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

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.

[1]  E. Sevick-Muraca,et al.  Quantitative optical spectroscopy for tissue diagnosis. , 1996, Annual review of physical chemistry.

[2]  N. Ramanujam.  Fluorescence spectroscopy of neoplastic and non-neoplastic tissues. , 2000, Neoplasia.

[3]  Veit Rohde,et al.  EXTENT OF RESECTION AND SURVIVAL IN GLIOBLASTOMA MULTIFORME: IDENTIFICATION OF AND ADJUSTMENT FOR BIAS , 2008, Neurosurgery.

[4]  R. Weissleder,et al.  Imaging in the era of molecular oncology , 2008, Nature.

[5]  H Brenner,et al.  Variation of sensitivity, specificity, likelihood ratios and predictive values with disease prevalence. , 1997, Statistics in medicine.

[6]  Mamta Khurana,et al.  Quantification of in vivo fluorescence decoupled from the effects of tissue optical properties using fiber-optic spectroscopy measurements. , 2010, Journal of biomedical optics.

[7]  Keith D. Paulsen,et al.  Estimation of Brain Deformation for Volumetric Image Updating in Protoporphyrin IX Fluorescence-Guided Resection , 2009, Stereotactic and Functional Neurosurgery.

[8]  F. Floeth,et al.  The value of metabolic imaging in diagnosis and resection of cerebral gliomas , 2005, Nature Clinical Practice Neurology.

[9]  F. Zanella,et al.  Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. , 2006, The Lancet. Oncology.

[10]  D. Shapiro,et al.  The interpretation of diagnostic tests , 1999, Statistical methods in medical research.

[11]  Arya Nabavi,et al.  FIVE‐AMINOLEVULINIC ACID FOR FLUORESCENCE‐GUIDED RESECTION OF RECURRENT MALIGNANT GLIOMAS: A PHASE II STUDY , 2009, Neurosurgery.

[12]  Gabriele Schackert,et al.  Resection and survival in glioblastoma multiforme: an RTOG recursive partitioning analysis of ALA study patients. , 2008, Neuro-oncology.

[13]  Michael S Patterson,et al.  Photobleaching kinetics, photoproduct formation, and dose estimation during ALA induced PpIX PDT of MLL cells under well oxygenated and hypoxic conditions , 2006, Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology.

[14]  R L Galloway,et al.  The process and development of image-guided procedures. , 2001, Annual review of biomedical engineering.

[15]  Johan Moan,et al.  On the selectivity of 5-aminolevulinic acid-induced protoporphyrin IX formation. , 2004, Current medicinal chemistry. Anti-cancer agents.

[16]  Xiaoyao Fan,et al.  Coregistered fluorescence-enhanced tumor resection of malignant glioma: relationships between δ-aminolevulinic acid-induced protoporphyrin IX fluorescence, magnetic resonance imaging enhancement, and neuropathological parameters. Clinical article. , 2011, Journal of neurosurgery.

[17]  Neda Haj-Hosseini,et al.  Optical touch pointer for fluorescence guided glioblastoma resection using 5‐aminolevulinic acid , 2010, Lasers in surgery and medicine.

[18]  R. Richards-Kortum,et al.  Optical spectroscopy for detection of neoplasia. , 2002, Current opinion in chemical biology.

[19]  Brian W Pogue,et al.  Review of Neurosurgical Fluorescence Imaging Methodologies , 2010, IEEE Journal of Selected Topics in Quantum Electronics.

[20]  Toru Itakura,et al.  The usefulness and problem of intraoperative rapid diagnosis in surgical neuropathology , 2007, Brain Tumor Pathology.

[21]  H Stepp,et al.  Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients. , 2000, Journal of neurosurgery.

[22]  D. Prayer,et al.  5‐Aminolevulinic acid is a promising marker for detection of anaplastic foci in diffusely infiltrating gliomas with nonsignificant contrast enhancement , 2010, Cancer.

[23]  N. Pouratian,et al.  Surgery Insight: the role of surgery in the management of low-grade gliomas , 2007, Nature Clinical Practice Neurology.