What is the Surgical Benefit of Utilizing 5-Aminolevulinic Acid for Fluorescence-Guided Surgery of Malignant Gliomas?

Abstract

The current neurosurgical goal for patients with malignant gliomas is maximal safe resection of the contrast-enhancing tumor. However, a complete resection of the contrast-enhancing tumor is achieved only in a minority of patients. One reason for this limitation is the difficulty in distinguishing viable tumor from normal adjacent brain during surgery at the tumor margin using conventional white-light microscopy. To overcome this limitation, fluorescence-guided surgery (FGS) using 5-aminolevulinic acid (5-ALA) has been introduced in the treatment of malignant gliomas. FGS permits the intraoperative visualization of malignant glioma tissue and supports the neurosurgeon with real-time guidance for differentiating tumor from normal brain that is independent of neuronavigation and brain shift. Tissue fluorescence after oral administration of 5-ALA is associated with unprecedented high sensitivity, specificity, and positive predictive values for identifying malignant glioma tumor tissue. 5-ALA-induced tumor fluorescence in diffusely infiltrating gliomas with non-significant magnetic resonance imaging contrast-enhancement permits intraoperative identification of anaplastic foci and establishment of an accurate histopathological diagnosis for proper adjuvant treatment. 5-ALA FGS has enabled surgeons to achieve a significantly higher rate of complete resections of malignant gliomas in comparison with conventional white-light resections. Consequently, 5-ALA FGS has become an indispensable surgical technique and standard of care at many neurosurgical departments around the world. We conducted an extensive literature review concerning the surgical benefit of using 5-ALA for FGS of malignant gliomas. According to the literature, there are a number of reasons for the neurosurgeon to perform 5-ALA FGS, which will be discussed in detail in the current review.

Figures

Figure 1. Comparison of specific intratumoral areas in a malignant glioma (illustrative case): Contrast-enhanced MRI, conventional white-light microscopy, 5-ALA induced PpIX fluorescence and histopathology

The central necrotic part of the GBM (1a) on imaging and (1b) during white-light resection does (1c) not show any visible PpIX fluorescence and (1d) corresponding histopathology confirms the presence of tissue necrosis. (2a) In the region of the ring-like contrast-enhancement on MRI, (2b) greyish/soft tumor tissue is found under white-light microscopy that shows (2c) strong PpIX fluorescence and (2d) corresponding histopathology reveals solidly proliferating tumor tissue with high tumor cell density. (3a) Outside the contrast-enhancing part on MRI, (3b) the tissue showing only slight pathological appearance under conventional white-light can be (3c) clearly visualized by weak PpIX fluorescence and (3d) corresponding histopathology depicts infiltrating glioma tissue with medium tumor cell density. At the assumed end of the infiltration zone (4a) on imaging and (4b) under white-light, (4c) no visible PpIX fluorescence can be found and (4d) corresponding histopathology is not able to detect obvious infiltrating glioma cells in this case. Reprinted from Widhalm. Intra-operative visualization of brain tumors with 5-aminolevulinic acid-induced fluorescence. Clin Neuropathol. 2014 Jul-Aug; 33(4): 260-78 , with permission Dustri-Verlag Dr. Karl Feistle GmbH & Co. KG

Figure 2. Detection of an anaplastic focus in a DIG with non-significant contrast-enhancement on MRI with visible 5-ALA induced fluorescence

A., During tumor resection, the glioma tissue shows a relatively homogenous appearance under conventional white-light microscopy. B., In contrast, a small circumscribed intratumoral area can be identified with 5-ALA induced PpIX fluorescence under violet-blue excitation light. Histopathological analysis of the fluorescing intratumoral area shows (C) malignant glioma tissue (D) with a high proliferation rate indicating the presence of an anaplastic focus. On the contrary, the surrounding non-fluorescing tissue reveals only (E) low-grade glioma tissue (F) with a low proliferation rate. Reprinted from Widhalm. Intra-operative visualization of brain tumors with 5-aminolevulinic acid-induced fluorescence. Clin Neuropathol. 2014 Jul-Aug; 33(4): 260-78 , with permission Dustri-Verlag Dr. Karl Feistle GmbH & Co. KG

Figure 3. Detection of residual newly-diagnosed GBM tumor with PpIX fluorescence after maximal white-light conventional resection

A., Left, Microsurgical white-light visualization of GBM resection cavity after maximal conventional resection. Right, Visualization of PpIX fluorescence at tumor margin after conventional microsurgical resection. B., Left, Preoperative MRI scan with gadolinium enhancement in right parietal lobe consistent with malignant glioma. Center and Right, postoperative MRI scans with and without gadolinium enhancement confirming complete resection of the enhancing tumor. C, Histopathologic examination (hematoxylin and eosin staining) of fluorescent tissue at tumor margin confirming presence of infiltrating tumor extending away from tumor bulk at 10 × (left) and 20 × (right) magnification.

Figure 3. Detection of residual newly-diagnosed GBM tumor with PpIX fluorescence after maximal white-light conventional resection

A., Left, Microsurgical white-light visualization of GBM resection cavity after maximal conventional resection. Right, Visualization of PpIX fluorescence at tumor margin after conventional microsurgical resection. B., Left, Preoperative MRI scan with gadolinium enhancement in right parietal lobe consistent with malignant glioma. Center and Right, postoperative MRI scans with and without gadolinium enhancement confirming complete resection of the enhancing tumor. C, Histopathologic examination (hematoxylin and eosin staining) of fluorescent tissue at tumor margin confirming presence of infiltrating tumor extending away from tumor bulk at 10 × (left) and 20 × (right) magnification.

Figure 3. Detection of residual newly-diagnosed GBM tumor with PpIX fluorescence after maximal white-light conventional resection

A., Left, Microsurgical white-light visualization of GBM resection cavity after maximal conventional resection. Right, Visualization of PpIX fluorescence at tumor margin after conventional microsurgical resection. B., Left, Preoperative MRI scan with gadolinium enhancement in right parietal lobe consistent with malignant glioma. Center and Right, postoperative MRI scans with and without gadolinium enhancement confirming complete resection of the enhancing tumor. C, Histopathologic examination (hematoxylin and eosin staining) of fluorescent tissue at tumor margin confirming presence of infiltrating tumor extending away from tumor bulk at 10 × (left) and 20 × (right) magnification.