SEARCH

SEARCH BY CITATION

Keywords:

  • Epilepsy;
  • Neoplasm;
  • PET;
  • Amino acid

Summary

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

Purpose: Long-term epilepsy associated tumors (LEATs) are a frequent cause of drug-resistant partial epilepsy. A reliable tumor diagnosis has an important impact on therapeutic strategies and prognosis in patients with epilepsy, but often is difficult by magnetic resonance imaging (MRI) only. Herein we analyzed a large LEAT cohort investigated by 18fluoroethyl-l-tyrosine–positron emission tomography (FET-PET).

Methods: Thirty-six patients with chronic partial epilepsy and a LEAT-suspect MRI lesion were analyzed by FET-PET using visual inspection and quantitative analysis of standard uptake values (SUV). PET results were correlated with clinical and histopathologic data.

Results: FET-PET study was positive in 22 of 36 analyzed lesions and in 14 of 22 histologically verified LEAT lesions. The precise World Health Organization (WHO) tumoral entity was not predicted by FET-PET. Notably, FET uptake correlated strikingly with age at epilepsy onset (p = 0.001). Further correlations were seen for age at surgery (p = 0.007) and gadolinium-contrast enhancement on MRI (p < 0.05).

Discussion: FET-PET is a helpful tool for LEAT diagnosis, particularly when MRI readings are ambiguous. FET uptake, which is likely mediated by the l-amino acid transporter (LAT) family, might indicate a principally important biologic property of certain LEATs, since LAT molecules also are involved in cell growth regulation.

Glioneuronal neoplasms are a common cause of medically refractory epilepsy affecting approximately 30% of patients in surgical epilepsy series (Zentner et al., 1997; Luyken et al., 2004; Stoffman et al., 2004; Schramm & Aliashkevich, 2007; Blümcke, 2009). Long-term epilepsy associated tumors (LEATs) encompass a spectrum of pathologies, including gangliogliomas (GGs), dysembryoplastic neuroepithelial tumors (DNETs), and some other low-grade tumor types, for example, pleomorphic xanthoastrocytoma (Blümcke, 2009). Although infrequent among all central nervous system (CNS) neoplasms (Louis et al., 2007), LEAT entities are commonly found in the context of chronic medically refractory partial epilepsy (Blümcke, 2009). Prior to the era of modern imaging techniques, detection of LEATs depended largely on tissue diagnosis after histopathologic workup (Cavanagh, 1958). Although LEAT lesions are now often detected much earlier in the disease course as a result of better and more frequent imaging, accurate methods of presurgical prediction of the specific histopathologic tumor type are still lacking. Moreover, currently many tumors still remain undetected or are not clearly identified as neoplastic lesions, owing to their variable imaging appearance (Oertzen et al., 2002). Therefore, a technique supporting a clear LEAT diagnosis would have great value for diagnosis and therapeutic approaches in refractory epilepsy.

18Fluoroethyl-l-tyrosine (FET) is a valuable positron emission tomography (PET) tracer for investigating the amino acid metabolism of different tissues, especially tumors (Weckesser et al., 2005). In comparison to other radiolabeled amino acid molecules like 11C-methionine (MET), FET provides advantages due to its stability, kinetics, and long half-life allowing multiple investigations following a single synthesis step (Langen et al., 2006). Data from in vitro experiments indicates that FET enters cells through a sodium-independent membrane amino acid transport mechanism involving transmembrane protein complexes of the so-called l-amino acid transporter or LAT family (Heiss et al., 1999). However, the exact cellular mechanism of FET transport and retention remains to be determined.

To date, FET has been used in several clinical neurooncologic settings. FET imaging has made a major contribution to glioma therapy due to better delineation of true tumor extent when combined with magnetic resonance imaging (MRI) compared to MRI alone (Pauleit et al., 2005). FET also has added to radiographic discrimination of glioma recurrence from radiation necrosis (Pöpperl et al., 2004). Classification of newly diagnosed brain lesions as neoplastic was aided by combination of MRI, MR spectroscopy, and FET-PET data (Floeth et al., 2005). By highlighting tumoral zones of metabolic activity, FET-PET enables targeted biopsy, resection, or radiation strategies in cerebral gliomas (Pauleit et al., 2005). Although FET uptake does not show a close correlation to individual histologic glioma grades (Pöpperl et al., 2007), analysis of uptake dynamics might better differentiate between high-grade and low-grade lesions (Weckesser et al., 2005; Pöpperl et al., 2007). Two-thirds of low-grade gliomas are reported to exhibit significant FET uptake (Floeth et al., 2007). Here, enhancement by FET has been shown to correlate to poorer prognosis: Notably, FET-negative and circumscribed low grade gliomas had a stable long-term course without progression (Floeth et al., 2007, 2008).

Previous data suggest a correlation between increased FET uptake and a neoplastic nature of the underlying brain lesion. Few LEAT lesions have been included in amino acid PET studies on primary brain neoplasms, and, therefore, knowledge about the uptake properties of these lesions is limited. We, therefore, retrospectively evaluated FET-PET data from a cohort of epilepsy patients displaying MRI lesions suspicious for tumor. The main questions addressed by this study are: How many unequivocal LEAT lesions show FET uptake? Is FET-PET helpful in establishing the LEAT diagnosis? Does FET uptake correlate to any clinical parameter concerning the patient’s seizure disorder?

Methods

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

Patient population

Thirty-six patients with medically refractory partial epilepsy due to a LEAT-suspect MRI lesion were retrospectively identified within the databases at Erlangen Epilepsy Center, the Departments of Neurosurgery and Neuroradiology, and the Clinic of Nuclear Medicine at Erlangen University/Germany, and included in this study. We selected patients if all of the following criteria were fulfilled: (1) MRI reports included features suspicious of a LEAT and/or LEAT had been diagnosed in the surgical specimen, (2) a FET-PET had been performed, and (3) epilepsy had been reported for at least 2 years with pharmacoresistant course after trial of several major anticonvulsant drugs. FET-PET had been performed as part of the routine presurgical diagnostic workup of tumor-suspect lesions at our institutions. All selected patients did undergo an extensive epileptologic workup within the epilepsy surgery program including long-term video-EEG monitoring, standardized epilepsy MRI protocol (at 1.5 or 3T), and neuropsychological testing. Based on discussion and decision by an interdisciplinary case conference, 22 patients had neurosurgical resection of the lesion and presumed epileptogenic zone after informed consent. An overview of the study group is given by Tables 1 and 2: 17 female patients and 19 male patients. Mean age at diagnostic workup was 35.5 ± 11.8 years (range 10–49 years, median 37.0 years). Age at epilepsy onset was 19.0 ± 12.0 years (range 1–38 years, median 15.5 years). All patients reported complex partial seizures and secondary generalization. Mean frequency of partial seizures was 8.0/month (range 0–30, median 5.0). The mean duration of epilepsy at PET investigation was 17.0 ± 12.2 years (range 1–41, median 14.5 years). The patients’ neurological status was unremarkable. Twenty-two patients underwent resection. Mean age at surgery was 34.3 years (range 12–43 years, median 36.0 years). The patients not undergoing surgery did so due to contraindications, that is, localization of the epileptogenic zone in or near eloquent cortex, or because of temporary seizure freedom. The study group also included two patients presenting with residual seizures after lesionectomy of a tumoral lesion (outside our center) prior to current surgery (one DNET and GG each); the latter two were included in the overall analysis including PET and histopathology data, but excluded from detailed subanalysis of MRI appearance, since their initial MRIs were not available for review.

Table 1.   Individual clinical, MRI, FET-PET, and pathologic data
 SexAgeOnsetLocationSideContrastFET visualSUVmaxSUV QuotientFirst-line MRI diagnosisPathology
  1. Cases 1–22: surgical cases with histopathology data, cases 23–36: nonsurgical cases; M, male; F, female; T, temporal; ET, extratemporal; +, contrast enhancing; GG, ganglioglioma; DNET, dysembryoplastic neuroepithelial tumor; GC, gangliocytoma; GPT, glioneuronal papillary tumor; cases 21 and 22 (a) had prior surgery, and no residual tumor was suspected on MRI.

1M1810TR+Pos1.501.88TumorGG
2M371TR+Pos3.303.30TumorGG
3M3224TR+Pos2.102.10TumorDNET
4M4539ETRNeg1.001.00No tumorDNET
5M4039TLNeg1.001.00TumorGC
6M4638TLPos1.401.27TumorDNET
7M3830TLNeg1.001.00No tumorGPT
8M2215TLPos2.302.30TumorGG
9M3011TL+Pos5.102.68TumorGG
10M2211TLPos1.401.40TumorGG
11F431TRPos2.102.63No tumorGG
12F5030TR+Neg1.001.00TumorGG
13F206TRPos3.122.86TumorGG
14F4517TRPos1.301.30No tumorGG
15F3514TLPos2.001.67TumorGG
16F4036TLNeg1.001.00TumorGG
17F319ETLPos1.201.20TumorDNET
18F103ETLPos1.501.36No tumorDNET
19F5438TLNeg1.001.00No tumorGG
20F2518TLPos2.101.62No tumorGG
21aF259ETLNeg1.001.00No tumorDNET
22aM3812TRNeg1.001.00No tumorGG
23M3634TRNeg1.001.00No tumorNo surgery
24M4313TRNeg1.001.00TumorNo surgery
25M3716TRNeg0.901.00TumorNo surgery
26M5418ETRPos3.003.33TumorNo surgery
27M1712ETR+Pos1.802.57TumorNo surgery
28M4739TLPos1.501.88TumorNo surgery
29M4313ETLPos1.001.44No tumorNo surgery
30M5918TLNeg1.001.00TumorNo surgery
31F3635TRNeg1.001.00TumorNo surgery
32F3611ETR+Pos2.201.57No tumorNo surgery
33F205TRPos2.012.23No tumorNo surgery
34F4115TR+Pos2.902.07No tumorNo surgery
35F4228TLNeg1.001.00TumorNo surgery
36F2018TLPos1.681.28TumorNo surgery
Table 2.   Summary of clinical data comparing the cases with and without FET enhancement
  nFET posFET negStatistics
  1. FETpos, FET-enhanced lesions; FETneg, nonenhancing lesions; GG, ganglioglioma, DNET, dysembryoplastic neuroepithelial tumor; PS, partial seizures; GS, generalized seizures; n.s., not significant.

GeneralGender
 Male36118n.s.
 Female 116
Age (at PET) (years)3631.6 ± 12.0 (10–54)41.6 ± 8.5 (25–59)p = 0.006
Age at surgery (years) [only 22/36 cases]2230.0 ± 10.6 (12–46)41.8 ± 8.7 (25–55)p = 0.007
Age at onset (years)3614.1 ± 9.8 (1–39)26.9 ± 11.0 (9–39)p = 0.001
Duration (years)3617.0 ± 11.8 (2–42)17.0 ± 13.4 (1–41)n.s.
PS/month369.6 ± 11.1 (0–30)5.6 ± 4.4 (0–15)n.s.
GS/month360.5 ± 0.9 (0–4)0.1 ± 0.5 (0–2)n.s.
Side
 Right36117n.s.
 Left 117
MRILocalization
 Temporal361612n.s.
 Extratemporal 62
Cortex involved
 Yes34187n.s.
 No 45
Amygdala involved
 Yes3499n.s.
 No 133
Cystic component
 Yes34158n.s.
 No 74
Edema present
 Yes3400n.s.
 No 2212
Gradient echo alteration
 Yes3451n.s.
 No 1711
Contrast enhancement
 Yes3680p = 0.013 (Fisher’s exact)
 No 1414 
HistologyTissue diagnosis
 GG22104n.s.
 DNET42
 Other02

MRI Review

All available presurgical MRI sequences were reviewed by a senior neuroradiologist (TS) blinded to PET results. All lesions except the two with prior surgery were reclassified according to a list of imaging parameters including exact anatomic localization, involvement of cortex, involvement of white matter, presence of cystic components, presence of contrast enhancement, presence of edema, and signal changes in gradient echo sequences. In addition, all first-line radiology reports were reviewed (BK, TS) for initial lesion classification.

Radiosynthesis of 18F-FET and 18F-FET-PET data acquisition

FET synthesis had been performed as described previously (Stadlbauer et al., 2008). FET-PET scans from the brain were performed with a PET/computed tomography (CT) scanner (Biograph 64; Siemens, Erlangen, Germany) 10 min after the intravenous injection of FET at 3 MBq/kg of body weight. Emission data were acquired over 30 min in the three-dimensional (3D) mode. For attenuation correction, a low-dose-CT (50 mAs, 100 keV) was used. Emission data corrected for randoms, dead time, and attenuation were reconstructed with an iterative reconstruction algorithm (ordered-subset expectation maximization; four iterations, eight subsets). Matrix size was 128 × 128 in plane, and the slice thickness was 3 mm. PET technology allows quantitative assessment of FET uptake by measuring the decay corrected tissue activity concentration (Bq/ml) of FET in a region of interest (ROI) and evaluating standardized uptake values (SUVs). In a first step, non-coregistered native PET scans were visually analyzed for a detectable spot of marked FET uptake. If present, these cases were classified as FETpos. To characterize the tumor-associated amino acid uptake, the standard uptake values (SUV) were calculated both in a manually defined ROI according to the highest FET uptake (maximum SUV in the tumor-suspicious area) and in the contralateral normal brain (average SUV for background information). To define the tumor area, FET-PET and MRI studies were coregistered and an elliptic 3D tumor ROI was drawn according to the lesion borders in MRI. For background information average SUV was calculated after the tumor ROI was mirrored to the contralateral brain and manually repositioned, if necessary, in order to exclude disturbing structures from the ROI, for example, adjacent bone, cerebrospinal fluid (CSF) spaces, or large vessels.

Statistical analysis

Statistical methods used were chi-square test, t-tests for independent samples, and Fisher’s exact test and correlation analysis (Pearson) performed by SPSS statistical software (PASW Statistics 17.0, Version 17.0.2, SPSS Inc., Chicago, IL, U.S.A.).

Results

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

Clinical data, MRI appearance, and FET-PET results

Twenty-eight lesions were localized within the temporal lobe; eight were localized extratemporally. Eighteen lesions were left-sided and 18 were right-sided. Table 2 summarizes the clinical data and detailed presurgical lesion MRI parameters according to the neuroradiologist’s review (for two cases with prior surgery this subanalysis is incomplete, because MR imaging preceding first surgery was unavailable). Additional evaluation of first-line routine MRI readings revealed only 22 (61%) of 36 lesions classified as clear-cut neoplasia belonging to the LEAT spectrum: In seven cases the neoplastic nature was only discussed among other differential diagnoses. The latter group included the following alternative diagnoses: cavernoma (2), nontumorous cyst (2), developmental defect (1), dysplasia (1), hamartoma (1), and defect zone with surrounding gliosis (1). In another seven cases, the lesion was classified as nonneoplastic; this group encompassed diagnoses of hippocampal sclerosis (1), suspected postinflammatory changes (2), neuroepithelial cyst (2), and the two cases with prior surgery that were classified as showing no evidence of residual tumor (2). In 22 patients epilepsy surgery was performed. Histopathologic diagnoses according to WHO classification (Louis et al., 2007) were ganglioglioma WHO I (n = 14), gangliocytoma WHO I (n = 1), DNET (n = 6), and glioneuronal papillary tumor WHO I (n = 1). In 20 surgical patients outcome data were available for a minimum of 3 months; for all these cases the most recent surgical outcome was Engel class IA, corresponding to complete seizure freedom; postsurgical outcome data were available after 3 months (n = 5), 6 months (n = 7), 12 months (n = 5), and 24 months (n = 5) (mean 10.8 months; median 6 months).

According to visual judgment of FET-PET images, 22 (61%) of 36 cases showed marked FET uptake (FETpos), and this was concordant to the tumor localization (Figs 1–3). SUVmax values of all cases were 1.7 ± 0.9 (median 1.5, range 0.9–4.2); quotient values of lesional SUVmax/contralateral SUV for all cases were 1.6 ± 0.7 (median 1.3. range 1.0–3.3).

image

Figure 1.   Multiplanar T1 images showing right temporomesial cystic tumor (lower row, crosslines) with spot of FET uptake in corresponding localization (upper row). Histopathology: ganglioglioma WHO I.

Download figure to PowerPoint

image

Figure 2.   Gradient echo/T2* image showing right frontal lesion diagnosed as cavernoma (left side, arrow) with spot of FET uptake in corresponding localization (right side, arrow). Histopathology: not available (no surgery).

Download figure to PowerPoint

image

Figure 3.   Multiplanar fluid-attenuated inversion recovery (FLAIR) images (lower row) of one patient showing a right frontal, tumorous lesion without MRI contrast enhancement (crosslines) with spot of increased FET uptake in corresponding localization (upper row). Histopathology: not available (no surgery).

Download figure to PowerPoint

By quantitative analysis, lesions ranked positive (“marked FET uptake”) had SUVmax values of 2.14 ± 0.9 (median 2.0, range 1.2–5.1) and SUV quotients of 2.0 ± 0.7 (median 1.9, range 1.2–3.3). Lesions ranked negative had SUVmax values of 1.0 ± 0.03 (median 1.0, range 0.9–1.0) and SUV quotients of 1.0 ± 0. A comparison of mean SUVmax and SUV quotient values according to selected characteristics is displayed in Table 3. A significant difference appeared for lesions with versus without contrast enhancement.

Table 3.   Quantitative values (SUVmax, SUV quotient; means ± SD; range below) related to selected parameters
 SUVmaxSUV quotientStatistics
  1. T, temporal; ET, extratemporal; GG, ganglioglioma; DNET, dysembryoplastic neuroepithelial tumor.

Patient genderMale1.73 ± 1.07 (0.90–5.10)Female1.65 ± 0.68 (1.00–3.12)Male1.69 ± 0.81 (1.00–3.33)Female1.51 ± 0.60 (1.00–2.86)n.s.
Affected hemisphereRight1.79 ± 0.84 (0.90–3.3)Left1.59 ± 0.97 (1.00–5.10)Right1.82 ± 0.84 (1.00–3.33)Left1.39 ± 0.48 (1.0–2.68)n.s.
Lesion localizationT1.70 ± 0.96 (0.90–5.10)ET1.65 ± 0.68 (1.00–3.00)T1.59 ± 0.69 (1.00–3.33)ET1.68 ± 0.83 (1.00–3.33)n.s.
Cortical involvementYes1.86 ± 0.99 (1.00–5.10)No1.39 ± 0.53 (0.90–2.03)Yes1.71 ± 0.74 (1.00–3.33)No1.45 ± 0.65 (1.00–2.63)n.s.
Cystic componentYes1.60 ± 0.68 (0.90–3.30)No2.00 ± 1.23 (1.00–5.10)Yes1.58 ± 0.68 (1.00–3.30)No1.79 ± 0.81 (1.00–3.33)n.s.
Contrast enhancementYes2.75 ± 1.14 (1.50–5.10)No1.39 ± 0.53 (0.90–3.00)Yes2.38 ± 0.57 (1.57–3.30)No1.39 ± 0.59 (1.00–3.33)p < 0.05
Histologic typeGG1.92 ± 1.22 (1.00–5.10)DNET1.37 ± 0.41 (1.00–2.10)GG1.68 ± 0.74 (1.0–3.30)DNET1.32 ± 0.41 (1.00–2.01)n.s.

Comparison of quantitative SUV measurements with clinical characteristics of age at PET investigation, age at surgery, duration of epilepsy, and age at epilepsy onset, revealed significant correlations for both SUVmax and SUV quotient with age at epilepsy onset (for SUVmax: Pearson-coefficient R = −0.46; p < 0.01, for SUV quotient: Pearson-coefficient R = −0.51; p < 0.01).

No significant correlation was found regarding histopathologic tissue diagnoses (GG vs. DNET) in the 22 operated cases, although gangliogliomas tended to show higher mean SUVmax values and mean SUV quotients.

Discussion

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

In this series of 36 patients with medically refractory lesional partial epilepsy, a surprisingly large subgroup of LEAT lesions showed an increase of 18fluoroethyl-l-tyrosine (FET) uptake. This result seems important, since FET uptake was a marker for malignant lesions in previous studies (Pöpperl et al., 2004; Pauleit et al., 2005; Floeth et al., 2007, 2008). However, knowledge about amino acid uptake properties in epilepsy-associated tumors is scarce so far, since no PET study has investigated this systematically and some studies explicitly excluded epilepsy patients (Floeth et al., 2008).

Regarding FET and epilepsy-related tumors, only one larger study on 44 primary brain tumors included a single DNET, which remained unvisualized (Weckesser et al., 2005). Other amino acid PET or SPECT studies on tumors, including at least some comparable LEAT cases. used different radiolabeled tracers, for example, methyl-11C-methionine (MET), 123Iod-alpha-methyl-tyrosin (IMT), or alpha-11C-methyl-l-tryptophan (AMT). One of the earliest reports refers to a ganglioglioma labelled by MET (Metsähonkala et al., 1996). A single case of desmoplastic infantile ganglioglioma was reported to show increased lesional IMT uptake (Woesler et al., 1998). Among 196 tumoral lesions investigated by MET, one DNET and one GG included in the series both did not enhance (Herholz et al., 1998). In a series of 34 tumors of various types, one DNT was not labelled, whereas one GG did show enhancement by MET (Braun et al., 2002). All five DNETs investigated by Kaplan (Kaplan et al., 1999) and four DNT included by Maehara (Maehara et al., 2004) did not show increased MET uptake. However, the latter series reported on a ganglioglioma, a pleomorphic xanthoastrocytoma, and a low grade astrocytoma enhanced by MET (Maehara et al., 2004). Interestingly, AMT was able to label the majority of 40 neoplastic brain lesions including all six DNETs and all three gangliogliomas within the series (Juhász et al., 2006). Another study again showed MET labelling in all investigated gangliogliomas (5 of 5) but few DNET (4 of 11) (Rosenberg et al., 2005). In summary, in these studies only 4 of 22 lesions diagnosed as DNET but 8 of 9 lesions diagnosed as GG showed MET enhancement (Table 3). All LEAT (nine lesions including six DNETs) were enhanced by AMT (Juhász et al., 2006). The results of previous studies including LEAT entities are summarized in Table 4.

Table 4.   Synopsis of gangliogliomas and DNETs within published amino acid PET studies
AuthorYearnStudy characteristicsPET-TracerGangliogliomas and DNETs included in the study
DNTGG
NUptakeNo uptakenUptakeNo uptake
  1. FET, 18Fluoroethyl-l-tyrosine ; MET, methyl-11C-methionine; AMT, alpha-11C-methyl-l-tryptophan; GG, ganglioglioma; DNET, dysembryoplastic neuroepithelial tumor; positive, enhanced by tracer; negative, nonenhanced by tracer.

Weckesser200544Various lesionsFET101000
Rosenberg200527All epilepsyMET1147550
Maehara20047All TLE related tumorsMET404110
Braun200234Various lesionsMET101110
Kaplan19995All childhood epilepsyMET5050
Herholz1998196Various lesionsMET101101
Metsähonkala19961Case reportMET0110
Juhasz200640Various neoplasmsAMT660330

Although the ability of FET-PET to detect the epileptogenic lesion was moderate in our study (22 of 36 or 61% overall; 14 of 22 or 64% of all histologically verified tumors), presence of FET uptake characteristically corresponded to neoplastic nature of an epilepsy associated suspect MRI lesion. Certainly, the fact that we did not prospectively include different lesion types, including non-neoplastic lesions is a limitation concerning the conclusion on tumor-specificity of FET. But notably, all surgically resected FETpos lesions from this series were tumors on the LEAT-spectrum, and no FETpos lesion was nontumorous on histopathology.

Previous studies on neoplastic CNS lesions suggested an increased FET uptake as strongly predictive for a diagnosis of malignant glioma and also a more aggressive tumoral grade (Pöpperl et al., 2007). Therefore, FET has been used to aid presurgical grading of tumor lesions, especially in gliomas (Pöpperl et al., 2004). Our results show that significant FET uptake does not necessarily indicate a tissue diagnosis of a malignant glioma. Certain LEATs display significant FET uptake, although pathologic analysis revealed stable lesions with very low proliferative activity corresponding to World Health Organization (WHO) grade I (e.g., GG and DNET). These lesions are classified by some authors as malformative lesions rather than representing active neoplasms (Barkovich et al., 2005). Rarely, GGs correspond to WHO grades II or III (Majores et al., 2008), none of which was encountered in the present study.

FET uptake in this series was not specific for a distinct histopathologic tumor type. In this study, for both DNET and GG tumors, two-thirds were labelled by FET (see Table 2). GGs showed higher values of mean SUVmax and SUV quotients than DNETs, mirroring findings recently reported for methyl-11C-Methionine (MET) (Phi et al., 2010). However, the pathologic appearance of GG and DNT is not homogenous (Louis et al., 2007) and other tissue characteristics not yet investigated in detail may correlate to presence or absence of FET uptake, such as varying inflammatory cell populations within the tumors. Although absence of FET uptake cannot rule out a neoplasm (as illustrated by our eight FETneg but histologically verified tumors including the two cases with residual tumor after first surgery), according to our data, significant FET uptake strongly suggests a neoplastic nature of a lesion underlying partial epilepsy. In particular, FET-PET may support the diagnostic process in cases with ambiguous MRI readings. LEATs on MRI often appear as rather unusual formations (often without mass effect, edema, contrast enhancement, often appearing as a “cyst,” making the clearcut classification as a neoplasia a matter of debate. LEATs are often misclassified by unexperienced observers in the setting of conventional MRI protocols (Oertzen et al., 2002). In our series, not all lesions were unequivocally defined as neoplastic in the first-line radiology report. In 8 of 14 cases (i.e., 57%), where diagnosis of a LEAT was refused or considered as differential diagnosis only, FET enhancement pointed to a LEAT; in all resected cases, histopathology proved the neoplastic diagnosis (surgery was not performed on four of the lesions). Notably, the exact definition of the substrate underlying a chronic partial seizure disorder is crucial in order to choose the optimal resective strategy.

Interestingly, there is some evidence that amino acid PET imaging could help differentiating LEATs and Taylor’s focal cortical dysplasia (T-FCD). This differentiation can be difficult on MRI alone, and neoplasms mimicking the MRI appearance of T-FCD have been described (Holthausen et al., 2006). A small group of three lesions histologically verified as T-FCD investigated by us using FET-PET so far, consistently showed no FET uptake (data not shown). A very recent study showed a similar difference for MET, suggesting the potential of aminoacid PET imaging for differentiating tumors from dysplasias in epilepsy (Phi et al., 2010). One unique case included in our study displayed both MRI-types of lesions, that is, a right-sided frontal tumor-suspicious lesion and a left-sided temporoparietal transmantle dysplasia: Only the tumor-suspect lesion showed FET uptake (Figs 3 and 5).

image

Figure 5.   Same patient as in Fig. 3. The left parietal focal cortical dysplasia with transmantle sign on coronary FLAIR (left side, arrow) is not showing increased FET uptake (right side, arrow).

Download figure to PowerPoint

Considering the possible cause of increased FET uptake seen in LEAT subpopulations, different possibilities must be considered: We did not find correlations of FET uptake to localization and standard MRI parameters except contrast enhancement. Interestingly, all tumors displaying gadolinium enhancement showed FET labelling, and their SUVmax values were significantly higher (see Table 3). However, the majority of FET-enhanced tumors did not display gadolinium contrast (see Tables 1 and 2). Therefore, it seems unlikely that increased FET uptake is solely caused by tracer leakage across the blood–brain barrier. Differences regarding the patient’s age at the time of PET acquisition or time of surgery are most frequently determined by patient selection and disease course. Interestingly, a striking difference was seen when comparing age at epilepsy onset (but not epilepsy duration) between FET enhancing and nonenhancing lesions: Patients with FET-enhancing lesions were significantly younger at epilepsy onset (14.1 vs. 26.9 years). Moreover, there was a negative correlation between SUVmax and SUV quotients with age at epilepsy onset (Fig. 4). This finding could indicate a principal biologic difference between these lesional groups (see below).

image

Figure 4.   Correlation between SUVmax and age at epilepsy onset.

Download figure to PowerPoint

Seizure numbers or epileptogenicity per se do not seem to account for differences in FET-PET: All patients had refractory seizures, seizure frequencies were not different between lesions with and without uptake, and T-FCDs, which are known for their intense intrinsic epileptogenicity, seem not to enhance (Phi et al., 2001). Notably, in the single patient displaying both lesion types on MRI (Figs 3 and 5), only seizures related to the left parietal dysplasia were present. An impact of the most recent seizure on PET result is possible, but was not investigated here. This factor is unlikely to be involved, since the few patients with T-FCD investigated so far experienced frequent daily seizures, but none of them showed enhancement (data not shown).

It remains unanswered whether FET enhancing and nonenhancing tumors differ in their precise histopathologic composition. Bearing in mind that diagnostic categories like “GG” or “DNET” encompass a spectrum of cytologic aberrations and that mixed tumor types have been described (Hirose & Scheithauer, 1998; Prayson, 1999), unknown but significant cytologic differences between enhancing and nonenhancing tumors might be present. We observe that LEATs show very different PET-imaging characteristics depending on the amino acid tracer used in the studies mentioned (see Table 4), although FET as well as MET, IMT, and AMT all are discussed as substrates of the l-aminoacid-transporter system (Floeth et al., 2008). This fact merits further investigation.

It should be clarified which cellular components within FETpos tumors are responsible for the detectable FET uptake. A detailed reinvestigation of tissue pathology addressing these issues will be the subject of a subsequent study. Therefore, the interpretation of increased FET uptake in certain LEATs is speculative at present. Interestingly, l-amino acid transporters (LAT) not only serve as transporter molecules, but are reported to display important roles for cell growth and survival (Fuchs & Bode, 2005). LAT1, for example, corresponds to TA1, an oncofetal antigen primarily expressed in fetal tissues and cancer cells (Mannion et al., 1998). LAT1 expression has been demonstrated in several tumor cell lines (Yanagida et al., 2001), and high LAT1 expression was related to poorer prognosis in astrocytic brain tumors (Nawashiro et al., 2006). It might, therefore, be important to observe the long-term course of LEATs that remain unresected, especially when enhanced by FET. Presence or absence of FET uptake might indicate a principal biologic difference inherent to the LEAT spectrum that could have influence future tumor classifications and therapeutic strategies.

Acknowledgments

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

The authors thank Wilhelm Hamkens and Prof. Dr. Willi Kalender (PET Net GmbH, Erlangen, Germany) for expert technical support and excellent collaboration.

We thank Scott Floyd, MD, PhD, Department of Radiation Oncology, Harvard Medical School, Boston, U.S.A., for carefully editing of the manuscript.

Disclosure

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

TK has served as a paid consultant for Siemens Medical Solutions; the remaining authors have no conflicts of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

References

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  • Barkovich AJ, Kuzniecky RI, Jackson GD, Guerrini R, Dobyns WB. (2005) A developmental and genetic classification for malformations of cortical development. Neurology 65:18731887.
  • Blümcke I. (2009) Neuropathology of focal epilepsies: a critical review. Epilepsy Behav 15:3439.
  • Braun V, Dempf S, Weller R, Reske SN, Schachenmayr W, Richter HP. (2002) Cranial neuronavigation with direct integration of (11)C methionine positron emission tomography (PET) data – results of a pilot study in 32 surgical cases. Acta Neurochir (Wien) 144:777782. discussion 782.
  • Cavanagh JB. (1958) On certain small tumors encountered in the temporal lobe. Brain 81:389405.
  • Floeth FW, Pauleit D, Wittsack HJ, Langen KJ, Reifenberger G, Hamacher K, Messing-Jünger M, Zilles K, Weber F, Stummer W, Steiger HJ, Woebker G, Müller HW, Coenen H, Sabel M. (2005) Multimodal metabolic imaging of cerebral gliomas: positron emission tomography with [18F]fluoroethyl-l-tyrosine and magnetic resonance spectroscopy. J Neurosurg 102:318327.
  • Floeth FW, Pauleit D, Sabel M, Stoffels G, Reifenberger G, Riemenschneider MJ, Jansen P, Coenen HH, Steiger HJ, Langen KJ. (2007) Prognostic value of O-(2-18F-fluoroethyl)-l-tyrosine PET and MRI in low-grade glioma. J Nucl Med 48:519527.
  • Floeth FW, Sabel M, Stoffels G, Pauleit D, Hamacher K, Steiger HJ, Langen KJ. (2008) Prognostic value of 18F-fluoroethyl-l-tyrosine PET and MRI in small nonspecific incidental brain lesions. J Nucl Med 49:730737.
  • Fuchs BC, Bode BP. (2005) Amino acid transporters ASCT2 and LAT1 in cancer: partners in crime? Semin Cancer Biol 15:254266.
  • Heiss P, Mayer S, Herz M, Wester HJ, Schwaiger M, Senekowitsch-Schmidtke R. (1999) Investigation of transport mechanism and uptake kinetics of O-(2-[18F]fluoroethyl)-l-tyrosine in vitro and in vivo. J Nucl Med 40:13671373.
  • Herholz K, Hölzer T, Bauer B, Schröder R, Voges J, Ernestus RI, Mendoza G, Weber-Luxenburger G, Löttgen J, Thiel A, Wienhard K, Heiss WD. (1998) 11C-methionine PET for differential diagnosis of low-grade gliomas. Neurology 50:13161322.
  • Hirose T, Scheithauer BW. (1998) Mixed dysembryoplastic neuroepithelial tumor and ganglioglioma. Acta Neuropathol 95:649654.
  • Holthausen H, Winkler P, Pieper T, Hildebrandt M, Kolodziejczyk D, Blümcke I. (2006) Ganglioglioma mimicking transmantle focal cortical dysplasia in a two-year old child with intractable epilepsy. Abstract (German) at Neurowoche 2006.
  • Juhász C, Chugani DC, Muzik O, Wu D, Sloan AE, Barger G, Watson C, Shah AK, Sood S, Ergun EL, Mangner TJ, Chakraborty PK, Kupsky WJ, Chugani HT. (2006) In vivo uptake and metabolism of alpha-[11C]methyl-l-tryptophan in human brain tumors. J Cereb Blood Flow Metab 26:345357.
  • Kaplan AM, Lawson MA, Spataro J, Bandy DJ, Bonstelle CT, Moss SD, Manwaring KH, Reiman EM. (1999) Positron emission tomography using [18F] fluorodeoxyglucose and [11C] l-methionine to metabolically characterize dysembryoplastic neuroepithelial tumors. J Child Neurol 14:673677.
  • Langen KJ, Hamacher K, Weckesser M, Floeth F, Stoffels G, Bauer D, Coenen HH, Pauleit D. (2006) O-(2-[18F]fluoroethyl)-l-tyrosine: uptake mechanisms and clinical applications. Nucl Med Biol 33:287294.
  • Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P. (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97109.
  • Luyken C, Blümcke I, Fimmers R, Urbach H, Wiestler OD, Schramm J. (2004) Supratentorial gangliogliomas Histopathological grading and tumor recurrence in 184 patients with a median follow-up of 8 years. Cancer 101: 146155.
  • Maehara T, Nariai T, Arai N, Kawai K, Shimizu H, Ishii K, Ishiwata K, Ohno K. (2004) Usefulness of [11C]methionine PET in the diagnosis of dysembryoplastic neuroepithelial tumor with temporal lobe epilepsy. Epilepsia 45:4145.
  • Majores M, von Lehe M, Fassunke J, Schramm J, Becker AJ, Simon M. (2008) Tumor recurrence and malignant progression of gangliogliomas. Cancer 113:33553363.
  • Mannion BA, Kolesnikova TV, Lin SH, Wang S, Thompson NL, Hemler ME. (1998) The light chain of CD98 is identified as E16/TA1 protein. J Biol Chem 273:3312733129.
  • Metsähonkala L, Aärimaa T, Sonninen P, Mikola H, Ruotsalainen U, Bergman J. (1996) CT, MRI, and PET in a case of intractable epilepsy. Childs Nerv Syst 12:421424.
  • Nawashiro H, Otani N, Shinomiya N, Fukui S, Oigawa H, Shima K, Matsuo H, Kanai Y, Endou H. (2006) l-type amino acid transporter 1 as a potential molecular target in human astrocytic tumors. Int J Cancer 119:484492.
  • Oertzen Jvon, Urbach H, Jungbluth S, Kurthe M, Reuber M, Fernandez G, Elger CE. (2002) Standard magnetic resonance imaging is inadequate for patients with refractory focal epilepsy. J Neurol Neurosurg Psychiatry 73:643647.
  • Pauleit D, Floeth F, Hamacher K, Riemenschneider MJ, Reifenberger G, Müller HW, Zilles K, Coenen HH, Langen KJ. (2005) O-(2-[18F]fluoroethyl)-l-tyrosine PET combined with MRI improves the diagnostic assessment of cerebral gliomas. Brain 128:678687.
  • Phi JH, Paeng JC, Lee HS, Wang KC, Cho BK, Lee JY, Park SH, Lee J, Lee DS, Kim SK. (2010) Evaluation of focal cortical dysplasia and mixed neuronal and glial tumors in pediatric epilepsy patients using 18F-FDG and 11C-methionine pet. J Nucl Med 51:728734.
  • Pöpperl G, Götz C, Rachinger W, Gildehaus FJ, Tonn JC, Tatsch K. (2004) Value of O-(2-[18F]fluoroethyl)-l-tyrosine PET for the diagnosis of recurrent glioma. Eur J Nucl Med Mol Imaging 31:14641470.
  • Pöpperl G, Kreth FW, Mehrkens JH, Herms J, Seelos K, Koch W, Gildehaus FJ, Kretzschmar HA, Tonn JC, Tatsch K. (2007) FET PET for the evaluation of untreated gliomas: correlation of FET uptake and uptake kinetics with tumour grading. Eur J Nucl Med Mol Imaging 34:19331942.
  • Prayson RA. (1999) Composite ganglioglioma and dysembryoplastic neuroepithelial tumor. Arch Pathol Lab Med 123:247250.
  • Rosenberg DS, Demarquay G, Jouvet A, Le Bars D, Streichenberger N, Sindou M, Kopp N, Mauguière F, Ryvlin P. (2005) [11C]-Methionine PET: dysembryoplastic neuroepithelial tumours compared with other epileptogenic brain neoplasms. J Neurol Neurosurg Psychiatry 76:16861692.
  • Schramm J, Aliashkevich AF. (2007) Surgery for temporal mediobasal tumors: experience based on a series of 235 cases. Neurosurgery 60: 285295.
  • Stadlbauer A, Prante O, Nimsky C, Salomonowitz E, Buchfelder M, Kuwert T, Linke R, Ganslandt O. (2008) Metabolic imaging of cerebral gliomas: spatial correlation of changes in O-(2-18F-fluoroethyl)-l-tyrosine PET and proton magnetic resonance spectroscopic imaging. J Nucl Med 49:721729.
  • Stoffman MR, Cohen-Gadol AA, Spencer SS, Spencer DD. (2004). Presurgical evaluation in patients with tumors. In RosenowF, LüdersHO (eds) Presurgical assessment of the epilepsies with clinical neurophysiology and functional imaging. Handbook of Clinical Neurophysiology Series, Vol 3. Elsevier, New York, 2004, pp. 383393.
  • Weckesser M, LAngen KJ, Rickert CH, Kloska S, Straeter R, Hamacher K, Kurlemann G, Wassmann H, Coenen HH, Schober O. (2005) O-(2-[18F]fluorethyl)-l-tyrosine PET in the clinical evaluation of primary brain tumors. Eur J Nucl Med Mol Imaging 32:422429.
  • Woesler B, Kuwert T, Kurlemann G, Morgenroth C, Probst-Cousin S, Lerch H, Gullotta F, Wassmann H, Schober O. (1998) High amino acid uptake in a low-grade desmoplastic infantile ganglioglioma in a 14-year-old patient. Neurosurg Rev 21:3135.
  • Yanagida O, Kanai Y, Chairoungdua A, Kim DK, Segawa H, Nii T, Cha SH, Matsuo H, Fukushima J, Fukasawa Y, Tani Y, Taketani Y, Uchino H, Kim JY, Inatomi J, Okayasu I, Miyamoto K, Takeda E, Goya T, Endou H. (2001) Human l-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines. Biochim Biophys Acta 1514:291302.
  • Zentner J, Hufnagel J, Wolf HK, Ostertun B, Behrens E, Campos MG, Elger CE, Wiestler OD, Schramm J. (1997) Surgical treatment of neoplasms associated with medially intractable epilepsy. Neurosurgery 41:378387.