Finding the anaplastic focus in diffuse gliomas: The value of Gd-DTPA enhanced MRI, FET-PET, and intraoperative, ALA-derived tissue fluorescence

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Abstract

Objective

Diffuse gliomas may harbor anaplastic foci which affect prognosis and determine adjuvant therapies. Such foci are not always detected by contrast-enhancement on MRI. Recently, other modalities have been introduced, such as FET-PET for pre-diagnostic imaging and 5-aminolevulinic derived tumor fluorescence for intraoperative identification of malignant glioma tissue. The relationship between these modalities and their value for guiding biopsies during resection has not yet been elucidated in the group of diffuse gliomas.

Methods

FET-PET was performed in 30 consecutive patients with intracerebral lesions suggestive of diffuse gliomas on MRI with or without areas of contrast-enhancement. Prior to surgery patients were given 5-ALA at a dose of 20 mg/kg body weight. Areas of FET uptake with a lesion/brain ratio of 1.6 or more were considered indicators of tumor. FET-PET data were corregistered with MRI data before surgery in order to obtain neuronavigated biopsies during resection, which were collected from FET positive and negative areas, analyzed for tumor fluorescence and correlated to contrast-enhancement on MRI.

Results

13 of 30 tumors were diagnosed as gliomas WHO Grade II, 15 as gliomas WHO Grade III and 2 as gliomas WHO Grade IV. The mean lesion/brain tissue ratio of FET uptake was significantly greater for high-grade than for low-grade gliomas (averages SD 2.323 ± 0.754 vs. 1.453 ± 0.538 p = 0.0014). A match of FET-pos/ALA-pos biopsies was found in 70.6% (12/17) of high-grade gliomas (WHO Grade III/IV) but only in 7.7% (1/13) of low grade gliomas. Gd-neg/FET-neg/ALA-neg biopsies yielded a low-grade tumor in 46.2% (6/13). A mismatch between FET uptake and 5-ALA (FET-pos/ALA-neg) was found in 46.2% (6/13) of the low-grade and in 17.6% (3/17) of the high-grade tumors. The combination of FET-PET- and 5-ALA-positivity yielded a sensitivity for identifying high-grade glioma foci of 70.5% and a specificity of 92.3%.

Conclusions

In low grade gliomas 5-ALA fluorescence is the exception and FET PET is more sensitive. High grade areas in diffuse gliomas with anaplastic foci usually fluoresce, if they are FET PET positive. As a result, FET PET appears valuable for pre-operative identification of anaplastic foci and hot spots are strongly predictive for ALA-derived fluorescence, which highlight anaplastic foci during resection.

Introduction

Diffuse gliomas sometimes harbor anaplastic foci which determine final histopathological grading, are an indicator of prognosis and dictate adjuvant therapies such as radio- or chemotherapy. Undergrading as a consequence of sampling non-representative tumor may result in necessary therapies being deferred. Gadolinium-enhanced MRI is not always sensitive for detecting anaplastic foci. Metabolic imaging of brain tumors with radiolabeled amino acids has been shown to be a valuable complementary method to improve the diagnostic yield of anatomical radiological methods such as MRI [7], [10]. 18F-labeled amino acids such as O-(2-[18F]fluoroethyl)-l-tyrosine (FET) allow a widespread use of amino acid imaging due to the longer half-life of 18F (109 min vs. 20 min for 11C) [5], [11], [12], [17], [24]. A comparison of FET and MET imaging in patients with brain tumors showed a significant correlation of tumor-to-brain ratios and similar intracerebral kinetics for both tracers [23], [32]. In contrast to MRI alone, advantages of FET PET combined with MRI in the work-up for cerebral gliomas are improved guidance of biopsies, improved planning of surgery and radiation therapy, and the differentiation of tumor recurrence from unspecific post-therapeutic tissue changes [13], [16]. Furthermore, FET PET appears to be particularly valuable in the prognosis of low-grade gliomas [4].

On the other hand, 5-aminolevulinic acid (5-ALA) is a natural biochemical precursor of haemoglobin that elicits synthesis and accumulation of fluorescent porphyrins within malignant glioma tissue [24], [25], [29]. However, the value of fluorescence-guided resection in low grade gliomas and in low grade gliomas with anaplastic foci has not been determined so far. Conceivably, ALA-derived tumor fluorescence may be of value for intra-operative identification of “hot spots” visible on pre-operative imaging through FET-PET-hypermetabolism or contrast-enhancement on MRI. It was the aim of the present study to prospectively determine the interdependency of FET imaging, contrast-enhancement on MRI and intraoperative fluorescence findings in diffuse gliomas with or without focal enhancement.

Section snippets

Materials and methods

Between November 2004 and July 2008, MR imaging and FET PET investigations with subsequent biopsies during gross cytoreductive surgery were conducted in 30 patients with MR imaging suggestive for diffuse gliomas with or without areas of focal contrast-enhancement. All patients gave written informed consent for participation in diagnostic procedures and surgery. FET PET imaging and cytoreductive surgery using fluorescence-guided resections with 5-ALA was performed within 4 weeks of diagnosis.

Results

Mean patient age was 42.1 years. The tumor was located frontally in 16 patients, in the parietal lobe in 1 patient, temporally in 2 patients, in the insula in 2 patients and in more than one lobe in 8 patients (fronto-parietal, fronto-temporal, temporo-parietal). Furthermore, the gliomas were located in the left hemisphere in 17 patients and in the right hemispheres in 13 patients, accordingly. Tumor volume, as determined from the FLAIR image was less than 5 ml in all patients. Histological

Discussion

The aim of this study was to determine the interrelationship between FET uptake in low and high grade gliomas and 5-ALA-derived tissue fluorescence and thus to assess the usefulness of 5-ALA-derived fluorescence for identifying “hot spots” intra-operatively. If 5-ALA were to highlight “hot spots” identified on MRI by their contrast-enhancement or by FET-PET, this would reduce the worry of missing the hot spot and possibly undergrading a glioma.

Several authors have confirmed the usefulness of

References (36)

  • F.W. Floeth et al.

    Prognostic value of O-(2-18F-fluoroethyl)-l-tyrosine PET and MRI in low-grade glioma

    J Nucl Med

    (2007)
  • M.A. Hatiboglu et al.

    Impact of intraoperative high-field magnetic resonance imaging guidanceon glioma surgery: a prospective volumetric analysis

    Neurosurgery

    (2009)
  • P.L. Jager et al.

    Radiolabeled amino acids: basic aspects and clinical applications in oncology

    J Nucl Med

    (2001)
  • M. Lacroix et al.

    A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival

    J Neurosurg

    (2001)
  • K.J. Langen et al.

    Recent advances of PET in the diagnosis of brain tumors

    Front Radiat Ther Oncol

    (1999)
  • G. Moulin-Romsee et al.

    Non-invasive grading of brain tumours using dynamic amino acid PET imaging does it work for 11C-methionine?

    Eur J Nucl Med Mol Imaging

    (2007)
  • M.N. Pamir et al.

    First intraoperative, shared-resource, ultrahigh-field 3-Tesla magnetic resonance imaging system and its application in low-grade glioma resection

    J Neurosurg

    (2009)
  • D. Pauleit et al.

    O-(2-[18F]fluoroethyl)-l-tyrosine PET combined with magnetic resonance imaging improves the diagnostic assessment of cerebral gliomas

    Brain

    (2005)
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