11
Brain Tumors
Michael J. Fisher and Peter C. Phillips
Brain tumors are the second most common malignancy of childhood, accounting for approximately 20% of all childhood cancers. The esti- mated incidence ranges from 2.4 to 4.1 cases per 100,000 children per year. Although nearly 60% of patients are now cured, brain tumors are still the principal cause of pediatric cancer mortality. Pediatric brain tumors are classified by histology. Medulloblastoma is the most common malignant brain tumor, and low-grade astrocytoma is the most common benign tumor.
The diagnosis and evaluation of brain tumors is directed by com- puted tomography (CT) and magnetic resonance imaging (MRI), which are excellent for anatomic imaging. Modern MRI, in particular, is able to identify structure with high resolution and is the standard for dis- tinguishing abnormal tissue from normal brain. Unfortunately, these modalities are limited in their ability to differentiate benign from malignant tumors, neoplasia from inflammatory or vascular processes, postoperative changes or edema from residual tumor, and relapsed disease from radiation injury.
In contrast to CT and MRI, positron emission tomography (PET) provides functional information on a range of cellular and biologic processes including glucose metabolism, protein synthesis, DNA syn- thesis, membrane biosynthesis, cerebral blood flow, and hypoxia. In addition, radioligands have been developed that permit in vivo imaging of specific receptors. Positron emission tomography is useful to detect and grade tumors, delineate tumor margins, predict progno- sis, and distinguish tumors from nonneoplastic processes (Fig. 11.1). It has also been used for treatment planning, guiding stereotactic biopsy, evaluating response to therapy, and for distinguishing relapse from radionecrosis. Functional PET imaging has the potential to be com- bined with anatomic MRI to further enhance the evaluation of these processes.
Positron emission tomography is commonly used for the evaluation of brain tumors in adults. The most common tracers are 18F-fluo- rodeoxyglucose (FDG) and 11C-methionine (MET). Although many of the adult trials include the occasional pediatric patient, there is a dearth
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of literature focusing on the use of PET for pediatric brain tumors. Early studies suggest that the metabolism of histologically comparable brain tumors is similar in children and adults. This chapter will therefore identify and emphasize the existing pediatric studies and use the known similarities between adult and pediatric brain tumors to expand the discussion. The focus is on FDG and MET, as they are the tracers most studied in brain tumors.
Tumor Detection
FDG-PET
FDG is the most common tracer used for PET imaging of brain tumors.
It was introduced in 1976, and one of the earliest reports of its use was in the evaluation of cerebral gliomas in 1982 (1). FDG-PET imaging is based on the similarity between FDG and glucose. FDG is phosphory- lated upon entering the cell; however, unlike glucose, it cannot be metabolized further and therefore accumulates. Even in the presence
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Figure 11.1. Detection of a left cortical lesion with MRI (A) and FDG-PET (B). PET shows focal uptake in this primary brain tumor. (Courtesy of Dr. P. Bhargava.)
of oxygen, tumors rely on anaerobic glycolysis for energy. To support the energy requirement for growth, malignant cells upregulate their glucose transporters. Hence tumor FDG accumulation, like glucose, is proportional to the metabolic rate of the cell. Normal brain, however, is also dependent on glucose for its energy needs. Therefore, there is a high background of FDG signal, with uptake in the gray matter about 2.5 times that of the white matter (2).
There are various methods to analyze FDG uptake in tumors. The most quantitative methods require multiple image acquisition as well as arterial blood sampling in order to calculate the metabolic rate of glucose. This is time-consuming and invasive and therefore is of par- ticular concern in studies of children. In addition, the calculation of the glucose metabolic rate from FDG uptake requires the use of the
“lumped constant (LC),” which accounts for the differences between FDG and glucose in transport and phosphorylation. This value is based on normal brain and is assumed to be comparable with tumor;
however, there is evidence that it is different for neoplastic tissue and may vary with histologic subtype (3). Given these concerns, most studies have used simple qualitative (visual scales) or semiquantitative (calculating ratios of uptake in the region of interest compared with a normal structure) approaches. Other semiquantitative approaches include calculation of the standard uptake value (SUV), which is used more often in PET imaging of the body. Numerous studies have shown that the evaluation of brain tumors with visual grading systems is at least as accurate as semiquantitative analysis (ratios of tumor to gray matter, white matter, or whole brain signal) (4,5) and SUV measure- ments (6). These approaches obviate the need for dynamic scanning and blood sampling, but the analysis of the “normal” comparative tissue can be confounding. Selection of the normal tissue can be diffi- cult, particularly when the tumor is midline in location, and the uptake into normal brain may change with time and treatment, thus altering the tumor-to-normal ratio (7). Of most concern is the lack of standard- ization of analysis methods between studies, which makes comparison of results extremely difficult.
Since Di Chiro et al.’s (1) first report of a correlation between FDG uptake and histologic grade of glioma, numerous studies have reported the use of FDG to evaluate gliomas in adults but have also included other primary brain tumors such as ganglioglioma, dysembryoplastic neuroepithelial tumor (DNET), germ cell tumors, primitive neuro- ectodermal tumor (PNET), meningioma, and lymphoma. Other case reports describe the utility of FDG in the evaluation of brainstem tumors (8) and Langerhans cell histiocytosis involving the central nervous system (CNS) (9). FDG-PET has also been used to differenti- ate CNS lymphoma from nonmalignant processes in patients with AIDS. Both lymphoma and toxoplasmosis, a common opportunistic infection in AIDS, are contrast-enhancing by anatomic imaging, but they have very different FDG signals. Rosenfeld et al. (10) initially showed that CNS lymphomas had high FDG uptake. In addition, uptake declined with steroid treatment in a patient imaged before and 3 weeks after initiating therapy. Additional studies in patients with
AIDS confirm the high FDG accumulation in CNS lymphomas (11–15).
Additionally, FDG-PET was able to distinguish between hypermeta- bolic lymphoma and hypometabolic toxoplasmosis lesions (11–15). In one review of 33 patients with biopsy-proven lymphoma or toxoplas- mosis, all 16 lymphoma patients had high FDG uptake and all toxo- plasmosis lesions were hypometabolic (16). Sensitivity is therefore high; however, the specificity of a hypermetabolic lesion is unclear. One study reported two patients with progressive multifocal leukoen- cephalopathy that had FDG signals indistinguishable from lymphoma (13).
FDG-PET has also been investigated for the identification of CNS metastases from non-CNS primary tumors (Fig. 11.2). Marom et al. (17)
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Figure 11.2. Young patient with a primary paraganglioma and evidence of multiple dural metastases visualized with MRI (A) and as very active lesions on FDG-PET (B). (Courtesy of Dr. P. Bhargava.)
evaluated FDG-PET for staging in 100 patients with newly diagnosed lung cancer and found nine patients with metastases detected by PET that were not apparent with conventional imaging. In contrast, in another study, FDG-PET identified only 68% (21 of 31) of CNS lesions in 19 patients (18). Of the 10 lesions that were missed, four had frankly decreased FDG uptake, but six may have been missed because of their small size and isointensity relative to adjacent gray matter. Soft tissue metastases usually have high glucose metabolism. Given the typical location of brain metastases at the cortical gray-white junction because of hematogenous seeding, it is not surprising that there would be dif- ficultly in distinguishing them from adjacent cortex on FDG-PET.
Larcos and Maisey (19) explored the value of routine CNS PET for detecting metastases in 273 patients with non-CNS primary tumors and detected cerebral pathology in only 2% and unsuspected metastases in only 0.7%. In addition, a blinded retrospective review evaluating FDG- PET for screening of cerebral metastases in 40 patients identified only 75% of the patients with metastases and detected only 61% of the lesions seen by MRI (20). In three patients, metastases were detected by PET that were not seen by MRI, but all three patients had other FDG-positive lesions; thus PET correctly identified them as having metastatic disease. In sum, few clinically relevant lesions were detected, and therefore Rohren et al. (20) no longer recommend routine FDG-PET imaging of the brain in patients undergoing staging with whole-body PET. Instead, they recommend anatomic imaging when indicated.
Many of the studies of FDG-PET for brain tumors include pediatric cases together with adult cases (6,8,20–27). Comparatively few studies focus exclusively on the evaluation of pediatric brain tumors (Table 11.1). Examples of tumors examined include DNET (28–30), gangli- oglioma (29,30), oligodendroglioma and oligoastrocytoma (28,29), low-grade astrocytoma (28,30–33), high-grade astrocytoma (30,31,34), brainstem tumors (30,31,33,35), cerebellar medulloblastoma and supra- tentorial PNET (30,32,33), ependymoma (30,31,33), germ cell tumors (30,31), choroids plexus papilloma (30), craniopharyngioma (30), and pituitary adenoma (30).
Hoffman et al. (33) evaluated 17 children with posterior fossa tumors.
They found the highest FDG uptake in the medulloblastomas and the lowest in the brainstem gliomas. Holthoff et al. (32) studied 15 children and found that the mean glucose metabolic rate was twice as high in medulloblastoma as in supratentorial PNET or low-grade glioma (although the latter two groups had only a few patients).
Work done at the Children’s Hospital of Philadelphia described 24 patients with neurofibromatosis type 1 (NF1) with low-grade astrocy- tomas of the optic pathway, thalamus, or brainstem and showed that clinical outcome correlated with FDG activity (36).
Bruggers et al. (35) demonstrated that FDG-PET was useful in the management of a child with intrinsic pontine glioma. Patients with this tumor often have transient clinical and MRI worsening after radio- therapy that is believed to be due to swelling and not tumor progres- sion. In addition, this group of patients often has clinical worsening
Table 11.1.Pediatric PET studies No. of StudyYearpatientsTracersPathologyPurpose Mineura et al. (34)19851FDGHGGDetection, response to therapy O’Tuama et al. (57)199013MetAstr, Ep, MblDetection Hoffman et al. (33)199217FDGAstr, BSG, CPP, Ep, JPA, MblDetection, prognosis Holthoff et al. (32)199315FDGJPA, LGA, Mbl, PNET Detection, response to therapy Bruggers et al. (35)19931FDGBSGDetection Plowman et al. (31)199710FDG, METBSG, Ep, GCT, LGG, Pc, METDetection, recurrence vs. radionecrosis Duncan et al. (29)199715FDG, MET, [15O]H2ODNET, Ggl, Oligo, NNTreatment planning Kaplan et al. (28)19995FDG, MET, [15O]H2ODNET, JPA, OligoTreatment planning Utriainen et al. (58)200227FDG, METDNET, Ep, Ggl, GCT,Detection, grading, prognosis HGG, JPA, LGG, Mbl, Oligo Messing-Junger et al. (140)20022FETHGG, LGGDirecting biopsy Pirotte et al. (92)20039FDG, METGgl, HGG, LGG, Oligo,Directing biopsy PNET, NN Borgwardt et al. (30)200538FDG, [15O]H2OBSG, CPP, Cranio, DNET,Detection, grading Ep, Ggl, GCT, HGG, JPA, LGG, Mbl, PNET, PitAd Astr, astrocytoma (unspecified); BSG, brainstem glioma; CPP, choroid plexus papilloma; Cranio, craniopharyngioma; DNET, dysembryoplastic neuroepithelial tumor; Ep, ependymoma; Ggl, ganglioglioma; GCT, germ cell tumor; HGG, high-grade glioma; JPA, juvenile pilocytic astrocytoma; LGG, low-grade glioma; Mbl, medul- loblastoma; MET, non-CNS metastasis; NN, nonneoplasia; Oligo, oligodendroglioma/oligoastrocytoma; PNET, primitive neuroectodermal tumor; Pc, pineocytoma; PitAd, pituitary adenoma.
before MRI evidence appears. It is important, therefore, to be able to distinguish the toxicity of therapy from true tumor progression in order to make appropriate treatment decisions. In this report, the patient had worsening of symptoms in the absence of significant MRI progression 8 months after radiotherapy. The PET scan at that time showed increased FDG uptake compared with a prior PET scan 3 months earlier. Subsequent MRI (4 weeks later) showed progression, and an autopsy 3 weeks thereafter confirmed tumor progression. Although this report is anecdotal, the authors concluded that changes in PET signal may precede changes on MRI scan.
FDG metabolism can be affected by several factors unrelated to the brain tumor itself. Patients with brain tumors are often treated with corticosteroids, the impact of which on FDG uptake has been explored.
Most studies have not shown an influence of steroid treatment on FDG uptake into brain tumors (37–39); however, steroids can decrease the uptake into normal cortex, thus affecting the tumor-to-background dif- ferences (37). In contrast, in the setting of high blood glucose (a common side effect of corticosteroid treatment), FDG uptake in brain tumors is decreased, but not to the same degree as the concurrent decrease in uptake into normal cortex (40). In addition, seizures can occur in the setting of a cortical brain tumor. A seizure during the time of the PET scan can markedly increase the FDG uptake and result in a false-positive scan (2), whereas PET scans performed within 24 hours after a seizure may be difficult to interpret because of “falsely” low FDG uptake.
Qualitatively, most low-grade tumors have FDG uptake less than or equal to that of normal white matter, whereas high-grade lesions have uptake greater than or equal to that of gray matter. Therefore, high-grade tumors within or adjacent to normal gray matter may be difficult to detect because of the low lesion-to-background contrast.
There is a similar problem with low-grade lesions within or bordering normal white matter that has similar FDG signal. Co-registration of PET images with CT or MRI may improve evaluation of FDG uptake by helping to delineate the margins of the lesion. Borgwardt et al.
(30) found that the diagnostic value of FDG-PET was improved by digital co-registration of PET and MRI in 28 of 31 pediatric cases. In particular, it improved the localization of tumor in 23 cases and the delineation of tumor margins in eight cases. In contrast, visual PET/MRI co-registration increased the diagnostic value in only three of seven cases.
Other methods to improve tumor delineation include extending the interval between FDG injection and scanning. Spence et al. (41) imaged 19 patients with supratentorial gliomas both early (0 to 90 minutes) and late (180 to 500 minutes) after injection. Compared with early imaging, delayed imaging improved the delineation of tumor relative to gray matter in 12 of the 19 patients. This was true for both high-grade gliomas (nine of 11) and progressing low-grade gliomas (three of five).
It is hypothesized that degradation of FDG-6-phosphate may occur more efficiently in normal brain than in tumor tissue, accounting for this result. For the three low-grade gliomas that were subsequently
shown to be stable, tumor delineation was not improved by delayed imaging.
Amino Acid PET
Because the uptake of amino acids into normal brain tissue is relatively low and appears to be less influenced by inflammation, amino acid PET imaging may have some advantages over FDG-PET in providing good contrast between tumor tissue and background (42). The higher pro- liferative rate of malignant cells requires an increase in protein syn- thesis with a consequent increased cellular need for amino acids. This results in an increased transport of amino acids into malignant cells, which is often more pronounced than the actual increase in protein syn- thesis (2,42). MET is the most common radiolabeled amino acid used in the imaging of brain tumors. Its uptake appears to reflect cell mem- brane transport more than protein synthesis (43), and its uptake in tumor is 1.2 to 3.5 times higher than in normal brain (2). There is no effect of corticosteroid treatment on MET uptake into normal brain (44) or low-grade glioma (45). MET uptake into glioblastoma is moderately decreased with steroids, but uptake persists at a level higher than low- grade gliomas (45).
Mosskin et al. (46) evaluated the uptake of MET in patients with supratentorial gliomas. In 22 of 32 cases, they found that increased MET uptake corresponded to areas of tumor on stereotactic biopsy. Five cases had tumor cells outside of the area of increased MET uptake, and five cases had MET uptake in areas without histologic evidence of tumor. Overall, in 24 cases, MET-PET was more accurate than contrast- enhanced CT in determining tumor margins. Other studies agree that tumor extent is often better determined by MET-PET than by CT or MRI (47,48); however, these studies were performed in the CT or early MRI era. Current MRI techniques represent the most sensitive means of identifying abnormal brain lesions that may be tumor, and PET may be more useful to discriminate neoplastic from nonneoplastic lesions.
In a study of 85 gliomas, De Witte et al. (49) found elevated MET uptake in 98%. Ogawa et al. (48) found a similar high MET uptake rate (97%) in high-grade gliomas, but MET uptake was only elevated in 61%
of low-grade gliomas. Herholz et al. (45) studied 196 consecutive patients with suspected low-grade glioma. The authors used a MET uptake (lesion-to-contralateral normal brain) threshold of 1.47, and MET-PET distinguished tumor from nonneoplastic lesion with a sensi- tivity of 76% and specificity of 87%. When lesions that turned out to be malignant were excluded, sensitivity for differentiating low-grade from nonneoplastic lesions fell to 67%. Chung et al. (50) revealed a sen- sitivity of 89% for detecting brain tumors (31 of 35) with MET and a specificity of 100% (all 10 nonneoplastic lesions had no MET uptake).
Of note, cerebrovascular lesions, such as infarction and hemorrhage, can also exhibit high MET uptake, felt to be secondary to a disrupted blood–brain barrier (51). Other 11C-radiolabeled amino acids, such as [11C]-tyrosine (TYR) are also useful in detecting primary brain tumors with a sensitivity of 91% and specificity of 67% (52).
Compared with FDG, MET is more sensitive for detecting tumor and delineating tumor margins. Ogawa et al. (53) evaluated 10 patients with glioma or meningioma and found MET to be superior to FDG in delineating the extent of tumor. Pirotte et al. (54) demonstrated abnor- mal MET uptake in 23 tumors, 11 of which had no FDG uptake or uptake equal to background. Sasaki et al. (55) found MET more useful than FDG in detecting tumor extent and in distinguishing benign from malignant astrocytomas. In a study of 54 patients with glioma, 95%
were clearly visualized with MET, whereas only 51% were hyperme- tabolic with FDG (24). For low-grade gliomas, MET identified over 90%, but FDG identified only 21%. Chung et al. (50) showed that 22 of 24 gliomas had greater extent and degree of uptake with MET than FDG. MET-PET was also better than FDG in detecting low-grade astro- cytoma and oligodendroglioma (56).
Pediatric studies have also shown the utility of MET for imaging primary brain tumors. O’Tuama et al. (57) reported that MET was useful to delineate tumor extent in 13 children. Plowman et al. (31) imaged 10 “pediatric” patients (only seven were less than 18 years old) with both FDG and MET and described PET’s utility in localizing viable tumor for radiosurgery, distinguishing recurrent tumor from radiation injury, and differentiating persistent tumor from posttreat- ment changes when evaluating residual enhancement on MRI after surgery or radiotherapy. In a larger study of 27 children with primary brain tumors, MET-PET had a sensitivity of 96% for the detection of tumor, which was higher than that of FDG (58).
Both FDG and MET are valuable for detecting tumor and differentiat- ing it from nonneoplastic tissue. FDG is most useful in evaluating more malignant lesions, such as high-grade glioma and lymphoma, which have particularly elevated glucose metabolism. Because of the minimal background MET uptake into normal brain, MET appears to have an advantage over FDG, particularly in detecting low-grade tumors.
Tumor Grading
FDG-PET
Most studies regarding PET grading of primary brain tumors have focused on gliomas and show a correlation between FDG uptake and histologic grade of glioma. Di Chiro and colleagues (1,59) showed that all high-grade gliomas had regions of high FDG uptake and that the mean glucose metabolic rate in high-grade gliomas was almost twice that of low-grade gliomas (7.4 versus 4.0). In addition, they reported that FDG uptake was better than contrast-enhancement on CT in pre- dicting tumor grade (60). Delbeke et al. (61) evaluated FDG uptake in 32 high-grade and 26 low-grade brain tumors, most of which were gliomas. They defined an “optimal cut-off level” that distinguished between high-grade and low-grade tumors. Ratios of tumor-to-gray matter greater than 0.6 or tumor-to-white matter greater than 1.5 pre- dicted high-grade pathology with a sensitivity of 94% and specificity
of 77%. As gliomas are often histologically heterogeneous, Goldman et al. (62) examined 161 stereotactic PET-guided biopsy specimens from 20 patients with gliomas to see whether glucose metabolism correlated with degree of anaplasia. Glucose uptake was significantly higher in anaplastic than non-anaplastic specimens. Histologic signs of anapla- sia were present in approximately 75% of samples with high FDG uptake but in only 10% of samples with low FDG uptake.
More recently, Padma et al. (63) evaluated FDG uptake in a large sample of patients with glioma scanned at various times during treat- ment. They found 166 patients had low uptake and 165 had high uptake. Among those with low FDG uptake, 86% were low-grade and 14% were high-grade gliomas. Of the 23 patients with high-grade glioma but low FDG uptake, all had their first PET scan after therapy, and low uptake may have been related to an effect of treatment. In contrast, 93% of the patients with high FDG uptake had high-grade gliomas, whereas only 7% had low-grade pathology. Of the latter, all 11 patients had increasing anaplasia on repeat biopsy and a rapidly declining clinical course.
One problem with the use FDG-PET to assess glioma grade is that FDG uptake may be influenced by volume averaging with adjacent tissue. For example, the apparent FDG signal of a high-grade glioma may appear artificially lower when the signal is averaged with adja- cent white matter, surrounding edema, or an associated necrotic area (all regions that are inherently low in FDG uptake).
Although degree of FDG uptake is correlated with histologic grade of glioma in most cases, juvenile pilocytic astrocytomas are an excep- tion. This is of particular importance in pediatrics, in which pilocytic astrocytomas comprise a large percentage of the brain tumor incidence.
These grade I gliomas, although benign in behavior, have repeatedly been shown to have high FDG uptake, similar to that of anaplastic astrocytoma (24,33,64,65). This may be due to their very vascular nature (64) or perhaps an increased expression of glucose transporters in this tumor type (65,66). Other benign tumors that have shown high FDG uptake include choroid plexus papillomas (30,33).
FDG uptake correlated with World Health Organization (WHO) his- tologic grade (67) in a study of 38 children with primary brain tumors (30). Borgwardt et al. (30), using a measure of glucose metabolism called the “mean index” (based on FDG uptake in a region of interest of tumor, white matter, and gray matter), found a mean index of 4.27 in four grade IV tumors, 2.47 in four grade III tumors, 1.34 in 10 grade II tumors, and -0.31 in eight of 12 grade I tumors. Four grade I tumors (three pilocytic astrocytomas and one choroid plexus papilloma), with a mean index of 3.26, were excluded because of the known lack of asso- ciation of FDG uptake and histologic grade in these tumors. Eight other patients had tumors in locations that were difficult or dangerous to biopsy (mostly brainstem) and were expected to be benign based on their appearance and subsequent clinical course. These tumors had a mean index of 1.04, consistent with low-grade histology. It is difficult to know how to interpret these results given the large number (greater than 10) of different histologies represented in this study. Although
there is a known correlation between grade and prognosis for gliomas, the comparability of grading systems between different histologic sub- groups of brain tumors has yet to be established. At a minimum, this report suggests a clear difference in FDG uptake between benign and malignant brain tumors.
Amino Acid PET
MET has been evaluated for grading gliomas. Derlon et al. (68) found a statistically significant relationship between MET uptake and tumor grade in 22 patients with glioma. The tumor-to-contralateral normal brain ratio was 1.04 for grade II, 1.68 for grade III, and 2.33 for grade IV lesions. The difference between grade II and the higher grade lesions was significant. In a larger study, De Witte et al. (49) found that MET uptake correlated with tumor grade in 85 patients with glioma (pilocytic astrocytomas were excluded). In addition, a tumor-to- contralateral normal brain threshold greater than 1.8 was more common for high-grade gliomas, but this dividing line did not uni- versally distinguish between high- and low-grade lesions. Other studies have shown a correlation between MET uptake and markers of tumor proliferation in gliomas [proliferating cell nuclear antigen (69) and Ki-76 staining (50)].
In a study of 23 patients, Sasaki et al. (55) found MET to be superior to FDG in distinguishing low-grade from high-grade gliomas.
Although the difference in MET uptake between grade II gliomas and higher-grade lesions was statistically significant, this was not the case for FDG. In contrast, Kaschten et al. (24) found a significant difference in FDG uptake between grade II and grade III or IV lesions, but the difference in MET uptake between grade II and III lesions did not reach significance. Ribom et al. (70) found a significant increase in MET uptake in 10 untreated low-grade gliomas from baseline to the time of progression. Of note, the tumor “hot spot” to normal cortex ratio at progression was 4.40 for patients who had developed anaplasia and 2.27 for those whose histology was unchanged.
MET may also be useful for grading oligodendrogliomas. In 47 patients, MET uptake was significantly higher in anaplastic than low- grade oligodendrogliomas (71). However, the amount of overlap was such that a threshold between anaplastic and low-grade lesions could not be identified. Although there was also a significant difference in FDG uptake between grades, this was not of the same magnitude as seen for MET. Similarly, in pediatric patients with various primary brain tumors, MET accumulation was higher in high-grade than low- grade tumors, but no clear cut-off distinguished between them (58).
With the exception of juvenile pilocytic astrocytomas, the correlation between FDG uptake and glioma grade has been repeatedly demon- strated. FDG signal thresholds can be defined that distinguish high- and low-grade tumors, but the overlap of signals does not allow com- plete segregation of the groups. In addition, the various methods of analysis used in different studies make between-study comparisons
difficult and thus limit the generalizability of the conclusions. In sum, FDG-PET may be helpful in differentiating high- from low-grade tumors, but it is not a substitute for biopsy. MET-PET has been less extensively studied and its use for tumor grading is less clear.
Prognosis
FDG-PET
Since the earliest studies of FDG metabolism in brain tumors, it has been explored as a marker of prognosis. In a study of 45 patients with high-grade glioma, FDG uptake correlated with survival (72). Patients with high tumor glucose metabolism had a mean survival of 5 months, whereas patients with lower metabolism survived an average of 19 months. Alavi et al. (73) found that median survival of patients with hypometabolic, primary brain tumors was 33 months but only 7 months in hypermetabolic tumors. For the subgroup of patients with high-grade glioma, 1-year survival was 78% for patients with hypo- metabolic tumors and 29% for those with high glucose metabolism.
Other studies of FDG-PET in gliomas, and in particular malignant gliomas, support the prognostic value of glucose metabolism (74). In addition, Schifter et al. (75) suggest that serial studies may improve the prognostic usefulness of FDG for primary brain tumors.
Given the correlation between FDG uptake and tumor grade, it is important to control for this variable when assessing the relationship between glucose metabolism and prognosis. In a study of 31 supra- tentorial high- and low-grade gliomas, Pardo et al. (76) reported that FDG uptake was at least as significant as histologic grade for progression-free and overall survival. However, this is based on univariate analysis. Padma et al. (63) suggest that FDG-PET may be better than pathology for predicting prognosis. In a study of 331 patients with benign or malignant gliomas, degree of FDG uptake was associated with survival. Although there was no difference in survival between those with tumors that had low FDG uptake and those that had no FDG uptake, there was a significant difference in survival between those with high uptake and those with low or no uptake.
Specifically, patients with low-uptake tumors had a median survival of 28 months compared with only 11 months for high-uptake tumors. In addition, 94% of patients with low-uptake tumors survived greater than 1 year and 19% survived greater than 5 years. One- and 5-year survival for patients with high-uptake tumors was 29% and 0%, respec- tively. The 23 high-grade glioma patients with low uptake had a median survival of 20 months, and the 11 low-grade glioma patients with high FDG uptake had a median survival of 5 months. Of note, however, the authors also showed that FDG uptake correlated with tumor grade, and no clear attempt was made to distinguish PET signal as an independent variable for prognosis.
Spence et al. (77) evaluated the relationship between glucose metab- olism and prognosis using multivariate analysis in a study of 30
patients with supratentorial high-grade glioma. They found that both tumor histology and pretreatment glucose metabolism independently correlated with survival. In a larger study of 91 patients with malig- nant astrocytoma, those with tumor FDG uptake greater than that in the contralateral gray matter had worse prognosis than those with uptake less than that in the gray matter (78). When considered sepa- rately, glucose metabolism was predictive for glioblastoma but not anaplastic astrocytoma. As the investigators used a three-point visual scale in their evaluation, it is possible that more precise measurements of glucose uptake might have improved the delineation of survival groups. In multivariate analysis, although FDG-PET was useful in predicting the outcome for glioblastoma, histologic grading was superior.
Predicting prognosis and, in particular, clinical behavior is extremely important for low-grade gliomas. Anatomic imaging with CT or MRI does not define the aggressiveness of the lesion or the likelihood of secondary malignant transformation, and therefore does not help in directing whether a lesion can be safely observed or warrants imme- diate treatment. Several studies have suggested that FDG-PET may be useful for predicting both malignant transformation and prognosis in low-grade gliomas. In a study of 12 low-grade glioma patients with malignant transformation, each tumor had an area of FDG uptake similar to that seen in high-grade gliomas (79). In addition, in three patients who underwent PET scans prior to malignant degeneration, there was an increase in FDG metabolism that coincided with malig- nant change. Similar results were seen by De Witte et al. (23) in their study of 28 patients with low-grade gliomas. They found that tumors with higher FDG uptake were more likely to progress and result in mortality that those without high uptake. Six of the nine patients with areas of high FDG uptake died and two others had tumor recurrence.
In contrast, all 19 patients with low FDG tumor uptake were alive, and only one had evidence of subsequent malignant transformation.
Similar applications of FDG-PET do not apply to juvenile pilocytic astrocytomas, which, as previously noted, may have focally high FDG uptake despite excellent prognosis (64,65).
The utility of FDG-PET for tumor prognosis has been studied in other clinical scenarios and tumors. Di Chiro et al. (80) found signifi- cantly higher FDG metabolism in meningiomas that progressed or recurred than in those that did not. Barker et al. (21) evaluated FDG uptake in 55 high-grade gliomas at the time of suspected recurrence because of enlarging areas of enhancement on MRI. There was a sig- nificant difference in survival between patients with high and those with low FDG uptake (10 versus 20 months). This difference might be even more profound because most patients believed to have recurrence based on PET were offered further therapy, whereas those assessed as radiation injury were more likely to be observed or treated with steroids alone. By contrast, in a study of malignant tumors suspected of recurrence after treatment, Janus et al. (81) found that decreased FDG uptake was associated with longer survival, whereas increased FDG
uptake was not predictive. Studies of patients with recurrent metasta- tic brain lesions after stereotactic irradiation have also found a signifi- cant prolongation of survival in those with low FDG uptake compared with those with high FDG uptake (82,83).
Very few reports have been published exploring the utility of FDG- PET to predict prognosis in children with primary brain tumors.
Hoffman et al.’s (33) study of 17 children with primary brain tumors demonstrated no clear correlation between FDG uptake and survival.
In particular, two patients with brainstem gliomas and low FDG uptake had shorter survival than two patients with higher FDG uptake. By contrast, FDG was an independent predictor of event-free survival in 21 children with newly diagnosed primary brain tumors (58). However, this study evaluated multiple different tumor types, and the small sample size limited the authors to univariate analysis.
In 24 pediatric patients with NF1 and low-grade astrocytomas of the optic pathway, thalamus, or brainstem, FDG uptake correlated with both the need for treatment and clinical outcome (36). Patients were divided into groups based on whether they required tumor therapy at some point and whether their tumors progressed or remained stable.
Of patients in the no-treatment group, 93% (13 of 14) had no increase in FDG uptake, consistent with benign tumors, whereas 70% (seven of 10) in the treatment group had increased uptake consistent with more malignant pathology. When considering clinical outcome, 94% (16 of 17) of patients with stable disease had no increase in FDG uptake, but all seven patients with progressive disease had increased uptake.
Overall, 96% (23 of 24) of patients had clinical outcomes that correlated with FDG activity.
Amino Acid PET
MET-PET has also been explored for predicting the prognosis of primary brain tumors. In a study of 54 low- and high-grade gliomas, a tumor-to-mean cortical MET uptake threshold of 2.1 divided patients into groups with median survival longer than 5 years (<2.1) or less than 8 months (≥2.1) (24). In comparison with FDG, the authors found MET to be slightly superior for predicting outcome. De Witte et al. (49) evaluated MET-PET in WHO grade II to IV gliomas. A tumor-to- contralateral normal brain uptake ratio greater than 2.2 was associated with poor outcome in grade II tumors. Grade III tumors had a thresh- old of 2.8 that distinguished the outcome. For grade IV tumors, there was no correlation between degree of uptake and survival (all had ele- vated uptake).
In studies of low-grade gliomas (all grade II), MET uptake correlates with clinical outcome. In 12 patients with low-grade gliomas, MET uptake distinguished patients with stable disease from those with tumor progression or death from disease (44). In addition, an SUV threshold of 3.5 differentiated aggressive from stable lesions. In a larger study of 89 patients with grade II glioma, MET uptake was inversely associated with survival for both astrocytomas and oligoden- drogliomas (84).
Only one study has attempted to evaluate MET as a predictor of sur- vival in pediatric patients (58). In 23 children with newly diagnosed brain tumors, increased MET uptake was associated with increased likelihood of tumor progression. Furthermore, patients who died of tumor progression had significantly higher MET uptake than those who survived. As noted above, this was a mixed tumor population, and multivariate analysis was not performed.
Although some studies show a correlation between FDG uptake in brain tumors and prognosis, it is unclear as of yet whether glucose metabolism is independent of tumor grade as a risk factor. However, although FDG-PET may not offer added value for prognosis when comparing different tumor types or grades, it does appear useful for predicting prognosis in tumors with homogeneous histology and grade. Studies of MET-PET are too few to draw conclusions about its utility for assessing prognosis at this time.
Guidance for Biopsy
Brain tumors, particularly gliomas, are typically heterogeneous. There is often a variation in histologic grade within the tumor. For example, in 1000 samples from 50 supratentorial gliomas, 62% of tumors con- tained both high- and low-grade regions (85). Tumor behavior, response to therapy, and survival are determined by the most malig- nant portion of a tumor. Because of the inherent risk of sampling error, stereotactic biopsy may miss the tumor altogether or miss the most malignant portion, resulting in understaging of the tumor. This has obvious implications for selection of appropriate therapy and for sub- sequent survival of the patient. Efforts have been made to maximize diagnostic yield by performing multiple trajectories and using CT or MRI guidance. Usually, biopsy is directed toward contrast-enhancing areas. However, biopsies in malignant gliomas have revealed tumor cells as far as 3 cm from the area of enhancement (86). In addition, the most contrast-enhancing portion of the tumor does not always repre- sent the most malignant area. Because MRI guidance has not been shown to reliably direct biopsy, many investigators have explored PET-directed stereotactic biopsies.
FDG-PET
Given the usefulness of FDG for detecting tumor and the correlation of FDG uptake with histologic grade, FDG may improve the diagnos- tic yield of stereotactic biopsy by targeting the areas of highest FDG uptake in an attempt to sample the likely most malignant area. Hanson et al. (87) manually combined anatomic imaging with visual analysis of FDG-PET images to determine the best site for stereotactic biopsy in three patients. In two of the patients, CT- or MR-guided biopsy was insufficient, but targeting to the region of high FDG uptake yielded diagnostic tissue.
Combing visual PET analysis with anatomic imaging is not suffi- ciently precise to direct stereotactic biopsy. Co-registration of stereo- tactically obtained CT images with nonstereotactically obtained PET scans can improve precision. However, obtaining both sets of images in stereotactic format by using a relocatable head frame is ideal (88).
This is accomplished by fixing the head frame for both PET and CT so that the patient’s head is similarly positioned for both. Using this pro- cedure, Pirotte et al. (89) performed 78 biopsy trajectories in 38 patients.
All trajectories into areas of increased FDG uptake were diagnostic, whereas six trajectories directed solely by CT were uninformative. A follow-up study from the same group used combined PET/CT to direct 90 stereotactic biopsy trajectories in 43 patients with suspected brain tumors (25). Thirty-six patients had an area of increased FDG uptake that guided at least one trajectory. If the area of FDG abnormality was smaller than the CT lesion, a biopsy was also done from a CT region that was FDG negative, and vice versa. Fifty-five trajectories were based on PET and 35 directed by CT. Only six of the 90 trajectories were nondiagnostic, and all were CT guided. Four of these trajectories were targeted to the contrast-enhancing area on CT. In all these patients, a diagnosis was subsequently made on a PET-guided biopsy.
Eleven patients had a PET-guided trajectory in an area that appeared normal on CT; nine yielded tumor tissue. The biopsy in the other two patients yielded normal brain; in both cases the region was felt to be
“displaced subcortical gray matter adjacent to the tumor.” In patients with contrast-enhancing lesions on CT, there was a statistically signi- ficant difference in the diagnostic yield between FDG-PET- and con- trast-enhanced CT-guided trajectories. In a subsequent review of PET-guided stereotactic biopsies in over 150 patients, Levivier et al. (90) suggested that PET is more accurate than CT for the selection of biopsy sites that will maximize the likelihood of obtaining tissue representa- tive of the tumor grade. It also may allow a decrease in the number of trajectories needed and thereby a decrease in the risks, without adversely affecting the diagnostic yield.
Stereotactic PET/MRI-directed biopsies have also been performed.
Massager et al. (8) performed PET and MRI in stereotactic conditions in 30 patients with a brainstem mass, and PET/MRI-directed biopsies resulted in improvement in targeting precision and in diagnostic yield.
Most PET scans were performed with FDG. Early in the study, if there was a discrepancy between the PET scan and the MRI, two trajectories were done. When similar conditions arose later in the study (after the accumulation of data supporting PET-guidance), targeting was guided by PET imaging alone. A total of 37 trajectories were performed. Diag- nosis was obtained in all patients and confirmed by the subsequent clinical course. Eighteen patients had a single PET-directed biopsy and the diagnostic yield was 100%. Seven patients had two different target areas due to discordance between PET and MRI; in four of these patients, PET guidance was better than MRI guidance in finding the area of highest tumor grade. Targeting in this way was very safe. There was no biopsy-related mortality and minimal morbidity (two patients
had a worsening of their preoperative neurologic deficits, that resolved with time).
Amino Acid PET
MET may be better than FDG for directing stereotactic biopsies. The minimal uptake of MET into normal brain cells results in excellent tumor-to-background contrast, thus maximizing the likelihood of iden- tifying an area of abnormal signal to direct biopsy. The increased sen- sitivity of MET for detecting low-grade tumors provides an advantage over FDG for guiding biopsy trajectories to regions of tumor as opposed to nonneoplastic tissue. In addition, the relatively fast kinet- ics and shorter half-life (20 minutes) of MET allows brief scanning times and therefore make it easier to perform multiple stereotactic studies as well as multitracer evaluations in the same day.
Co-registration of MET-PET and MR images helped guide stereotac- tic biopsy in a patient with a grade II oligodendroglioma (91). Biopsy from a contrast-enhancing area with low MET uptake yielded necrotic tissue, whereas tissue from a nonenhancing, hypermetabolic MET region was tumor. Pirotte et al. (54) compared MET with FDG for guiding stereotactic biopsies in 23 patients with brain tumors. There was an area of elevated MET uptake in all 23 brain tumors. Biopsy was directed by FDG in the 12 tumors with elevated FDG uptake. The other tumors had either no FDG uptake (mostly low-grade astrocytomas or oligodendrogliomas) or uptake that was indistinguishable from the adjacent gray matter and therefore required MET guidance for biopsy.
All MET-guided trajectories yielded diagnostic tissue.
In a follow-up study, Pirotte and colleagues (27) performed stereo- tactic PET with MET and FDG and combined those images with stereo- tactically obtained CT or MR images in 45 patients with lesions located within or adjacent to the cortical and subcortical gray matter. All studies were performed on the same day. FDG was used to direct stereotactic biopsy if the signal was high enough to distinguish it from the background gray matter; otherwise, MET was used. Thirty-nine patients had tumors, and target selection was directed by FDG in 18 and by MET in the other 21. The six nonneoplastic lesions had no FDG or MET uptake and were biopsied under CT or MRI guidance. All 39 tumors had an area of abnormal MET uptake. All 73 trajectories in MET-positive areas yielded tumor tissue, and all 24 trajectories in areas of no MET uptake yielded nontumorous tissue. Fourteen patients had both FDG- and MET-guided biopsies; tissue from both trajectories yielded the same diagnosis. Overall, MET was superior to FDG in dif- ferentiating tumor from surrounding brain and was the only usable tracer for targeting in 21 of 39 tumors.
Pirotte et al. (92) have also used combined PET/MRI in the planning of stereotactic biopsies in nine children with infiltrative, ill-defined brain lesions. FDG was used in four, MET in two, and both tracers in three cases. Biopsy trajectories were directed to regions of high tracer uptake. For lesions located in functional areas of brain, fewer trajecto-
ries were needed without compromising the diagnostic yield. All lesions were accurately diagnosed using PET-guided biopsies.
The integration of PET into the planning of stereotactic trajectories clearly improves the diagnostic yield of biopsies compared with guid- ance based on anatomic imaging alone. MET appears better than FDG for identifying targets, although its shorter half-life limits its use to institutions with their own cyclotron. The use of multitracer PET may further improve the accuracy of stereotactic biopsy. In addition, the improved yield may allow a decrease in the number of trajectories required and consequently decrease the risk involved.
Treatment Response
One promising use for PET is in the evaluation of tumor response to treatment. It can be difficult at times to determine whether a given course of therapy has been effective. Low-grade tumors often do not decrease in size after therapy. However, if the tumor has responded to treatment with death of tumor cells, one would expect its level of glucose metabolism or protein synthesis to decline following therapy.
Similarly, declining PET signal 3 months into a planned 12 months of therapy may indicate that the therapy is working and validate that it should be continued.
FDG-PET
Several investigators have explored the use of FDG metabolism in pre- dicting tumor response to treatment. It is expected that tumors that respond to treatment will have a decrease in FDG uptake (Fig. 11.3).
Surprisingly, several studies have found the opposite: an increase in glucose metabolism after therapy correlated with longer survival.
Maruyama et al. (93) evaluated two patients with primary brain tumors and six patients with metastatic brain tumors treated with stereotactic radiosurgery. FDG-PET scans were performed before and 4 hours after treatment. Eighteen of the 19 treated tumors had a significant increase in FDG uptake (mean 29.7%) after treatment compared with eight non- irradiated tumors. For the 17 metastatic lesions, the increase in FDG uptake correlated with a subsequent decrease in tumor size. The other tumor that had an increase in FDG-PET with treatment did not signif- icantly decrease in size, but its follow-up period was short. Of note, one patient had a second follow-up PET scan performed 2 weeks after treatment; FDG uptake had decreased to below baseline values at that time. Spence et al. (77) found similar results in 14 patients with malig- nant gliomas imaged with both 1-[11C]glucose and FDG within 2 weeks before and within 2 weeks after external beam radiotherapy (although the exact timing for each patient is not noted). Increase in glucose metabolism after treatment correlated with prolonged survival, whereas a decrease in metabolism correlated with poorer survival.
Changes in glucose metabolism with chemotherapy have also been explored (94). Ten patients with recurrent glioblastoma multiforme
were imaged with FDG-PET before and 24 hours after a first dose of carmustine. An increase in FDG uptake correlated with longer survival.
No changes in FDG uptake were seen in normal brain tissue.
Theories to explain this seemingly paradoxical relationship between increase in glucose metabolism and survival have been reviewed by Spence et al. (95). One possibility is that the stress associated with cel- lular injury leads to an increase in glucose transport and thus an increase in FDG uptake. Studies show that cellular stress causes an increase in glucose transport that is associated with an increase in the amount of glucose transporters on the cell surface (96,97). Several in vitro and small-animal studies show an increase in FDG or deoxyglu- cose uptake shortly after treatment with chemotherapy or radiation (98–102), and this increase is associated with an increase in glucose transport (101,102). However, if the increase in FDG uptake is due to cellular stress alone, then even patients who do not respond to therapy might be expected to show an initial increase in FDG uptake, and this is not usually seen (77,94).
A B
Figure 11.3. Six weeks status post radiation of a primary brain tumor, MR images (A,B) show a focal and diffuse signal abnormality. Lack of FDG uptake on PET (C) suggests that the tumor may no longer be viable. (Courtesy of Dr. P. Bhargava.)
C
