Quantitative fluorescence using 5-aminolevulinic acid-induced protoporphyrin IX biomarker as a surgical adjunct in low-grade glioma surgery

Pablo A. Valdés Department of Neurosurgery, Brigham and Women’s/Boston Children’s Hospitals, Harvard Medical School;
Geisel School of Medicine at Dartmouth, Hanover;
Section of Neurosurgery, Dartmouth-Hitchcock Medical Center, Lebanon;
Thayer School of Engineering, Hanover, New Hampshire;

Search for other papers by Pablo A. Valdés in
Current site
Google Scholar
PubMed
Close
 MD, PhD
,
Valerie Jacobs Geisel School of Medicine at Dartmouth, Hanover;
Department of Neurology, Boston Children’s Hospital, Boston, Massachusetts;

Search for other papers by Valerie Jacobs in
Current site
Google Scholar
PubMed
Close
 MD, PhD
,
Brent T. Harris Georgetown University Medical Center, Washington, DC;

Search for other papers by Brent T. Harris in
Current site
Google Scholar
PubMed
Close
 MD, PhD
,
Brian C. Wilson Ontario Cancer Institute, University of Toronto, Ontario; and

Search for other papers by Brian C. Wilson in
Current site
Google Scholar
PubMed
Close
 PhD
,
Frederic Leblond Department of Engineering Physics, Polytechnique Montreal, Quebec, Canada

Search for other papers by Frederic Leblond in
Current site
Google Scholar
PubMed
Close
 PhD
,
Keith D. Paulsen Thayer School of Engineering, Hanover, New Hampshire;

Search for other papers by Keith D. Paulsen in
Current site
Google Scholar
PubMed
Close
 PhD
, and
David W. Roberts Geisel School of Medicine at Dartmouth, Hanover;
Section of Neurosurgery, Dartmouth-Hitchcock Medical Center, Lebanon;

Search for other papers by David W. Roberts in
Current site
Google Scholar
PubMed
Close
 MD
Restricted access

Purchase Now

USD  $45.00

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $536.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $636.00
USD  $45.00
USD  $536.00
USD  $636.00
Print or Print + Online Sign in

OBJECT

Previous studies in high-grade gliomas (HGGs) have indicated that protoporphyrin IX (PpIX) accumulates in higher concentrations in tumor tissue, and, when used to guide surgery, it has enabled improved resection leading to increased progression-free survival. Despite the benefits of complete resection and the advances in fluorescence-guided surgery, few studies have investigated the use of PpIX in low-grade gliomas (LGGs). Here, the authors describe their initial experience with 5-aminolevulinic acid (ALA)-induced PpIX fluorescence in a series of patients with LGG.

METHODS

Twelve patients with presumed LGGs underwent resection of their tumors after receiving 20 mg/kg of ALA approximately 3 hours prior to surgery under an institutional review board-approved protocol. Intraoperative assessments of the resulting PpIX emissions using both qualitative, visible fluorescence and quantitative measurements of PpIX concentration were obtained from tissue locations that were subsequently biopsied and evaluated histopathologically. Mixed models for random effects and receiver operating characteristic curve analysis for diagnostic performance were performed on the fluorescence data relative to the gold-standard histopathology.

RESULTS

Five of the 12 LGGs (1 ganglioglioma, 1 oligoastrocytoma, 1 pleomorphic xanthoastrocytoma, 1 oligodendroglioma, and 1 ependymoma) demonstrated at least 1 instance of visible fluorescence during surgery. Visible fluorescence evaluated on a specimen-by-specimen basis yielded a diagnostic accuracy of 38.0% (cutoff threshold: visible fluorescence score ≥ 1, area under the curve = 0.514). Quantitative fluorescence yielded a diagnostic accuracy of 67% (for a cutoff threshold of the concentration of PpIX [CPpIX] > 0.0056 μg/ml, area under the curve = 0.66). The authors found that 45% (9/20) of nonvisibly fluorescent tumor specimens, which would have otherwise gone undetected, accumulated diagnostically significant levels of CPpIX that were detected quantitatively.

CONCLUSIONS

The authors’ initial experience with ALA-induced PpIX fluorescence in LGGs concurs with other literature reports that the resulting visual fluorescence has poor diagnostic accuracy. However, the authors also found that diagnostically significant levels of CPpIX do accumulate in LGGs, and the resulting fluorescence emissions are very often below the detection threshold of current visual fluorescence imaging methods. Indeed, at least in the authors’ initial experience reported here, if quantitative detection methods are deployed, the diagnostic performance of ALA-induced PpIX fluorescence in LGGs approaches the accuracy associated with visual fluorescence in HGGs.

ABBREVIATIONS

ALA = 5-aminolevulinic acid; AUC = area under the curve; CPpIX = concentration of PpIX; HGG = high-grade glioma; LGG = low-grade glioma; NPV = negative predictive value; PpIX = protoporphyrin IX; PPV = positive predictive value; ROC = receiver operating characteristic.
  • Collapse
  • Expand
  • 1

    Beez T, , Sarikaya-Seiwert S, , Steiger HJ, & Hänggi D: Fluorescence-guided surgery with 5-aminolevulinic acid for resection of brain tumors in children—a technical report. Acta Neurochir (Wien) 156:597604, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Bekelis K, , Valdés PA, , Erkmen K, , Leblond F, , Kim A, & Wilson BC, et al.: Quantitative and qualitative 5-aminolevulinic acid-induced protoporphyrin IX fluorescence in skull base meningiomas. Neurosurg Focus 30:5 E8, 2011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Bradley RS, & Thorniley MS: A review of attenuation correction techniques for tissue fluorescence. J R Soc Interface 3:113, 2006

  • 4

    Colditz MJ, & Jeffree RL: Aminolevulinic acid (ALA)-protoporphyrin IX fluorescence guided tumour resection Part 1: Clinical, radiological and pathological studies. J Clin Neurosci 19:14711474, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Colditz MJ, , Leyen Kv, & Jeffree RL: Aminolevulinic acid (ALA)-protoporphyrin IX fluorescence guided tumour resection Part 2: theoretical, biochemical and practical aspects. J Clin Neurosci 19:16111616, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    DeAngelis LM: Brain tumors. N Engl J Med 344:114123, 2001

  • 7

    Ewelt C, , Floeth FW, , Felsberg J, , Steiger HJ, , Sabel M, & Langen KJ, et al.: Finding the anaplastic focus in diffuse gliomas: the value of Gd-DTPA enhanced MRI, FET-PET, and intraoperative, ALA-derived tissue fluorescence. Clin Neurol Neurosurg 113:541547, 2011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Fitzmaurice GM, , Laird NM, & Ware JH: Applied Longitudinal Analysis Hoboken, NJ, Wiley, 2004

  • 9

    Fitzmaurice M: Principles and pitfalls of diagnostic test development: implications for spectroscopic tissue diagnosis. J Biomed Opt 5:119130, 2000

  • 10

    Floeth FW, , Sabel M, , Ewelt C, , Stummer W, , Felsberg J, & Reifenberger G, et al.: Comparison of (18)F-FET PET and 5-ALA fluorescence in cerebral gliomas. Eur J Nucl Med Mol Imaging 38:731741, 2011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Floeth FW, & Stummer W: The value of metabolic imaging in diagnosis and resection of cerebral gliomas. Nat Clin Pract Neurol 1:6263, 2005

  • 12

    Haj-Hosseini N, , Richter J, , Andersson-Engels S, & Wårdell K: Optical touch pointer for fluorescence guided glioblastoma resection using 5-aminolevulinic acid. Lasers Surg Med 42:914, 2010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Hefti M, , von Campe G, , Moschopulos M, , Siegner A, , Looser H, & Landolt H: 5-aminolevulinic acid induced protoporphyrin IX fluorescence in high-grade glioma surgery: a one-year experience at a single institution. Swiss Med Wkly 138:180185, 2008

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Hirose Y, , Sasaki H, , Abe M, , Hattori N, , Adachi K, & Nishiyama Y, et al.: Subgrouping of gliomas on the basis of genetic proflies. Brain Tumor Pathol 30:203208, 2013

  • 15

    Ishihara R, , Katayama Y, , Watanabe T, , Yoshino A, , Fukushima T, & Sakatani K: Quantitative spectroscopic analysis of 5-aminolevulinic acid-induced protoporphyrin IX fluorescence intensity in diffusely infiltrating astrocytomas. Neurol Med Chir (Tokyo) 47:5357, 2007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Kim A, , Khurana M, , Moriyama Y, & Wilson BC: Quantification of in vivo fluorescence decoupled from the effects of tissue optical properties using fiber-optic spectroscopy measurements. J Biomed Opt 15:067006, 2010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Marbacher S, , Klinger E, , Schwyzer L, , Fischer I, , Nevzati E, & Diepers M, et al.: Use of fluorescence to guide resection or biopsy of primary brain tumors and brain metastases. Neurosurg Focus 36:2 E10, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    McGirt MJ, , Chaichana KL, , Attenello FJ, , Weingart JD, , Than K, & Burger PC, et al.: Extent of surgical resection is independently associated with survival in patients with hemispheric infiltrating low-grade gliomas. Neurosurgery 63:700708, 2008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Millesi M, , Kiesel B, , Woehrer A, , Hainfellner JA, , Novak K, & Martínez-Moreno M, et al.: Analysis of 5-aminolevulinic acid-induced fluorescence in 55 different spinal tumors. Neurosurg Focus 36:2 E11, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Montcel B, , Mahieu-Williame L, , Armoiry X, , Meyronet D, & Guyotat J: Two-peaked 5-ALA-induced PpIX fluorescence emission spectrum distinguishes glioblastomas from low grade gliomas and infiltrative component of glioblastomas. Biomed Opt Express 4:548558, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Nabavi A, , Thurm H, , Zountsas B, , Pietsch T, , Lanfermann H, & Pichlmeier U, et al.: Five-aminolevulinic acid for fluorescence-guided resection of recurrent malignant gliomas: a phase II study. Neurosurgery 65:10701077, 2009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Nakazato Y: Revised WHO classification of brain tumours. Brain Nerve 60:5977, 2008. (Jpn)

  • 23

    Pichlmeier U, , Bink A, , Schackert G, & Stummer W: Resection and survival in glioblastoma multiforme: an RTOG recursive partitioning analysis of ALA study patients. Neuro Oncol 10:10251034, 2008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Pogue BW, , Gibbs-Strauss S, , Valdés PA, , Samkoe K, , Roberts DW, & Paulsen KD: Review of neurosurgical fluorescence imaging methodologies. IEEE J Sel Top Quantum Electron 16:493505, 2010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Richards-Kortum R, & Sevick-Muraca E: Quantitative optical spectroscopy for tissue diagnosis. Annu Rev Phys Chem 47:555606, 1996

  • 26

    Roberts DW, , Valdés PA, , Harris BT, , Fontaine KM, , Hartov A, & Fan X, 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. J Neurosurg 114:595603, 2011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Roberts DW, , Valdés PA, , Harris BT, , Hartov A, , Fan X, & Ji S, et al.: Adjuncts for maximizing resection: 5-aminolevuinic acid. Clin Neurosurg 59:7578, 2012

  • 28

    Roberts DW, , Valdés PA, , Harris BT, , Hartov A, , Fan X, & Ji S, et al.: Glioblastoma multiforme treatment with clinical trials for surgical resection (aminolevulinic acid). Neurosurg Clin N Am 23:371377, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Ruge JR, & Liu J: Use of 5-aminolevulinic acid for visualization and resection of a benign pediatric brain tumor. J Neurosurg Pediatr 4:484486, 2009

  • 30

    Sanai N, , Snyder LA, , Honea NJ, , Coons SW, , Eschbacher JM, & Smith KA, et al.: Intraoperative confocal microscopy in the visualization of 5-aminolevulinic acid fluorescence in low-grade gliomas. J Neurosurg 115:740748, 2011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Schomas DA, , Laack NN, , Rao RD, , Meyer FB, , Shaw EG, & O’Neill BP, et al.: Intracranial low-grade gliomas in adults: 30-year experience with long-term follow-up at Mayo Clinic. Neuro Oncol 11:437445, 2009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Shapiro DE: The interpretation of diagnostic tests. Stat Methods Med Res 8:113134, 1999

  • 33

    Smith JS, , Chang EF, , Lamborn KR, , Chang SM, , Prados MD, & Cha S, et al.: Role of extent of resection in the long-term outcome of low-grade hemispheric gliomas. J Clin Oncol 26:13381345, 2008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Stockhammer F, , Misch M, , Horn P, , Koch A, , Fonyuy N, & Plotkin M: Association of F18-fluoro-ethyl-tyrosin uptake and 5-aminolevulinic acid-induced fluorescence in gliomas. Acta Neurochir (Wien) 151:13771383, 2009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Stummer W, , Novotny A, , Stepp H, , Goetz C, , Bise K, & Reulen HJ: Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients. J Neurosurg 93:10031013, 2000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Stummer W, , Pichlmeier U, , Meinel T, , Wiestler OD, , Zanella F, & Reulen HJ: Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 7:392401, 2006

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Stummer W, , Reulen HJ, , Meinel T, , Pichlmeier U, , Schumacher W, & Tonn JC, et al.: Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias. Neurosurgery 62:564576, 2008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Stummer W, , Stepp H, , Möller G, , Ehrhardt A, , Leonhard M, & Reulen HJ: Technical principles for protoporphyrin-IX-fluorescence guided microsurgical resection of malignant glioma tissue. Acta Neurochir (Wien) 140:9951000, 1998

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Stummer W, , Tonn JC, , Goetz C, , Ullrich W, , Stepp H, & Bink A, et al.: 5-ALA-derived tumor fluorescence: the diagnostic accuracy of visible fluorescence qualities as corroborated by spectrometry and histology and post-operative imaging. Neurosurgery 74:310319, 2013

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40

    Stummer W, , Tonn JC, , Mehdorn HM, , Nestler U, , Franz K, & Goetz C, et al.: Counterbalancing risks and gains from extended resections in malignant glioma surgery: a supplemental analysis from the randomized 5-aminolevulinic acid glioma resection study. J Neurosurg 114:613623, 2011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41

    Utsuki S, , Oka H, , Sato S, , Suzuki S, , Shimizu S, & Tanaka S, et al.: Possibility of using laser spectroscopy for the intraoperative detection of nonfluorescing brain tumors and the boundaries of brain tumor infiltrates. Technical note J Neurosurg 104:618620, 2006

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Valdés PA, , Bekelis K, , Harris BT, , Wilson BC, , Leblond F, & Kim A, et al.: 5-Aminolevulinic acid-induced protoporphyrin IX fluorescence in meningioma: qualitative and quantitative measurements in vivo. Neurosurgery 10:Suppl 1 7483, 2014

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Valdés PA, , Fan X, , Ji S, , Harris BT, , Paulsen KD, & Roberts DW: Estimation of brain deformation for volumetric image updating in protoporphyrin IX fluorescence-guided resection. Stereotact Funct Neurosurg 88:110, 2010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    Valdés PA, , Leblond F, , Jacobs VL, , Paulsen KD, & Roberts DW: In vivo fluorescence detection in surgery: A review of principles, methods, and applications. Curr Med Imaging Rev 8:211232, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45

    Valdés PA, , Jacobs VL, , Wilson BC, , Leblond F, , Roberts DW, & Paulsen KD: System and methods for wide-field quantitative fluorescence imaging during neurosurgery. Opt Lett 38:27862788, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46

    Valdés PA, , Kim A, , Brantsch M, , Niu C, , Moses ZB, & Tosteson TD, et al.: d-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. Neuro Oncol 13:846856, 2011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47

    Valdés PA, , Kim A, , Leblond F, , Conde OM, , Harris BT, & Paulsen KD, et al.: Combined fluorescence and reflectance spectroscopy for in vivo quantification of cancer biomarkers in low- and high-grade glioma surgery. J Biomed Opt 16:116007, 2011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48

    Valdés PA, , Leblond F, , Jacobs VL, , Wilson BC, , Paulsen KD, & Roberts DW: Quantitative, spectrally-resolved intraoperative fluorescence imaging. Sci Rep 2:798, 2012

  • 49

    Valdés PA, , Leblond F, , Kim A, , Harris BT, , Wilson BC, & Fan X, et al.: Quantitative fluorescence in intracranial tumor: implications for ALA-induced PpIX as an intraoperative biomarker. J Neurosurg 115:1117, 2011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50

    Valdés PA, , Leblond F, , Kim A, , Wilson BC, , Paulsen KD, & Roberts DW: A spectrally constrained dual-band normalization technique for protoporphyrin IX quantification in fluorescence-guided surgery. Opt Lett 37:18171819, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51

    Weissleder R, & Pittet MJ: Imaging in the era of molecular oncology. Nature 452:580589, 2008

  • 52

    Widhalm G, , Wolfsberger S, , Minchev G, , Woehrer A, , Krssak M, & Czech T, et al.: 5-aminolevulinic acid is a promising marker for detection of anaplastic foci in diffusely infiltrating gliomas with nonsignificant contrast enhancement. Cancer 116:15451552, 2010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

Metrics

All Time Past Year Past 30 Days
Abstract Views 485 485 47
Full Text Views 1822 134 0
PDF Downloads 1337 122 1
EPUB Downloads 0 0 0