Evaluation of Single Photon Emission Computerised Tomography (SPECT) using Tc99m-Tetrofosmin as a Diagnostic Modality for Recurrent Posterior Fossa TumoursS Barai1, GP Bandopadhayaya1, PK Julka2, AK Haloi3, A Seith3, A Malhotra1
1 Departments of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, India
2 Departments of Radiotherapy, All India Institute of Medical Sciences, New Delhi, India
3 Departments of Radiology, All India Institute of Medical Sciences, New Delhi, India
BACKGROUND: Brain Single Photon Emission Computerised Tomography (SPECT) has been established as a potentially useful tool for the assessment of recurrent brain tumours. Though brain SPECT is exquisitely sensitive in detecting viable tumour tissue in the supratentorial region, its efficacy has not been evaluated till date in case of infratentorial posterior fossa tumours. AIM OF THE STUDY: To evaluate the diagnostic utility of brain SPECT in differentiating recurrence of tumour from post-radiation gliosis in the posterior fossa of the brain. SUBJECTS AND METHODS: Twenty-one patients with primary malignant posterior fossa brain tumour were evaluated by brain SPECT with Tc99m-Tetrofosmin as the tumour-seeking agent. Clinical behaviour of the tumour observed for a minimum period of one year after the SPECT study was taken as the gold standard. STATISTICAL ANALYSIS: The Chi-square test has been used to note the significance of the association between the clinical outcome and the SPECT finding. In addition, the sensitivity and specificity of brain SPECT were also calculated. RESULT: Brain SPECT in 4 patients revealed increased tracer concentration over the primary tumour bed, which was consistent with recurrent tumour. The clinical course was consistent with tumour recurrence in 13 of the 21 patients, which included 3 patients with positive SPECT study and 10 patients with negative SPECT study. Brain SPECT revealed recurrent tumour in 4 patients whereas clinical follow-up suggested recurrence in 13 patients. The clinical course was consistent with radiation necrosis in the remaining 8 patients. In 1 brain SPECT positive patient the clinical course was consistent with post-radiation gliosis. CONCLUSION: This study demonstrates that brain SPECT is not a sensitive diagnostic modality to differentiate recurrent tumour from post-radiation gliosis in the posterior fossa of the brain.
Keywords: Posterior fossa, Tetrofosmin, Fanbeam collimator, Post-radiation gliosis.
Accurate neuroimaging can assist in the diagnosis, management and follow-up of patients with posterior fossa brain tumour. Brain SPECT has been established as a potentially useful tool for the assessment of recurrent brain tumours.,,,,,, Though brain SPECT is exquisitely sensitive in detecting viable tumour tissue in the supratentorial region, its efficacy has not been evaluated till date in case of infratentorial posterior fossa tumours. We undertook a pilot study and evaluated 21 patients of malignant posterior fossa tumour by brain SPECT with Tc99m-Tetrofosmin as the tumour-seeking agent. The aim of the study was to evaluate whether brain SPECT is a reliable modality for differentiating recurrent tumour from post-radiation gliosis in posterior fossa tumours
Brain SPECT was acquired one-hour post intravenous administration of 185-1000 Mega Bequeral (MBq) tc99m-Tetrofosmin, using a dual-head single photon emission computed tomography system (Varicam, Elscint, Israel) fitted with a low-energy ultrahigh resolution fan beam collimator. The dose was calculated as body surface area divided by 1.73 and then multiplied by the standard adult dose of 1,000 MBq. The energy setting was 140 kiloelectrovolt, with 20% energy window. In total, 90 views were obtained with one view at every 40, for 25 seconds per view in a 128 x 128 matrix. The projection data was prefiltered before back projection and reconstruction was done with a two-dimensional Butterworth filter (cut off=0.90 cm, order 10). Attenuation correction was done by Chang's method. No scatter correction was done. Reconstructed images had a slice thickness of 7 mm and were displayed and analysed using transverse, sagittal and coronal views.
Computed tomography (CECT) was performed 15 minutes after intravenous administration of contrast with a dose of 2ml/Kg body weight. Axial cuts of 3 x 3 mm were taken through the region of interest, whereas 10 x 10 mm cuts were taken through the rest of the brain.
An oncologist from the same institution experienced in neuro-oncology evaluated the patients on follow-up visits. All the patients were assessed monthly for the first six months, two-monthly for the next six months and three-monthly thereafter. The neurological status of the patients was assessed by the Karnofsky performance scale and MRC neurological scale if applicable. Any patient with a stable score or improvement of score was considered to have post-radiation gliosis whereas any patient with deterioration of score was considered to have recurrent tumour.
Two experienced nuclear medicine physicians evaluated the scan findings independently, blinded from the imaging and clinical findings. Increased radiotracer uptake, equal to or more than the scalp activity over the primary tumour bed was considered indicative of viable tumour. The absence of any abnormal tracer uptake over the site of the primary tumour was considered indicative of post-radiotherapy gliosis. The intensity of tracer concentration in the tumour mass was expressed as tumour to background ratio (Tetrofosmin index).
Two radiologists experienced in neuroradiology interpreted the CT/MRI findings independently and were blinded from the SPECT finding. The lesions were interpreted as post-radiation gliosis if their HU-values were close to CSF-density with no evidence of any mass-effect, whereas lesions showing effacement of adjacent sulcal spaces (mass-effect) with or without contrast-enhancement were reported as recurrent tumour.
An irregular region of interest (ROI) was drawn around the tumour, encircling it completely. The ROI was drawn on the transverse slice with the highest radiotracer concentration and the average pixel count in the ROI was obtained. A similar ROI was drawn on the corresponding area of the contralateral side by computer-assisted software and the average pixel count in the ROI was obtained. The ratio of the two average pixel counts was obtained and defined as the Tetrofosmin Index.
Thus, the Tetrofosmin retention index was calculated as follows:
Tetrofosmin index = Average pixel count in the ROI Index around tumour
Average pixel count in the ROI on the contralateral side
No ROI was drawn in patients who did not show Tetrofosmin concentration and Tetrofosmin index was not calculated in them.
The sensitivity and specificity analysis for brain SPECT was performed considering the clinical behaviour of the disease as the gold standard. The Chi-square test was applied to see the significance of association between the SPECT finding and the clinical course of the disease.
In this study, brain SPECT in 4 patients revealed increased tracer concentration over the primary tumour bed, which was consistent with recurrent tumour [Figure - 1] & [Figure - 2]. The Tetrofosmin retention index was 5.26+1.64. The remaining 17 patients did not reveal any abnormal tracer concentration over the site of primary tumour [Figure - 3] & [Figure - 4].
CECT was consistent with recurrence in 13 of the 21 patients. This included 3 patients with positive SPECT study, but the fourth patient with a positive SPECT study had a normal CT brain. On the other hand CT brain was consistent with post-radiation gliosis in 8 out of the 21 patients.
The clinical course was consistent with tumour recurrence in 13 of the 21 patients, which included 3 patients with positive SPECT study and 10 patients with negative SPECT study [Table - 2]. One patient with a positive brain SPECT study remained clinically asymptomatic during follow-up and had a normal CT brain constituting a false positive SPECT study. The clinical course was consistent with radiation necrosis in the remaining 8 patients. The Chi-square test did not reveal any significant association between the SPECT findings and the clinical outcome with a P of 1.00.
In the paediatric age group (< 16 years, n= 11), brain SPECT was able to detect 1 of the 7 patients with recurrence of tumour as suggested by the clinical follow-up. It was false positive in one patient and was true negative in 4 patients. Amongst the adult patients (> 16 years, n=10) brain SPECT was able to detect 2 of the 6 patients with recurrence of tumour as suggested by the clinical follow-up. It was not false positive in any patient and was true negative in 3 patients.
The results of brain SPECT as a whole and according to age are compared in [Table - 3].
Tetrofosmin was introduced as a myocardial perfusion agent, which can differentiate ischaemic but viable myocardium from scarred myocardium. Initial results suggest that Tetrofosmin concentrates in solid malignancies like thyroidal carcinoma, non-Hodgkin's lymphoma and hepatocellular carcinoma.,, This principle was applied to image brain tumours with Tetrofosmin. Various investigators have reported its utility in imaging recurrent brain tumours. However; no study has evaluated posterior fossa tumours exclusively. Usually, there is little or no Tetrofosmin uptake in normal brain tissue. Tetrofosmin shows intense physiological uptake in the choroid plexus of ventricles, extra ocular muscles and temporalis muscle. Therefore Tetrofosmin brain SPECT is not suitable for the evaluation of tumours close to these structures, but otherwise it allows good visualisation of tumour margins.
The main observation of this study is the poor sensitivity (23.07%) of brain SPECT for the detection of tumour recurrence in the posterior fossa in contrast to the high sensitivity of SPECT reported in the case of supratentorial tumours. The sensitivity in the paediatric group was 16.6% whereas it was considerably better in the adult group (28.5%)[Table - 5].
The mechanism of Tc99m-Tetrofosmin accumulation has been studied in myocardial cells, and it seems to be dependent on cellular metabolism because mitochondria take up the tracer with a process that is dependent on their membrane potential and their coupling state (i.e. their ability to couple oxidative phosphorilation).,, In the present study no Tetrofosmin uptake was noted in normal brain tissue, so the breakdown or increased permeability of the blood brain barrier (BBB) seems to be a condition necessary for uptake in the tumour. Nevertheless, it is known that in a tumour cell line, the uptake mechanism, intracellular distribution and washout kinetics of Tetrofosmin are influenced by compounds that interfere with metabolic processes and that the mechanism by which the tracer enters the cells depends upon both the cell membrane (Na+/K+ pump) and the mitochondrial potential.
Endothelial cells of the BBB express the multidrug resistance 1 gene, the product of which is an adenosine triphosphatase membrane pump extruding a variety of toxins from the cells. Tc99m-Tetrofosmin is one of these substrates. The inhibition of multidrug resistance has been shown to delay the excretion of Tc99m-Tetrofosmin. Without inhibition the pump prevents the tracer from reaching the interstitial space. The choroid plexus tissue, the vasculature of which expresses neither tight junctions nor multidrug resistance 1 gene, accumulates Tc99m-Tetrofosmin, supporting this concept. In this study, 3 patients who showed Tetrofosmin uptake have not received chemotherapy before the SPECT study and in all cases the histological type was medulloblastoma.
Secondly, the posterior fossa of the brain is a compact anatomical space, which provides relatively less space for the tumour to grow without compressing the neuronal structures. Thus a tumour smaller than 1 cm can produce considerable clinical symptoms without being detected on SPECT, as the resolution of brain SPECT is around 1 cm. There are relatively more venous sinuses in relatively less space in the posterior fossa, and frequently these sinuses contain high amounts of retained radioactivity, which sometimes mask an adjacent tumour having equal or less tracer intensity. Lastly, it is possible that when brain SPECT was performed, some lesions may have been gliosis and showed no Tetrofosmin accumulation. After SPECT study, during the long follow-up period, the lesion, which was gliosis, may have changed into tumour or tumour recurrence.
One 12-year-old male patient with desmoplastic medulloblastoma had a false positive brain SPECT study. The primary tumour was situated in the cerebellum in the midline, close to the confluence of sinuses. The venous blood of the brain drains out via the confluence of sinuses, which consequently retain high amount of radioactivity inside them. The high amount of retained radioactivity at a small place can induce SPECT reconstruction artifact, which can mimic a tumour mass.
Although Tetrofosmin brain SPECT is an excellent modality for diagnosing tumour recurrence at supratentorial locations, this study demonstrates that brain SPECT is not so sensitive in case of posterior fossa tumours. Therefore any negative brain SPECT study in suspected patients of posterior fossa tumour recurrence should be treated with caution and should be correlated with another imaging modality for optimum patient care.
[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5], [Figure - 6], [Figure - 7], [Figure - 8][Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5], [Table - 6]