title: 5-Aminolevulinic acid induced fluorescence is a powerful intraoperative marker for precise histopathological grading of gliomas with non-significant contrast-enhancement.
abstract: BACKGROUND
  Intraoperative identification of anaplastic foci in diffusely infiltrating gliomas (DIG) with non-significant contrast-enhancement on MRI is indispensible to avoid histopathological undergrading and subsequent treatment failure. Recently, we found that 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PpIX) fluorescence can visualize areas with increased proliferative and metabolic activity in such gliomas intraoperatively. As treatment of DIG is predominantely based on histopathological World Health Organisation (WHO) parameters, we analyzed whether PpIX fluorescence can detect anaplastic foci according to these criteria.
  
  
  METHODS
  We prospectively included DIG patients with non-significant contrast-enhancement that received 5-ALA prior to resection. Intraoperatively, multiple samples from PpIX positive and negative intratumoral areas were collected using a modified neurosurgical microscope. In all samples, histopathological WHO criteria and proliferation rate were assessed and correlated to the PpIX fluorescence status.
  
  
  RESULTS
  A total of 215 tumor specimens were collected in 59 patients. Of 26 WHO grade III gliomas, 23 cases (85%) showed focal PpIX fluorescence, whereas 29 (91%) of 33 WHO grade II gliomas were PpIX negative. In intratumoral areas with focal PpIX fluorescence, mitotic rate, cell density, nuclear pleomorphism, and proliferation rate were significantly higher than in non-fluorescing areas. The positive predictive value of focal PpIX fluorescence for WHO grade III histology was 85%.
  
  
  CONCLUSIONS
  Our study indicates that 5-ALA induced PpIX fluorescence is a powerful marker for intraoperative identification of anaplastic foci according to the histopathological WHO criteria in DIG with non-significant contrast-enhancement. Therefore, application of 5-ALA optimizes tissue sampling for precise histopathological diagnosis independent of brain-shift.
authors.affiliation: Department of Neurosurgery, Medical University Vienna, Vienna, Austria ; Institute of Neurology, Medical University Vienna, Vienna, Austria ; Comprehensive Cancer Center - Central Nervous System Tumours Unit (CCC-CNS), Medical University Vienna, Vienna, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Widhalm
authors.forename: Barbara
authors.initials: B
authors.lastname: Kiesel
authors.forename: Adelheid
authors.initials: A
authors.lastname: Woehrer
authors.forename: Tatjana
authors.initials: T
authors.lastname: Traub-Weidinger
authors.forename: Matthias
authors.initials: M
authors.lastname: Preusser
authors.forename: Christine
authors.initials: C
authors.lastname: Marosi
authors.forename: Daniela
authors.initials: D
authors.lastname: Prayer
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Hainfellner
authors.forename: Engelbert
authors.initials: E
authors.lastname: Knosp
authors.forename: Stefan
authors.initials: S
authors.lastname: Wolfsberger
mesh_terms: D000328:Adult; D000368:Aged; D000622:Aminolevulinic Acid; D015415:Biomarkers / Q000737:chemistry / Q000378:metabolism*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000601:surgery; D005260:Female; D005453:Fluorescence; D005910:Glioma / Q000175:diagnosis* / Q000378:metabolism / Q000601:surgery; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D016343:Monitoring, Intraoperative / Q000379:methods; D011446:Prospective Studies; D011524:Protoporphyrins / Q000737:chemistry / Q000378:metabolism; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D055815:Young Adult
chemical_list: D015415:Biomarkers; D011524:Protoporphyrins; D000622:Aminolevulinic Acid; C028025:protoporphyrin IX