|Year : 2021 | Volume
| Issue : 3 | Page : 132-144
Intraoperative imaging in the management of brain tumors: A review of contemporary adjuncts used in routine practice
Aliasgar V Moiyadi1, Salman T Shaikh2
1 Department of Surgical Oncology, Neurosurgical Oncology Services, Tata Memorial Centre; Homi Bhabha National Institute, Health Sciences Section, Mumbai, Maharashtra, India
2 Department of Neurosurgery, University Hospital of Coventry and Warwickshire, Coventry, United Kingdom
|Date of Web Publication||02-Nov-2021|
Dr. Aliasgar V Moiyadi
Tata Memorial Centre, Mumbai - 400 012, Maharashtra
Source of Support: None, Conflict of Interest: None
Optimizing the extent of resection remains a primary goal of surgery for diffuse gliomas and most brain tumors. Limitations of capabilities of human visualization necessitate the use of adjuncts to augment and improve outcomes. This review serves to encapsulate the commonly used adjuncts in neurosurgical oncology. There exists a plethora of such techniques which can broadly be divided into image-guided techniques (including navigation and real-time intraoperative imaging modalities such as ultrasound, computed tomography, and magnetic resonance imaging) as well as optical imaging techniques (of which fluorescence is the most widely used one). This review describes these techniques briefly and reviews pertinent literature focusing on the utility and benefits of these modalities. Both diagnostic accuracy and the therapeutic outcomes are discussed. Although each modality is supported by published literature, the quality of the evidence is variable. It is difficult to make comparisons across studies due to variability in study design, populations included, and the techniques used for the assessment of outcomes. It is likely that a combination of modalities will be synergistic and judicious use of the range of adjuncts is advisable.
Keywords: Fluorescence, intraoperative, magnetic resonance imaging, review, ultrasound
|How to cite this article:|
Moiyadi AV, Shaikh ST. Intraoperative imaging in the management of brain tumors: A review of contemporary adjuncts used in routine practice. Int J Neurooncol 2021;4, Suppl S1:132-44
| Introduction|| |
It is now unanimously agreed and well documented in literature that the extent of resection for gliomas (both high-grade gliomas [HGG]; as well as low-grade gliomas [LGG]), which constitute the most common type of brain tumors, is a key prognostic marker in terms of outcome. Due to their infiltrative growth pattern, with tumors merging imperceptibly into native brain parenchyma, gross total resection (GTR) is difficult, a challenge compounded manifold by close proximity to eloquent substrates. The complex three-dimensional (3D) structure and intraoperative deformation of the brain further poses unique challenges during neurosurgical procedures, very often leading to significant discordance between the subjectively estimated extent of resection and the true objectively assessed extent. Most of these “misses” are due to inadequate intraoperative visualization of tumor residue. Therefore, augmentation of this visualization is invaluable when dealing with such tumors. Moreover, unintended damage to eloquent substrates can be minimized or completely avoided. Intraoperative image guidance modalities assist in planning the surgical approach, localization of the disease in relation to adjacent eloquent regions and offer accurate resection control in brain tumors.
The well-established adjuncts can be broadly categorized into image-guided surgery (IGS) techniques, enhanced optical imaging (OI), and visualization techniques and intraoperative neuromonitoring adjuncts. Whereas the first two comprise techniques that facilitate extended resections by the demonstration of the tumor extent, neuromonitoring (awake as well as under anesthesia) is indispensable for ensuring function preservation.
This review will focus on the former category (IGS and OI tools) as applied to neuro-oncological surgeries. IGS includes neuronavigation (NN) (static, preoperative imaging-based) as well as real-time intraoperative imaging tools such as intraoperative ultrasound (IUS), intraoperative magnetic resonance imaging (IMRI), and intraoperative computed tomography (ICT). Fluorescence-guided surgery (FGS) will encompass the use of either 5-aminolevulinic acid (5-ALA) or sodium fluorescein (SF). The scope of this review article includes a broad description of the various established intraoperative adjuncts outlining their mechanism of action and application in neuro-oncological surgeries, advantages and disadvantages, as well as a review of available literature as regard to their role. We will restrict our review to established techniques touching upon newer developments as related to these techniques.
| Methodology|| |
A PubMed search was performed by adjusting filters for articles in the English language from 2001 onward. We chose to selectively include studies which were either meta-analysis and/or systematic reviews or large clinical studies with/without reviews. MESH terms searched for were neurosurgery, brain tumor, glioma, intraoperative, resection, ultrasound, navigation, fluorescence, magnetic resonance imaging (MRI), computed tomography, and imaging. Boolean operators used were AND and OR variably. Studies of spinal tumors/pathologies and articles focusing on neuromonitoring were excluded from the results. The authors reviewed the studies and identified significant meta-analysis and systematic reviews for each modality and the results were tabulated [Table 1].,,,,,,,,,,,,,,,,, Further, for each of the individual modalities, major studies published during this time period were screened and identified. Cross references were checked to identify key studies. They were categorized into studies evaluating the role of these adjuncts as diagnostic agents (diagnostic accuracy with histopathology [and IMRI in some series] as gold standard variably) [Table 2],,,,,,,,,,,,,, as well as studies assessing therapeutic outcomes (in terms of extent of resection with postoperative MRI as gold standard and survival) [Table 3].,,,,,,,,,,,,,,,,, Being imaging tools, the diagnostic accuracy is a key outcome parameter, and yet, by virtue of the effect of the imaging tool on the resection outcomes, survival may be potentially influenced. Hence, a dual assessment was thought to be important. To assess the level of evidence, the AANS guidelines for studies of diagnostic accuracy and therapeutic efficacy were followed., As this was not a systematic review, the authors selected the studies on a thorough review and assessment of key studies based on their personal experience.
|Table 1: Summary of important systematic reviews and meta-analyses published|
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|Table 2: Summary of major studies of diagnostic accuracy (histopathology or intraoperative magnetic resonance as gold standard)|
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|Table 3: Summary of major studies assessing the therapeutic efficacy of various modalities (using postoperative magnetic resonance as gold standard for resection control estimation)|
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Image guided surgery
IGS is omnipresent in neurosurgical operating theaters. IGS utilizes radiological images acquired either preoperatively (”static” NN) or in real-time intraoperatively.
This has been one of the most widely used adjuncts in neurosurgery. NN provides “static images” much like standard directional GPS/navigational aids. This helps in planning craniotomy, to identify location of known anatomical landmarks and tumors [Figure 1], and can be particularly useful for biopsies of deep seated/small lesions. However, due to the phenomenon of brain shift, leading to inaccuracies in image registration, its role in resection control for tumors is equivocal at best. Two retrospective studies showed a benefit of NN alone (31% vs. 19% GTR; 64% vs. 38% GTR) in gliomas,, whereas a single randomized controlled trial (RCT) showed no such benefit. Diffusion tensor imaging (DTI)-based navigation may be superior to routine NN as evidenced by the findings of a RCT of 238 patients by Wu et al. They found that, in HGG, GTR was much higher (74.4% vs. 33.3%), and postoperative motor deterioration was much lower in DTI navigation group (15.3% vs. 32.8%).
|Figure 1: Screenshots from the navigation screen showing a left frontal glioma operated under awake conditions. (a) The relation of the tumor with the various white matter tracts is clearly visible. This can be rotated “virtually” to provide a 360° view while planning the surgery. (b) The navigation helps delineate the tumor boundaries and eloquent substrates, thereby allowing appropriate placement of the craniotomy|
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Despite its widespread use, NN by itself is of limited value in the resection control of tumors, where updated (and often repeated) images are necessary. The most widely used forms of intraoperative imaging in neurological surgery are IMRI and IUS and will be reviewed further. ICT is less useful in the context of brain tumors. [Table 4] compares these various types of intraoperative imaging techniques.
|Table 4: Comparison of intra-operative radiological imaging techniques|
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Intraoperative magnetic resonance imaging
This was first described close to 30 years ago. The early systems were ultra-low field in strength (0.2 T) subsequently progressing to low field (0.5 T) and high field strengths (>1.5T). IMRI overcomes the fallacy of brain shift which can occur once resection is commenced. IMRI has shown to improve the extent of resection in HGG as well as LGG., Given its superior tissue resolution and image quality, IMRI remains the gold standard imaging modality for brain tumors. However, as interobserver variation exists in the interpretation of the residual tumor (though this is much less than for ultrasound), it has been difficult to establish a causal relationship between the use of IMRI and improvement in the extent of resection. So far, three RCTs have been conducted to study its role. A recent meta-analysis studied the RCTs and 12 observational studies and concluded that IMRI leads to a statistically significant improvement in extent of resection in LGG but not for HGG. In terms of therapeutic benefit, although a RCT performed in 2011 by Senft et al., found a longer progression-free survival (PFS) with IMRI (218 vs. 110 days without IMRI), the meta-analysis found that there was no significant improvement in the PFS or overall survival (OS). Considering the huge logistical challenges in setting up an IMRI and the complexities of acquiring repeated intraoperative magnetic resonance scans, it has not found widespread application, as would have been expected. Besides, cost-effectiveness issues need to be addressed. Multipurpose (two room) IMRI solutions would seem to be more cost effective and less resource draining than dedicated IMRI systems. Miniaturization and development of portable solutions are likely to increase the acceptability of IMRI.
B-mode gray scale ultrasound imaging is one of the oldest diagnostic imaging modalities used in medicine. It was also one of the earliest applications of an imaging adjunct intraoperatively to examine the brain (possible after the overlying bone was removed). Although older machines and probes were not very user friendly, and resultant images were of poor quality, this is no longer the case. With advances in technology, the modern generation of ultrasound machines and variable frequency tunable probes provide superior image resolution, resulting in a growing interest and application of IUS. Ultrasound is able to characterize lesions and even differentiate various types of tumors.,,,,, Relative cost-effectiveness, widespread availability, and ease of application combined with the advantage of providing repeated, convenient, on-demand, intraoperative scans in relatively little time, make it an extremely attractive tool. The ability of IUS to provide rapid image updates is a key element in its utility as a resection control tool. However, IUS remains highly operator dependent. The device image orientation and interpretation requires experience, and has a learning curve. Multimodal image fusion (combining preoperative MRI-based navigation with IUS) has shown to be overcoming some of these limitations, leading to improved outcomes.,,,,, Both two-dimensional (2D) and 3D ultrasound can be combined with navigation. With 3D US, navigating on multiplanar US slices (akin to MRI) is possible and serial resection control becomes easier [Figure 2]. Image artifacts can significantly affect image quality and thereby reduce its utility, especially as the resection proceeds. Ultrasound scans obtained toward the end of resection can have many more artifacts. Artifact minimization is an important skillset for a successful implementation of IUS. Acoustic coupling fluid under development can potentially minimize some of the enhancement artifacts. Regardless of whether one uses 2D or 3D IUS (with or without navigation), the key element remains the correct and optimal use of the basic B-mode gray scale ultrasound image (both its acquisition and image interpretation). Besides the anatomical images, IUS can also provide functional information in the form of color Doppler, power Doppler angiogram (flow independent evaluation of larger vessels), and contrast-enhanced angiosonography (providing accurate microvasculature imaging and perfusion). Elastosonography, which can differentiate tissues based on their stiffness, provides a complementary approach to tissue characterization (as opposed to conventional ultrasound which uses reflected echoes).,
|Figure 2: Left frontal glioblastoma resection using navigated three-dimensional ultrasound. (a) The operative setup with the navigation (Brainlab Kick®) and BK 5000 ultrasound system. (b) The navigated ultrasound probe with localizer (inset – curvilinear ultrasound probe used). (c) Multimodal image fusion of preoperative magnetic resonance and intraoperative ultrasound images. (d) The multiplanar serially acquired three-dimensional ultrasound images used for resection control|
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A meta-analysis of IUS studies showed that, when assessed using histological sampling, pooled sensitivity and specificity of IUS in diffuse gliomas was 72 and 93%, respectively, indicating that IUS may miss small tumor residues (low sensitivity) but is more reliable in confirming the absence of residue (high specificity). Another meta-analysis showed that, regardless of the type of IUS modality used, GTR rates up to 77% may be achievable in tumors amenable to complete resection [Table 1]. Although few studies have compared IUS directly with IMRI, IMRI is likely to have higher sensitivity., Given the logistics with frequent IMR acquisitions, the use of IUS for frequent intermediate intraoperative updates with a final IMRI control scan may be complementary. The versatility and multifaceted nature of IUS makes it a very useful tool.
As opposed to IGS, OI techniques enhance visualization of microscopic tumor utilizing an optically active biomarker coupled to a specific detection technique. A variety of OI techniques have been described with varying degrees of utility., Among them, FGS using 5-ALA and SF constitute two of the widely used techniques. Although both utilize the principles of fluorescence imaging, the mechanism of action differs for both the dyes. SF is a passive fluorophore which localizes to the extracellular space in areas of high permeability and breach of blood–brain barrier, following intravenous administration. The uptake occurs within minutes and hence is faster acting than 5-ALA. However, the positive predictive value (PPV) remains an issue with uptake also seen in areas of gliosis, edema, and tissue damage due to surgical manipulation, leading to numerous false positives. Low-dose fluorescein (5–10 mg/kg boluses) with visualization using a special filter (yellow 560 nm) has replaced the older high-dose fluorescein technique with visualization under ambient light and promises better accuracy with fewer false positives [Figure 3]. Timing of injection seems to play a significant role in the eventual accuracy of the technique. 5-ALA is a prodrug which is administered orally and converted intracellularly to the active metabolite protoporphyrin IX through the heme pathway. Protoporphyrin IX in the tumor tissue then absorbs the light energy (visible blue 400 nm) and emits it at a higher wavelength (dual emission peak in the visible red range at 635 and 705 nm) highlighting fluorescing cells within the tumor using a suitably modified filter [Figure 4]. Being an “active” metabolically transformed agent, it confers higher specificity as compared to sodium-fluorescein. [Table 5] shows the comparative analysis of the two common fluorescence techniques. 5-ALA remains the most widely studied dye, with plenty of literature confirming its advantage in improving the diagnostic accuracy of intraoperative tumor detection as well as therapeutic efficacy for HGG. Although the specificity and PPV are markedly high with 5-ALA, there are some shortcomings which one must be aware of. The peak action only occurs after 4-6 h of oral administration (dose 20 mg/kg) though activity may persist for more than 12 h also, and there exists a theoretical risk of photosensitivity if exposed to sunlight in the immediate postoperative period.
|Figure 3: (a and b) Pre- and post-operative images confirmed a gross total resection (image courtesy Dr Francesco Acerbi, Milan, Italy) Sodium-fluorescein guided resection of a malignant glioma. (c and d) Dotted line in corresponds to a necrotic area inside the tumor, which is usually less fluorescent than the more vital counterpart. *Is the fluorescent vital tumor area. Arrow corresponds to nontumoral white matter|
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|Figure 4: Right temporal glioblastoma operated using 5-aminolevulinic acid. (a) Preoperative T1 contrast (left) and T2 magnetic resonance imaging images. (b) Postoperative postcontrast T1 images showing complete excision. (c) Intraoperative image under white light microscope. (d) Same tumor seen under BLUE light revealing strong red fluorescence|
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|Table 5: Comparison between 5-aminolevulinic acid and sodium fluorescein induced fluorescence techniques|
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5-ALA remains the only fluorescent dye to have been evaluated in a RCT, demonstrating an almost doubling of GTR rates [Table 3]. Since then, there have been numerous studies documenting the diagnostic accuracy as well as therapeutic benefits of ALA and numerous meta-analysis and systematic reviews have consolidated these results [Table 1], [Table 2], [Table 3]. Most report high PPV of strong fluorescence in detecting tumor residue, thereby increasing GTR rates and indirectly improving the survival. False positives still occur, especially in recurrent/previously treated cases. One must be cautious in interpreting these studies as sampling of tissues for ascertaining diagnostic accuracy can lead to biases in the results.
SF has been less studied, but the number of reports is slowly increasing. Although there is no level I evidence, the FLUGLIO study reported comparably high diagnostic accuracy and GTR rates. Further, studies comparing ALA and SF in HGG found no significant differences in the two techniques., A hybrid OI strategy using both has been described and may be potentially useful. Although both 5-ALA and fluorescein have been applied in many other brain tumors (including meningiomas, metastases, pituitary tumors, and even spinal tumors), the bulk of the published evidence is limited to gliomas and benefit in any of the other tumors remains to be conclusively proven.
| Head-to Head Comparison of the Various Modalities|| |
It is exceedingly difficult to interpret studies comparing the various modalities because of heterogeneity in the type of tumors selected and the outcomes measured. [Table 1], [Table 2], [Table 3] enumerate some of these studies. A comparative meta-analysis of the various modalities was performed by Eljamel and Mahboob. It was found that GTR after 5-ALA, SF, IUS, and IMRI was 69.1%, 84.4%, 73.4%, and 70%, respectively. The cost/quality-adjusted life in years was lowest for SF and IUS and the highest for IMRI.
| Combined Multimodality Adjuncts|| |
As each adjunct has a unique (and mutually exclusive) mechanism of tumor visualization, it is compelling and intuitive to believe that their use in combination is likely to yield synergistic results and augment outcomes. Whereas IGS techniques based on physical characteristics of tissues generally provide tomographic (2D as well as 3D cross-sectional and multiplanar) images interpreted by the naked eye, OI tools provide microscopic/cellular details using aided visualization tools (microscope/spectroscope/detector systems) and are generally restricted to superficial imaging [Figure 5] and [Figure 6]. A combination of modalities is also likely to overcome the limitations of individual techniques and thereby complement each other. 5-ALA when combined with NN leads to a higher specificity as compared to 5-ALA alone, while 5-ALA when used together with IMRI leads to a higher sensitivity. Further, 5-ALA in combination with IMRI has shown to increase the PFS, OS, and GTR rates than with either modality alone.,,, Similarly, IUS in combination with ALA has shown better outcomes with IUS better visualizing the nonenhancing infiltrating component of the tumor which fluorescence may not.
|Figure 5: Hyper smart cyber operating theater at the Tokyo Women's Medical University - An operating room where almost all equipment is connected through a network. Time-synchronized data are linked to the navigation location and displayed at the Strategy Desk. Equipped with intraoperative magnetic resonance imaging equipment (0.4Tesla, Hitachi, Tokyo), navigation, and a 4K exoscope (image courtesy – Professor Y Muragaki, Tokyo, Japan)|
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|Figure 6: Comparison of image-guided surgery and optical imaging techniques highlighting their complementary roles|
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With an explosion of information available to the surgeon intraoperatively, technology to integrate the same in real time is essential. State-of-the-art multimodal operating theaters provide a glimpse into future of neurosurgery. The advanced multimodality image-guided operating suite provides real-time anatomic imaging modalities such as radiographs and ultrasonography combined with cross-sectional digital imaging systems such as CT, MRI, and positron emission tomography (PET). In addition, molecular image-guided therapy with the use of multiple molecular probes, such as PET, OI, and targeted mass spectrometry, is available to increase the sensitivity and specificity of cancer detection. The application of these technologies is expected to improve the ability to define tumor margins enabling a more complete excision or to thermally ablate residual tumor. In addition, several navigational devices, robotic devices, and delivery instruments can deploy precise and targeted therapies. The Smart Cyber Operating Theater [Figure 5], a next-generation treatment room developed in Japan, allows online uniform management of devices within the treatment room and enables time synchronization and relocation of their data using a proprietary communication interface. It permits collection of various data such as images obtained from intraoperative modalities and surgical instrument position from surgical navigation systems, as well as surgical field images and biometric patient data and presentation of the same to the surgeon in an actionable format. Incorporation of robotic technology and artificial intelligence algorithms are likely to further augment these solutions.
| Perspectives on the Role of Intraoperative Imaging Adjuncts|| |
With a plethora of intraoperative adjuncts available to neurosurgeons today, it is imperative to sift through the vast amounts of published literature and objectively assess their practical utility. Whereas there is little doubt regarding the need for such adjuncts to improve resections, the quality of evidence to support individual techniques is heterogeneous. The present review, though selective in the evaluation of published works, underlines this variability. Differences in study designs, characteristics of patients included, application of adjuncts, and outcome assessments can all contribute to this. It is not a surprise that there is precious little Class I evidence. Inherent problems with the design and conduct of studies assessing diagnostic accuracy of intraoperative adjuncts is well known. The individual surgeon's training and expertise with a particular adjunct may also play a significant role in influencing the outcomes of these techniques and therefore general extrapolation of study results may be erroneous. The issue of defining the “resectability” in diffuse gliomas is also challenging.Further, it is not easy to control for the impact of neuromonitoring adjuncts in determining the final outcomes, especially for tumors close to eloquent regions. Well-designed randomized trials and prospective studies are the need of the hour. Above all, there can be no substitute for judicious surgical decision-making and meticulous adherence to standard microsurgical principles. The adjuncts can only augment and not supplant the surgeon's capabilities.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]