Quantitative fluorescence in intracranial tumor: Implications for ALA-induced PpIX as an intraoperative biomarker - Clinical article

Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire, USA.
Journal of Neurosurgery (Impact Factor: 3.74). 03/2011; 115(1):11-7. DOI: 10.3171/2011.2.JNS101451
Source: PubMed


Accurate discrimination between tumor and normal tissue is crucial for optimal tumor resection. Qualitative fluorescence of protoporphyrin IX (PpIX), synthesized endogenously following δ-aminolevulinic acid (ALA) administration, has been used for this purpose in high-grade glioma (HGG). The authors show that diagnostically significant but visually imperceptible concentrations of PpIX can be quantitatively measured in vivo and used to discriminate normal from neoplastic brain tissue across a range of tumor histologies.
The authors studied 14 patients with diagnoses of low-grade glioma (LGG), HGG, meningioma, and metastasis under an institutional review board-approved protocol for fluorescence-guided resection. The primary aim of the study was to compare the diagnostic capabilities of a highly sensitive, spectrally resolved quantitative fluorescence approach to conventional fluorescence imaging for detection of neoplastic tissue in vivo.
A significant difference in the quantitative measurements of PpIX concentration occurred in all tumor groups compared with normal brain tissue. Receiver operating characteristic (ROC) curve analysis of PpIX concentration as a diagnostic variable for detection of neoplastic tissue yielded a classification efficiency of 87% (AUC = 0.95, specificity = 92%, sensitivity = 84%) compared with 66% (AUC = 0.73, specificity = 100%, sensitivity = 47%) for conventional fluorescence imaging (p < 0.0001). More than 81% (57 of 70) of the quantitative fluorescence measurements that were below the threshold of the surgeon's visual perception were classified correctly in an analysis of all tumors.
These findings are clinically profound because they demonstrate that ALA-induced PpIX is a targeting biomarker for a variety of intracranial tumors beyond HGGs. This study is the first to measure quantitative ALA-induced PpIX concentrations in vivo, and the results have broad implications for guidance during resection of intracranial tumors.

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    • "During prolonged surgeries possible problems with detection of fluorescence may result from its time-dependent deterioration or bleaching due to excessive or prolonged use of the ultraviolet light or microscope illumination [29] [30]. Finally, tissue fluorescence may be below the threshold of the visual perception [34] [35]. On the other hand, false positive tissue fluorescence may be identified in the areas of high vascularization , reactive astrocytosis and fibrosis, macrophages infiltration, inflammation, brain edema, or BBB impairment in the absence of the neoplastic elements [31] [36] [37] [45] [48] [49]. "
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    • "PpIX is lipophilic; in vivo it is in contact with the lipid membrane of mitochondria and its microenvironment is complex. The emission peak at 634 nm is known to be predominant in HGG [2,3,6,7]. However some results indicate that the emission spectrum can be more complicated [10–12] due to either a shift in the position of the emission maximum towards shorter wavelength or the presence of photoproducts. In the former case, PpIX fluorescence emission is the result of the two PpIX states which are simultaneously present. "
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    • "Perhaps more convincing in addressing the issue of auto-fluorescence is the fact that the levels of ALA-induced PpIX fluorescence from brain tumors (including high-and low-grade gliomas, meningiomas and metastases) are two to three orders of magnitude larger when compared to normal adjacent brain tissue. The high specificity of this contrast mechanism is such that fluorescence emanating from areas other than the tumor is in the vast majority of cases negligible (Valdes et al 2011). We expect that the point-like approximation will not be compromised by the presence of auto-fluorescence and non-specific fluorescence in clinical applications such as ALA-induced PpIX fluorescenceguided resection. "
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