Quantitative fluorescence in intracranial tumor: implications for ALA-induced PpIX as an intraoperative biomarker

Clinical article

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  • 1 Thayer School of Engineering, and
  • 2 Dartmouth Medical School, Dartmouth College, Hanover;
  • 4 Norris Cotton Cancer Center,
  • 5 Department of Pathology, and
  • 6 Section of Neurosurgery, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire; and
  • 3 University of Toronto, Ontario Cancer Institute/University Health Network, Toronto, Ontario, Canada

Object

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.

Methods

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.

Results

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.

Conclusions

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.

Abbreviations used in this paper: ALA = δ-aminolevulinic acid; AUC = area under the curve; A615 = total light intensity associated with the integration of the fluorescence emission spectrum from λ = 615 to 740 nm; A660 = total light intensity associated with the integration of the fluorescence emission spectrum from λ = 660 to 740 nm; CPpIX = absolute concentration of PpIX; HGG = high-grade glioma; LGG = low-grade glioma; NPV = negative predictive value; PpIX = protoporphyrin IX; PPV = positive predictive value; P635 = peak intensity of the fluorescence emission spectrum at λ = 635 nm; P710 = peak intensity of the fluorescence emission spectrum at λ = 710 nm; ROC = receiver operating characteristic.

Contributor Notes

Address correspondence to: David W. Roberts, M.D., Section of Neurosurgery, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, New Hampshire 03756. email: David.W.Roberts@dartmouth.edu.

Please include this information when citing this paper: published online March 25, 2011; DOI: 10.3171/2011.2.JNS101451.

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