title: δ-aminolevulinic acid-induced protoporphyrin IX concentration correlates with histopathologic markers of malignancy in human gliomas: the need for quantitative fluorescence-guided resection to identify regions of increasing malignancy.
abstract: Extent of resection is a major goal and prognostic factor in the treatment of gliomas. In this study we evaluate whether quantitative ex vivo tissue measurements of δ-aminolevulinic acid-induced protoporphyrin IX (PpIX) identify regions of increasing malignancy in low- and high-grade gliomas beyond the capabilities of current fluorescence imaging in patients undergoing fluorescence-guided resection (FGR). Surgical specimens were collected from 133 biopsies in 23 patients and processed for ex vivo neuropathological analysis: PpIX fluorimetry to measure PpIX concentrations (C(PpIX)) and Ki-67 immunohistochemistry to assess tissue proliferation. Samples displaying visible levels of fluorescence showed significantly higher levels of C(PpIX) and tissue proliferation. C(PpIX) was strongly correlated with histopathological score (nonparametric) and tissue proliferation (parametric), such that increasing levels of C(PpIX) were identified with regions of increasing malignancy. Furthermore, a large percentage of tumor-positive biopsy sites (∼40%) that were not visibly fluorescent under the operating microscope had levels of C(PpIX) greater than 0.1 µg/mL, which indicates that significant PpIX accumulation exists below the detection threshold of current fluorescence imaging. Although PpIX fluorescence is recognized as a visual biomarker for neurosurgical resection guidance, these data show that it is quantitatively related at the microscopic level to increasing malignancy in both low- and high-grade gliomas. This work suggests a need for improved PpIX fluorescence detection technologies to achieve better sensitivity and quantification of PpIX in tissue during surgery.
authors.affiliation: Dartmouth Medical School, Dartmouth College, Hanover, New Hampshire, USA.
authors.forename: Pablo A
authors.initials: PA
authors.lastname: Valdés
authors.forename: Anthony
authors.initials: A
authors.lastname: Kim
authors.forename: Marco
authors.initials: M
authors.lastname: Brantsch
authors.forename: Carolyn
authors.initials: C
authors.lastname: Niu
authors.forename: Ziev B
authors.initials: ZB
authors.lastname: Moses
authors.forename: Tor D
authors.initials: TD
authors.lastname: Tosteson
authors.forename: Brian C
authors.initials: BC
authors.lastname: Wilson
authors.forename: Keith D
authors.initials: KD
authors.lastname: Paulsen
authors.forename: David W
authors.initials: DW
authors.lastname: Roberts
authors.forename: Brent T
authors.initials: BT
authors.lastname: Harris
mesh_terms: D000328:Adult; D000368:Aged; D000622:Aminolevulinic Acid; D015415:Biomarkers / Q000378:metabolism*; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000601:surgery; D003952:Diagnostic Imaging; D005260:Female; D005453:Fluorescence; D005470:Fluorometry; D005910:Glioma / Q000175:diagnosis* / Q000378:metabolism / Q000601:surgery; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D016343:Monitoring, Intraoperative; D017319:Photosensitizing Agents; D011524:Protoporphyrins; D012680:Sensitivity and Specificity; D055815:Young Adult
chemical_list: D015415:Biomarkers; D017319:Photosensitizing Agents; D011524:Protoporphyrins; D000622:Aminolevulinic Acid; C028025:protoporphyrin IX