tumour cell lines of neuroendocrine and neuroectodermal origin. European Journal of Cancer 1997 33 24112417. (https://doi.org/10.1016/S0959-8049(97)00302-X)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29

    Geomela PA, Kontos CK, Yiotakis I, Fragoulis EG, Scorilas A. L-DOPA decarboxylase mRNA expression is associated with tumour stage and size in head and neck squamous cell carcinoma: a retrospective cohort study. BMC Cancer 2012 12 484. (https://doi.org/10.1186/1471-2407-12-484)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Florou D, Papadopoulos IN, Fragoulis EG & Scorilas A. L-Dopa decarboxylase (DDC) constitutes an emerging biomarker in predicting patients survival with stomach adenocarcinomas. Journal of Cancer Research and Clinical Oncology 2013 139 297306. (https://doi.org/10.1007/s00432-012-1326-8)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Kontos CK, Papadopoulos IN, Fragoulis EG & Scorilas A. Quantitative expression analysis and prognostic significance of L-DOPA decarboxylase in colorectal adenocarcinoma. British Journal of Cancer 2010 102 13841390. (https://doi.org/10.1038/sj.bjc.6605654)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Sakakura C, Takemura M, Hagiwara A, Shimomura K, Miyagawa K, Nakashima S, Yoshikawa T, Takagi T, Kin S & Nakase Y et al. Overexpression of dopa decarboxylase in peritoneal dissemination of gastric cancer and its potential as a novel marker for the detection of peritoneal micrometastases with real-time RT-PCR. British Journal of Cancer 2004 90 665671. (https://doi.org/10.1038/sj.bjc.6601544)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Koutalellis G, Stravodimos K, Avgeris M, Mayridis K, Scorilas A, Lazaris A & Constantinides C. L-dopa decarboxylase (DDC) gene expression is related to outcome in patients with prostate cancer. BJU International 2012 110 267273. (https://doi.org/10.1111/j.1464-410X.2012.11152.x)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34

    Bozzi F, Luksch R, Collini P, Gambirasio F, Barzano E, Polastri D, Podda M, Brando B & Fossati-Bellani F. Molecular detection of dopamine decarboxylase expression by means of reverse transcriptase and polymerase chain reaction in bone marrow and peripheral blood: utility as a tumour marker for neuroblastoma. Diagnostic Molecular Pathology 2004 13 135143. (https://doi.org/10.1097/01.pdm.0000128699.14504.06)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35

    Yanagida O, Kanai Y, Chairoungdua A, Kim DK, Segawa H, Nii T, Cha SH, Matsuo H, Fukushima J & Fukasawa Y et al. Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumour cell lines. Biochimica et Biophysica Acta 2001 1 291302. (https://doi.org/10.1016/S0005-2736(01)00384-4)

    • Search Google Scholar
    • Export Citation
  • 36

    Uchino H, Kanai Y, Kim DK, Wempe MF, Chairoungdua A, Morimoto E, Anders MW & Endou H. Transport of amino acid –related compounds mediated by L-type amino acid transporter 1 (LAT1): insight into the mechanisms of substrate recognition. Molecular Pharmacology 2002 61 729737. (https://doi.org/10.1124/mol.61.4.729)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37

    Kongpracha P, Nagamori S, Wiriyasermkul P, Tanaka Y, Kaneda K, Okuda S, Ohgaki R & Kanai Y. Structure-activity relationship of novel series of inhibitors for cancer type transporter L-type amino acid transporter 1 (LAT1). Journal of Pharmacological Sciences 2017 133 96102. (https://doi.org/10.1016/j.jphs.2017.01.006)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Lamberti G, Brighi N, Maggio I, Manuzzi L, Peterle C, Ambrosini V, Ricci C, Casadei R & Campana D. The role of the mTOR in neuroendocrine tumors: future cornerstone of a winning strategy? International Journal of Molecular Sciences 2018 19 E747. (https://doi.org/10.3390/ijms19030747)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Kobayashi H, Ishii Y & Takayama T. Expression of L-type amino acid transporter 1 (LAT1) in esophageal carcinoma. Journal of Surgical Oncology 2005 90 233238. (https://doi.org/10.1002/jso.20257)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40

    Youland RS, Kitange GJ, Peterson TE, Pafundi DH, Ramiscal JA, Pokomy JL., Giannini C, Laack NN, Parney IF & Lowe VJ et al. The role of LAT1 in (18)F-DOPA uptake in malignant gliomas. Journal of Neurooncology 2013 111 1118. (https://doi.org/10.1007/s11060-012-0986-1)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41

    Isoda A, Kaira K, Iwashina M, Oriuchi N, Tominaga H, Nagamori S, Kanai Y, Oyama T, Asao T & Matsumoto M et al. Expression of L-type amino acid transporter 1 (LAT1) as a prognostic and therapeutic indicator in multiple myeloma. Cancer Science 2014 105 14961502. (https://doi.org/10.1111/cas.12529)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Betsunoh H, Fukuda H, Anzai N, Nishihara D, Mizuno T, Yuki H, Masuda A, Yamaguchi Y, Abe H & Yashi M et al. Increased expression of system large amino acid transporter (LAT)-1 mRNA is associated with invasive potential and unfavorable prognosis of human clear cell renal cell carcinoma. BMC Cancer 2013 13 509. (https://doi.org/10.1186/1471-2407-13-509)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Nakanishi K, Ogata S, Matsuo H, Kanai Y, Endou H, Hiroi S, Tominaga S, Aida S, Kasamatsu H & Kawai T. Expression of LAT1 predicts risk of progression of transitional cell carcinoma of the upper urinary tract. Virchows Archiv 2007 451 681690. (https://doi.org/10.1007/s00428-007-0457-9)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 44

    Li J, Qiang J, Chen SF, Wang X, Fu J & Chen Y. The impact of L-type amino acid transporter 1 (LAT1) in human hepatocellular carcinoma. Tumor Biology 2013 34 29772981. (https://doi.org/10.1007/s13277-013-0861-5)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 45

    Uno K, Kuwabara H, Terado Y, Kojima K, Kawakami T, Kamma H, Sakurai H, Sakamoto A & Kurata A. Divergent expression of L-type amino acid transporter 1 during uterine cervical carcinogenesis. Human Pathology 2011 42 16601666. (https://doi.org/10.1016/j.humpath.2011.01.013)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46

    Nikkuni O, Kaira K, Toyoda M, Shino M, Sakakura K, Takahashi K, Tominaga H, Oriuchi N, Suzuki M & Iijima M et al. Expression of amino acid transporters (LAT1 and ASCT2) in patients with stage III/IV laryngeal squamous cell carcinoma. Pathology and Oncology Research 2015 21 11751181. (https://doi.org/10.1007/s12253-015-9954-3)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 47

    Ichinoe M, Mikami T, Yoshida T, Igawa I, Tsuruta T, Nakada N, Anzai N, Suzuki Y, Endou H & Okayasu I. High expression of L-type amino-acid transporter 1 (LAT1) in gastric carcinomas; comparison with non-cancerous lesions. Pathology International 2011 61 281289. (https://doi.org/10.1111/j.1440-1827.2011.02650.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48

    Kaira K, Oriuchi N, Imai H, Shimizu K, Yanagitani N, Sunaga N, Hisada T, Tanaka S, Ishizuka T & Kanai Y et al. Prognostic significance of L-type amino acid transporter 1 expression in resectable stage I-III nonsmall cell lung cancer. British Journal of Cancer 2008 98 742748. (https://doi.org/10.1038/sj.bjc.6604235)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49

    Kaira K, Oriuchi N, Takahashi T, Nakagawa K, Ohde Y, Okumura T, Murakami H, Shukuya T, Kenmotsu H & Naito T et al. L-type amino acid transporter 1 (LAT1) expression in malignant pleural mesothelioma. Anticancer Research 2011 31 40754082.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50

    Sakata T, Ferdous G, Tsuruta T, Satoh T, Baba S, Muto T, Ueno A, Kanai Y, Endou H & Okayasu I. L-type amino acid transporter 1 as a novel biomarker for high-grade malignancy in prostate cancer. Pathology International 2009 59 718. (https://doi.org/10.1111/j.1440-1827.2008.02319.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51

    Yanagisawa N, Ichinoe M, Mikami T, Nakada N, Hana K, Koizumi W, Endou H & Okayasu I. High expression of L-type amino acid transporter 1 (LAT1) predicts poor prognosis in pancreatic ductal adenocarcinomas. Journal of Clinical Pathology 2012 65 10191023. (https://doi.org/10.1136/jclinpath-2012-200826)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52

    de la Ballina LR, Cano-Crespo S, González-Munoz E, Bial S, Estrach S, Cailleteau L, Tissot F, Daniel H, Zorzano A & Ginsberg MH et al. Amino acid transport associated to cluster of differentiation 98 heavy chain (CD98hc) is at the cross-road of oxidative stress and amino acid availability. Journal of Biological Chemistry 2016 291 97009711. (https://doi.org/10.1074/jbc.A116.750653)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 53

    Wang Q, Holst J. L-type amino acid transport and cancer: targeting the mTORC1 pathway to inhibit neoplasia. American Journal of Cancer Research 2015 5 12811294.

    • PubMed
    • Search Google Scholar
    • Export Citation

 

     European Society of Endocrinology

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  • View in gallery

    Flowchart of re-evaluation of the 6-[18F]fluor-l-3,4-dihydroxyphenylalanine PET (18F-FDOPA PET) scan reports.

  • View in gallery

    6-[18F]fluor-l-3,4-dihydroxyphenylalanine (18F-FDOPA) uptake in a histologically proven squamous cell carcinoma of the cervix. Transverse reconstruction of the pelvic area of (A) low-dose CT, (B) fused 18F-FDOPA PET (PET)/CT, (C) 18F-FDOPA PET only images, and (D) sagittal maximum intensity projection of the whole body 18F-FDOPA PET.

  • View in gallery

    6-[18F]fluor-l-3,4-dihydroxyphenylalanine (18F-FDOPA) uptake in a histologically proven hepatocellular carcinoma of the liver. Maximum intensity projection of the whole body 18F-FDOPA PET.

  • View in gallery

    Histology and immunohistochemical staining pattern of selected lesions: (A, B, C and D) adrenocortical carcinoma with: (A) Hematoxylin and eosin staining. (B) Positive immunohistochemical staining for aromatic-l-amino acid decarboxylase (AADC). (C) Negative staining for Chromogranin A. (D) Positive staining for synaptophysin. (E and F) Squamous cell carcinoma of the larynx with: (E) Hematoxylin and eosin staining. (F) Negative staining for AADC.

  • 1

    Hoegerle S, Ghanem N, Altehoefer C, Schipper J, Brink I, Moser E & Neumann HP. 18F-DOPA positron emission tomography for the detection of glomus tumours. European Journal of Nuclear Medicine and Molecular Imaging 2003 30 689694. (https://doi.org/10.1007/s00259-003-1115-3)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Koopmans KP, de Vries EGE, Kema IP, Elsinga PH, Neels OC, Sluiter WJ, van der Horst-Schrivers ANA & Jager PL. Staging of carcinoid tumours with 18F-DOPA PET: a prospective, diagnostic accuracy study. Lancet Oncology 2006 7 728734. (https://doi.org/10.1016/S1470-2045(06)70801-4)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3

    Koopmans KP, Neels ON, Kema IP, Elsinga PH, Links TP, de Vries EGE & Jager PL. Molecular imaging in neuroendocrine tumours: molecular uptake mechanisms and clinical results. Critical Reviews in Oncology/Hematology 2009 71 199213. (https://doi.org/10.1016/j.critrevonc.2009.02.009)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Fiebrich HB, Brouwers AH, Kerstens MN, Pijl ME, Kema IP, de Jong JR, Jager PL, Elsinga PH, Dierckx RA & van der Wal JE et al. 6-[F-18]Fluoro-l-dihydroxyphenylalanine positron emission tomography is superior to conventional imaging with (123)I-metaiodobenzylguanidine scintigraphy, computed tomography, and magnetic resonance imaging in localizing tumours causing catecholamine excess. Journal of Clinical Endocrinology and Metabolism 2009 94 39223930. (https://doi.org/10.1210/jc.2009-1054)

    • Search Google Scholar
    • Export Citation
  • 5

    Treglia G, Cocciolillo F, Di, Nardo F, Poscia A, de, Waure C, Giordano A & Rufini V. Detection rate of recurrent medullary thyroid carcinoma using fluorine-18 dihydroxyphenylalanine positron emission tomography: a meta-analysis. Academic Radiology 2012 19 12901299. (https://doi.org/10.1016/j.acra.2012.05.008)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Kauhanen S, Schalin-Jäntti C, Seppänen M, Kajander S, Virtanen S, Schildt J, Lisinen I, Ahonen A, Heiskanen I & Väisänen M et al. Complementary roles of 18F-DOPA PET/CT and 18F-FDG PET/CT in medullary thyroid cancer. Journal of Nuclear Medicine 2011 52 18551863. (https://doi.org/10.2967/jnumed.111.094771)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    Janssen I, Taieb D, Patronas NJ, Millo CM, Adams K, Nambuba J, Chen CC, Herscovitch P, Sadowski SM & Fojo AT et al. 68Ga-DOTATATE PET/CT in the localization of head and neck paragangliomas compared with other functional imaging modalities and CT/MRI. Journal of Nuclear Medicine 2016 57 186191. (https://doi.org/10.2967/jnumed.115.161018)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8

    Imani F, Agopian VG, Auerbach MS, Walter MA, Imani F, Benz MR, Dumont RA, Lai CK, Czernin JG & Yeh MW. 18F-FDOPA PET and PET/CT accurately localize pheochromocytomas. Journal of Nuclear Medicine 2009 50 513519. (https://doi.org/10.2967/jnumed.108.058396)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9

    Bozkurt MF, Virgolini I, Balogova S, Beheshti M, Rubello D, Decristoforo C, Ambrosini V, Kjaer A, Delgado-Bolton R & Kunikowska J et al. Guideline for PET/CT imaging of neuroendocrine neoplasms with 68Ga-DOTA-conjugated somatostatin receptor targeting peptides and 18F-DOPA. European Journal of Nuclear Medicine and Molecular Imaging 2017 44 15881601. (https://doi.org/10.1007/s00259-017-3728-y)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Zhao Y, Wang L & Pan J. The role of L-type amino acid transporter 1 in human tumours. Intractable and Rare Diseases Research 2015 4 165169. (https://doi.org/10.5582/irdr.2015.01024)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Timmers HJLM, Chen CC, Carrasquillo JA, Whatley M, Ling A, Havekes B, Eisenhofer G, Martiniova L, Adams KT & Pacak K. Comparison of 18F-fluoro-l-DOPA, 18F-fluoro-deoxyglucose, and 18F-fluorodopamine PET and 123I-MIBG scintigraphy in the localization of pheochromocytoma and paraganglioma. Journal of Clinical Endocrinology and Metabolism 2009 94 47574767 (https://doi.org/10.1210/jc.2009-1248)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12

    Treglia G, Cocciolillo F, de Waure C, Di Nardo F, Gualano MR, Castaldi P, Rufini V & Giordano A. Diagnostic performance of 18F-dihydroxyphenylalanine positron emission tomography in patients with paraganglioma: a meta-analysis. European Journal of Nuclear Medicine and Molecular Imaging 2012 39 11441153. (https://doi.org/10.1007/s00259-012-2087-y)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Chondrogiannis S, Marzola MC, Al-Nahhas A, Venkatanarayana TD, Mazza A, Opocher G & Rubello D. Normal biodistribution pattern and physiologic variants of 18F-DOPA PET imaging. Nuclear Medicine Communications 2013 34 11411149. (https://doi.org/10.1097/MNM.0000000000000008)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Calabria FF, Chiaravalloti A, Jaffrain-Rea ML, Zinzi M, Sannino P, Minniti G, Rubello D & Schillaci O. 18F-DOPA PET/CT Physiological distribution and pitfalls: experience in 215 patients. Clinical Nuclear Medicine 2016 41 753760. (https://doi.org/10.1097/RLU.0000000000001318)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Boellaard R, O’Doherty MJ, Weber WA, Mottaghy FM, Lonsdale MN, Stroobants SG, Oyen WJG, Kotzerke J, Hoekstra OS & Pruim J et al. FDG PET and PET/CT: EANM procedure guidelines for tumour PET imaging: version 1.0. European Journal of Nuclear Medicine and Molecular Imaging 2010 37 181200. (https://doi.org/10.1007/s00259-009-1297-4)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Osinga TE, Korpershoek E, de Krijger RR, Kerstens MN, Dullaart RPF, Kema IP, van der Laan BF, van der Horst-Schrivers AN & Links TP. Catecholamine-synthesizing enzymes are expressed in parasympathetic head and neck paraganglioma tissue. Neuroendocrinology 2015 101 289295. (https://doi.org/10.1159/000377703)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Weissferdt A, Phan A, Suster S & Moran CA. Adrenocortical carcinoma: a comprehensive immunohistochemical study of 40 cases. Applied Immunohistochemistry and Molecular Morphology 2014 22 2430. (https://doi.org/10.1097/PAI.0b013e31828a96cf)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18

    Clift AK, Drymousis P, Al-Nahhas A, Wasan H, Martin J, Holm S & Frilling A. Incidence of second primary malignancies in patients with neuroendocrine tumours. Neuroendocrinology 2015 102 2632. (https://doi.org/10.1159/000381716)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Dietemann S, Debry C, Onea A, Namer IJ & Imperiale A. Epiglottic squamous cell carcinoma showing unexpected 18F-FDOPA uptake on PET/CT investigation. Clinical Nuclear Medicine 2015 40 370371. (https://doi.org/10.1097/RLU.0000000000000818)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20

    Pauleau G, Palazzo FF, Essamet W, Sebag F & Taïeb D. Hürthle cell neoplasma: a new differential diagnosis for 18F-FDOPA-avid thyroid nodules? Journal of Clinical Endocrinology and Metabolism 2013 98 865866. (https://doi.org/10.1210/jc.2012-3687)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21

    Imperiale A, Addeo F, Averous G, Namer IJ & Bachellier P. Solid-pseudopapillary pancreatic tumour mimicking a neuroendocrine neoplasm on 18F-FDOPA PET/CT. Journal of Clinical Endocrinology and Metabolism 2013 98 26432644. (https://doi.org/10.1210/jc.2013-1942)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    Heimburger C, Averous G, Charlin E, Lang H, Kurtz JE & Imperiale A. Adrenal metastasis of a poorly differentiated adenocarcinoma mimicking a pheochromocytoma on 18F-FDOPA PET/CT. Clinical Nuclear Medicine 2016 41 691692. (https://doi.org/10.1097/RLU.0000000000001299)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Bergmann R, Pietzsch J, Fuechtner F, Pawelke B, Beuthien-Baumann B, Johannsen B & Kotzerke J. 3-O-methyl-6-18F-fluoro-l-dopa, a new tumour imaging agent: investigation of transport mechanism in vitro. Journal of Nuclear Medicine 2004 45 21162122.

    • Search Google Scholar
    • Export Citation
  • 24

    Haase C, Bergmann R, Fuechtner F, Hoepping A & Pietzsch J. L-type amino acid transporters LAT1 and LAT4 in cancer: uptake of 3-0-Methyl-6-18F-fluoro-l-dopa in human adenocarcinoma and squamous cell carcinoma in vitro and in vivo. Journal of Nuclear Medicine 2007 48 20632071. (https://doi.org/10.2967/jnumed.107.043620)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25

    Wimalasena K. Vesicular monoamine transporters: structure-function, pharmacology, and medicinal chemistry. Medicinal Research Reviews 2011 31 483519. (https://doi.org/10.1002/med.20187)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Rubi B, Maechler P. Minireview: new roles for peripheral dopamine on metabolic control and tumour growth: let’s seek the balance. Endocrinology 2010 151 55705581. (https://doi.org/10.1210/en.2010-0745)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Osinga TE, Links TP, Dullaart RPF, Pacak K, van der Horst-Schrivers ANA, Kerstens MN & Kema IP. Emerging role of dopamine in neovascularization of pheochromocytoma and paraganglioma. FASEB Journal 2017 31 22262240. (https://doi.org/10.1096/fj.201601131R)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28

    Vachtenheim J & Novotna H. Expression of the aromatic L-amino acid decarboxylase mRNA in human tumour cell lines of neuroendocrine and neuroectodermal origin. European Journal of Cancer 1997 33 24112417. (https://doi.org/10.1016/S0959-8049(97)00302-X)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29

    Geomela PA, Kontos CK, Yiotakis I, Fragoulis EG, Scorilas A. L-DOPA decarboxylase mRNA expression is associated with tumour stage and size in head and neck squamous cell carcinoma: a retrospective cohort study. BMC Cancer 2012 12 484. (https://doi.org/10.1186/1471-2407-12-484)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Florou D, Papadopoulos IN, Fragoulis EG & Scorilas A. L-Dopa decarboxylase (DDC) constitutes an emerging biomarker in predicting patients survival with stomach adenocarcinomas. Journal of Cancer Research and Clinical Oncology 2013 139 297306. (https://doi.org/10.1007/s00432-012-1326-8)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Kontos CK, Papadopoulos IN, Fragoulis EG & Scorilas A. Quantitative expression analysis and prognostic significance of L-DOPA decarboxylase in colorectal adenocarcinoma. British Journal of Cancer 2010 102 13841390. (https://doi.org/10.1038/sj.bjc.6605654)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Sakakura C, Takemura M, Hagiwara A, Shimomura K, Miyagawa K, Nakashima S, Yoshikawa T, Takagi T, Kin S & Nakase Y et al. Overexpression of dopa decarboxylase in peritoneal dissemination of gastric cancer and its potential as a novel marker for the detection of peritoneal micrometastases with real-time RT-PCR. British Journal of Cancer 2004 90 665671. (https://doi.org/10.1038/sj.bjc.6601544)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Koutalellis G, Stravodimos K, Avgeris M, Mayridis K, Scorilas A, Lazaris A & Constantinides C. L-dopa decarboxylase (DDC) gene expression is related to outcome in patients with prostate cancer. BJU International 2012 110 267273. (https://doi.org/10.1111/j.1464-410X.2012.11152.x)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34

    Bozzi F, Luksch R, Collini P, Gambirasio F, Barzano E, Polastri D, Podda M, Brando B & Fossati-Bellani F. Molecular detection of dopamine decarboxylase expression by means of reverse transcriptase and polymerase chain reaction in bone marrow and peripheral blood: utility as a tumour marker for neuroblastoma. Diagnostic Molecular Pathology 2004 13 135143. (https://doi.org/10.1097/01.pdm.0000128699.14504.06)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35

    Yanagida O, Kanai Y, Chairoungdua A, Kim DK, Segawa H, Nii T, Cha SH, Matsuo H, Fukushima J & Fukasawa Y et al. Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumour cell lines. Biochimica et Biophysica Acta 2001 1 291302. (https://doi.org/10.1016/S0005-2736(01)00384-4)

    • Search Google Scholar
    • Export Citation
  • 36

    Uchino H, Kanai Y, Kim DK, Wempe MF, Chairoungdua A, Morimoto E, Anders MW & Endou H. Transport of amino acid –related compounds mediated by L-type amino acid transporter 1 (LAT1): insight into the mechanisms of substrate recognition. Molecular Pharmacology 2002 61 729737. (https://doi.org/10.1124/mol.61.4.729)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37

    Kongpracha P, Nagamori S, Wiriyasermkul P, Tanaka Y, Kaneda K, Okuda S, Ohgaki R & Kanai Y. Structure-activity relationship of novel series of inhibitors for cancer type transporter L-type amino acid transporter 1 (LAT1). Journal of Pharmacological Sciences 2017 133 96102. (https://doi.org/10.1016/j.jphs.2017.01.006)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Lamberti G, Brighi N, Maggio I, Manuzzi L, Peterle C, Ambrosini V, Ricci C, Casadei R & Campana D. The role of the mTOR in neuroendocrine tumors: future cornerstone of a winning strategy? International Journal of Molecular Sciences 2018 19 E747. (https://doi.org/10.3390/ijms19030747)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Kobayashi H, Ishii Y & Takayama T. Expression of L-type amino acid transporter 1 (LAT1) in esophageal carcinoma. Journal of Surgical Oncology 2005 90 233238. (https://doi.org/10.1002/jso.20257)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40

    Youland RS, Kitange GJ, Peterson TE, Pafundi DH, Ramiscal JA, Pokomy JL., Giannini C, Laack NN, Parney IF & Lowe VJ et al. The role of LAT1 in (18)F-DOPA uptake in malignant gliomas. Journal of Neurooncology 2013 111 1118. (https://doi.org/10.1007/s11060-012-0986-1)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41

    Isoda A, Kaira K, Iwashina M, Oriuchi N, Tominaga H, Nagamori S, Kanai Y, Oyama T, Asao T & Matsumoto M et al. Expression of L-type amino acid transporter 1 (LAT1) as a prognostic and therapeutic indicator in multiple myeloma. Cancer Science 2014 105 14961502. (https://doi.org/10.1111/cas.12529)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Betsunoh H, Fukuda H, Anzai N, Nishihara D, Mizuno T, Yuki H, Masuda A, Yamaguchi Y, Abe H & Yashi M et al. Increased expression of system large amino acid transporter (LAT)-1 mRNA is associated with invasive potential and unfavorable prognosis of human clear cell renal cell carcinoma. BMC Cancer 2013 13 509. (https://doi.org/10.1186/1471-2407-13-509)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Nakanishi K, Ogata S, Matsuo H, Kanai Y, Endou H, Hiroi S, Tominaga S, Aida S, Kasamatsu H & Kawai T. Expression of LAT1 predicts risk of progression of transitional cell carcinoma of the upper urinary tract. Virchows Archiv 2007 451 681690. (https://doi.org/10.1007/s00428-007-0457-9)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 44

    Li J, Qiang J, Chen SF, Wang X, Fu J & Chen Y. The impact of L-type amino acid transporter 1 (LAT1) in human hepatocellular carcinoma. Tumor Biology 2013 34 29772981. (https://doi.org/10.1007/s13277-013-0861-5)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 45

    Uno K, Kuwabara H, Terado Y, Kojima K, Kawakami T, Kamma H, Sakurai H, Sakamoto A & Kurata A. Divergent expression of L-type amino acid transporter 1 during uterine cervical carcinogenesis. Human Pathology 2011 42 16601666. (https://doi.org/10.1016/j.humpath.2011.01.013)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46

    Nikkuni O, Kaira K, Toyoda M, Shino M, Sakakura K, Takahashi K, Tominaga H, Oriuchi N, Suzuki M & Iijima M et al. Expression of amino acid transporters (LAT1 and ASCT2) in patients with stage III/IV laryngeal squamous cell carcinoma. Pathology and Oncology Research 2015 21 11751181. (https://doi.org/10.1007/s12253-015-9954-3)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 47

    Ichinoe M, Mikami T, Yoshida T, Igawa I, Tsuruta T, Nakada N, Anzai N, Suzuki Y, Endou H & Okayasu I. High expression of L-type amino-acid transporter 1 (LAT1) in gastric carcinomas; comparison with non-cancerous lesions. Pathology International 2011 61 281289. (https://doi.org/10.1111/j.1440-1827.2011.02650.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48

    Kaira K, Oriuchi N, Imai H, Shimizu K, Yanagitani N, Sunaga N, Hisada T, Tanaka S, Ishizuka T & Kanai Y et al. Prognostic significance of L-type amino acid transporter 1 expression in resectable stage I-III nonsmall cell lung cancer. British Journal of Cancer 2008 98 742748. (https://doi.org/10.1038/sj.bjc.6604235)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49

    Kaira K, Oriuchi N, Takahashi T, Nakagawa K, Ohde Y, Okumura T, Murakami H, Shukuya T, Kenmotsu H & Naito T et al. L-type amino acid transporter 1 (LAT1) expression in malignant pleural mesothelioma. Anticancer Research 2011 31 40754082.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50

    Sakata T, Ferdous G, Tsuruta T, Satoh T, Baba S, Muto T, Ueno A, Kanai Y, Endou H & Okayasu I. L-type amino acid transporter 1 as a novel biomarker for high-grade malignancy in prostate cancer. Pathology International 2009 59 718. (https://doi.org/10.1111/j.1440-1827.2008.02319.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51

    Yanagisawa N, Ichinoe M, Mikami T, Nakada N, Hana K, Koizumi W, Endou H & Okayasu I. High expression of L-type amino acid transporter 1 (LAT1) predicts poor prognosis in pancreatic ductal adenocarcinomas. Journal of Clinical Pathology 2012 65 10191023. (https://doi.org/10.1136/jclinpath-2012-200826)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52

    de la Ballina LR, Cano-Crespo S, González-Munoz E, Bial S, Estrach S, Cailleteau L, Tissot F, Daniel H, Zorzano A & Ginsberg MH et al. Amino acid transport associated to cluster of differentiation 98 heavy chain (CD98hc) is at the cross-road of oxidative stress and amino acid availability. Journal of Biological Chemistry 2016 291 97009711. (https://doi.org/10.1074/jbc.A116.750653)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 53

    Wang Q, Holst J. L-type amino acid transport and cancer: targeting the mTORC1 pathway to inhibit neoplasia. American Journal of Cancer Research 2015 5 12811294.

    • PubMed
    • Search Google Scholar
    • Export Citation