Characterizing the heterogeneity in 5-aminolevulinic acid-induced fluorescence in glioblastoma

J Neurosurg. 2019 May 24;1-9. doi: 10.3171/2019.2.JNS183128. Online ahead of print.


Objective: 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) fluorescence is an effective surgical adjunct for the intraoperative identification of tumor tissue during resection of high-grade gliomas. The use of 5-ALA-induced PpIX fluorescence in glioblastoma (GBM) has been shown to double the extent of gross-total resection and 6-month progression-free survival. The heterogeneity of 5-ALA-induced PpIX fluorescence observed during surgery presents a technical and diagnostic challenge when utilizing this tool intraoperatively. While some regions show bright fluorescence after 5-ALA administration, other regions do not, despite that both regions of the tumor may be histopathologically indistinguishable. The authors examined the biological basis of this heterogeneity using computational methods.

Methods: The authors collected both fluorescent and nonfluorescent GBM specimens from a total of 14 patients undergoing surgery and examined their gene expression profiles.

Results: In this study, the authors found that the gene expression patterns characterizing fluorescent and nonfluorescent GBM surgical specimens were profoundly different and were associated with distinct cellular functions and different biological pathways. Nonfluorescent tumor tissue tended to resemble the neural subtype of GBM; meanwhile, fluorescent tumor tissue did not exhibit a prominent pattern corresponding to known subtypes of GBM. Consistent with this observation, neural GBM samples from The Cancer Genome Atlas database exhibited a significantly lower fluorescence score than nonneural GBM samples as determined by a fluorescence gene signature developed by the authors.

Conclusions: These results provide a greater understanding regarding the biological basis of differential fluorescence observed intraoperatively and can provide a basis to identify novel strategies to maximize the effectiveness of fluorescence agents.

Keywords: 5-ALA = 5-aminolevulinic acid; 5-aminolevulinic acid; GBM = glioblastoma; GSEA = Gene Set Enrichment Analysis; GTR = gross-total resection; IPA = Ingenuity Pathway Analysis; PC = principal component; PCA = PC analysis; PpIX = protoporphyrin IX; RMA = robust multichip analysis; TCGA = The Cancer Genome Atlas; fluorescence-guided surgery; glioblastoma; oncology; tumor heterogeneity.