5-Aminolevulinic acid induced fluorescence is a powerful intraoperative marker for precise histopathological grading of gliomas with non-significant contrast-enhancement - PubMed (original) (raw)

5-Aminolevulinic acid induced fluorescence is a powerful intraoperative marker for precise histopathological grading of gliomas with non-significant contrast-enhancement

Georg Widhalm et al. PLoS One. 2013.

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.

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Conflict of interest statement

Competing Interests: Dr. Stefan Wolfsberger is at present a technological advisory board member and educational consultant of Medtronic. All other authors have declared no competing interests.

Figures

Figure 1

Figure 1. Pattern of contrast-enhancement (CE) on magnetic resonance imaging (MRI) of gliomas with non-significant CE.

T1-weighted contrast-enhanced MR images demonstrate examples of gliomas with (a) no visible ( = none) CE, (c) unspecific ( = patchy/faint) CE and (e) a small regional ( = focal) CE in an otherwise non-enhancing tumor. (b,d,f) T2-weighted MR images show the corresponding hyperintense glioma lesions.

Figure 2

Figure 2. Example of 5-ALA application in a left temporal glioma with non-significant contrast-encencement (CE) on magnetic resonance imaging (MRI).

(a) Preoperative contrast-enhanced T1-weighted MR images show patchy/faint CE and (g) hyperintensity on FLAIR sequences. (b) The intratumoral area outside the region of maximum positron emission tomography (PET) tracer uptake verified by the intraoperative navigation system (c) appeared as whitish glioma tissue under the surgical microscope, (d) with no detectable PpIX fluorescence. (e) The corresponding histopathology reveals low-grade glioma tissue according to the WHO criteria in the H&E stain (f) with a low proliferation rate (MIB-1: <10%). (h) In contrast, the intratumoral area inside the region of maximum PET tracer uptake (i) showed similar glioma tissue appearance in the microscopic view, (j) but revealed strong PpIX fluorescence under violet-blue excitation light. (k) The corresponding histopathology reveals high-grade glioma tissue in accordance with an anaplastic focus according to the WHO criteria in the H&E stain (l) with a high proliferation rate (MIB-1: 32%). The final histopathological diagnosis revealed a focally anaplastic astrocytoma (WHO grade III) and the patient was treated with radiochemotherapy. The width of each histopathological image (e, f, k, l) was 300 micrometers (µm).

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