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Fluorescein-guided surgery for malignant gliomas: a review

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Abstract

Fluorescein is widely used as a fluorescent tracer for many applications. Its capacity to accumulate in cerebral areas where there has been blood–brain barrier damage makes it particularly suitable as a dye for the intraoperative visualization of malignant gliomas (MGs). In this report, we describe the results of a comprehensive review on the use of fluorescein in the surgical treatment of MGs. A comprehensive literature search and review for English-written articles concerning the use of fluorescein in the resection of MGs has been conducted. The search was executed through a PubMed literature search using the following keywords: malignant gliomas, glioblastomas, high-grade gliomas, YELLOW 560, total removal, dedicated filter, neurosurgery, brain tumors, intracranial tumors, and confocal microscopy. The literature search resulted in the retrieval of 412 evidence-based articles. Of these, 17 were found to be strictly related to the resection of MG with the aid of fluorescein. In addition to these 17, we have included 2 articles derived from a personal database of the corresponding author (FA). The analysis of the articles reviewed revealed three major applications of fluorescein during surgery for MGs that was documented: Fluorescein-guided resection of MGs with white-light illumination, fluorescein-guided resection of MGs with a surgical microscope equipped with a dedicated filter for fluorescein, and confocal microscopy for intraoperative histopathological analysis on MGs. The systemic review conducted on the use of fluorescein in MGs explored the applications and the different modalities in which fluorescein has been used. The data we have gathered indicates that fluorescein-guided surgery is a safe, effective, and convenient technique to achieve a high rate of total removal in MGs. Further prospective comparative trials, however, are still necessary to prove the impact of fluorescein-guided surgery on both progression-free survival and overall survival.

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Authors and Affiliations

  1. Neurosurgical Department, Foundation IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, 20133, Milan, Italy

    Francesco Acerbi, Claudio Cavallo, Morgan Broggi, Roberto Cordella, Marco Schiariti, Giovanni Broggi & Paolo Ferroli

  2. Molecular Neuro-oncology, Foundation IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

    Elena Anghileri & Marica Eoli

Authors
  1. Francesco Acerbi
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  2. Claudio Cavallo
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  3. Morgan Broggi
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  4. Roberto Cordella
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  5. Elena Anghileri
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  6. Marica Eoli
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  7. Marco Schiariti
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  8. Giovanni Broggi
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Correspondence to Francesco Acerbi.

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Comments

Peter Nakaji, Phoenix, USA

In this review, Acerbi et al. from Paolo Ferroli’s group at the Besta in Milan describe the literature and their personal experience using fluorescein as a fluorophore to guide the resection of malignant gliomas. This technique involves the preoperative injection of intravenous fluorescein and subsequent visualization under a microscope designed to detect fluorescence in the 560 nm range. The brain lights up in yellow under white-light visualization and, generally, the tumor lights up even more, although it varies. This is where things get interesting. Fluorescein is a non-specific fluorophore whose concentration in the tumor relies upon the increased vascular permeability of the tumor compared to normal brain. The advantage of fluorescein compared to metabolized fluorophores such as 5-ALA is that it can be seen while still in the unaugmented visual range, allowing the surgeon to operate and still see the whole surgical field. The tumor generally does appear even brighter yellow. The hope of all of us who are working with fluorescein is that it can be used to guide resection. The underlying premise of cytoreductive surgery is that a lower volume of tumor correlates with better control of the tumor. While there is evidence for this, there is both nuanced debate on this subject and the concern that increased resection in some locations will entail greater risk of deficit, with attendant impact on both survival and functional outcome. These challenges face not only fluorescein-guided resection of malignant gliomas but also all resection guided by intraoperative adjuncts, whether they be visual indicators such as 5-ALA, image guidance, ultrasound, asleep mapping, awake surgery, or endomicroscopes. The principal advantage gained in the use of these agents is if they improve our resection of the marginal tissue whose appearance blends with normal brain. Fluorescein is fairly non-specific, but with experience, there is mounting reason to think that it can help us make this particular distinction. Consideration of the merits of fluorescein immediately invites a deeper comparison with 5-ALA. 5-ALA is a prodrug which is used in the heme synthesis pathway, and in most gliomas, undergoes conversion into protoporphyrin IX, which fluoresces in the 400-nm (ultraviolet) range. It is more specific in the sense that tumor cells preferentially metabolize it, and therefore, it is concentrated in the target tissue. In theory, high specificity of a dye for the tumor is advantageous, but as tumor cells are always found beyond the visible margin, macrofluorescence alone may drive under-resection. At the same time, careful removal of only macrofluorescent tumor also may not be enough to prevent deficits, if the normal tissue is so closely entwined with the tumor that its manipulation alone mandates tampering with eloquent structures. The debate continues on. Perhaps the best role for these agents is in limiting the unintentional leaving of small amounts of residual tumor in non-eloquent areas.

In practical terms, fluorescein has advantages that are considerable for intraoperative use. Fluorescein is a molecule with a long history of safe human administration and a low cost around the world. As the authors recognize, questions about fluorescein remain. The exact dose and timing that is optimal remain to be worked out. The normal brain does fluoresce somewhat; the threshold for distinguishing tumor from brain from necrosis has yet to be firmly established and to be rigorously confirmed through correlative histology.

In the future, surgery may benefit from fluorophores that are highly specific to high-grade glioma—and indeed to any other type of tumor—helping surgeons to identify more accurately what is tumor and what is not, while other technologies tell us whether that tissue can be removed safely. In the meantime, this kind of intermediate technology has advantages that bear continued exploration as the authors and others are doing.

ᅟ

Andreas Raabe, Bern, Switzerland

This interesting article reviews the use of sodium fluorescein as a dye to visualize tumor tissue during surgery of malignant gliomas. These invasive and often poorly delineated tumors may be “gross total resection (GTR)” eligible, or more precisely, “complete resection of enhancing tumor (CRET)” eligible in many cases, but GTR or CRET are achieved in a disappointingly low percentage of patients only. Depending on the selection of patients, this percentage ranges from 20 to 60 % even when neuronavigation or intraoperative ultrasound is used. The only “resection enhancing” technologies that are proven to detect concealed tumor tissue are intraoperative MRI and fluorescence imaging, both of which were shown to increase the CRET rate in eligible glioblastoma patients to 65 to 95 %.

Sodium fluorescein fluorescence is a promising technology for glioblastoma surgery. The integration of a specific yellow light filter into the surgical microscope makes it a straightforward intraoperative technique. The experience and images suggest that this method adds to the surgical artillery that improves the extent of resection. However, as the authors emphasize, hard data are still missing, and a randomized controlled trial comparing white-light and sodium fluorescein is needed to quantify the effect on glioblastoma surgery.

In my view, different methods have different advantages, and the surgeon should have all of them in his or her toolbox to decide what is best for any given situation and patient. When 5-ALA and sodium fluorescein are compared in this review, we should keep in mind that most data about the latter technique are from single-center retrospective studies. Although I agree with the authors that this technology has the potential to increase the extent of resection, the numbers in Table 3 are somewhat biased in favor of the authors’ method and remain to be proven.

How much tumor tissue is included in the sodium fluorescein fluorescence remains unclear. While 5-ALA is metabolized within the tumor cell, sodium fluorescein appearance in the glioma tissue depends on blood–brain-barrier (BBB) leakage. Taking contrast-enhanced MRI as a marker for BBB damage, we expect that this is the volume stained with extracellular sodium fluorescein. In contrast, intracellularly metabolized 5-ALA fluorescence is found beyond the BBB-damaged tumor volume, and the tissue volume resected with 5-ALA is indeed larger than the T1-gadolinium-enhancing tumor [1]. A methodological advantage of sodium fluorescein over 5-ALA is unlikely; however, the low price for this drug may be a deciding factor in many countries.

References

1. Schucht P, Knittel S, Slotboom J, Seidel K, Murek M, Jilch A, Raabe A, Beck J (2014) 5-ALA complete resections go beyond MR contrast enhancement: shift corrected volumetric analysis of the extent of resection in surgery for glioblastoma. Acta Neurochir (Wien) 156(2):305–12

ᅟ

Walter Stummer, Münster, Germany

I gladly grasp the opportunity to write a comment to the review of Dr. Acerbi and co-workers which is being published in Neurosurgical Review on the use of fluorescein sodium for enhancing surgery of malignant gliomas.

Fluorescein sodium has been around a while and was first used by Moore et al. 1948 [1] for finding gliomas when CT and MRI was still science fiction at best. Even in those early reports, the authors were aware of the lack of selectivity of fluorescein for these malignant tumors, noting that a “brilliant yellow-green fluorescence characterizes tumor tissue whereas the normal brain, which retains appreciably less dye, appears white. Edematous tissue surrounding the tumor does fluoresce, but to a lesser degree so that it can be readily separated both from normal brain and the tumor itself.” The senior neurosurgeons reading this comment will remember that after the reports by Moore and his colleagues, fluorescein has not found its way into neurosurgery, but was initially abandoned.

A second round with fluorescein occurred in the late 1990s by Kuoriwa and co-workers from Japan, and three publications can be found by this group, the last in 1999 [2, 3, 4]. This group has also stopped using fluorescein sodium, switching to ALA. To date, they have published a considerable number of articles on malignant gliomas and ALA, the last in 2013 [5, 6, 7, 8, 9, 10, 11, 12].

So why did surgeons not continue using fluorescein sodium for brain tumor surgery? The answer is simple. Fluorescein sodium is hardly specific for tumor because it is a blood-borne dye. Wherever there is blood, there will be fluorescein. Is this a good basis for the surgeon to rely upon for intraoperative tumor identification?

So today, we are seeing a second renaissance of fluorescein sodium, as reflected by the present review. But what is new? It is certainly not the biology of the dye. Fluorescein sodium is still located in the blood and leaks into the tumor through the broken down blood–brain barrier.

What is new is that a novel filter system is available, the Yellow 560 filter, which is now being provided to the community by a microscope company. In contrast to older systems, which visualized yellow fluorescein fluorescence on a black background, this filter system retains background tissue information. What the surgeon sees is (almost) the normal brain and the superimposed fluorescein signal. Please note that this system is superb for vascular surgery, and in this particular context, a real advance. With the new system, the surgeon does not have to rely on the playback on an external video screen with the established indocyanine green (ICG), because ICG fluorescence is invisible to the human eye. As opposed to ICG, fluorescein fluorescence in vessels is clearly visible to the human eye. Thus, the surgeon can directly inspect and manipulate the vessels, which is a real advantage, and extravasated fluorescein is not of importance.

But is fluorescein sodium with this filter also reliable for tumor surgery? As a matter of fact, the image initially appears nice, with the brain being beautifully visible in the background, and the fluorescein fluorescence appearing somewhat selective in the foreground. But be careful; this image is deceptive, since much of the weaker and aberrant fluorescein signal in vessels, edema, and blood in the cavity is now obscured by the additional, bright tissue background information, particularly in the late stages of surgery where discrimination becomes especially important. Normally, with fluorescence, the background is maintained dark to not lose the information that fluorescence conveys. In the context of the YELLOW 560 filter, the surgeon believes he is receiving selective information, where in fact, he is only seeing peak fluorescence. The filter system simply does not change the biology of the dye in the blood. The reader may wish to see an example of the use of fluorescein for glioma surgery in a video posted on abcNEWS and freely available (http://abcnews.go.com/Health/making-brain-tumors-glow-saves-lives/story?id=17076243). Please note the fluorescein, which is in all vessels, is distributed weakly throughout the normal brain and is visible in the dura, the CSF, especially at the resection edge due to tissue injury, and even in the remote brain locations obviously injured during the course of resection.

The reader of the review by Dr. Acerbi and co-workers should give this aspect some thought, as he should critically give thought to the authors’ assertion that fluorescein is so much cheaper than ALA, which is true. However, fluorescein has not been tested in expensive randomized GCP conform clinical studies for safety and efficacy in many hundreds of patients, as was ALA, nor has it been approved for brain tumor surgery, as is ALA. In all studies, so far fluorescein has been used off-label. This in itself bears a number of implications. The authors do not mention this important aspect, and the uncritical user should be well aware of this, especially if his patients experience ill side effects of fluorescein, which have been reported [13].

In the end, the authors themselves acknowledge the necessity of controlled clinical studies to elucidate safety and value of fluorescein in conjunction with novel technology. The community is certainly looking forward to those studies in the ongoing effort to increase the quality of our surgical care while keeping economical restraints in mind.

References

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2. Kuroiwa T, Kajimoto Y, Ohta T. Surgical management for supratentorial astrocytic tumors. Minim Invasive Neurosurg. 1999 Dec;42(4):182–6. PubMed PMID: 10667822.

3. Kuroiwa T, Kajimoto Y, Ohta T. Comparison between operative findings on malignant glioma by a fluorescein surgical microscopy and histological findings. Neurol Res. 1999 Jan;21(1):130–4. PubMed PMID: 10048072.

4. Kuroiwa T, Kajimoto Y, Ohta T. Development of a fluorescein operative microscope for use during malignant glioma surgery: a technical note and preliminary report. Surg Neurol. 1998 Jul;50(1):41–8; discussion 48–9. PubMed PMID: 9657492.

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Acerbi, F., Cavallo, C., Broggi, M. et al. Fluorescein-guided surgery for malignant gliomas: a review. Neurosurg Rev 37, 547–557 (2014). https://doi.org/10.1007/s10143-014-0546-6

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