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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?
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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
|Author||Year||n||Study characteristics||PET-Tracer||Gangliogliomas and DNETs included in the study|
|N||Uptake||No uptake||n||Uptake||No uptake|
|Maehara||2004||7||All TLE related tumors||MET||4||0||4||1||1||0|
|Kaplan||1999||5||All childhood epilepsy||MET||5||0||5||0||−||−|
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).
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).
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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).
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.