|Year : 2020 | Volume
| Issue : 4 | Page : 162-167
Re-understanding of edema zone from the nerve fiber bundles: A narrative review
Yong Huang, Haixia Ding, Yahua Zhong
Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei Province, China
|Date of Submission||01-Dec-2020|
|Date of Decision||16-Dec-2020|
|Date of Acceptance||07-Jan-2021|
|Date of Web Publication||1-Feb-2021|
Dr. Yahua Zhong
Department of Zhongnan Hospital, Wuhan University, Shuiguohu Street, 168 Donghu Road, Wuhan
Source of Support: None, Conflict of Interest: None
Spread along nerve fiber bundles is one of the most important modes of glioma invasion; however, the current guidelines for radiotherapy target areas recommend a 1–2-cm margin in all directions from the tumor border based on pretreatment imaging findings. In this article, we analyzed the relationship between edema and nerve fiber bundles in 60 glioma patients and aimed to clarify the effect of including edema on delineation of the target volume.
Keywords: Edema, glioma, nerve fiber bundles, radiotherapy
|How to cite this article:|
Huang Y, Ding H, Zhong Y. Re-understanding of edema zone from the nerve fiber bundles: A narrative review. Glioma 2020;3:162-7
| Introduction|| |
Radiation therapy is one of the most important treatments for malignant glioma. Because of an incomplete understanding of tumor invasion patterns, current guidelines for radiotherapy recommend that the target volume be expanded 1–2 cm in all directions from the tumor border based on pretreatment imaging. However, tumor invasion is not the same in all directions; tumors usually spread in a certain direction according to their own invasion pattern. Therefore, there is a critical need to redesign the recommended irradiation field according to the diffusion patterns of glioma.
The main modes of glioma spread are as follows: (1) Along nerve fiber bundles; (2) along the ependymal membrane; (3) along the pia mater; (4) along cerebrospinal fluid; and (5) distant metastasis. Of these five, spread along nerve fiber bundles is the most important and most closely related with radiotherapy. Distant metastasis within the brain also can be considered as fiber bundle spread, but differ in the distance between the metastatic lesion and the primary tumor. For most cases, imaging techniques can be used to identify the nerve fiber bundles that may be relevant to tumor spread and the direction of the neural tracts.
Nerve fiber bundles include association fibers, projection fibers, and commissural fibers. Although early studies have confirmed that gliomas spread along nerve fiber bundles, it is difficult to identify nerve fiber bundles by conventional magnetic resonance imaging (MRI). Diffusion tensor imaging (DTI) can clearly show the main nerve fiber bundles. However, there are many nerve fiber bundles and they overlap, so it is very difficult to predict which fiber bundle or bundles will be relevant for tumor spread.,
Edema is a common imaging change in gliomas, and its significance has largely been overlooked. It is generally accepted that peripheral edema is a typical finger pressure sign, which seems to be irregular. In addition, the edema zone plays an important role in the spread of glioma. Edema is conducive to the spread of tumor cells by increasing the gap between fiber bundles. This idea has been supported by the identification of tumor cells in the edema area by postoperative pathology and by reports of more than 80% of recurrences occurring in the edema area. Edema is conducive to the spread of tumors, and the spread of tumors further aggravates edema, creating a vicious cycle.
Therefore, the edema zone provides the direction for the tumor to spread, that is, diffusion along the nerve fiber bundle. Moreover, the edema zone increases the interstitial space, which facilitates tumor spread, whereas areas without edema are difficult for tumor cells to reach. In this way, the edema zone paves the way for glioma spread. With this concept at its foundation, this article discusses the major nerve fiber bundles, or edema bands, by which gliomas spread.
| Retrieval Strategy|| |
Literature review was electronically performed using PubMed database. The following combinations of key words were used to initially select the articles to be evaluated: Glioma migration invasion; glioma peripheral edema; nerve fiber bundles and DTI; nerve fiber bundles and edema zone; Commissural fibers and association fibers. Most of the selected studies (80% of all references) were published from 2015 to 2020.
| Limitations of the Current Guidelines for Glioma Irradiation Field|| |
In [Figure 1]A, the tumor grew along the hippocampal nerve fiber bundle. When the initial treatment plan was made according to the current guidelines, some malignancy would be out of the target area and a substantial amount of normal tissue would accept unnecessary irradiation. Therefore, it is important to redesign the irradiation field according to the diffusion patterns of glioma.
|Figure 1: Magnetic resonance imaging characteristics of three patients with primary brain tumors. (A) In a patient with low grade glioma, the tumor grows along the hippocampal nerve fiber bundle (black arrows); (B) in a patient with high grade glioma, T1-weighted magnetic resonance imaging reveals a lesion with enhancement (black arrow) and T2 Flair shows extensive edema in the entire corpus callosum (green arrow), including the contralateral side before surgery (black arrow). New metastases adjacent to the contralateral corpus callosum appear 9 months after surgery (blue arrow); (C) in a patient with primary intracranial basal ganglia lymphoma, edema spreads along the projection fibers to the ipsilateral brainstem (red arrow), contralateral brainstem and contralateral cerebellum (green arrow). Figure 1 is sourced from our hospital and has not been published yet. The patients included signed the informed consent and their medical records were used|
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| Relationship of the Edema Zone and the Direction of Nerve Fiber Bundles|| |
The shape of the edema zone is not random but is extremely regular. Water molecules in the brain undergo random diffusion, but their movement is restricted when they encounter nerve fiber bundles and the water molecules will move along the direction of the nerve fiber bundle. DTI maps nerve fiber bundles by detecting the diffusion of water molecules. Tumor-induced changes in vascular permeability result in a large amount of water moving along the nerve fiber bundle. Therefore, edema follows the path of the nerve fiber bundle shown by DTI. This allows us to model edema based on the nerve fiber bundles. As shown in [Figure 2], the edema zone was consistent with the direction of nerve fiber bundles in an example patient.
|Figure 2: Relationship between edema and nerve fiber bundles. (A) Edema forms along the path of the inferior longitudinal fasciculus in a patient with low grade glioma; (B) the edema runs through the frontal, the parietal, the occipital, and the temporal lobe, along the same path as the superior longitudinal fasciculus. Thus, the tumor appears to easily spread between the lobes along the superior longitudinal fasciculus in a patient with high grade glioma; (C) a lesion in the occipital lobe spreads along the superior fronto-occipital bundle. Three months after initial scan, new nodules appeared in the ipsilateral frontal lobe, and the tumor had spread along the splenium and genu of corpus callosum to the contralateral ventricle and frontal lobe in a patient with high grade glioma. Figure 2 is sourced from our hospital and has not been published yet. The patients included signed the informed consent and their medical records were used|
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| Commissural Fibers and Association Fibers|| |
The commissural fibers are bundles of nerve fibers connecting the cerebral hemispheres and include the corpus callosum, anterior commissure, posterior commissure, and commissure of fornix.
Corpus callosum: The corpus callosum is the largest commissural fiber in the brain, including the splenium, body, and knee of corpus callosum., The cerebral falx is a barrier that prevents a tumor from spreading from one hemisphere to the other. However, a tumor can easily spread along the corpus callosum, which connects the hemispheres [Figure 3]A. In [Figure 1]B, T1-weighted MRI revealed a lesion with enhancement and T2 Flair showed extensive edema in the entire corpus callosum, including the contralateral side before surgery. New metastases adjacent to the contralateral corpus callosum appeared 9 months after surgery. This indicates that postoperative edema may facilitate tumor spread, which eventually forms a contralateral distant metastasis. As shown in [Figure 3]B, the tumor did not pass through the cerebral falx but spread to the contralateral hemisphere through the corpus callosum. The two lesions shown appeared to be independent of each other, but the next scan showed that the tumor spread along the body of the corpus callosum to the opposite side.
|Figure 3: Relationship between the metastatic lesion and the primary tumor found by identifying the nerve fiber bundles and their connection patterns. (A) The tumor can easily spread along the corpus callosum, which connects the hemispheres (red arrows) in a patient with high grade glioma. (B) The tumor did not pass through the cerebral falx but spread to the contralateral hemisphere through the corpus callosum. The two lesions shown appeared to be independent of each other, but the next scan showed that the tumor spread along the body of the corpus callosum (blue arrow) to the opposite side in a patient with low grade glioma. (C) Tumor in the temporal lobe spreads along the anterior commissure (red arrows) in a patient with high grade glioma. Figure 3 is sourced from our hospital and has not been published yet. The patients included signed the informed consent and their medical records were used|
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Anterior commissure and posterior commissure
The anterior commissure is a bundle of commissural fibers above the lamina terminalis that crosses the midline. It connects the temporal lobes of the cerebral hemispheres. The anterior commissure forms a loop with the fibers of the corpus callosum. It is not common for a tumor to spread across the frontal lobe to the opposite hemisphere, but once a lesion of the temporal lobe is large, it is necessary to take a closer look at whether the anterior commissure is involved. [Figure 3]C shows a case whose tumor in the temporal lobe spread along the anterior commissure.
Commissure of fornix
Commissure of fornix, which connects the hippocampus of both hemispheres, is the main outgoing fiber of the hippocampus, moving anteriorly under the corpus callosum. As shown in [Figure 4]A, the look-like isolated nodules connected together when viewed continuously by thin-layer scanning technique. The tumor traveled along the hippocampal nerve fiber bundle from anterior to posterior and involved the lower part of the corpus callosum, then spread anterior along the foramen of Monro and folded back down to the hypothalamus.
|Figure 4: Edema zone spreads along the nerve fiber bundles. (A) The look-like isolated nodules connect together when viewed continuously by thin-layer scanning technique (white and red arrows) in a patient with low grade glioma. (B) Edema spreads from the basal ganglia to the brainstem along the projection fibers (green arrows) in a patient with low grade glioma. (C) T2 Flair images show that the temporal lobe tumor (white arrows) is merging to the brainstem (blue arrows) through edema of the projection nerve fiber bundle in a patient with low grade glioma. Figure 4 is sourced from our hospital and has not been published yet. The patients included signed the informed consent and their medical records were used|
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The association fiber connects areas of the cortex within the same hemisphere. Short association fibers connect adjacent cerebral gyri. Long association fibers connect distant areas within the hemisphere, and include the arcuate fasciculus, fronto-occipital fasciculus, superior longitudinal fasciculus, inferior longitudinal fasciculus, and uncinate fasciculus.
The superior longitudinal fasciculus, which is located outside the caudate nucleus, is the longest contact fiber in the brain. It travels anterior to posterior, below the corpus callosum and above the lenticular nucleus and the Insula lobe, connecting the frontal, parietal, occipital, and temporal lobe. [Figure 2]B shows that the edema runs through the frontal, the parietal, the occipital, and the temporal lobe, along the same path as the superior longitudinal fasciculus. Thus, the tumor appears to easily spread between the lobes along the superior longitudinal fasciculus.,
The fronto-occipital fasciculus travels through the outer capsule to occipital lobes. The tract initiates in the inferior frontal gyrus, and its fibers travel to the parietal and occipital lobes., As shown in [Figure 2]A and [Figure 2]C lesion in the occipital lobe spreads along the superior fronto-occipital bundle. Three months after initial scan, new nodules appeared in the ipsilateral frontal lobe, and the tumor had spread along the splenium and genu of corpus callosum to the contralateral ventricle and frontal lobe.
The inferior longitudinal fasciculus is located in the occipital lobe, lateral to the lateral ventricle. It extends from the occipital pole to the sacral pole, crossing the long axis of the temporal lobe, and thus connecting the temporal lobe and the occipital lobe., As shown in [Figure 2]A, edema formed along the path of the inferior longitudinal fasciculus.
The arcuate fiber connects adjacent brain gyri, where peritumoral edema formation is a typical thumb-print sign. The formation of the edema is not a random event; the edema is always distributed along the fibers. Such as the edema located in the semi-oval center, it is generally wide, the possible reason is that the distribution of nerve fiber bundles is loosen in semi-oval center. In addition, the gap of the fiber bundles in the edema zone is large, which is beneficial for water molecule diffusion.
Uncinate fasciculus and cingulum bundle
The uncinate fasciculus connects the frontal and temporal lobes. The cingulum bundle is located beneath the cingulate gyrus, connecting the frontal lobe with the limbic system., Water molecules easily diffuse along these large nerve fiber bundles to form edema, thereby promoting tumor spread.
Projection fibers connect the cerebral cortex, deep brain nuclei, brainstem, cerebellum, and spinal cord. They include afferent and efferent fibers, such as the corticospinal tract, corticopontine tract, corticobulbar tract, and corticocerebellar tract. Projection fibers accumulate around the basal ganglia and the thalamus. Tumors can spread along the projection fibers to the basal ganglia and the thalamus, and further spread to the brainstem and cerebellum. Therefore, once a tumor invades the basal ganglia and the thalamus, the brainstem is at high risk for subsequent tumor invasion. Thus, it should be outlined as part of the clinical target area. As shown in [Figure 4]B, edema spread from the basal ganglia to the brainstem along the projection fibers. [Figure 4]C shows two isolated glioma lesions in the brainstem and temporal lobe; however, the observation of serial MRI T2 Flair images showed that the temporal lobe tumor was merging to the brainstem tumor through edema of the projection nerve fiber bundle. [Figure 1]C shows a patient with primary intracranial basal ganglia lymphoma, and showed that edema spread along the projection fibers to the ipsilateral brainstem, contralateral brainstem and contralateral cerebellum. These findings indicate that lesions of the basal ganglia and the contralateral cerebellum may not be isolated or multi-centered but rather are closely related, and nerve fiber bundle edema is the pathway between the two lesions.
| Conclusions|| |
The formation of edema should not be overlooked, as this report shows that the edema guides the path and extent of tumor spread. This has important clinical significance both for understanding the biological behavior of glioma and for improving delineation of the radiotherapy target area. First, edema patterns indicate the nerve fiber bundles involved, so the area of edema zone can be divided into the corresponding nerve fiber bundles. Second, we can determine the direction and distance of tumor spread through the edema zone, which will facilitate precise positioning of the radiotherapy target area.
At present, whether the edema zone should be delineated with tumor remains under debate. The Radiation Therapy Oncology Group (RTOG) recommends that the target area include the enhanced tumor lesion and edema zone, and then by expand 2 cm, whereas The European Organization for Research and Treatment of Cancer (EORTC) recommends that only the enhanced lesion be outlined and then expanded by 2 cm. Our study found that according to the EORTC guidelines, if we expand the lesion area by 2 cm, most of the edema zone will be in the target area, meaning that target areas defined by EORTC guidelines also largely irradiate the edema zone. This could explain why current clinical studies have not found differences in local recurrence and survival between the two target delineation methods. These findings indicate that the difference between the EORTC and RTOG target areas is not in the edema zone, but in the inclusion of surrounding tissue. According to the theory of tumor diffusion along nerve fiber bundles and edema, if edema does not form, the route of tumor migration is limited, and the possibility of tumor cells infiltrating the nonedema area is very small. This has been confirmed in previous postoperative pathology and clinical recurrence patterns. Thus, we do not recommend including the region outside of edema in the target area.
The RTOG target area not only includes the edema zone, but also adds a 2-cm margin, and we suggest that the resulting target area is too large. EORTC is uniformly expanded by 2 cm from the boundary of enhanced tumor lesions, which likely includes most of the surrounding edema in the target area, and a small amount of normal tissues without edema. In the present study, we found that target areas delineated by edema were nearly one-quarter to one-third smaller than target areas delineated by tumor plus a margin of 2 cm. Thus, we recommend that the volume of the target area should be reduced to irradiate only the edema area, which would reduce normal tissue radiation exposure.
Financial support and sponsorship
This work was supported by the National Natural Science Foundation of China (No. 81641116) and Health and Family Planning Commission Foundation of Hubei Province of China (No. WJ2017H0007).
Conflicts of interest
The authors declare no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]