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Table of Contents
Year : 2020  |  Volume : 3  |  Issue : 2  |  Page : 53-60

Surgical resection of glioma involving eloquent brain areas: Tumor boundary, functional boundary, and plasticity consideration

Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China

Date of Submission14-May-2020
Date of Acceptance10-Jun-2020
Date of Web Publication27-Jun-2020

Correspondence Address:
Dr. Xuejun Yang
Department of Neurosurgery, Tianjin Medical University General Hospital, 154 An-shan Road, Tianjin 300052
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/glioma.glioma_16_20

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Glioma is the most refractory intracranial tumor, and its diffuse infiltrative growth characteristics make total resection impossible in a biological sense, especially when tumors invade eloquent brain areas. Thus, identifying the equilibrium between tumor resection and functional preservation remains a challenge in glioma surgery. The accurate identification of tumor boundaries, precise mapping of functional boundaries, and an in-depth understanding of functional plasticity are key factors for accomplishing this challenge. This article reviews these three key points and highlights potential perspectives for the development of glioma surgery.

Keywords: Function mapping, glioma, neuroplasticity, surgical resection, tumor boundary

How to cite this article:
Lin Y, Yang X. Surgical resection of glioma involving eloquent brain areas: Tumor boundary, functional boundary, and plasticity consideration. Glioma 2020;3:53-60

How to cite this URL:
Lin Y, Yang X. Surgical resection of glioma involving eloquent brain areas: Tumor boundary, functional boundary, and plasticity consideration. Glioma [serial online] 2020 [cited 2022 Dec 8];3:53-60. Available from: http://www.jglioma.com/text.asp?2020/3/2/53/288179

  Introduction Top

Gliomas are the most common primary tumors of the central nervous system. At present, the standard of care for glioma is comprehensive treatment based on surgical resection, which is the first and most important step of treatment. Several studies have revealed that the extent of surgical resection is closely related to patient prognosis.[1],[2],[3],[4] However, gliomas often exhibit an infiltrative growth pattern, including extensive brain invasion. The infiltration range of gliomas far exceeds the visible abnormal areas on routine images and often involves eloquent brain areas. Therefore, the balance between preserving neurological function and maximizing tumor resection has not been clarified.

Because of their infiltrative growth pattern, gliomas have no obvious boundary with brain tissue.[5],[6] Experienced surgeons can judge the tumor boundary by sensing the change of brain tissue texture, color, and suction force, but it is difficult for even experienced surgeons to ensure a radiological total resection. Preoperative multimodal imaging and intraoperative auxiliary technology can help improve the extent of glioma resection to radiological supratotal resection.[7],[8],[9],[10] The current review will introduce some promising technologies at the experimental level, including the polarized light scattering imaging technique under development by our group.

The existence of individual differences and their impact on lesions make it impossible for us to rely on anatomical landmarks alone to protect eloquent brain areas.[11] With the development of brain mapping technology, we can achieve individualized mapping of functional areas. Among the available techniques, intraoperative direct electrical stimulation remains the gold standard for functional mapping.[12],[13],[14] With direct cortical electrical stimulation, tumors in functional areas that were previously considered unresectable have been completely resected without neurological dysfunction.[15],[16],[17] Among the emerging brain mapping technologies, navigated transcranial magnetic stimulation (nTMS) has good applicability. nTMS both provide precise function mapping and play a unique role in the longitudinal study of functional plasticity.[18],[19],[20] In addition to technological innovation, the scope of functional protection is also expanding. Series of studies have been conducted on the mapping of higher-order cognitive functions such as calculation, attention, executive function, and memory.[21],[22],[23] Tailored function mapping based on tumor location can permit more detailed functional assessments, which may further improve the functional prognosis of patients.

The hindrance to the concept of “maximum safe resection” is residual tumor tissue in eloquent brain areas. Residual tumor will lead to recurrence or malignant transformation, affecting patient prognosis.[24],[25] With a deepened understanding of brain functional plasticity, staged surgery, or inducing functional plasticity preoperatively may represent a solution to this difficulty.

  Retrieval Strategy Top

Literature review was electronically performed using the PubMed database. The following combinations of keywords were used to initially select the articles to be evaluated: glioma and eloquent area; glioma and tumor boundary; glioma and function mapping; glioma and infiltrative; glioma and neuroplasticity. Most of the selected studies were published from 2010 to 2019.

  Tumor Boundary Top

Multimodal neuronavigation

Multimodal imaging technologies include contrast-enhanced magnetic resonance imaging (MRI), perfusion-weighted imaging, positron emission tomography, magnetic resonance spectroscopy (MRS), and diffusion MRI. A series of studies revealed that multimodal techniques combined with neuronavigation systems can improve the extent of resection and patient prognosis.[26],[27],[28],[29] A comparison of multitarget biopsy guided by multimodal imaging with pathological results suggested that multimodal imaging can detect tumor tissue beyond the boundary identified by traditional MRI.[30] The prediction model based on multimodal imaging data can even predict the location of tumor recurrence, thus providing guidance for the direction of extended resection.[31] Multimodal neuronavigation-guided surgery is useful for the precise localization of tumors before craniotomy. However, the accuracy of tumor boundary determination depends on the ratio between the preoperative multimodal image and brain shift intraoperatively.[32] The opening of the skull and dura, the loss of cerebrospinal fluid, and the removal of tumor tissue will cause brain shift, which will lead to inaccurate neural navigation, thus making the tumor boundary identified via preoperative imaging meaningless.[33] The accuracy of navigation can be improved to a certain extent using intraoperative MRI (iMRI) and intraoperative B-ultrasound in the correction of brain shift, but further improvement is needed.

Intraoperative B-ultrasound

Traditional intraoperative B-ultrasound equipment is relatively inexpensive and convenient, making it widely useful for the intraoperative localization of a variety of brain tumors in the clinic. However, prior research indicated that the specificity and sensitivity of traditional intraoperative B-ultrasound in identifying glioma residuals are not ideal,[34],[35] and the technique is susceptible to peritumoral edema, hemorrhage, and other causes of interference.[36] With the development of new ultrasound technologies, such as three-dimensional (3D) ultrasound and linear array ultrasound, the quality of ultrasound images has been improved.[37],[38] Numerous studies have illustrated that emerging B-mode ultrasound technologies can improve the extent of glioma resection and patient prognosis. However, biopsies beyond the boundary identified by 3D ultrasound can detect tumor cells, exposing the limitations of the emerging B-ultrasound techniques in determining tumor boundaries.[39] Currently, emerging B-ultrasound techniques can achieve the same accuracy as iMRI in identifying residual tumors, but they cannot identify the biological boundaries of gliomas. The authors of this review believe that the real advantage of intraoperative B-ultrasound lies in intraoperative real-time guidance. By identifying blood vessels and cortical structures, B-ultrasound images can co-register multimodal preoperative images, the tissue deformation caused by surgical resection can be corrected in real time, and then the tumor boundary can be accurately guided by preoperative multimodal images.[40] Surgical resection of residual glioma tissue will be more precise with an updated compensation algorithm for brain shift.[41] Our research team has conducted some preliminary research on the use of intraoperative ultrasound in correcting brain shift, which will be introduced later.

Intraoperative magnetic resonance imaging

iMRI plays an extremely important role in image-guided neurosurgery, and it is widely used in large neurosurgery centers. iMRI can identify the boundary of residual tumors after the first resection and update the neuronavigation data to compensate for brain shift caused by cerebrospinal fluid loss and brain tissue removal.[42] Several studies revealed that the use of iMRI can improve the extent of resection, thereby improving patient prognosis.[7],[43] However, a iMRI study comparing biopsies from the border of the initial resection cavity with iMRI contrast enhancement identified tumor invasion in contrast-enhanced and nonenhanced areas of iMRI, indicating that contrast-enhanced iMRI alone may be unable to delineate the biological boundaries of gliomas because of their high invasiveness.[44] Intraoperative MRS may help to identify the biological boundaries of gliomas. In previous research, additional resection was performed in regions with choline (Cho)/N-acetyl-aspartate (NAA) and/or Cho/creatine (Cr) ratios >1. In addition, resected tissues were examined pathologically to evaluate the association between MRS data and pathological findings. The results demonstrated that tissues with a high Cho/NAA or Cho/Cr ratio had residual tumor cells and high Ki-67 indices.[45] Although iMRI can help identify the boundary of glioma by using multiple scanning sequences, the increase of scanning sequences will inevitably prolong the operative time, increase the risk of infection, and require additional anesthesia. Further research is needed to optimize the scanning sequence, shorten the scanning time, and improve the imaging quality and accuracy.

5-Aminolevulinic acid

5-Aminolevulinic acid (5-ALA) acts as a precursor that can be metabolized to the endogenous photosensitizer protoporphyrin IX (PpIX). Under blue light (405 nm) excitation, the red fluorescence of PpIX can be observed using a fluorescence microscope. Compared with normal brain cells, glioma cells exhibit decreased levels of ferrochelatase and selective uptake of this enzyme by an ATP-binding cassette transporter, leading to enhanced PpIX accumulation.[46] PpIX accumulation is much higher in glioma tissue than in normal brain tissue; thus, the tumor and its infiltrated brain tissue will exhibit more obvious red fluorescence, which helps the surgeon to distinguish the boundary of tumor under a microscope and guides surgical resection. A randomized, multicenter phase III clinical trial confirmed that compared with the findings in the control group, more patients in the 5-ALA group underwent gross total resection (65% vs. 36%), and they had a higher 6-month progression-free survival rate.[47] Subsequent reviews also revealed that 5-ALA can improve the extent of glioma resection.[48],[49] Further research found that different grades of gliomas have different levels of fluorescence intensity, and fluorescence intensity also differs between glioma and the invaded brain tissue.[50],[51] The fluorescence intensity will be higher in areas with high tumor density, metabolism, and proliferation. However, the fluorescence intensity of the invaded brain tissue was low, being undetectable in some cases. To overcome the problem of undetectably low fluorescence intensity, some research teams have further applied fiber scanning endoscopy technology to detect 5-ALA–induced fluorescence to improve the recognition accuracy of infiltrative glioma.[52] Based on the clinical trial results of 5-ALA, the US FDA also approved its use for the intraoperative visualization of malignant tissue.[53]

Emerging technique: Toward a biological boundary

Raman spectroscopy is an optical technique for detecting inelastic scattered light generated by the interaction of light with matter, providing chemical fingerprints of cells, tissues, or biological fluids.[54] Raman spectroscopy can distinguish white matter, gray matter, glioma, and necrosis, thereby representing a potential modality for identifying residual tumors intraoperatively. With a handheld probe placed in direct contact with the resection margin, Raman spectroscopy can detect cancer cells intraoperatively that cannot be detected using MRI.[55] Several Raman spectroscopy techniques have subsequently been developed, including surface-enhanced Raman scattering, surface-enhanced resonant Raman spectroscopy, coherent anti-Stokes Raman spectroscopy, and stimulated Raman spectroscopy, which were demonstrated to be useful for identifying the boundary of gliomas.[56]

Optical coherence tomography (OCT) is a real-time, label-free imaging technique that can obtain 3D images of biological tissues with high resolution (approximately 2 μm). OCT is similar to ultrasound imaging in that both techniques detect reflected waves (light or sound). However, OCT uses near-infrared light sources (in the 700–1300 nm wavelength range). OCT is mainly used in the noncontact imaging of retinas, but it remains in its infancy in tumor boundary recognition. OCT is a promising method for intraoperative guidance in the resection of glioma.[57]

Polarized light scattering imaging: most biological tissues are high-scattering media in the visible light band. When light propagates through the tissue, the scattering will change the polarization state of the photons when the incident, which will make the polarization chaotic, lead to the loss of the original phase and polarization information and affect the contrast and resolution of optical imaging. By properly filtering the polarization state of the photons, the effect of “diffusing photons” that repeatedly scatter and lose the original polarization state on the image is suppressed, and the number of scattered “ballistic photons” and “snake photons” that maintain the original polarization is improved, thereby improving image quality.[58] The change of the polarization state of the photon during the scattering process is closely related to the microstructure of the scattering medium. Measurement of the polarization state of the scattered light can provide rich structural information on the tissue responsible for the scattering. Therefore, the polarized optical imaging method has broad applicability in the field of biomedical research. Jacques et al.[59] first experimentally proved that polarization imaging can help define the boundaries of early cancerous lesions such as squamous epithelium. Pierangelo et al.[60],[61] analyzed intestinal cancerous tissue using surface-illuminated polarized light imaging technology. By comparing the intestinal cancerous tissue at different stages back to the Mueller matrix and normal tissue, they found that the performance of the Mueller matrix differs under the condition of different wavelengths of incident light illumination, revealing the great potential of Mueller matrix parameters in the early diagnosis of bowel cancer. At present, it is hoped that polarized light scattering imaging will be a simple and high-resolution technique for determining the tumor boundary during glioma surgery.

  Functional Boundary Top

The functional mapping techniques commonly used in the clinic can be divided into two types. One is activation-observation methods, including functional magnetic resonance and magnetoencephalography. Taking functional magnetic resonance as an example, its basic principle relies on the coupling of neural and blood vessels. This technology uses hemoglobin as an endogenous contrast agent to reflect the changes of blood oxygen saturation levels when neurons in the functional area of the cerebral cortex are activated. Therefore, functional magnetic resonance technology statistically analyzes the signal changes dependent on blood oxygen levels.[62] However, the biggest disadvantage of such methods is that they do not reflect the direct causal relationship between the activation of brain regions and functional tasks, and the essential brain regions cannot be distinguished from the participating brain regions. The so-called participating brain areas refer to regions related to a certain neurological function task when it is completed, but disturbing the neuronal electrical activity in these areas does not affect the completion of a specific functional task. The essential brain areas are regions necessary for the completion of a functional task. Once an essential brain area is disturbed, the task will not be completed normally.[63] The second method type is stimulus-interference methods. Direct cortical electrical stimulation, the gold standard for localizing brain functional areas, can determine the location of functional areas by interfering with the completion of motor, language, and other related tasks. Another promising technology is nTMS, which can generate magnetic fields through magnetic stimulation coils and then noninvasively penetrate the skull to form an induced current in the cerebral cortex.[64] This current at an appropriate intensity can induce neuronal depolarization and then generate action potentials. A single magnetic stimulus can stimulate the target cortex. Repetitive stimulation at a certain frequency can excite or inhibit the cortex. Therefore, by properly choosing the stimulation mode, the technique can temporarily disturb function in the cerebral cortex. By integrating the transcranial magnetic stimulation (TMS) of the neuronavigation system, we can directly look at the location of the brain stimulated via TMS in real time under the guidance of the individual's MRI data, thereby accurately locating the stimulated cortex. The noninvasiveness of nTMS technology, which permits longitudinal study, is an ideal means for studying brain functional localization and dynamic changes (neuroplasticity).

At present, the understanding of brain functional areas is far from sufficient. From the neurosurgeon's viewpoint, when resecting a part of brain tissue will affect the patient's ability to complete a certain functional task, we believe that this brain region has key functions. In essence, the removal of any part of brain tissue may result in the loss of neurological function in patients, but we did not fully and effectively evaluate neurological function. Thus, we believe that part of the brain tissue does not have any function, which is termed a nonfunctional areas area. The functional brain areas of greatest concern for neurosurgeons during surgery include motor and language areas. In recent years, some researchers have also expanded the scope of functional protection to areas associated with writing, memory, and more complex cognitive functions.

  Functional Plasticity Top

Residual tumor tissue will continue to grow progressively, causing tumor recurrence or malignant transformation, thereby affecting patient prognosis. The removal of tumor tissue located in eloquent brain areas is difficult during glioma surgery, and the mechanism of brain function plasticity is the key. In recent years, with the development of neuroimaging technology, it has been found that when pathological damage occurs in the brain, especially in the face of chronic progressive pathological damage, the brain displays an ability to maintain the homeostasis of neurological function is observed, illustrating its neuroplastic potential.[65] At present, several hypotheses have been formulated concerning the neural remodeling induced by gliomas in areas associated with language function [Figure 1].
Figure 1: Hypothesis of neuroplasticity. (A) Hierarchy hypothesis, (B) recruitment hypothesis, and (C) functional redundancy hypothesis. Modified from Ius et al.,[69] Robles et al.,[72] Duffau,[68] and Lin et al.[73]

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Hierarchy hypothesis [Figure 1]A: Studies have revealed that functional recovery is possible after cortical damage, whereas subcortical fiber damage usually leads to permanent dysfunction.[66],[67] Different cortices exhibit different levels of plasticity when they are invaded by glioma. For example, the left prefrontal cortex plays an important role in higher-order cognition, executive ability, and semantic recognition. However, when the region is invaded by a tumor, the patient's functions mostly remain unaffected. Once language cortices such as the Wernicke area in the posterior part of the superior temporal gyrus and motor cortices such as the precentral gyrus are damaged, severe dysfunction can occur.[68] By summarizing the data of patients with the WHO grade II glioma, the inherent plasticity of different brain regions was presented using a probabilistic map, which supports the existence of a “minimal common brain” among patients.[69] Recruitment hypothesis [Figure 1]B: This refers to the recruitment of neurons around the damaged brain area to complete the reconstruction of neural function, and its main mechanism occurs through local synaptic plasticity.[70] It has been revealed that the plasticity of the language function cortex can recruit the cortices around the lesion or the homologous region of the contralateral hemisphere.[71] With the progression of the disease and the intervention of surgery, the form of language function plasticity through the recruitment mode may be dynamic.[72] Functional redundancy hypothesis [Figure 1]C: Another widely accepted hypothesis is neural functional redundancy. The core of this hypothesis is that when some neurons are damaged, the inhibitory effect on their adjacent neurons is removed. The activity of the originally inhibited neurons is restored, thereby reshaping neural function.[68] Our previous study also confirmed the high level of redundancy of language-related cortices through functional area localization and subcortical white matter fiber tracking. Only a small part of the arcuate fasciculus-projecting brain area harbors language function, whereas most of these regions may have redundant roles.[73]

In addition to function plasticity associated with pathological changes, activity-induced function plasticity is another research direction. Previous studies revealed that functional plasticity is closely related to the speed of lesion progression.[74],[75] Stroke usually progresses rapidly, and it is difficult to recover from the associated functional impairment. Similarly, the failure to protect the functional area intraoperatively usually results in dysfunction that is difficult to reverse.[76] Animal experiments demonstrated that resection of the entire motor area of rats simultaneously will result in an obvious loss of motor function even after 36 days, whereas no differences in motor function relative to sham-operated mice are observed when the same area is resected in stages. This study demonstrated that the speed of pathological changes will lead to the failure of brain functional plasticity; thus, it is extremely important to preserve the eloquent areas of the brain during the first operation,[77] because it is always difficult to avoid the recurrence of gliomas, especially in functional areas with residual tumors. In many studies that used functional MRI and cortical electrical stimulation, the plasticity of functional areas in patients with recurrent gliomas was demonstrated, which permitted the removal of unresectable tumors located in functional areas without any function deterioration.[78],[79] Because of the dynamic changes of functional areas, it is possible to employ a staging operation strategy for gliomas located in eloquent brain areas.[80]

A tumor-mimicking effect may induce the plasticity process. Recently, researchers found that high-frequency cortical subdural stimulation mimicked the ability of tumors to cause dysfunction and induced the plasticity of language function in patients with glioma.[81] Invasion of functional areas was discovered in awake surgery in a patient with anaplastic astrocytoma involving the left frontal lobe, and some of the tumor tissue could not be resected directly. The research team placed high-frequency cortical stimulation electrodes on the surface of the unresectable invaded functional area. After the operation, the high-frequency stimulation electrodes were activated to interfere with the normal language function of the patient. After 25 days of interference, the patient's language functional areas were displaced as confirmed by functional imaging techniques and direct cortical electrical stimulation in the secondary operation. Another team also reported a number of cases in which intracranial electrodes were implanted to interfere with normal language function, and plasticity of language function was subsequently induced.[82] However, the disadvantage of intracranial electrode implantation for simulating lesion is that patients require two surgeries to resect the tumor to the maximal extent. High-frequency repetitive TMS can disturb language function and act as virtual lesions noninvasively.[83] This technique has great potential for inducing functional plasticity before surgery.

  Future Perspective–the Frontier Surgical Planning and Guiding System for Glioma With Precise Mapping of Lesional and Functional Boundaries Top

Precision surgery is the current development trend of modern surgery and the unremitting goal of researchers and clinicians. The combination of multimodal imaging and neurological function information to guide surgical planning and intraoperative navigation is an indispensable and important frontier technology for precise neurosurgery. Our team is working on an integrated system that aims to solve the key hindrances to the precise delineation of glioma boundaries and brain functional areas [Figure 2].
Figure 2: Flowchart of the “Frontier Surgical Planning and Guiding System for Glioma with Precise Mapping of Lesion and Function Boundaries.” BUS: B-mode ultrasound, DTI: Diffusion tensor imaging, fMRI: Functional magnetic resonance imaging, MRA: Magnetic resonance angiography, MRI: Magnetic resonance imaging, MRS: Magnetic resonance spectroscopy, nTMS: Navigated transcranial magnetic stimulation, PET-CT: Positron emission tomography-computed tomography

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The frontier surgical planning and the guiding system will integrate multimodal tumor images with functional information. The structure quantitative analysis of multimodal quantitative images combined with function information obtained from TMS will permit the automatic segmentation of tumors, functional areas, and surrounding tissue. During the operation, polarized light scattering imaging will be introduced to monitor the residual tumor in the resection interface in real time.

To effectively guide the resection during surgery, the system will also incorporate a bidirectional projection augmented reality visualization system that allows the bidirectional tracking and visualization of brain structure, functional areas, lesions on the navigation system screen and surgical field.

To resolve brain drift during surgery, this system will permit the use of automatic registration methods that do not depend on body surface markers and that can resist imaging and intraoperative surface deformation. Information from intraoperative modalities such as ultrasound fusion imaging and neurological activity monitoring will be integrated into the navigation system, and preoperative planning will be corrected in real time to achieve accurate navigation.

  Conclusion Top

At present, through the application of various advanced technologies, the identification of tumor and functional boundaries can be easily completed in glioma surgery to achieve the goal of maximal safe resection. With an in-depth understanding of neuroplasticity, the strategy of surgery for glioma in eloquent areas has also changed to permit the maximal resection of such lesions. It is believed that with the progress of technology and understanding, the surgical treatment of glioma will eventually achieve the goal of “total and safe resection.”

Financial support and sponsorship

The work was funded by the National Key Research and Development Program of China (No. 2018YFC0115603) and Clinical Medicine Research Project of Tianjin Medical University of China (No. 2018kylc001).

Conflicts of interest

There are no conflicts of interest.

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