False positive findings on 6-[18F]fluor-L-3,4-dihydroxyphenylalanine Positron Emission Tomography (18F-FDOPA-PET) performed for imaging of neuroendocrine tumors.
Annika. M.A. Berends1 (MD), Michiel N. Kerstens1 (MD, PhD), Janne W. Bolt1, Thera P. Links1 (MD, PhD), Esther Korpershoek2 (MD, PhD), Ronald R. de Krijger2 (MD, PhD), Annemiek M.E Walenkamp3 (MD, PhD), Walter Noordzij4 (MD, PhD), Boudewijn van Etten5 (MD, PhD), Gursah Kats-Ugurlu6 (MD, PhD), Adrienne H. Brouwers4 (MD, PhD), Anouk N.A. van der Horst-Schrivers1 (MD, PhD).
University of Groningen, University Medical Center Groningen, The Netherlands, Departments of 1Endocrinology, 3Medical Oncology, 4Nuclear Medicine and Molecular Imaging, 5Surgical Oncology, 6Pathology. Erasmus University Medical Center, Rotterdam and Reinier de Graaf Hospital, Delft, The Netherlands, 2Department of Pathology
Short Title: Uptake of 18F-FDOPA in non NETs.
Correspondence to:
Annika M.A. Berends, MD University Medical Center Groningen, Department of Endocrinology Hanzeplein 1, 9713 GZ Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands Phone: +031 50 361 39 62 Email: m.a.berends@umcg.nl
Keywords: 6-[18F]fluor-L-3,4-dihydroxyphenylalanine Positron Emission Tomography (18F- FDOPA PET), neuro-endocrine tumor, aromatic-L-aminoacid decarboxylase (AADC).
Word Count: 2467
ABSTRACT
Background/Aim: Positron Emission Tomography (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-centre 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 (MTC), phaeochromocytomas (PCC), paragangliomas (PGL) 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. Positron Emission Tomography (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 [1-9]. 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-aminoacid 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 biodistribution 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 centre 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 biodistribution 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 a 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 2 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 hours before the examination and were allowed to continue their medication. The whole-body PET images were acquired 60 minutes after the intravenous injection of 200 MBq 18F-FDOPA. Carbidopa (2 mg/kg, max 150 mg) was given 60 minutes 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 8 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 minutes emission and 3 minutes transmission for attenuation correction) for the PET-only- and 1-3 minutes (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. Standardised uptake values (SUV) 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, Glostrup, Denmark), 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. 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).
The 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%) (Figure 1). In 507 out of 709 (72%) scans, histology of a 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).
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) (Table 1, Figure 2 and 3). 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).
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 (Figure 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 (Table 1, Figure 4).
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 biodistribution, 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 has 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 xenografts 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 has yet to be established. AADC primarily catalyses the conversion of L-DOPA towards 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 favourable 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 [28-34].
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) [10,35-38]. 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 [10,39-51]. 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 scinitgraphy 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 intens 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
All authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Author contributions
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, 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
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Figure 1 Flowchart of re-evaluation of the 6-[18F]fluor-L-3,4-dihydroxyphenylalanine Positron Emission Tomography (18F-FDOPA PET) scan reports
Table 1: Results of 6-[18F]fluor-L-3,4-dihydroxyphenylalanine (18F-FDOPA) uptake and immunohistochemical staining in non-neuroendocrine tumors
F: female, M: male, yrs: years, GEP-NET: gastroenteropancreatic neuroendocrine tumor, CgA: chromogranin A, MN: metanephrines, 18F-FDOPA PET: L-6-fluor-3,4- dihydroxyphenylalanine-Position emission tomography. * Confirmed by anatomical imaging (Computed Tomography (CT)/ Magnetic Resonance Imaging (MRI)) - lesion to lesion comparison. NA: not assessed.
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 Computed Tomography (CT), (B) fused 18F-FDOPA Positron Emission Tomography (PET)/CT, (C) 18F-FDOPA PET only images, and (D) sagittal maximum intensity projection of the whole body 18F-FDOPA PET.
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.
Figure 4 Histology and immunohistochemical staining pattern of selected lesions: A-D: adrenocortical carcinoma with: (A) Hematoxylin and eosin staining. (B) Positive immunohistochemical staining for aromatic-L-aminoacid decarboxylase (AADC). (C) Negative staining for Chromogranin A. (D) Positive staining for synaptophysin. E-F: Squamouos cell carcinoma of the larynx with: (E) Hematoxylin and eosin staining. (F) Negative staining for AADC.
| Gender and age | Clinical picture | Indication 18F-FDOPA PET scan: suspicion of | Uptake in* | Final pathology | Immunohistoch emical staining for AADC |
|---|---|---|---|---|---|
| 1# F, 60 yrs. | New-onset diabetes, pancreas lesion*, elevated CgA | GEP-NET | Iliac bone, right ☐ humerus | ☐ Multiple myeloma | ☐ Negative |
| 2ª F, 67 yrs. | Malaise, liver lesion*, elevated CgA | ☐ GEP-NET | ☐ Liver | ☐ Hepatocellular ☐ carcinoma | ☐ Positive |
| 3# M, 47 yrs. | Tumor of carotid body* deafness, peripheral facialis paresis | ☐ Paraganglioma | ☐ Carotid body | ☐ Multiple myeloma | ☐ Positive |
| 4# F, 34 yrs. | Neck mass, elevated MN | ☐ Paraganglioma | ☐ Neck | ☐ Schwannoma | ☐ NA |
| 5# F, 41 yrs. | Tumor of skull base*, elevated MN | ☐ Paraganglioma | ☐ Skull base | ☐ ☐ Skeletal myxoid chondrosarcoma | ☐ Negative |
| 6# F, 64 yrs. | Hypertension, elevated MN | ☐ Phaeochromocytoma | ☐ Pelvic region | ☐ ☐ Squamous cell carcinoma cervix | ☐ Positive |
| 7# M, 62 yrs. | ☐ Flank pain, nausea, flushes, retroperitoneal mass* | Phaeochromocytoma | ☐ Left adrenal gland and liver ☐ lesions | ☐ Adrenocortical ☐ carcinoma | ☐ Positive |
F: female, M: male, yrs: years, GEP-NET: gastroenteropancreatic neuroendocrine tumor, CgA: chromogranin A, MN: metanephrines, 18F-FDOPA PET: L-6-fluor-3,4-dihydroxyphenylalanine-Position emission tomography. *Confirmed by anatomical imaging (Computed Tomography (CT)/ Magnetic Resonance Imaging (MRI)) - lesion to lesion comparison. NA: not assessed.
18F-FDOPA scans n = 1070
No pathological uptake n = 361
Pathological uptake n = 709
Single lesion n = 224
Multiple lesions n = 485
No histology n = 76
Histology n = 148
No histology n = 126
Histology n = 359
Not compatible with diagnosis NET n = 5
Not compatible with diagnosis NET n = 2
A
B
C
D
297x210mm (200 x 200 DPI)
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
161x283mm (300 × 300 DPI)
A
B
C
E
E
138x116mm (300 × 300 DPI)