Non-FDG PET imaging of brain tumors

Non-FDG PET imaging of brain tumors

Available online at ScienceDirect NUCLEAR SCIENCE AND TECHNIQUES Nuclear Science and Techniques, Vo1.18, No.3 (2007)154-158 Non...

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Nuclear Science and Techniques, Vo1.18, No.3 (2007)154-158

Non-FDG PET imaging of brain tumors HUANG Zemin

GUAN Yihui* ZUO Chuantao ZHANG Zhengwei XUE Fangping LIN Xiangtong

(PET Centec Huashan Hospital, Fudan University, Shanghai 200235. China)

Abstract Due to relatively high uptake of glucose in the brain cortex, the use of FDG PET imaging is greatly limited in brain tumor imaging, especially for low-grade gliomas and some metastatic tumours. More and more tracers with higher specificity were developed lately for brain tumor imaging. There are 3 main types of non-FDG PET tracers:

amino acid tracers, choline tracers and nucleic acid tracers. These tracers are now widely applied in many aspects of brain tumor imaging. This article summarized the general use of non-FDG PET in different aspects of brain tumor


Key words Positron emission tomography, Brain tumor, Non-FDG

CLC numbers R817.4,R739.41 ~~



Brain tumors can be divided into primary and metastasis according to their origin. The most common primary brain tumors in adults are gliomas and meningiomas. The gliomas can be histologically divided into asrrocytomas, oligodendrogliomas, mixed gliomas, ependymal tumors and tumors of the choroid plexus. Based on World Health Organization (WHO) criteria, they can be classified into 4 grades, i.e. WHO grade I WHO grade IV.Despite continuous improvements in multimode treatments, the median survival of patients with gliomas is limited, varying from 1 year for glioblastoma, to 5-10 years for grade II gliomas. Therefore, early diagnosis and grading of brain tumors are crucial to treatment and prognosis of the patients. Computer Tomography (CT) and Magnetic Resonance Imaging (MRI) with contrast media are now the primary diagnostic methods of brain tumors due to their high spatial resolution and good tissue contrast. However, the two methods are merely anatomical and nonspecific, as tumor imaging requires more evolutionary ways to discriminate malignancy from benignancy. In the field of metabolic imaging, Positron Emission Tomography (PET) is the most advanced tech-


* Corresponding author. E-mail: [email protected] Received date: 2007-03-27

nique. As a tracer of glucose metabolism, 2-[18F] fluoro-2-deoxy-D-glucose (FDG) is widely used in detecting, grading, treatment effect determination and prognosis evaluation of brain tumors. Owing to relatively high glucose uptake of the cortex, specificity and sensitivity of FDG PET imaging on low-grade brain tumors are limited. However, new tracers are developed constantly and they shed light on the future of PET imaging in brain tumors. 2

Diagnosis of brain tumors with PET

2.1 Amino acid imaging Radiolabeled tracers available for amino acid metabolism are: Methyl-["CI-L-Methionine (MET), ["CI-tyrosine, ['8F]-flouoro-tyrosine, and O-(2-[l8F]fluoroethy1)-L-tyrosine (FET), etc. Their advantages are low uptaking by normal cortex. As a result, they have a better delineation of the tumor contour, especially for tumors that uptake low or moderate amount of FDG Chung et al. [I1 showed that, for brain tumors that were hypo- or isometabolic on I8F-FDG PET, the sensitivity and specificity of "C-MET were 89% and loo%, respectively, and the sensitivity for gliomas was


HUANG Zemin et al.: Non-FDG PET imaging of brain tumors

92%. Herholz et al. [*I showed that, in 80% of WHO 11 grade I1 gliomas, C-MET uptake was 1.5-fold greater than in normal brain tissue, whereas glucose metabolism was reduced in comparison to gray matter (Fig. 1). In fact, increased 11C-MET uptake (1.3-3.5 times greater than a contralateral control region) does not represent directly increased synthesis of the tumor protein but rather correlates with increased transport rate mediated by L-amino acid tran~porter.[~'~' Other ~ t u d i e s " ~confirmed ~'~' that the "C-MET uptake correlates with the expression of Ki-67 (a histological index of proliferative activity), proliferating cell nuclear antigen, and microvessel density. These indicate that 11 C-MET is a suitable marker of tumor proliferating activity. Iuchi et al. [71 showed that the "C-MET uptake significantly correlated not only with the count of nucleolar organizer regions (NORs), a histological index of protein synthesis, but also with Ki-67 index, whereas 18F-FDGuptake showed no significant correlation with Ki-67 index or clinical malignancy. Due to its high uptake in most low-grade gliomas, the use of "C-MET in WHO grading is relatively limited. The uptake of I'C-MET depends on histological type of the tumor, too. Oligodendrogliomas uptakes much more 11 C-MET than astrocytomas of the same grade.@' However, there are limitations of "C-MET. Sunada et al. [91 reported high uptake of "C-MET in benign choroid plexus papilloma as a false positive result. Acutely ischemic and inflammatory brain tissue also uptake 'lC-MET"ol and this interferes diagnostic use of "C-MET. As an "C-labeled radioactive pharmaceutical, however, the short half-life (20.4 min) of "CMET hinders its wide application, and its catabolism rate is too fast to be easily kinetically analyzed. Another radiolabeled amino acid tracer is FET, which makes up some of the disadvantages of MET. FET has a significantly longer half-life (109.6 min), which enables its application in PET centers without a cyclotron. Results from animal experiments revealed that, unlike FDG and MET, FET showed low uptake in non-tumor diseases and inflammations.u1.w Other studies showed that FET imaging result of brain tumor was similar to MET.[I3' As FET has lower sensitivity (88%) than Magnetic Resonance Spectrum (MRS) (100%) but higher specificity (88%) than MRS ( 81%) in glioma imaging, the combining use of FET and M R S can significantly improve the accuracy of diagnosis.'14' Pauleit et aZ."'] showed that the uptake of


FET was also histological dependent and increased FET-uptake was common in most squamous cell cancer, whereas adenocarcinomas and lymphomas showed low FET uptake, hence limited diagnostic value of FET for metastatic brain tumors. Besides, Frank et al. found no correlation between the FET uptake and the WHO grading of gliomas, almost the same as MET."4'

Fig.1 H ermetabolism of "C-MET but isokypornetabolism of 3F-FDG for grade I1 rneningioma PET diagnosis.


2.2 Choline imaging Proliferation rate of malignant tumor cells is far greater than normal cells. This leads to a significant increase of need of lecithin to synthesize the cellular membrane. Choline is a substrate for lecithin synthesis, and the increased regional metabolism of choline theoretically represents the status of tumor proliferation. Blood clearance of "C-choline is so fast that the radioactivity distribution in vivo can be stable 5 min after the injection, hence speeding up the entire examination greatly. Normal brain tissue showed low uptake of choline, so "C-choline imaging can acquire high contrast images of brain tumors (Fig.2). Ohtani et ~ 1 . "found ~ ~ that high-grade gliomas uptakes much more 11 C-choline than low-grade gliomas does. This suggests that "C-choline might be valuable in glioma grading, though confirmation by further studies is needed. 11C-choline can be used to differentiate gliomas from tumor-like demyelinating diseases. And FET is more effective than MRS.[17' The uptake degree of "C-choline is related to histological type of the tumors. Mei Tian et a1."81 showed significant uptake of "C-choline in squamous cell cancer, lymphoma, and proliferating lymph tissues: moderate uptake in pleomorphic adenoma and fibroma durum; astrocytoma and lipoma showed low-uptake of "C-Choline. However, benign diseases, such as in-



flammatory granuloma, fibroma, meningioma, and low-grade pilocytic astrocytoma, show significantly high uptake of "C-choline. This leads to a conclusion that it is difficult to differentiate low-grade gliomas from non-tumor diseases with "C-choline. The false positive results mentioned above were thought to be caused by high rate choline utilization in the cell


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membrane of tissue cells or giant cells."9' According to our experience in "C-choline PET imaging, combined FDGPET imaging has a diagnosis accuracy of 90.91%, with the rest of 4.55% being false positive, and 3.67%, false negative. This is a subject dederving extensive exploration, but not yet up to now.

"C-Choline PET with good contrast of a metastasis of lung cancer, whereas FDG is isometabolism due to the high-background uptake of the grey matter.

2.3 Nucleic acid imaging Unlike the tracers that indirectly reflect the tumor proliferation, 3'-deoxy-3'-'*F-fluorothymidine (FIT) enables direct evaluation of the thymidine kinase (TK) activity in cells. FLT is phosphorylized in viva by TKl and trapped in the cell. The TKl activity in normal cells is elevated about 10 times during the synthesis phase of DNA. In malignant tumors, however, the TKl activity is much higher and more Rasey et al. '24' found that the FLT uptake correlates well with the percentage of cells in S phase and ~' that the TLF the TKI activity. Chen et ~ 1 . ' ~revealed uptake in tumors reached the highest value in 5-l0min after injection and remained at a relatively constant level for 75min. The study also showed that the correlation between FLT uptake and Ki-67 index was much better than that of FDG, and the uptake was much higher in high-grade gliomas than in low-grade ones and the contrast. It is true that FLT can be a marker reflecting the proliferating activity of gliomas. Unfortunately, studies so far showed that the sensitivity of FLT in glioma (78.3%) is lower than MET (91.3%) and the FLT value is limited when differentiating low-grade gliomas from non-tumor diseases, especially for low-grade astrocytomas.1261


Treatment planning of brain tumors

FDG is useful in grading brain tumors, but this is limited by its high background uptake. FDG cannot specify extension of the tumors by distinguishing them from normal brain tissues around, especially for the low-grade ones. Unlike FDG all the tracers mentioned above can provide high contrast image of brain tumors. Compared with enhanced MRI imaging, non-FDG PET imaging usually shows the tumor with greater extension. It can provide more information for the planning of operation or radiotherapy. Heterogeneity is common inside a tumor. The highest active area is not always the area that shows the most contrast on MRI images. Instead, it should be the area where the metabolism is the most active. And PET is now the best method for metabolism imaging. Many malignant tumors grow so fast that the central part of the tumor cannot get enough blood supply, hence necrosis of the center. In this case, the most active part usually locates near the margin of the tumor or its infiltrated areas. A series of biopsy studies showed existence of tumor cells 3cm outside the margin of enhanced MRI images, and 80% of tumor relapses occurred 2cm away from the original enhanced area.'14' Other studies showed that not only the sub-


HUANG Zemin ef al.: Non-FDG PET imaging of brain tumors

stantial part of the tumor but also its infiltrated areas can be "C-MET avid. This seems to be a better choice for PET guided Grosu et al. stereotaxis needle biopsy than FDG[27728' '291 have successfully combined "C-MET imaging with stereotactic fractionated radiotherapy. Their results indicated that patients with high-grade glioma recurrences treated according to I I C-MET imaging planning have an average life-span of 9 months, rather than 5 months with radiotherapy planned with CT/MRI @=0.03). "C-MET can also be used to determine the sensitiveness to radiotherapy in low-grade g l i ~ m a s . ' The ~ ~ ' information is crucial to the treatment planning for such tumors. FET is also a better choice for delineating solid gliomas than MRI. It seems to have a good application in stereotaxis needle biopsy and 3D-CRT.[I4'Although FLT has a lower absolute SUV value than "C-MET, its higher ratio of tumorhackground indicates that FLT may delineate tumor better than "C-MET.'261 From April 2005 to April 2006, we used "C-choline for radiotherapy planning for 35 patients with various brain tumors. Our experience in I 1C-choline PET imaging shows that it can be successfully applied with radiation planning system (Fig.3). The delineation of tumors was clear especially in low grade gliomas as compared to '*F-FDG imaging.

Fig3 Radiotherapy planning using "C-Choline.

Therapeutic effect monitoring, recurrence differentiation and prognosis evaluation 4

FDG has been widely used in therapeutic effect monitoring and prognosis evaluation of brain tumors. It is advantageous over conventional imaging methods. However, FDG has its limitation in some aspects, especially the recurrence differentiation. With "C-MET, nicer results can be obtained in


recurrence differentiation and prognosis evaluation of glioma. The MET uptake can be treated as an independent factor of glioma prognosi~.'~'' Van Laere et al. examined 30 post-treatment glioma patients using FDG or "C-MET and performed a Kaplan-Meier survival analysis. The results showed that MET uptake could be an independent factor for both recurrence differentiation and survival period prediction, while FDG could Walter et al. reported the diagnoses with FET for glioma recurrence after treatment, the sensitivity and specificity was 100% and 92.9%, respecti~ely.'~~' As for FLT, its uptake demonstrated better reliability in predicting the tumor progress and the survival period of the patients @=0.0005 and p=O.OOl, respectively).[251 Compared to the tracers mentioned above, there are fewer reports of using "C-choline in this field, and its value of application needs further studies. 5


There is no single ideal imaging method for brain tumors. The combination of multi-method of imaging is the best choice for non-invasive exam. Non-FDG PET imaging has become more and more important as a complement for conventional imaging methods and FDG imaging. They reflect the abnormal metabolism of brain tumors from different aspects. Their common advantage is their low background uptake, and thus they can provide better specificity of diagnosis and delineation of the tumors. Unfortunately, there is no tracer can perfectly differentiate low-grade gliomas from non-tumor diseases, so close cooperation with clinical information and combination with other imaging methods is extremely important. With more and more specific tracer being developed and the experience gained with available tracers, the diagnosis and treatment of brain tumor are sure to be improved.

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