5-aminolevulinic-acid fluorescence-guided resection of brain metastases [Neurosurgery Wiki]

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====== 5-aminolevulinic-acid fluorescence-guided resection of brain metastases ======

//J.Sales-Llopis//

//Neurosurgery Department, Alicante University General Hospital, Alicante, Spain.//

===== Latest PubMed related Articles =====

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===== Introduction =====
[[5-aminolevulinic acid]] (5-ALA) [[fluorescence]]-guided [[resection]] is a technique used in neurosurgery, particularly for brain [[tumor resection]], including metastases. This method involves the administration of 5-ALA to the patient before surgery, which is then metabolized by the tumor cells to produce fluorescent porphyrins. The fluorescence emitted by these porphyrins can be visualized using special surgical microscopes equipped with a blue light source, allowing neurosurgeons to distinguish between normal and cancerous tissue during the operation.

Here is an overview of the process:

Administration of 5-ALA: Before surgery, the patient is given a dose of 5-ALA orally. 5-ALA is a precursor in the heme biosynthetic pathway and is preferentially taken up by rapidly dividing cells, such as tumor cells.

Metabolism in Tumor Cells: In the presence of tumor cells, 5-ALA is metabolized to fluorescent porphyrins, particularly protoporphyrin IX (PpIX). This accumulation is higher in malignant cells compared to normal brain tissue.

Fluorescence Visualization: During surgery, a special surgical microscope equipped with a blue light source is used. When the neurosurgeon illuminates the surgical field with blue light, the accumulated PpIX in the tumor cells emits a red fluorescence, making the tumor cells stand out from the surrounding normal brain tissue.

Tumor Resection: The surgeon can use this fluorescence guidance to more precisely identify and remove tumor tissue while sparing healthy brain tissue. This enhances the extent of tumor removal and minimizes damage to normal brain structures.

The benefits of 5-ALA fluorescence-guided resection include:

Improved Tumor Visualization: The fluorescence allows for better visualization of tumor margins, helping the surgeon distinguish between tumor and normal brain tissue.

Increased Complete Resection Rates: With enhanced visualization, surgeons can strive for more complete removal of tumor tissue, potentially improving patient outcomes.

Reduced Damage to Normal Tissue: The technique aims to minimize damage to surrounding normal brain tissue by selectively targeting and removing fluorescent tumor tissue.

This approach is commonly used in the treatment of high-grade gliomas, including glioblastoma multiforme, but it has also been investigated and applied in the resection of brain metastases. The goal is to enhance the precision of surgery and improve patient outcomes by achieving maximal tumor removal while minimizing damage to healthy brain tissue.
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===== Systematic reviews =====

With regard to [[brain metastases treatment]] and their surgical adjuncts, there is still much to be explored. This is mainly related to the heterogeneity of patients, the primary tumour histology and the extent of systemic disease; regardless, surgery plays a paramount role in obtaining a local disease control, and more standardised surgical protocols need to be made, with the aim of optimizing the use of the available surgical adjuncts and in order to increase the rate of GTR
((Di Cristofori A, Carone G, Rocca A, Rui CB, Trezza A, Carrabba G, Giussani C. Fluorescence and Intraoperative Ultrasound as Surgical Adjuncts for Brain Metastases Resection: What Do We Know? A Systematic Review of the Literature. Cancers (Basel). 2023 Mar 29;15(7):2047. doi: 10.3390/cancers15072047. PMID: 37046709; PMCID: PMC10092992.))
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Current studies regarding [[5-aminolevulinic acid guided resection]] of [[brain metastases]] are limited and do not confirm efficacy for improving the [[extent of resection]] or postoperative survival. [[Fluorescence]] is variable across and within tumor types. Further studies are necessary to evaluate whether specific tumors may benefit from 5-ALA FGS or if changes in delivery protocols or fluorescence quantification may affect intraoperative utility
((Shah HA, Leskinen S, Khilji H, Narayan V, Ben-Shalom N, D'Amico RS. Utility of 5-ALA for fluorescence-guided resection of brain metastases: a systematic review. J Neurooncol. 2022 Dec;160(3):669-675. doi: 10.1007/s11060-022-04188-0. Epub 2022 Nov 12. PMID: 36370294.)).

===== Case series =====

Critics have argued that tumor cells at the resection margins might be overlooked under microscopic visualization because of technical limitations. Therefore, an endoscope, which is capable of inducing fluorescence, has been applied with the aim of improving exposure of fluorescent tumor tissue. In this retrospective analysis, authors assessed the utility of endoscope assistance in 5-aminolevulinic acid (5-ALA) fluorescence-guided resection of brain metastases.

Between June 2013 and December 2016, a standard 20-mg/kg dose of 5-ALA was administered 4 hours prior to surgery in 26 patients with suspected single brain metastases. After standard neuronavigated microsurgical tumor resection, a microscope capable of inducing fluorescence was used to examine tumor margins. The authors classified the remaining fluorescence into 3 grades (0 = none, 1 = weak, and 2 = strong). Endoscopic assistance was employed if no or only weak fluorescence was visualized at the resection margins under the microscope. Endoscopically identified fluorescent tissue at the margins was resected and evaluated separately via histological examination to prove or disprove tumor infiltration.

Under the microscope, weakly fluorescent tissue was seen at the margins of the resection cavity in 15/26 (57.7%) patients. In contrast, endoscopic inspection revealed strongly fluorescent tissue in 22/26 (84.6%) metastases. In 11/26 (42.3%) metastases no fluorescence at the tumor margins was detected by the microscope; however, strong fluorescence was visualized under the endoscope in 7 (63.6%) of these 11 metastases. In the 15 metastases with microscopically weak fluorescence, strong fluorescence was seen when using the endoscope. Neither microscopic nor endoscopic fluorescence was found in 4/26 (15.4%) cases. In the 26 patients, 96 histological specimens were obtained from the margins of the resection cavity. Findings from these specimens were in conjunction with the histopathological findings, allowing identification of metastatic infiltration with a sensitivity of 95.5% and a specificity of 75% using endoscope assistance.

Fluorescence-guided endoscope assistance may overcome the technical limitations of the conventional microscopic exposure of 5-ALA-fluorescent metastases and thereby increase visualization of fluorescent tumor tissue at the margins of the resection cavity with high sensitivity and acceptable specificity
((Bettag C, Hussein A, Schatlo B, Barrantes-Freer A, Abboud T, Rohde V, Mielke D. Endoscope-assisted visualization of 5-aminolevulinic acid fluorescence in surgery for brain metastases. J Neurosurg. 2022 Apr 29;137(6):1650-1655. doi: 10.3171/2022.3.JNS212301. PMID: 35535845.))
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Fluorescence-assisted tumor resection was performed in 27 patients with brain metastases. Patients received 20 mg/kg 5-ALA 3 hours before anesthesia. After resection, biopsy specimens of the surrounding parenchyma were analyzed for 5-ALA fluorescence and histologic evidence of infiltrating tumor cells. The correlation between 5-ALA positivity and immunohistochemical evidence of tumor in the peritumoral zone was also assessed.

Of 27 metastases, 23 (85%) were 5-ALA positive. For qualitative tissue analysis, 110 of 125 samples were collected. Metastatic infiltration was present in 49 samples with faint or red fluorescence; 33 samples without fluorescence were tumor-free. The presence of metastatic infiltration correlated with fluorescence (P < 0.001). Tumor infiltration correlated with fluorescence (blue fluorescence 0.09% ± 0.04% and red or faint fluorescence 3.26%; P = 0.003).

Infiltration of surrounding brain tissue is a common finding in brain metastases in selected primary tumors. 5-ALA fluorescence correlates with tumor cell infiltration and might guide more radical resection
((Schatlo B, Stockhammer F, Barrantes-Freer A, Bleckmann A, Siam L, Pukrop T, Rohde V. 5-Aminolevulinic Acid Fluorescence Indicates Perilesional Brain Infiltration in Brain Metastases. World Neurosurg X. 2019 Dec 16;5:100069. doi: 10.1016/j.wnsx.2019.100069. PMID: 32095783; PMCID: PMC7026613.)).
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Yagi et al. retrospectively reviewed the cases of 16 patients with metastatic brain tumors who underwent intraoperative 5-ALA fluorescence-guided resection. Patients were given 20 mg/kg of 5-ALA orally 2 h prior to the surgery. High-powered excitation illumination and a low-pass filter (420, 450, or 500 nm) were used to visualize the fluorescence of protoporphyrin IX (PpIX), the 5-ALA metabolite. We evaluated the relationships between the fluorescence and histopathological findings in both tumoral and peritumoral brain tissue.

Tumoral PpIX fluorescence was seen in only 5 patients (31%); in the remaining 11 patients (69%), there was no fluorescence in the tumor bulk itself. In 14 patients (86%), vague fluorescence was seen in peritumoral brain tissue, at a thickness of 2-6 mm. The histopathological examination found cancer cell invasion of adjacent brain tissue in 75% of patients (12/16), at a mean ± SD depth of 1.4 ± 1.0 mm (range 0.2-3.4 mm) from the microscopic border of the tumor. There was a moderate correlation between vague fluorescence in adjacent brain tissue and the depth of cancer cell invasion (P = 0.004).

Peritumoral fluorescence may be a good intraoperative indicator of tumor extent, preceding more complete microscopic gross total resection.

Trial registration: Institutional Review Board of Osaka Medical College No. 42, registered February 17, 1998, and No. 300, registered April 1, 2008. They were retrospectively registered
((Yagi R, Kawabata S, Ikeda N, Nonoguchi N, Furuse M, Katayama Y, Kajimoto Y, Kuroiwa T. Intraoperative 5-aminolevulinic acid-induced photodynamic diagnosis of metastatic brain tumors with histopathological analysis. World J Surg Oncol. 2017 Sep 29;15(1):179. doi: 10.1186/s12957-017-1239-8. PMID: 28962578; PMCID: PMC5622438.))
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Utsuki et al. performed a pathological study to identify the locus of production of [[protoporphyrin IX]] (PPIX) in human metastatic brain tumors. Patients with metastatic brain tumors (n = 11) received 1 g of 5-aminolevulinic acid (5-ALA) perorally 2 h before undergoing surgery. The target region was exposed to laser light with a peak wavelength of 405 +/- 1 nm and an output of 40 mW. Tissue samples from the tumor bulk and surrounding areas were examined by histological and fluorescence methods. Of the 11 tumors, 9 manifested PPIX fluorescence in the tumor bulk and peritumoral brain tissue. The findings indicate that PPIX fluorescence can be observed in peritumoral edematous areas that are free of neoplastic cells, because PPIX produced by neoplastic cells leaks into the surrounding edematous area
((Utsuki S, Miyoshi N, Oka H, Miyajima Y, Shimizu S, Suzuki S, Fujii K. Fluorescence-guided resection of metastatic brain tumors using a 5-aminolevulinic acid-induced protoporphyrin IX: pathological study. Brain Tumor Pathol. 2007;24(2):53-5. doi: 10.1007/s10014-007-0223-3. Epub 2007 Nov 28. PMID: 18095131.))

===== Summary =====

In conclusion, the treatment of brain metastases and the utilization of surgical adjuncts remain areas of ongoing exploration and refinement. The complexity arising from patient heterogeneity, variations in primary tumor histology, and differences in the extent of systemic disease underscores the need for a more comprehensive understanding and standardized approaches.

Surgery continues to play a paramount role in achieving local disease control, emphasizing the importance of optimizing surgical protocols. However, the pursuit of gross total resection (GTR) faces challenges, prompting the call for more standardized surgical protocols. The overarching goal is to enhance the utilization of available surgical adjuncts and improve the rate of GTR.

A specific focus on 5-aminolevulinic acid (5-ALA) guided resection of brain metastases reveals current limitations in confirming its efficacy for enhancing resection extent or postoperative survival. The variable fluorescence observed across different tumor types and within the same tumor types raises questions about its consistency. Further studies are deemed necessary to discern whether specific tumors may derive benefits from 5-ALA fluorescence-guided surgery. Additionally, potential modifications to delivery protocols or fluorescence quantification methods warrant investigation to optimize intraoperative utility.

The integration of endoscope assistance in 5-ALA fluorescence-guided resection presents a promising avenue to overcome technical limitations associated with conventional microscopic exposure. This approach, assessed in retrospective analyses, demonstrated increased visualization of fluorescent tumor tissue at resection margins, particularly in cases where conventional microscopic visualization may fall short. The use of endoscopic assistance, in conjunction with 5-ALA, exhibited high sensitivity and acceptable specificity in identifying tumor infiltration.

The correlation between 5-ALA fluorescence and histologic evidence of infiltrating tumor cells in the peritumoral zone further strengthens the potential of 5-ALA in guiding more radical resection. Studies assessing the utility of 5-ALA in brain metastases consistently highlight its ability to correlate with tumor cell infiltration, providing valuable guidance for achieving a more extensive resection.

In summary, the evolving landscape of surgical adjuncts, particularly 5-ALA fluorescence-guided resection and endoscopic assistance, reflects the dynamic nature of neurosurgical advancements. As research progresses, the field is moving towards more refined and individualized approaches to enhance the precision and effectiveness of brain metastases treatment.

===== References =====