Fluorescein sodium, a fluorescent compound discovered by Adolf von Baeyer in 1871, it has typically been used in ocular retinal angiography[13, 14]. However, as early as 1947, Moore et al. studied the role of fluorescein sodium in neuro-oncological procedures and explored the differences in the intensity of fluorescein signals between malignant and benign tissues[15]. The mechanism of action of fluorescein sodium is thus very similar to that of gadolinium. Therefore, the value of fluorescein as a surgical adjunct lies in its ability to generate signals intraoperatively similar to those generated by gadolinium during radiography. This reduces the impact of deficiencies in conventional neuronavigation, such as brain displacement or registration errors, observes neurosurgeons to visualize contrast-enhanced areas of tumors in real time[10, 14, 16-18].
A number of studies have demonstrated that fluorescein-guided surgery can significantly improve the GTR rate of high-grade gliomas[4, 10, 13, 19-21]. Smith et al. evaluated the GTR rate of high-grade gliomas with fluorescein guidance in a meta-analysis study. A pooled cohort of 336 patients underwent fluorescein -guided resection of high-grade gliomas, with a GTR rate of 81% (95% confidence interval 73%-89%; P < 0.001). They further analyzed 10 case-controlled studies and reported a 29.5% increase in the GTR rate in the fluorescein-guided group compared with that in the non-fluorescein-guided group[22]. Acerbi et al. analyzed data from 412 articles, 17 of which were closely related to fluorescein-guided resection of high-grade gliomas, and reported that fluorescein-guided surgery was a safe, effective, and convenient technique for achieving high GTR rates of high-grade gliomas. However, the impact of fluorescein-guided surgery on progression-free and overall survival needs to be demonstrated in further prospective comparative trials[17]. In line with the above-mentioned study, our data revealed a significantly higher rate of GTR in the fluorescein group compared to the non-fluorescein group (42.67% vs. 21.31%, P = 0.005; Table 2). We further investigated the difference in GTR rates between the fluorescein and non-fluorescein groups based on different tumors locations in the supratentorial region and found that for patients with tumors located in the temporal lobe, occipital lobe, and deep supratentorial area, the GTR rate was higher in the fluorescein patients than in the non-fluorescein patients; for patients with tumors located in the frontal and parietal lobes, the GTR rate was not statistically significantly in both populations. We speculate that the above findings may be related to the fact that cerebral language and motor areas are mainly located in the frontal and parietal lobes. The current surgical strategy for tumors involving the cerebral language and motor areas is to safely remove the tumor to the maximum extent possible; the aim is to preserve as much vital neurological function as possible while prolonging the patient's survival to improve the patient's postoperative quality of life, rather than to pursue total neuroimaging-based resection of the tumor[23-25].
Current studies do not provide a clear consensus on the dose and timing of fluorescein sodium administration before surgery[17, 18, 22, 26]. We achieved satisfactory intraoperative tumor staining by administering 0.5 mL of fluorescein sodium intravenously prior to general anesthesia for skin testing (aimed at confirming the absence of an allergic reaction) and subsequently administering a single intravenous injection. However, the extravasation and distribution of fluorescein sodium followed a certain time course. Intravascular fluorescein leaks out after a half-life of 264 min and may stain edema in peritumoral normal brain parenchyma, increasing the risk of resection of non-tumor tissue. Therefore, the timing of administration should be carefully planned to minimize these confounding factors[26]. Hong et al. retrospectively analyzed 82 patients in total, 42 with fluorescein-guided surgery (fluorescein group) and 40 without fluorescein guidance during surgery (non-fluorescein group) and found that the fluorescein group experienced less intraoperative bleeding and shorter operative times compared to the non-fluorescein group[4]. Our results also showed that the duration of operative was significantly shorter in the fluorescein group than in the non-fluorescein group (P = 0.008; Table 2). However, there was no statistically significant difference in the amount of intraoperative bleeding between the two groups (P = 0.094, Table 2). Further statistical analysis showed that there was no statistically significant difference in intraoperative bleeding for tumors at different locations in the supratentorial region (P = 0.890 for frontal, P = 0.153 for temporal, P = 0.137 for parietal, P = 0.711 for occipital, and P = 0.324 for deep supratentorial regions, Table 4). For patients with tumors in the frontal and occipital lobes, the duration of operation was significantly shorter in the fluorescein group than in the non-fluorescein group (frontal, P = 0.036; occipital, P = 0.041; Table 4), whereas for patients with tumors in the temporal, parietal, and deep supratentorial lobes, there was no statistically significant difference between the two groups in this regard (temporal P = 0.597, parietal P = 0.321, deep supratentorial P = 0.083, Table 4). Based on our previous surgical experience, we conclude that the use of fluorescein sodium facilitates the visualization of tumor tissue and the determination of tumor boundaries, which theoretically reduces the amount of surgical bleeding and shortens the duration of operative. However, the increase in gross total/subtotal resection rate also increases the workload of surgical resection and correspondingly prolongs the operative time. In addition, surgical manipulation of brain tissue inherently disrupts the BBB, resulting in the non-selective leakage of fluorescein sodium from the bloodstream along the cut edges of tumor tissue during surgery; this also affects the reliable delineation of tumor and normal tissue. In addition, the reduced illumination intensity in the fluorescence mode makes it more difficult to identify bleeding points and to stop bleeding in the operative field. Thus, switching to the non-fluorescence mode is often required for hemostasis, resulting in increased intraoperative bleeding and prolonged operative time; these effects are more pronounced for deeper tumor tissues. In addition, fluorescein sodium can stain the cerebrospinal fluid. If the ventricular system is opened during resection for tumors in the ventricular system and the cerebrospinal fluid flows into the operative field, the field will appear yellow-green in the fluorescence mode, making it more difficult to operate and requiring a switch back to the non-fluorescence mode. This can also lead to increased intraoperative bleeding and prolonged operative time.
Our study also showed that there was no statistically significant difference in the overall complication rate between the fluorescein and non-fluorescein patients (6.67% vs. 4.92%, P = 0.668; Table 2). Complication rates based on tumors at different locations in the supratentorial region (frontal 6.90% vs. 10.53%, P = 0.660; temporal 7.41% vs. 0.00%, P = 0.187; parietal 0.00% vs. 0.00%, P = 1.000; occipital 0.00% vs. 0.00%, P = 1.000; deep supratentorial 7.50% vs. 11.76%, P = 0.606; Table 4) were also not significantly different between the two groups. This result is similar to that reported by Hong et al.[4] In 2017, Acerbi et al. conducted a multicenter prospective phase II trial on fluorescein sodium-guided high-grade glioma resection (FLUOGLIO), during which 40 serious adverse events occurred in 56 patients; none of the adverse events were considered to be related to fluorescein sodium administration[27]. In agreement with the above-mentioned results, the current study also showed that fluorescein-guided glioma resection does not significantly increase the incidence of postoperative complications compared to conventional non-fluorescein procedures.
Two prospective controlled studies assessed the effect of fluorescein sodium-guided glioma resection on survival: Koc et al. reported a median survival time of 43.9 weeks for patients in the fluorescein group and 41.8 weeks in the non-fluorescein group. There was no statistically significant difference in survival between the two groups[28]. Progression-free survival was significantly longer with fluorescein (7.2 months vs. 5.4 months; P = 0.033) in a study conducted by Chen et al. However, the study lacked randomization and did not use special microscope filters to visualize fluorescence; only white light was used[19]. Thus, to date, no studies have reported reliable data on the prognostic and survival impact of fluorescein-guided glioma resection[26, 27, 29, 30].