10 Fluorescein-Guided Tumor Resection in Neurosurgical Oncology Abstract Keywords: extent of resection, fluorescein, fluorescence imaging, fluoroscopy, glioblastoma, intracranial neoplasm, intraoperative imaging, meningioma, metastasis, neurosurgical oncology, tumor resection Fluorescein, discovered in 1871, was the first clinical fluorophore, and it has been broadly used in chemistry, biological sciences, and clinical medicine.1 Clinically, other than in neurosurgery, fluorescein is routinely used in emergency departments to evaluate corneal abrasions with a Wood lamp. This technique exploits the robust fluorescence visualized when fluorescein is excited with the appropriate wavelength of light. Since the 1960s, fluorescein has been used in neurosurgery to detect cerebrospinal fluid leaks, and it is commonly used to detect dural compromise during transsphenoidal surgery.2,3,4 In a landmark clinical study in 2006, Stummer et al5 showed that fluorescence-guided tumor resection could improve brain tumor extent of resection (EOR). Since EOR is positively correlated with patient survival, neurosurgeons have aimed to discover additional fluorescent contrast agents to better visualize brain tumors and their margins intraoperatively.6,7,8,9 In this chapter, we focus on the applications of fluorescein in neurosurgical oncology. In 1947, Moore10 made the first report of fluorescein localizing to brain tumors. In the initial studies prior to the advent of dedicated fluorescence surgical microscopes, ultraviolet light was used to excite the fluorophore, and fluorescence was visualized without dichroic filters in the light path.10,11 This method (without the dichroic filters) highlighted fluorescein’s high quantum yield and minimal photobleaching with excitation. These studies revealed that fluorescein localized to tumor regions and provided minimal fluorescence of normal brain.10,11 In the biological sciences, fluorescence imaging began to revolutionize data collection in the 1980s with the development of the first commercially available confocal microscope.12 Advances in imaging technologies and the development of novel fluorophores created a new era of live-cell imaging, which allowed scientists to visualize cellular processes in real time. Development of clinical fluorescence imaging technology began to follow suit. A surgical microscope capable of bright field and fluorescence imaging became available in 1998.13 This technology was described in 1998 in the first report of a dedicated fluorescence microscope for fluorescein-guided brain tumor resection. Kuroiwa et al13 used Zeiss OPMI MD and OPMI CS-NC operative microscopes (Carl Zeiss Meditec AG, Oberkochen, Germany) with appropriate excitation and emission filters to intraoperatively visualize tumors in patients with high-grade gliomas (HGGs). They reported that fluorescein localized well to areas where the blood–brain barrier was compromised, regions that also correlated with areas of gadolinium-based contrast on magnetic resonance imaging. In 2003, Shinoda et al11 compared the gross-total resection (GTR) rates of patients who underwent fluorescein-guided resection of glioblastoma (GBM) with the GTR rates of patients who underwent resection of GBM without fluorescein. In this study, fluorescein was administered in high doses after the dura was opened, and it was visualized under white light. The researchers reported that fluorescein localized to 100% of the GBMs in fluorescein-exposed patients and that it dramatically increased GTR rates (84.4% [27 of 32 patients with fluorescein] vs. 30.1% [22 of 73 patients without fluorescein]). Before 2012, no study had evaluated the long-term clinical benefits of fluorescein-guided tumor resection. Results of a study correlating the effects of fluorescein-guided resection of brain tumors on progression-free survival (PFS) were published in 2012.14 In this report, the outcomes of 10 glioma patients who underwent fluorescein-guided resection were compared with the outcomes of 12 similar controls. In the fluorescein group, mean PFS increased (mean > 7.2 vs. > 5.4 months). In 2013, the Zeiss Pentero YE560 (YE560) became the first commercially available operative microscope with dedicated filter sets for fluorescein imaging. This microscope offers blue-light excitation and 540- to 690-nm emission filters for visualizing fluorescein ( Fig. 10.1 Fluorescence intraoperative surgical microscope. An intraoperative photograph shows the blue light from the Zeiss YE560 (Carl Zeiss Meditec AG) over a brain tumor exposure. (Reproduced with permission of Barrow Neurological Institute, Phoenix, Arizona.) Multiple studies of fluorescein-guided brain tumor resection have focused on HGGs, reinforcing the fact that increased cytoreduction can improve survival of both newly diagnosed patients and patients with recurrent HGGs.23,24 Since fluorescence guidance with 5-aminolevulinic acid (5-ALA) was reported to enhance glioma EOR, neurosurgeons have sought contrast agents with a similar utility that are approved for clinical use by the U.S. Food and Drug Administration. Fluorescein was an obvious candidate; it had been used clinically for decades, was inexpensive, and provided bright fluorescence.25 To date, the utility of fluorescein contrast in HGG surgery has been documented in at least 11 peer-reviewed publications.26 These studies have investigated specificity, dosing, EOR, timing for use, and potential adverse effects. Since the introduction of commercially available fluorescence surgical microscopes, four peer-reviewed studies have evaluated the sensitivity and specificity of fluorescein-guided glioma resection.15,16,17,19 These reports show sensitivity and specificity of 90% and greater. For the surgeon, this means that fluorescence correlates reliably with high-grade tumors, and it appears to correspond well with enhancement on magnetic resonance images. In the current era (since 2013), GTR can be expected in up to 80% of glioma cases in which fluorescein guidance is used.1 GTR of intracerebral metastases is an independent predictor of patient survival, PFS, and postsurgical neurological status.27,28,29 Therefore, intraoperative techniques that increase the EOR, such as fluorescence-guided surgery, may improve patient survival and outcome. Several case series have evaluated the utility of fluorescein-guided resection of intracerebral metastases.1,20,29 Initial studies did not use standardized fluorescein dosages or standardized imaging hardware. The lack of standardization precludes the accurate comparison of data from these studies. In this chapter, we focus on studies published since 2013, after the introduction of the YE560 and subsequent dose standardization. These studies have shown that fluorescein-guided microsurgery enhances EOR and GTR beyond the capabilities of traditional white-light microsurgery.19,20 Current data show that fluorescein preferentially localizes to metastatic tissue within the brain compared to adjacent normal brain.30 Furthermore, fluorescein appears to enable superior EOR of intracranial metastases compared to 5-ALA, although a direct comparison has never been performed.20,31 Researchers have subjectively assessed the usefulness of fluorescein-guided resection of intracerebral metastatic disease, and several authors have quantified the EOR by comparing intraoperative and postoperative magnetic resonance images. Use of intraoperative fluorescein contrast is considered helpful in identifying tumors and tumor margins in 95 to 97% of cases.19,20 Furthermore, fluorescein-guided resection of intracerebral metastases can achieve 83 to 100% GTR. By comparison, traditional white-light microsurgery yields GTR of 54 to 76%.32,33 Some users have noted that the fluorescence of fluorescein seems to extend slightly beyond the margin of the tumor, leading to the risk of supramaximal resection, although this possibility has not been rigorously studied. When operating at the periphery of metastatic lesions, surgeons should keep the possible extension of fluorescence in mind and should apply caution in eloquent regions of the brain until they are further interrogated.
This chapter reviews fluorescein-guided resection of intracranial neoplasms such as gliomas, meningiomas, and metastases. Fluorescein’s utility in the management of intracerebral abscesses and nonoperative lesions, such as central nervous system lymphoma, is also discussed. Fluorescein is the first fluorescent contrast agent to gain widespread clinical use, and its neurosurgical applications have undergone refinement alongside advancements in clinical fluorescence imaging technology. In the early 2010s, the first dedicated commercial surgical fluorescence microscope with fluorescein-specific excitation and emission filters was introduced. The introduction of dedicated fluorescence surgical microscopes led to renewed interest in optimizing protocols for fluorescein-guided tumor surgery. Recently, the neurosurgery field has moved toward administering lower doses of fluorescein for fluorescence-guided tumor resection. Data from studies of low-dose protocols indicate that fluorescein localizes well to intracranial lesions with disrupted blood–brain barriers in patterns similar to those of gadolinium contrast on magnetic resonance imaging (MRI). Current literature suggests that fluorescein contrast during tumor resection increases gross-total resection (GTR), with 100% GTR reported in one case series of fluorescein-guided glioblastoma resection. To date, no reports of significant deleterious effects have been reported with low-dose fluorescein for brain tumor visualization. This chapter focuses on studies that use a standardized administration protocol as reported after the introduction of commercial fluorescence surgical microscopes, with a review of the literature before this era. Although the utility of fluorescein for intraoperative visualization of intracranial tumors was first reported in the 1940s, the advantages of fluorescein guidance and techniques optimizing its administration and visualization continue to be discovered.
10.1 History
Fig. 10.1). Peer-reviewed reports detailing this microscope’s efficacy for intraoperative brain tumor imaging began to appear in 2013.15,16 In 2015, Diaz et al17 reported that YE560-guided resection of HGGs could yield 100% GTR. Since the introduction of dedicated filter sets for fluorescence imaging in surgical microscopes (now available from multiple manufacturers), most studies evaluating their usefulness have included similar dosing and imaging protocols for fluorescein. In this chapter, data are presented from studies that implement fluorescein-guided surgery that follows the clinical protocol commonly used with commercially available fluorescence surgical microscopes, such as the YE560 (
Table 10.1).15,16,17,18,19,20,21,22
10.2 High-Grade Gliomas
10.3 Metastatic Disease
10.3.1 Usefulness and Extent of Resection
Related posts:
Intraoperative Fluorescence Guidance in Meningiomas
5-Aminolevulinic Acid and Recurrent High-Grade Gliomas
Current Fluorescence-Guided Neurosurgery and Moving Forward
Confocal Endomicroscopy
Indocyanine Green Videoangiography and Arteriovenous Malformations
Cancer-Targeted Alkylphosphocholine Analogs for Intraoperative Visualization
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