Simultaneous FET-PET and contrast-enhanced MRI based on hybrid PET/MR improves delineation of tumor spatial biodistribution in gliomas: a biopsy validation study

For patients with malignant glioma, continuous efforts were made to improve the overall survival and prognosis [1, 2]. Recently, several promising treatment methods, such as the addition of lomustine or tumor-treating fields into standard temozolomide maintenance therapy, shed light on the treatment of malignant glioma, which effectively prolonged 30–55% of median overall survival compared with temozolomide standard therapy [3, 4]. These novel treatments indicated the advancement of the chemotherapies on malignant gliomas and may become new standards of patient care.

As the widely accepted standard treatment for malignant glioma, surgical resection mainly relies on noninvasive imaging to delineate tumor extent. The extent of surgical resection and the residual tumor volumes are pivotal factors that affect the recurrence rate and the prognosis of glioma patients [5, 6]. In general, multimodality imaging plays an essential role in the diagnosis and neurosurgical planning for gliomas [7‐10]. Among these approaches, contrast-enhanced (CE) magnetic resonance imaging (MRI) is the mainstay to delineate tumor boundaries and guide further therapies [11]. However, CE MRI, when used alone or in combination with T2 and fluid-attenuated inversion recovery (FLAIR) imaging, may not reliably reflect the entire tumor burden [12, 13]. Consequently, a technique that could delineate the tumor extent more precisely is needed for therapeutic target planning.

The increasing application of positron emission tomography (PET) has improved the diagnosis and clinical management of gliomas [14‐18]. The European Association of Nuclear Medicine (EANM), the Society of Nuclear Medicine and Molecular Imaging (SNMMI), the European Association of Neurooncology (EANO), and the working group for Response Assessment in Neurooncology with PET (PET-RANO) have published joint practice guidelines for the use of amino acid PET tracers in glioma imaging and recommended that molecular imaging should be used as a supplement to MRI in the clinical management of gliomas [17]. Compared with 2-deoxy-2-[¹⁸F]fluoro-d-glucose (¹⁸F-FDG), amino acid PET tracers, such as ¹¹C-methyl-methionine (¹¹C-MET), O-(2-¹⁸F-fluoroethyl)-L-tyrosine (¹⁸F-FET), and 3,4-dihydroxy-6-[¹⁸F]fluoro-l-phenylalanine (¹⁸F-DOPA), exhibit lower uptake in normal brain and inflammatory tissues than in gliomas and thus present clearer tumor borders with a higher tumor-to-background contrast [19, 20]. The half-life of ¹⁸F (110 min) is longer than that of ¹¹C (20 min), making ¹⁸F-FET more suitable for routine clinical applications in neurooncology [21]. Furthermore, FET has high in vivo stability and is efficiently synthesized by nucleophilic reactions.

Compared with CE MRI, amino acid PET imaging, when used with tracers such as ¹¹C-MET [19, 22] and ¹⁸F-FET [23], often reveals a larger tumor spatial distribution in GBM patients. Among these previous studies, simultaneous PET and MRI acquisition was used with a hybrid PET/MR only in Lohnmann’s study (35 of 50 patients). Other studies used PET and MRI scans obtained on separate occasions, which would therefore not reflect the spatial distribution characteristics of glioma in the same pathological state. In addition, these previous studies were based only on imaging feature assessment without any pathological validation.

In this study, we evaluated the clinical value of hybrid FET-PET/MR in delineating tumor extent and guiding stereotactic biopsies in patients with glioma. The spatial similarity, overlap, discrepancy, and spatial correlation of tumor volumes were analyzed and compared between FET-PET and CE MRI. To better comprehend the imaging findings, several stereotactic biopsy samples were taken from regions showing either substantial overlap or mismatch between FET-PET and CE MR to further assess and validate the clinical potential of hybrid scans in guiding biopsy and surgery.

We found that, in gliomas, a larger proportion of tumor extent was identified by FET-PET than by CE MRI. The histopathology of stereotactic biopsies obtained under the guidance of hybrid FET-PET/MRI confirmed these results. This is the first clinical study to assess tumor volumes simultaneously delineated by FET-PET and MRI using a hybrid PET/MR for gliomas in which the results were validated by stereotactic biopsy. These findings may provide critical information to guide biopsy, surgical, and radiation therapy in patients with gliomas.

During the last few years, interest has increased in the development of applications of ¹⁸F-FET PET for tumor grading, differential diagnosis, biopsy guidance, and the assessment of treatment response [11, 17, 20, 33]. The amino acid tracer FET may play a more critical role than FDG in the imaging of gliomas because normal brain tissues show a much lower FET uptake; hence, FET provides clearer borders of lesions. Conventional MRI is the primary clinical reference for image-guided surgery. Therefore, it is meaningful to investigate how the data supplied by FET-PET and conventional MRI are different and whether the application of FET-PET shows superiority in gliomas. We found that the contrast-enhanced regions observed on MRI in gliomas were generally contained within V_PET and there was a positive correlation between V_PET and V_CE. The mechanisms underlying FET uptake and enhancement on MRI are entirely different. FET is transported by specific stereo-selective amino acid transporters, particularly the large neutral amino acid transporter 1 (LAT1). The transportation of FET is not affected by the blood-brain-barrier [21, 34]. Several recent studies have revealed that areas with increased FET uptake correspond to the tumor cell distribution [16, 35, 36]. However, MR contrast accumulates in gliomas due to blood-brain-barrier disruption and is correlated with the histological features of malignant glioma, including cellularity and proliferation [37]. Additionally, the positive correlation between tumor volumes obtained via FET-PET and CE MRI indicates that some underlying pathophysiological factors may exist. Our results indicate that surgical resection guided by CE MRI alone is inadequate for maximizing patient benefits, whereas FET-PET identifies a greater tumor extent, which is critical for planning therapeutic strategies.

The DSC and OV are different parameters used to evaluate the spatial similarity between tumor volumes on FET-PET and CE MRI, with higher DSC values indicating better consistency between V_PET and V_CE. The OV value represents the ratio of spatial coincidence volume to the smallest tumor volume. In our study, V_CE was smaller than V_PET in 93.94% of the patients. We found that the spatial similarity between FET-PET and CE was low (average DSC, 0.56), while the OV was high (average, 0.95). These findings illustrate that the spatial biodistribution of gliomas is quite different when manifested using FET-PET versus CE MRI and that basing interpretations on the OV alone may be misleading. Combining DSC and OV could produce a more accurate assessment of the spatial similarity between V_PET and V_CE. Furthermore, V_PET is larger than V_CE, and V_PET includes most of V_CE areas. To validate our findings, we further applied point-to-point stereotactic biopsy studies in 21 regions that showed increased FET uptake with or without MR enhancement. As expected, all samples were confirmed as tumor tissues based on histopathology, but CE MRI identified only 13 (62%) of these regions. Our results support the reliability of FET-PET and the importance of combining both FET-PET and CE MRI to delineate the tumor spatial biodistribution.

To further analyze the differences in glioma spatial biodistribution on FET-PET and CE MRI, we calculated the percentage discrepancy. Two groups of patients with different tendencies were identified. In one group of 30 patients (90.91%), almost all V_CE areas were included in V_PET, and the discrepancy-CE was less than 10%. However, the other group presented higher discrepancy percentages (> 10%) for both V_PET and V_CE. These findings are slightly different from those presented in Javier’s study [19],which evaluated the tumor volumes of 23 patients with glioma who preoperatively underwent ¹¹C-MET and MRI. In their study, 9 of 23 patients manifested another pattern in which almost all of the tumor volume observed on MET-PET was contained within the MRI (T1 CE MRI or T2WI)-derived volume. However, seven of these 9 patients were pathologically confirmed to have low-grade II gliomas that were negative on contrast enhancement. We recruited only patients with gliomas that were positive on both FET-PET and CE MRI.

Notably, we visually assessed the relationship between tumor extent on FLAIR and FET-PET images and found that 11 patients (33.33%) showed V_PET areas that partly beyond the abnormal signal area on FLAIR images, in agreement with the study by Lohmann et al. [23]. A similar result was also reported by Grosu et al., who found that areas with higher MET uptake were identified beyond the high-signal areas identified on T2W images in 50% of the patients [38]. These findings indicate that even the combination of CE MRI and FLAIR images is inadequate to delineate the full extent of the tumor in glioma patients. In contrast, Pafundi et al. found that all areas showing increased ¹⁸F-DOPA uptake were included in the abnormal signal areas on T2W or FLAIR images [12]. In our study, three samples were taken from regions that showed abnormal signal intensity on FLAIR images but were outside V_PET. Based on histopathology, two of these 3 samples were confirmed to be normal brain tissue, but one had a small amount of tumor cell infiltration. This result was consistent with those of Arvizu et al. [19]. In addition, several studies have indicated that tumor volumes based on FLAIR or FET-PET imaging findings are predictive of prognosis in glioma [39‐41]. Justin et al. proposed that performing maximum tumor resection according to findings on T2 and FLAIR images was associated with better prognosis in low-grade glioma [41]. Sidsel et al. found that a large tumor volume on FET-PET was an independent predictor of poor survival in GBM patients [42]. The postoperative tumor volume, when based on FET-PET, has also been shown a significant impact on prognosis in GBM patients [39]. FET-PET and FLAIR images show different tumor volumes, and they both play an important role in the evaluating prognosis in glioma; hence, a combination of multimodality imaging to tumor spatial delineation could be valuable for optimal treatment planning.

According to our results, PET/MR is an excellent imaging tool for delineating tumor volumes and identifying glioma boundaries. The integration of PET/MR into the navigation system as well as the development of a preoperative plan are highly recommended. The following limitations should be considered. First, we included a heterogeneous cohort consisting of both newly diagnosed primary and recurrent gliomas in our study. The inclusion of recurrent glioma may have affected the tumor volume assessments because of the effects of previous treatment. However, we did not exclude areas of necrosis or postoperative residual cavities in lesions without enhancement or FET uptake during the tumor volume delineation process according to surgical criteria. Second, no samples were obtained from areas that showed contrast enhancement but no increased FET uptake due to the limited corresponding volumes or their locations (e.g., in eloquence areas or close to blood vessels). Furthermore, a larger cohort of gliomas is needed to confirm the clinical value of multimodality imaging for the management of glioma. Whether FET-PET/MR-guided glioma treatment could improve patient prognosis remains to be investigated in our future work.

In summary, a larger extent of tumor spatial biodistribution was delineated by FET-PET than by CE MRI according to histological confirmation. The spatial similarity between FET-PET and CE MRI was relatively low. Furthermore, our results highlight the importance of combining molecular metabolic imaging (e.g., FET-PET) and anatomic MRI imaging before developing a treatment plan in glioma. Hybrid PET/MR is a promising simultaneous modality that provides opportunities for this application.