Routinely, the diagnosis of glial tumors recurrence is made on the basis of MR examinations, including T1WI (without and with contrast injection), T2WI and FLAIR sequences. As these techniques do not measure specifically the tumor activity, more advanced imaging techniques have been employed: DWI, DCE or MRS. The recent meta-analysis of van Dijken et al. [20] showed that pooled sensitivity and specificity of anatomical MR in the evaluation of treatment response amounted to 68% and 77%, respectively. Pooled apparent diffusion coefficients demonstrated a sensitivity of 71% and specificity of 87%. DSC perfusion sensitivity was 87% with a specificity of 86% and DCE perfusion sensitivity was 92% and specificity was 85%.
PSMA is a transmembrane glycoprotein expressed in the endothelial cells of neovasculature of various tumors (breast and renal carcinoma) [21, 22]. Based on immunohistochemical examinations, Wernicke et al. reported the PSMA expression in all 32 grade IV glioma tumors, specifically in their vasculature [7]. Other authors confirmed a positive result of the PSMA staining in high-grade glioma specimens [8, 23]. In contrast, the PSMA expression was relatively infrequent in low-grade gliomas [11, 24].
These in-vitro results laid the foundation for the new imaging option of glial tumors with radiolabeled PSMA ligands with the use of PET/CT technology. The first case report of [68Ga]Ga-PSMA-11 accumulation in glioblastoma multiforme was published in 2015 [25]. Later studies showed very promising results on some larger patient series (from 3 to 15 cases) that concordantly reported positive [68Ga]Ga-PSMA-11 PET/CT scans in all the examined glioblastoma multiforme cases [10–12, 14, 17]. In the present preliminary study, the cohort of 34 patients with glial tumors is analyzed. As many as 28 of them had the diagnosis of grade IV glioma, and the results in this subgroup, similarly to the papers mentioned above, demonstrate high tracer uptake in the recurrent tumor. The areas of recurrence presented as foci of intense tracer accumulation with a median SUVmax of 7.1 (the highest SUVmax value in one of the patients was 15.6 – Fig. 3). On the other end of the uptake range, there were some patients with glioblastoma multiforme, with relatively low SUVmax (1.3 was the lowest value recorded in this subgroup). However, even these foci of recurrence could be easily delineated at the PET/CT scans because of generally extremely low [68Ga]Ga-PSMA-11 uptake in the normal brain parenchyma. The median SUVmax of the normal brain was as low as 0.1. Adequately, the contrast between the malignant infiltration and the background was very good in all the grade IV cases. The subsequently high TBR values (median 89.6) are concordant with the in-vitro findings of absent PSMA expression in the normal brain vasculature [7, 8]. Due to the remarkable TBR, [68Ga]Ga-PSMA-11 PET/CT offers an advantage over other tracers. For example, a median TBR of 3.8 was reported recently for [11C]methionine PET/MR in newly diagnosed glioblastoma [26] and median TBR of 3.2 was obtained in [18F]fluoroethyltyrosine PET/MR in a group of 32 patients with high-grade glioma recurrence [27].
Interestingly, we did not record any false-positive scans. A single case of an increased PSMA ligand accumulation in radionecrosis has been published till now [28]. This finding may represent a potential limitation to the application of PSMA-targeted agents, but it is not supported by our data.
The representation of cases with glial tumors of other grades than IV seems to be an additional value of our study. Despite the fact that the subgroup of grade III contains only 6 cases, it can still be considered the largest collective reported so far. Considering that three of these patients had a multifocal recurrence, the per-lesion analysis of 11 tumors in total could be performed. Moreover, the uptake parameters in multiple tumors of the same patient were not always similar. For example, in the patient with four foci of oligodendroglioma relapse (patient No.4), the SUVmax ranged from 0.9 to 11.2. This anecdotal observation provides another evidence of biological heterogeneity of multifocal tumors. In general, performance of [68Ga]Ga-PSMA-11 PET/CT in grade III was as excellent as in grade IV. Similarly, high uptake parameters were measured in this subgroup. Some positive experiences with the PSMA imaging in grade III gliomas were also shared by Sasikumar et al., whose 2 patients with anaplastic oligodendroglioma and anaplastic astrocytoma presented with TBR of 11.9 and 27.0 [12].
Comparison of PET and MR scans showed that the accumulation of [68Ga]Ga-PSMA-11 was found precisely in the tumor regions that showed contrast enhancement. Gadolinium-based contrast agents shorten T1 relaxation times and increase tissue contrast by accentuating areas where contrast agents have leaked into the interstitial tissues crossing the blood-brain barrier. The breakdown of the barrier and neoangiogenesis are key features seen not only in primary tumors but also in the recurrences. A better indicator of angiogenesis is the increase in rCBV. In the group of 15 patients for whom this study was available, a clear correlation was found between the accumulation of [68Ga]Ga-PSMA-11 and rCBV. On the other hand, the region of T2WI/FLAIR hyperintense signal abnormality surrounding the enhancing part of a tumor or its recurrence is typically referred to as peritumoral edema and can be of vasogenic or infiltrative nature. The infiltrative edema in gliomas represents a mixture of vasogenic edema and infiltrating tumor cells and can be considered as a non-enhancing tumor without pathological angiogenesis and with preserved integrity of the blood-brain barrier. In fact, in many gliomas, the T2WI/FLAIR hyperintense signal abnormality may be indistinguishable from the primary mass lesion. It seems that the processes responsible for both, the imaging patterns in MR and the uptake of [68Ga]Ga-PSMA-11, are similar and this explains the obtained results.
The discovery of PSMA expression in glial tumors has provided rationale for this particular imaging modality but it can also be considered in the context of the targeted radionuclide therapy with β or α-emitters. First experimental therapy of glioblastoma multiforme using [177Lu]Lu-PSMA-617 applied intravenously has been recently published by our group [29]. Despite earlier concern about a quick washout of the compound due to the non-specific uptake in microvascular endothelium (instead of the tumor cells), we were able to demonstrate a long-lasting accumulation of the β -emitting radioligand within the tumor. This finding seems to predict good chances for the development of this kind of treatment. For the qualification to PSMA-based radionuclide targeted therapy the TLR of more than 1.5 is commonly used as a qualification criterion to the radionuclide therapy [30]. If the [68Ga]Ga-PSMA-11 PET/CT had been used for qualification to the radionuclide therapy in this group, the criterion of TLR > 1.5 would have been fulfilled by one third of the patients.
There are some limitations to this study. First, the sample size in grade III is small, so the differences in the measured parameters between grade III and grade IV subgroups, if any, do not reach statistical significance. Therefore, more extensive research on a larger number of patients, possibly multicenter trials, are warranted. The relatively small number of cases included is the result of strict inclusion criteria: only patients with a suspicion of recurrence were qualified. PET/CT scans obtained at different clinical settings, i.e. for staging or treatment response were not included. This rule should be appreciated as an advantage of this paper. But on the other hand, it could be considered as weakness, since only true-positive scans were acquired. Presence of patients without recurrence, with false-positive findings or with a negative scan despite relapse, would allow us to calculate the sensitivity and specificity.