Evaluation of intracranial space-occupying lesion with Tc99m-glucoheptonate brain single photon emission computed tomography in treatment-naïve patientsS Jaiswal1, S Barai2, Rajkumar1, S Gambhir2, M Ora2, AK Mahapatra1
1 Department of Neurosurgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
2 Department of Nuclear Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.57397
Source of Support: None, Conflict of Interest: None
Background : Glucoheptonate is a glucose analog with strong affinity for neoplastic brain tissues. Though extensively used as a tracer for detection of brain tumor recurrence, it's utility for characterization of intracranial lesions as neoplastic or otherwise has not been evaluated in treatment-naοve patients. Aim : The study was conducted to determine if glucoheptonate has sufficient specificity for neoplastic lesions of brain so that it can be utilized as a single photon emission computed tomography (SPECT)-tracer for differentiating neoplastic intracranial lesions from non-neoplastic ones in treatment-naοve patients. Settings and Design : A cross-sectional analysis of treatment-naοve patients with intracranial space-occupying lesion done in a tertiary care hospital. Materials and Methods : Fifty-four consecutive patients with clinical and radiological features of space-occupying lesion were included in this study. Glucoheptonate brain SPECT was performed before any definitive therapeutic intervention. Histopathological verification of diagnosis was obtained in all cases. Statistical Analysis Used : Descriptive statistics and student's 't' test. Result : Increased glucoheptonate uptake over the site of radiological lesion was noted in 41 patients and no uptake was noticed in 13 patients. Histopathology of 12 out of the 13 glucoheptonate non-avid lesions turned out to be non-neoplastic lesion; however, one lesion was reported as a Grade-2 astrocytoma. Histology from all the glucoheptonate concentrating lesions was of mitotic pathology. The sensitivity, specificity and accuracy of glucoheptonate for neoplastic lesion was 97.6%, 100% and 98.1%. Conclusions : Glucoheptonate has high degree of specificity for neoplastic tissues of brain and may be used as a tracer for SPECT study to differentiate neoplastic intracranial lesions from non-neoplastic ones.
Keywords: Glucoheptonate, intracranial space-occupying lesions, single photon emission computed tomography
The exact nature of many intracranial space-occupying lesions (ICSOLs) cannot be characterized with reasonable certainty solely by anatomical imaging modalities. Hence there is a need for complementary imaging techniques. , Glucoheptonate is a seven-carbon glucose analog that has very strong affinity for neoplastic brain tissues and is used as a tumor tracer in single photon emission computed tomography (SPECT) imaging of brain to detect tumor recurrence.  However, glucoheptonate brain SPECT has not been evaluated for its diagnostic utility in treatment-naïve patients for characterizing an intracranial lesion as neoplastic or non-neoplastic. Accumulation of glucoheptonate in neoplastic tissue has been partially attributed to blood-brain barrier (BBB) breakdown, thus raising the possibility of nonspecific accumulation in all intracranial lesions with BBB damage. , In order to evaluate whether glucoheptonate has sufficient specificity for neoplastic ICSOLs, a study was designed to evaluate glucoheptonate brain SPECT in its ability to differentiate neoplastic ICSOLs from non-neoplastic ICSOLs.
Consecutive patients referred to neurosurgery outpatient department with clinical and radiological features suggestive of ICSOL were included in the study that was conducted from November 2006 to March 2008. Patients willing to participate in the study protocol were recruited. The diagnosis of mass lesion was established by gadolinium-enhanced magnetic resonance imaging (MRI) brain. Brain SPECT using Technetium99m-labeled glucoheptonate as the tracer was done in all the 54 cases before a definitive surgical or other therapeutic intervention and within seven days of MRI brain. All patients were managed according to standard therapeutic guidelines. Histological verification of the diagnosis was obtained in all cases mostly by surgery or rarely by biopsy, which was considered as gold standard. Patients with clinical or radiological features suggestive of vascular insufficiency or malformation were excluded from this study. Informed consent either from the patient or from legal guardian in case of minor was obtained in all cases prior to recruitment and institute ethics committee approved the study.
Tc99m-glucoheptonate SPECT study
Brain SPECT was performed 30 min post intravenous injection of 740-925 MBq of technetium-99m-glucoheptonate, using a dual-head gamma camera (SMV DxTL from Ranalsofa, Buc, France) fitted with a high-resolution collimator. The dose of glucoheptonate for children was calculated as follows: The body surface area was divided by 1.73 and then multiplied by the adult dose of 925 MBq. Energy settings were 140 keV with a 20% energy window. The SPECT data were acquired in 128 x 128 matrix using step and shoot method with a view at every 4° for 25 sec per view, with a total of 90 views. Reconstruction was done by filtered back projection, projection data were filtered before back projection and reconstruction was performed using a two-dimensional Metz filter (cutoff : 0.43 cm, P : 30, value of max : 124, position of max : 23, FWHM : 100). Reconstructed images had a slice thickness of 8 mm and were displayed and analyzed using transverse, sagittal and coronal views.
Two experienced nuclear medicine physicians evaluated the scan findings independently and were blinded to the MRI scan findings and clinical profile. Images were interpreted as either showing or not showing definitive evidence of tracer concentration. Lesions showing glucoheptonate concentration were considered as neoplastic lesions and lesions not showing glucoheptonate concentration were regarded as non-neoplastic lesions.
To calculate the lesion to background ratio (glucoheptonate uptake index), a region of interest (ROI) was drawn on the transverse slice with maximum tumor activity and an average pixel count was obtained. To obtain the background activity a similar ROI was drawn on the opposite lobe or site and average pixel count was obtained. The ratio of the two average pixel counts was considered as the lesion to background ratio (glucoheptonate uptake index).
Method of interpretation of gadolinium-enhanced magnetic resonance imaging
Radiologists experienced in neuroradiology interpreted the MRI findings independently and were blinded to the SPECT findings. Lesions with thin-walled rim with central area of hypointensity on T-1 wt images with peripheral contrast enhancement were considered as inflammatory lesions. Lesions which were more heterogeneous in signal intensity with convex irregular peripheral margins with varying enhancement on contrast administration were considered as tumor mass.
Descriptive statistics like sensitivity, specificity, positive and negative predictive value and accuracy of glucoheptonate brain SPECT was calculated considering histological findings as reference. Statistical analysis using student's t test was applied. A P value of < 0.05 was considered statistically significant.
Fifty-four consecutive patients (34 males, 20 females with mean age of 36.33 ± 19.3 years) were included in the study. Increased glucoheptonate uptake over the site of radiologically detected lesion was noted in 41 patients suggesting neoplastic lesions [Figure 1]a and b. No glucoheptonate concentration over the corresponding site of radiological lesion was noted in 13 patients [Figure 2]a and b.
Histopathology of 12 out of 13 glucoheptonate-non-concentrating lesions turned out to be non-neoplastic lesion [Table 1]; however one lesion was reported as a Grade-2 astrocytoma. There was a statistically significant difference in lesion to background ratio of glucoheptonate-concentrating and nonconcentrating lesions (6.01 ± 1.76 vs. 1.01 ± 0.18; P < 0.001). Histology of all the 41 glucoheptonate-concentrating lesions was suggestive of neoplastic pathology. Out of the 42 patients with mitotic lesions, histopathology revealed glioblastoma multiforme in 12 patients, Grade-3 astrocytoma in eight patients, Grade-2 astrocytoma in five patients, Grade-1 astrocytoma in six patients, meningioma in eight patients, medulloblastoma in two patients and lymphoma in one patient.
The calculated sensitivity was 97.6% and specificity of glucoheptonate concentration for neoplastic lesion was100%. Positive predictive value was 100% and negative predictive value was 92.3% and overall accuracy of the test was 98.15%.
The main observation of this study is the high degree of specificity of Tc99m-glucoheptonate for neoplastic tissues. No glucoheptonate concentration was noted in any of the inflammatory lesions. However, there was one false-negative result. Hence in this series Tc99m-glucoheptonate SPECT had a sensitivity of 97.62%, specificity of 100% and overall accuracy of test 98.15%.
The mechanism of specificity of glucoheptonate for neoplastic tissue is not fully understood. Increased permeability in the tumor due to disruption of BBB and subsequent intracellular binding is considered to be the predominant mechanism of tracer uptake. , Disruption of BBB is a nonspecific pathological alteration seen in diverse type of brain lesions.  Though the benign lesions included in the present study like tuberculoma, brain abscess and granuloma do produce BBB breakdown, none of the lesions revealed any glucoheptonate uptake. , It may be postulated from the above observations that the mechanism of glucoheptonate localization inside the lesion is not critically dependent on BBB breakdown and non-neoplastic tissues lack the mechanism required for intracellular trapping of glucoheptonate. It also appears that normal brain tissue also lacks the required intracellular mechanism for glucoheptonate trapping.
Since glucoheptonate uptake was thought to be a reflection of BBB breakdown, its specificity for neoplastic lesions has always been debated. There are anecdotal reports of glucoheptonate concentration in ocular and retroperitoneal abscess. , However, in our study we were not able to demonstrate glucoheptonate concentration in any of the inflammatory lesions.
Myocardial perfusion markers like Thallium-201, sistamibi, tetrofosmin have been used to image recurrent brain tumors with the assumption that their uptake in tumor is independent of BBB disruption. But over the years it has been demonstrated that disruption of BBB is an essential condition for uptake of any tumor-seeking tracer including tracer used in positron emission tomography like Carbon-11-L-methionine. ,,
Physiological distribution of glucoheptonate in intracranial and pericranial areas is ideal for SPECT imaging of brain with no confounding uptakes inside ventricles, orbital and temporalis muscle. All these above reasons have led to the resurgence of interest in glucoheptonate as brain SPECT tracer. However, spatial resolution of 8 mm remains a drawback as in any SPECT study.
A weakness of this study is that all histological types of benign ICSOLs could not be included. It is possible that some of them might have different avidity for glucoheptonate.
Glucoheptonate has high degree of specificity for neoplastic tissues of brain and hence can be used as a tracer for SPECT study to differentiate neoplastic intracranial lesions from non-neoplastic ones. The relative role of glucoheptonate brain SPECT in treatment-naïve patients remains to be defined. A larger prospective study recruiting more histologically different benign ICSOLs will be helpful in addressing this issue.
[Figure 1], [Figure 2]