Resection of Brain Tumors: Intraoperative Confocal Microscopy Technology

  • Nader SanaiEmail author
  • Robert F. Spetzler
Part of the Tumors of the Central Nervous System book series (TCNS, volume 13)


The ability to diagnose brain tumors in vivo and reliably identify tumor margins in the course of resection are two innovations that could impact the neurosurgical oncologist’s ability to maximize resection and minimize morbidity. Recent advances in optical imaging and miniaturization have enabled the production of a hand-held intraoperative confocal microscope. We present a first-look feasibility analysis of the intraoperative confocal microscope as an adjunct for brain tumor resection. Intraoperative confocal microscopy is an emerging and practicable technology for the resection of human brain tumors. Our preliminary assessment indicates the reliability of this technique for a variety of lesions in identifying tumor cell populations, as well as the tumor-brain interface, in situ. Further refinement of this technology may depend upon the approval of tumor-specific fluorescent contrast agents for human use.


Central Neurocytomas Optical Biopsy Anaplastic Transformation Glioma Surgery Meningothelial Meningioma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Alexander E III, Moriarty TM, Kikinis R, Black P, Jolesz FM (1997) The present and future role of intraoperative MRI in neurosurgical procedures. Stereotact Funct Neurosurg 68:10–17PubMedCrossRefGoogle Scholar
  2. Becker DE, Ancin H, Szarowski DH, Turner JN, Roysam B (1996) Automated 3-D montage synthesis from laser-scanning confocal images: application to quantitative tissue-level cytological analysis. Cytometry 25:235–245PubMedCrossRefGoogle Scholar
  3. Brezinski ME, Tearney GJ, Bouma B, Boppart SA, Pitris C, Southern JF et al (1998) Optical biopsy with optical coherence tomography. Ann N Y Acad Sci 838:68–74PubMedCrossRefGoogle Scholar
  4. Bussau LJ, Vo LT, Delaney PM, Papworth GD, Barkla DH, King RG (1998) Fibre optic confocal imaging (FOCI) of keratinocytes, blood vessels and nerves in hairless mouse skin in vivo. J Anat 192(Pt 2):187–194PubMedCentralPubMedCrossRefGoogle Scholar
  5. Delaney PM, King RG, Lambert JR, Harris MR (1994) Fibre optic confocal imaging (FOCI) for subsurface microscopy of the colon in vivo. J Anat 184(Pt 1):157–160PubMedCentralPubMedGoogle Scholar
  6. Dowling C, Bollen AW, Noworolski SM, McDermott MW, Barbaro NM, Day MR et al (2001) Preoperative proton MR spectroscopic imaging of brain tumors: correlation with histopathologic analysis of resection specimens. AJNR Am J Neuroradiol 22:604–612PubMedGoogle Scholar
  7. Duffner F, Ritz R, Freudenstein D, Weller M, Dietz K, Wessels J (2005) Specific intensity imaging for glioblastoma and neural cell cultures with 5-aminolevulinic acid-derived protoporphyrin IX. J Neurooncol 71:107–111PubMedCrossRefGoogle Scholar
  8. Eschbacher J, Martirosyan NL, Nakaji P, Sanai N, Preul MC, Smith KA et al (2012) In vivo intraoperative confocal microscopy for real-time histopathological imaging of brain tumors. J Neurosurg 116:854–860PubMedCrossRefGoogle Scholar
  9. Floeth FW, Sabel M, Ewelt C, Stummer W, Felsberg J, Reifenberger G et al (2011) Comparison of (18)F-FET PET and 5-ALA fluorescence in cerebral gliomas. Eur J Nucl Med Mol Imaging 38:731–741PubMedCrossRefGoogle Scholar
  10. Flusberg BA, Cocker ED, Piyawattanametha W, Jung JC, Cheung EL, Schnitzer MJ (2005) Fiber-optic fluorescence imaging. Nat Methods 2:941–950PubMedCentralPubMedCrossRefGoogle Scholar
  11. Flusberg BA, Nimmerjahn A, Cocker ED, Mukamel EA, Barretto RP, Ko TH et al (2008) High-speed, miniaturized fluorescence microscopy in freely moving mice. Nat Methods 5:935–938PubMedCentralPubMedCrossRefGoogle Scholar
  12. Helmchen F (2002) Miniaturization of fluorescence microscopes using fibre optics. Exp Physiol 87:737–745PubMedCrossRefGoogle Scholar
  13. Hoffman A, Goetz M, Vieth M, Galle PR, Neurath MF, Kiesslich R (2006) Confocal laser endomicroscopy: technical status and current indications. Endoscopy 38:1275–1283PubMedCrossRefGoogle Scholar
  14. Ishihara R, Katayama Y, Watanabe T, Yoshino A, Fukushima T, Sakatani K (2007) Quantitative spectroscopic analysis of 5-aminolevulinic acid-induced protoporphyrin IX fluorescence intensity in diffusely infiltrating astrocytomas. Neurol Med Chir (Tokyo) 47:53–57CrossRefGoogle Scholar
  15. Khoshyomn S, Penar PL, McBride WJ, Taatjes DJ (1998) Four-dimensional analysis of human brain tumor spheroid invasion into fetal rat brain aggregates using confocal scanning laser microscopy. J Neurooncol 38:1–10PubMedCrossRefGoogle Scholar
  16. Kiesslich R, Goetz M, Vieth M, Galle PR, Neurath MF (2005) Confocal laser endomicroscopy. Gastrointest Endosc Clin N Am 15:715–731PubMedCrossRefGoogle Scholar
  17. Koenig F, Knittel J, Stepp H (2001) Diagnosing cancer in vivo. Science 292:1401–1403PubMedCrossRefGoogle Scholar
  18. Kondziolka D, Lunsford LD, Martinez AJ (1993) Unreliability of contemporary neurodiagnostic imaging in evaluating suspected adult supratentorial (low-grade) astrocytoma. J Neurosurg 79:533–536PubMedCrossRefGoogle Scholar
  19. LeRoux PD, Berger MS, Ojemann GA, Wang K, Mack LA (1989) Correlation of intraoperative ultrasound tumor volumes and margins with preoperative computerized tomography scans. An intraoperative method to enhance tumor resection. J Neurosurg 71:691–698PubMedCrossRefGoogle Scholar
  20. Liao H, Noguchi M, Maruyama T, Muragaki Y, Kobayashi E, Iseki H et al (2012) An integrated diagnosis and therapeutic system using intra-operative 5-aminolevulinic-acid-induced fluorescence guided robotic laser ablation for precision neurosurgery. Med Image Anal 16:754–766PubMedCrossRefGoogle Scholar
  21. Lim DA, Cha S, Mayo MC, Chen MH, Keles E, VandenBerg S et al (2007) Relationship of glioblastoma multiforme to neural stem cell regions predicts invasive and multifocal tumor phenotype. Neuro Oncol 9:424–429PubMedCentralPubMedCrossRefGoogle Scholar
  22. Muragaki Y, Chernov M, Maruyama T, Ochiai T, Taira T, Kubo O et al (2008) Low-grade glioma on stereotactic biopsy: how often is the diagnosis accurate? Minim Invasive Neurosurg 51:275–279PubMedCrossRefGoogle Scholar
  23. Nabavi A, Thurm H, Zountsas B, Pietsch T, Lanfermann H, Pichlmeier U et al (2009) Five-aminolevulinic acid for fluorescence-guided resection of recurrent malignant gliomas: a phase ii study. Neurosurgery 65:1070–1076PubMedCrossRefGoogle Scholar
  24. Papworth GD, Delaney PM, Bussau LJ, Vo LT, King RG (1998) In vivo fibre optic confocal imaging of microvasculature and nerves in the rat vas deferens and colon. J Anat 192(Pt 4):489–495PubMedCentralPubMedCrossRefGoogle Scholar
  25. Polglase AL, McLaren WJ, Skinner SA, Kiesslich R, Neurath MF, Delaney PM (2005) A fluorescence confocal endomicroscope for in vivo microscopy of the upper- and the lower-GI tract. Gastrointest Endosc 62:686–695PubMedCrossRefGoogle Scholar
  26. Roberts DW, Valdes PA, Harris BT, Fontaine KM, Hartov A, Fan X et al (2011) Coregistered fluorescence-enhanced tumor resection of malignant glioma: relationships between delta-aminolevulinic acid-induced protoporphyrin IX fluorescence, magnetic resonance imaging enhancement, and neuropathological parameters. Clinical article. J Neurosurg 114:595–603PubMedCentralPubMedCrossRefGoogle Scholar
  27. Sanai N, Berger MS (2008) Glioma extent of resection and its impact on patient outcome. Neurosurgery 62:753–764PubMedCrossRefGoogle Scholar
  28. Sanai N, Varez-Buylla A, Berger MS (2005) Neural stem cells and the origin of gliomas. N Engl J Med 353:811–822PubMedCrossRefGoogle Scholar
  29. Sanai N, Snyder LA, Honea NJ, Coons SW, Eschbacher JM, Smith KA et al (2011) Intraoperative confocal microscopy in the visualization of 5-aminolevulinic acid fluorescence in low-grade gliomas. J Neurosurg 115:740–748PubMedCrossRefGoogle Scholar
  30. Stockhammer F, Misch M, Horn P, Koch A, Fonyuy N, Plotkin M (2009) Association of F18-fluoro-ethyl-tyrosin uptake and 5-aminolevulinic acid-induced fluorescence in gliomas. Acta Neurochir (Wien) 151:1377–1383CrossRefGoogle Scholar
  31. Stummer W, Stepp H, Moller G, Ehrhardt A, Leonhard M, Reulen HJ (1998) Technical principles for protoporphyrin-IX-fluorescence guided microsurgical resection of malignant glioma tissue. Acta Neurochir (Wien) 140:995–1000CrossRefGoogle Scholar
  32. Stummer W, Reulen HJ, Novotny A, Stepp H, Tonn JC (2003) Fluorescence-guided resections of malignant gliomas – an overview. Acta Neurochir Suppl 88:9–12PubMedGoogle Scholar
  33. Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ (2006) Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 7:392–401PubMedCrossRefGoogle Scholar
  34. Tadrous PJ (2000) Methods for imaging the structure and function of living tissues and cells: 3. Confocal microscopy and micro-radiology. J Pathol 191:345–354PubMedCrossRefGoogle Scholar
  35. Tilgner J, Herr M, Ostertag C, Volk B (2005) Validation of intraoperative diagnoses using smear preparations from stereotactic brain biopsies: intraoperative versus final diagnosis—influence on clinical factors. Neurosurgery 56:257–265PubMedCrossRefGoogle Scholar
  36. Toms SA, Lin WC, Weil RJ, Johnson MD, Jansen ED, Mahadevan-Jansen A (2005) Intraoperative optical spectroscopy identifies infiltrating glioma margins with high sensitivity. Neurosurgery 57:382–391PubMedCrossRefGoogle Scholar
  37. Tonn JC, Stummer W (2008) Fluorescence-guided resection of malignant gliomas using 5-aminolevulinic acid: practical use, risks, and pitfalls. Clin Neurosurg 55:20–26PubMedGoogle Scholar
  38. Uematsu Y, Owai Y, Okita R, Tanaka Y, Itakura T (2007) The usefulness and problem of intraoperative rapid diagnosis in surgical neuropathology. Brain Tumor Pathol 24:47–52PubMedCrossRefGoogle Scholar
  39. Van Meir EG, Hadjipanayis CG, Norden AD, Shu HK, Wen PY, Olson JJ (2010) Exciting new advances in neuro-oncology: the avenue to a cure for malignant glioma. CA Cancer J Clin 60:166–193PubMedCentralPubMedCrossRefGoogle Scholar
  40. Widhalm G, Wolfsberger S, Minchev G, Woehrer A, Krssak M, Czech T et al (2010) 5-Aminolevulinic acid is a promising marker for detection of anaplastic foci in diffusely infiltrating gliomas with nonsignificant contrast enhancement. Cancer 116:1545–1552PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  1. 1.Department of Neurosurgical Oncology, Barrow Brain Tumor Research Center, Barrow Neurological InstituteSt. Joseph’s Hospital and Medical CenterPhoenixUSA

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