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Table of Contents
Year : 2018  |  Volume : 1  |  Issue : 6  |  Page : 189-195

Intraoperative fluorescence-guided resection of high-grade glioma: A systematic review

1 Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China
2 Department of Preventive Medicine, West-China School of Public Health, Sichuan University, Chengdu, Sichuan, China
3 Department of Neurosurgery, Bishan Hospital, Chongqing Medical University, Chongqing, China

Date of Web Publication27-Dec-2018

Correspondence Address:
Dr. Sheng-Qing Lv
Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing 400037
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/glioma.glioma_41_18

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High-grade glioma (HGG) is a devastating disease with very poor prognosis. Maximal resection of HGG improves survival and maximal visualization of the tumor, if reliable, improves the resection. Fluorescence is widely used as guidance mechanism and has demonstrated potential in maximizing the extent of HGG resection. Our goal is to summarize the current techniques using fluorescence during the resection of HGG and demonstrate how its use increases gross total resection rates, overall survival (OS), and progression-free survival (PFS). However, further prospective, multicenter, randomized controlled trials are still in need to prove the advantage of fluorescence-guided surgery on patients' OS/PFS.

Keywords: Fluorescence-guided resection, malignant glioma, total removal

How to cite this article:
Yang L, Xiang Y, Huang GH, Lyu HY, Mou KJ, Lv SQ. Intraoperative fluorescence-guided resection of high-grade glioma: A systematic review. Glioma 2018;1:189-95

How to cite this URL:
Yang L, Xiang Y, Huang GH, Lyu HY, Mou KJ, Lv SQ. Intraoperative fluorescence-guided resection of high-grade glioma: A systematic review. Glioma [serial online] 2018 [cited 2023 Oct 2];1:189-95. Available from: http://www.jglioma.com/text.asp?2018/1/6/189/248708

  Introduction Top

Brain tumors are a major cause of central nervous system (CNS) morbidity and mortality,[1] contributing to approximately 23,130 new cases and 14,080 deaths annually in the United States.[1] Glioma accounts for about 80% of brain tumors,[1] which includes both low-grade gliomas (LGGs) and high-grade glioma (HGG), and is the most common primary malignancy of the CNS. This catastrophic disease causes more loss of life than any other type of tumor.[1] Although the median survival for glioblastomas increased from 12.1 to 14.6 months after adoption of maximal surgical resection followed by radiotherapy with concomitant and adjuvant temozolomide chemotherapy, the overall outcome of patients remains extremely unsatisfactory.[2] The major challenge to cure these devastating diseases is their potential for migration and invasion. Most relapses occur within 2 cm of the primary resection cavity, but even radical hemicerebral resection performed in the past failed to eradicate tumor growth.[3] However, a retrospective analysis of 416 glioblastoma multiforme (GBM) patients conducted by Lacroix et al.[4] indicated that a resection of 98% or greater was related to a survival advantage (median survival 13 vs. 8.8 months, P < 0.0001). Sanai et al.[5] also retrospectively analyzed a database of 500 patients with GBM and found that there was a stepwise correlation between the extent of resection (EOR) and overall survival (OS) starting at an EOR of 78%. Particularly, 95% and greater EOR was the strongest predictor of OS. In practice, the surgical dilemma is how to balance maximum resection against minimizing postoperative complications. In general, the degree of surgical resection is most directly dependent on surgical technique and the surgeon's ability to identify the tumor–brain interface intraoperatively.[5] The desire to have a safe, but maximal resection has accelerated the advancement of intraoperative assistive technologies. New advances now include computer-assisted technology (stereotaxis[6] and neuronavigation[7]), traditional radiologic imaging (intraoperative magnetic resonance imaging [iMRI],[8],[9] mobile computerized tomography system, and intraoperative ultrasonography[10],[11]), and optical imaging (5-aminolevulinic acid [5-ALA],[12],[13] hypericin,[14],[15] indocyanine green,[14],[16],[17] and fluorescein sodium [NaFL]).[14],[18] Each tool has advantages and disadvantages, and they are often combined during surgery. For example, due to intraoperative brain shift, there was an increasing need for tumor topographic localization beyond the ability of neuronavigation and iMRI, and they lead to the development of operative adjuncts with real-time recognition and continuous update. Another innovation is fluorescence-based labeling, which is used to better identify the tumor–brain interface and recognize residual tumor intraoperatively. The purpose of this study is to review and analyze the advantages and limitations of intraoperative fluorescence-guided resection of HGG and provide insights on the future novel techniques.

  Basic Mechanisms of Fluorescence Top

When light hits certain atoms or molecules, the energy from light excites some electrons around the nucleus to jump from their original orbital (S0) to a higher energy orbital (S1), that is, from ground state to the first excited monolayer (singlet) state or the second excited monolayer state.[19],[20] The first excited singlet or second excited singlet states are unstable, so the ground state will be restored. When the electron moves from the excited singlet state to the ground state, energy is released in the form of light and fluorescence occurs. In general, excitation energy of aromatic molecules is between 1.5 and 3.5 EV; this corresponds to a wavelength of 800–300 nm. In general, the fluorescent radiation is of longer wavelength and lower energy than the corresponding excitation light. This energy transfer typically happens in the time frame of picoseconds to nanoseconds.[21]

  5-Aminolevulinic Acid Top

5-ALA is widely found in animals, plants, and microbial cells and is a precursor of tetrapyrrole compounds such as chlorophyll, hemoglobin, porphyrin, and Vitamin B12.[22],[23] Exogenous 5-ALA orally administered has unprecedented penetration of the blood–brain barrier (BBB) and tumor–brain interface.[24],[25],[26] In glioma cells, 5-ALA is a natural precursor of hemoglobin that promotes the metabolic synthesis of fluorescent protoporphyrin IX (PpIX).[27] PpIX, stimulated by blue light at 405 nm, fluoresces red in brain tumor tissue. Currently, 5-ALA is the only known oral agent that accumulates in malignant brain tumors and can be used in fluorescence-guided surgery. The preferential accumulation of 5-ALA in malignant glioma cells is thought to be due to its ability to cross a disrupted BBB, but several studies have demonstrated that this ability is not sufficient and hint that it may have specificity for glioma cells.[28],[29]

Factors that are associated with greater fluorescence by 5-ALA in tumor cells include cellular density, proliferation activity, neovascularization, and permeability to the BBB.[13],[25],[28],[30],[31] Stummer et al.[28] studied PpIX fluorescence in 144 biopsies from 66 patients. The intensity of PpIX fluorescence was assessed using spectral methods. CD-31 staining was measured to determine the density of new blood vessels within selected biopsies. Multivariate regression models showed that CD-31 staining was not significant, suggesting that new vascularity and BBB abnormalities were not the only factors associated with fluorescence accumulation. In another report, excess PpIX production in neoplastic cells was found to be associated with low expression of ferrochelatase (a heme production enzyme that produces heme with the addition of iron [Fe]) and decreased selective uptake capacity of an ATP-binding cassette transporter (ABCB6).[29]

The selective accumulation of PpIX within tumor cells makes it easier for a surgeon to identify the tumor–brain interface intraoperatively. There is also evidence that PpIX accumulates more in HGGs than LGGs.[32],[33] Thus, intraoperative imaging with PpIX fluorescence allows neurosurgeons to visualize HGGs, thereby increasing the likelihood of maximum resection without further neurological deficits.

To be used effectively in HGG resection, the fluorescence molecule must label tumor cells with high accuracy. Toward this end, many studies have demonstrated that during intraoperative HGG resection, 5-ALA has a very high sensitivity and specificity for tumor [Table 1].
Table 1: Sensitivity, specificity, positive predictive value, and negative predictive value for 5-aminolevulinic acid-induced fluorescence and malignant glioma tissue

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In a randomized controlled multicenter phase III trial conducted by Stummer et al.,[13] 322 patients with HGGs were randomized between a conventional white-light microsurgery group (n = 161) and a 5-ALA fluorescence-guided resection group (n = 161). The patients enrolled in the 5-ALA fluorescence-guided resection group were administered 5-ALA orally at a dosage of 20 mg/kg, 3 h before the intubation. The extent of surgical resection was performed as widely as it was thought safe and accessible on the basis of preoperative imaging and the experience of surgeons. The rates of gross total resection (GTR) were judged by postoperative MRI and the radiologists were blinded. All patients underwent a standard postoperative protocol including radiotherapy and chemotherapy. After a mean follow-up of 35.4 months, full analysis including progression-free survival (PFS), residual tumor, OS, neurologic deficits, and side effects was conducted on 270 patients. This study found that compared with the group given standard surgery under white light, the proportion of patients with residual tumors in the 5-ALA group decreased by 29% on the postoperative MRI (36% vs. 65%, P < 0.0001). Importantly, no significant differences in neurological functions were noted between the two groups. The PFS at 6 months of the 5-ALA group was higher than that of the white-light group (41.0% vs. 21.1%, P < 0.0001). OS did not significantly differ between groups. However, a follow-up study on the trial by Stummer et al.[43] found that patients without residual tumor survived longer (16.7 months vs. 11.8 months, P < 0.0001). This study provided Level 2B evidence that complete resection was associated with OS.

Sadly, in LGGs, tumor fluorescence is usually not visible using the current surgical microscope. However, using a new method, “quantitative fluorescence,” improved detection capability of PpIX in LGGs can approach that of HGGs using surgical microscopy.[13],[24],[28],[34],[44] Such a method could extend the resection range of tumors (not just for HGGs) for 5-ALA-guided surgery.

Despite the benefits mentioned above using 5-ALA in resection, the technique still has limitations, mostly based on subjective fluorescence interpretation, especially at the tumor–brain interface (the most likely site for glioma recurrence). In some rare cases, 5-ALA-guided fluorescence was found independent of malignant tumor tissue, such as abnormal accumulation of PpIX in abscesses, metastasis, lymphoma, and necrotic tissue.[44] In addition, some studies found that no visible 5-ALA-induced fluorescence was found in tumor tissue, which can be attributed to the following specific conditions:[36] (1) a tight BBB limiting 5-ALA from reaching tumor cells, preventing consistently successful fluorescence;[45],[46] (2) the deep fluorescent tissue covered by normal brain or other nonfluorescent tissue may be overlooked in tumor resection because of the blue-violet light's penetrating power of only 0.5 mm from the tissue surface;[36],[44] and (3) prolonged exposure to light (>25 min of blue light or 87 min of standard white light) can lead to so-called fluorescent bleaching, the chemical degradation of a fluorophore, which can lead to a decrease in fluorescence intensity.[20] The timing of oral 5-ALA is an important application defect: 5-ALA is most suitable to be taken orally 3–6 h before tumor resection. The intensity of fluorescence induced by 5-ALA was decreased by oral 5-ALA for too long or too short time before endotracheal intubation, which can lead to a lack of fluorescence in some cases,[36] and limit the use of 5-ALA in emergency situations. Moreover, the need to avoid direct exposure of patients to sunlight or strong room light for 24–48 h after using 5-ALA because of the risk of skin sensitization,[44] and high costs of 5-ALA (around €900 for each vial) are also factors that limit the widespread use of 5-ALA fluorescence as a guide for the resection of HGGs.

  Hypericin Top

Hypericin, a component of St. John's Wort, is a photosensitizer and fluorescent dye (excitation 415–495 nm; emission 590–650 nm) that has been demonstrated to preferentially accumulate in malignant tissue.[47],[48],[49] In 2012, Ritz et al.[15] used a water-soluble formulation of hypericin (0.1 mg/kg body weight) 6 h before surgery for fluorescence-guided tumor resection in five patients with recurrent glioblastoma. Resections were performed under conventional white light, whenever the surgeons needed to distinguish tumor tissue from normal brain parenchymal, they would switch the filter designed for visualization of the red fluorescence induced by hypericin. All surgeries were performed under intraoperative monitoring including tracking of motor evoked potentials and somatosensory evoked potentials. Tumor tissue was clearly distinguishable by red fluorescence from the normal brain tissue. All fluorescence presented tumor tissue was removed completely without inducing new neurological deficits. After surgery, all patients were treated with standardized postoperative treatment. Histopathological review of 110 tissue specimens demonstrated a specificity of 90%–100% and sensitivity of 91%–94%. No side effects with administration of intravenous hypericin, including hematotoxicity, brain swelling, phototoxic reactions, and allergic reactions, were evident.

In addition to advantages of hypericin and 5-ALA in visualizing tumor tissue from normal brain, hypericin and 5-ALA can also be used simultaneously in photodynamic therapy (PDT). 5-ALA administered at the same dose as used in fluorescence intraoperative guidance studies has also been used as a photosensitizer for laser-induced PDT in a case report of glioblastoma.[50] In this report, a single patient was described, and after PDT, the patient remained recurrence-free for 56 months, suggesting other potential applications for these molecules.

PDT is an interesting modality of cancer treatment and is based on the administration of a photosensitizer such as hypericin, which selectively accumulates in malignant tissue.[51] When light of the appropriate wavelength strikes the photosensitizer molecule, it produces reactive oxygen species (ROS).[47] ROS react with various biological molecules (such as proteins) to kill tumor cells through necrosis or apoptosis.[52],[53] Although the diagnostic benefit of the fluorescence marker 5-ALA-induced PpIX is well known, 5-ALA-induced PpIX seems less suitable for PDT due to its relatively low phototoxicity, because the depth of penetration is only about 2–3 mm.[34],[44] Hypericin is one of the most powerful photosensitizers in nature compared to PpIX induced by 5-ALA.[51],[54] Moreover, the fluorescence marker hypericin has additional properties, for example, it has antiviral, antitumoral, and antiangiogenic activities during PDT. Thus, hypericin can be used as both a fluorescence marker during resection and in pre/postoperative PDT in gliomas. Limitations of PDT include the fact that photosensitizers such as PpIX and hypericin can accumulate in the skin, leading to phototoxic reactions; in addition, the penetration of stimulated light in PDT may be too weak for deep tumors. Future studies will need to find ways to produce more penetrating excitation light while reducing the accumulation of hypericin in the skin. Finally, larger cohort studies will be needed to evaluate the utility of hypericin during fluorescence-guided surgery and whether PDT improves clinical outcomes.

  Indocyanin Green Top

Indocyanin green (ICG) is a cyanine dye that has an excitation peak around 800 nm and a major emission peak of 830 nm in tissues.[55],[56] In a rat glioma models, intravenously injected ICG had the ability to stain and demarcate brain tumor margins from normal adjacent brain parenchyma. The area of tissue staining was contained within 1 mm of the peritumor region.[55] This preclinical study showed that ICG can be used as a potential adjunct for demarcating the edge of brain tumors.[17] Haglund et al.[55] reported that after intravenous administration of a maximum dose of 2 mg/kg of ICG, malignant tumors showed faster ICG ingestion and slower clearance compared with normal brain, and this phenomenon was more pronounced in higher grade tumors. The sites of delayed clearance were used for biopsy, which showed that these samples were positive for tumors.

During tumor resection, surgeons also need to assess the blood supply around the tumor to prevent postoperative complications due to the vascular injury which can impact cerebral perfusion and drainage.[16],[57],[58],[59],[60] Acerbi et al.[61] showed the feasibility of intravenous NaFL injection and ICG videoangiography during a surgical procedure. In this study, ICG videoangiography helped to assess the flow dynamics and patency of cortical drainage veins and to assess the impact of venous sacrifice. Although the co-occurrences of intracranial aneurysms and tumors are uncommon (the frequency is reported to range between 0.3% and 4%), they can sometimes coexist and this study indicated that they can be comanged with ICG videoangiography.[61],[62],[63],[64],[65]

Despite these promising findings, there are limitations of ICG usage. ICG is metabolized by the liver and excreted through the hepatobiliary system with a half-life of about 3–4 min.[56] Despite its low toxicity, intravenous injection of ICG can cause side effects, including sore throat, hot flashes, and occasional allergic reactions.[14] Since the fluorescence (830 nm) induced by ICG does not exist within the visible range, the detection of ICG fluorescence requires special near-infrared cameras and software for image display.

  Fluorescein Sodium Top

Fluorescein isothiocyanate is a green fluorescent synthetic organic compound widely used in a myriad of medical applications and commonly named fluorescein (FL). One particular fluorescein, NaFL (NaC20H10 Na2O5), has a major blue excitation peak in the region of 465–490 nm and a major green emission peak in the region of 510–530 nm.[66],[67],[68] The green fluorescence induced by NaFL occurs naturally and may be observed by the human eye (at high dose) directly or through a dedicated filters of modified surgery microscope.[66],[68],[69] As early as 1948, fluorescein was used as an adjunct for intracranial tumors navigation and resection; however, due to imaging requirements, it is mainly used in ophthalmology.[66],[67],[68],[70],[71] The recent application of dedicated filters for operating microscopes has peaked interest again in fluorescein. Intraoperative optical changes in tissues after fluorescein administration are recognized both macroscopically and microscopically. The causes of fluorescein accumulation include malignancy, vascular leaking defects, pooling defects, and abnormal vasculature or neovascularization.[14] The causes of low fluorescein accumulation include blocking defects, filling defects, and a normal BBB.[14] As fluorescein does not pass the normal BBB, in most cases, it is a marker of BBB damage.[17],[72] Any disturbance to the BBB's integrity or increase in the vascular permeability will allow fluorescein to accumulate in the tumor tissue. Using a dedicated filter on a modified surgical microscope, tumor cells become visible after 30–40 min at a fluorescein dose of 5 mg/kg. If intravenous injection of fluorescein occurs after the dura has been opened, the fluorescence of tumors can commonly last until the end of the procedure (mean duration time about 150 min).[18]

Murray[73] reported a study that enrolled 23 patients who underwent intraoperative fluorescence resection for malignant brain tumor. In this study, 111 fluorescein and 75 without fluorescein-stained tissue biopsies were reviewed for histopathological examination. Of the 75 unstained specimens, 71 (94.7%) were negative for tumors and 4 were positive. Of the 111 stained specimens, 94 samples (84.7%) showed tumors, while the other 17 showed consistent features with necrotic debris (false positives). Their findings highlight the value of the fluorescence technique, especially at the periphery of the tumor.

Subsequently, Koc et al.[67] reported a prospective, nonrandomized study to evaluate the effects of intraoperative fluorescence-guided glioma resection on the rates of GTR, overall prognosis, and side effects. Of the 80 patients, 47 received high doses of intravenous NaFL (20 mg/kg body weight) after the craniectomy was started but before the dural opening. Standard resection was performed in the second group (n = 33). Using high-dose fluorescein, the authors used either standard operating room microscopes without filters or special cameras to observe the fluorescence signals. All patients received the same dose of radiation within 20 days after surgery. Results showed a significant increase in the rates of GTR (83% vs. 55%) in patients receiving an administration of fluorescein. However, there was no statistically significant difference in OS rates between the two groups.

Similarly, Shinoda et al.[71] reported that the rate of GTR was 84.4% in patients that received NaFL, compared to 30.1% with conventional white-light imaging. In patients with resectable lesions which were not in eloquent, periventricular, or dominant hemisphere locations, GTR was up to 100% in patients pretreated with fluorescein, compared with 44.8% without pretreatment. Despite these encouraging results, no differences were observed in the overall prognosis. However, no significant side effects were found in these studies.[67],[71],[73]

In both the studies by Koc et al.[67] and Shinoda et al.,[71] when used in high dose (20 mg/kg), NaFL does not require any special imaging equipment and has been shown to be clinically safe,[74] but it can still have side effects, especially in the case of rapid injection or at high dosage.[75] As a result, any intraoperative technique that minimizes the required dose of fluorescein and maximizes the signal intensity and tumor contrast could be a key step toward promoting the widespread use of the technique.

In 2012, the Carl Zeiss Company specifically designed a fluorescein filter (YELLOW 560) for guided resection of glioma. The YELLOW 560 filter has an excitation wavelength range from 460 to 500 nm and an observation wavelength range from 540 to 690 nm, which is designed to improve visualization of both pathology and normal anatomy. Furthermore, due to this filter's high specificity for fluorescein, the dose of fluorescein can be further reduced during clinical applications.

Catapano et al.[18] evaluated the resection of HGGs using newer imaging equipment. This retrospective study analyzed the use of NaFL in newly diagnosed HGGS after NaFL was intravenously injected after bone flap removal but before dural opening in a low dose (5 mg/kg). All surgeries were performed under the YELLOW 560 filter integrated into an OPMI Pentero 900 (Carl Zeiss). The control group included cases operated by the same neurosurgeon but without the use of NaFL. No side effects or anaphylactic reactions related to NaFL occurred. Examination of the peritumoral area of the biopsy showed fluorescein had 84.61% sensitivity and 95% specificity. GTR rate was significantly increased (83% vs. 55%) in patients receiving fluorescein. Karnofsky performance status did not significantly differ between preoperatively and postoperatively patients in either group.

Due to its simplicity and potential use during intraoperative resection of HGGs [Table 2], many studies have evaluated that the use of NaFL in the resection of other lesions where the BBB's integrity is compromised. Xiang et al.[76] studied the relationship between the accumulation of fluorescein and the integrity of BBB. In this study, anti-claudin-5 staining was measured by immunohistochemical (IHC) analysis to determine the integrity of BBB. The results showed that fluorescein-guided resection is an effective and convenient technique for HGGs surgery but not for LGGs' surgery. Claudin-5 expression is closely correlated with the presence of fluorescence during fluorescein-guided procedures.
Table 2: Comparison between 5-aminolevulinic acid, hypericin, indocyanin green, and fluorescein sodium for surgery of high-grade gliomas

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Although the destruction of BBB's integrity is the basis for NaFL to accumulate in tumor tissue and leads to the intraoperative fluorescence-guided resection, other studies[18],[76] have found that tumor resection, in and of itself, can damage the BBB. Whether this can lead to false-positive fluorescence has to be considered to avoid removing nontumor tissue. Thus, technical innovations that allow for the interpretation and removal of areas where the BBB's integrity was naturally broken by tumor will be needed. Other future technologies may need to be combined to solve such issues. For instance, using nanoparticles such as quantum dots or iron oxide-based nanoparticles with unique properties that promote coupling with fluorescent markers may improve the identification of tumor tissues.[24],[77]

  Conclusion and Perspective Top

The extent of HGGs resection has been shown to have a positive effect on patient outcome. Intraoperative fluorescence-guided resection is a safe, effective, and convenient technique, which has shown considerable promise in improving GTR rate (using both 5-ALA and NaFL) and PFS (5-ALA). In addition to inducing fluorescence to guide tumor resection, 5-ALA and hypericin can also be used as photosensitizers during PDT, which may prove beneficial when combined with other treatments for glioma. In addition to HGGs, NaFL can be used to guide the resection of other intracranial lesions that destroy the integrity of BBB. Finally, other techniques such as nanoparticles paired with fluorescein markers that specifically bind to tumor cells remain to be validated but could be future tools for the treatment of HGG.

Financial support and sponsorship

This study was partly supported by the Joint Research Foundation from Chongqing Science and Technology Bureau and Chongqing Municipal Health Commission (2018ZDXM011).

Conflicts of interest

There are no conflicts of interest.

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  [Table 1], [Table 2]

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