Skip to main content
SpringerLink
Log in

Möglichkeiten und Grenzen der Fluoreszenzdiagnostik und photodynamischen Therapie

Teil 1: Fluoreszenzdiagnostik

  • Weiterbildung—Zertifizierte Fortbildung
  • Published:
HNO Aims and scope Submit manuscript

Zusammenfassung

Fluoreszenzdiagnostische Verfahren ermöglichen eine visuelle Tumordarstellung durch gezielte Anregung gewebeeigener oder von außen zugeführter, tumorselektiver Fluoreszenzmarker und Messung der hierbei hervorgerufenen Fluoreszenzsignale. In der folgenden Übersicht sollen dem Leser die HNO-relevanten Aspekte dieser Verfahren anschaulich und umfangreich näher gebracht werden. Nebst einer Veranschaulichung der klinischen Problematik in der Diagnostik von Malignomen des oberen Aerodigestivtraktes, einem geschichtlichen Abriss der Fluoreszenzdiagnostik sowie einer Klärung der biophysikalischen Grundlagen liegen die Schwerpunkte dieser Publikation in einer ausführlichen Darstellung des derzeitigen Forschungsstandes sowie einer kritischen Auseinandersetzung mit 2 kommerziell erhältlichen Systemen für die HNO-Onkologie. Durch einen kurzen Ausblick auf zukünftige Aktivitäten in diesem Gebiet wird der Themenkreis für den Leser abgerundet.

Abstract

Fluorescence diagnostic methods enable tumor visualization via specific excitation of endogenous or exogenous tumor-selective fluorescent markers and subsequent optical measurement of the induced fluorescence signals. In the following review, the reader will be given a clear and extensive understanding of all aspects of these methods relevant for ENT specialists. Apart from a demonstration of the clinical difficulties in the diagnosis of malignant tumors of the upper aerodigestive tract, a historical synopsis of fluorescence diagnosis and an explanation of the biophysical basics, this publication focuses mainly on a detailed discussion of the current status of research and a critical consideration of the commercially available systems for fluorescence diagnosis in ENT oncology. The topic is rounded off by a short account of possible future activities in this field.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1
Abb. 2
Abb. 3
Abb. 4
Abb. 5
Abb. 6
Abb. 7
Abb. 8

Literatur

  1. Ackermann G, Abels C, Bäumler W et al. (1998) Simulations on the selectivity of 5-aminolaevulinic acid-induced fluorescence in vivo. J Photochem Photobiol B 38: 121–128

    Article  Google Scholar 

  2. Alfano RR, Tata DB, Cordero J et al. (1984) Laser induced fluorescence spectroscopy from native cancerous and normal tissue. IEEE J Quant Electron QE-20: 1507–1511

    Google Scholar 

  3. Andersen FA (2001) Final report on the safety assessment of Hypericum perforatum extract and Hypericum perforatum oil. Int J Toxicol 20 (Suppl 2): 31–39

    Article  PubMed  Google Scholar 

  4. Arens C, Malzahn K, Dias O, Andrea M, Glanz H (1999) Endoskopische bildgebende Verfahren in der Diagnostik des Kehlkopfkarzinoms und seiner Vorstufen. Laryngorhinootologie 78: 685–691

    Article  CAS  PubMed  Google Scholar 

  5. Auler H, Banzer G (1942) Untersuchungen über die Rolle der Porphyrine bei geschwulstkranken Menschen und Tieren. Z Krebsforsch 53: 65–68

    CAS  Google Scholar 

  6. Baumgartner R, Kriegmair M, Hofstetter A (1999) Fluoreszenzdiagnostik des Harnblasenkarzinoms mit 5-Aminolävulinsäure (Grundlagen und Ergebnisse). Endo-Press, Tuttlingen

  7. Betz CS, Mehlmann M, Rick K et al. (1999) Autofluorescence imaging and spectroscopy of normal and malignant mucosa in patients with head and neck cancer. Lasers Surg Med 25: 323–334

    PubMed  Google Scholar 

  8. Betz CS, Stepp H, Janda P et al. (2002) A comparative study of normal inspection, autofluorescence and 5-ALA- induced PPIX fluorescence for oral cancer diagnosis. Int J Cancer 97: 245–252

    Article  CAS  PubMed  Google Scholar 

  9. Chen B, de Witte PA (2000) Photodynamic therapy efficacy and tissue distribution of hypericin in a mouse P388 lymphoma tumor model. Cancer Lett 150: 111–117

    CAS  PubMed  Google Scholar 

  10. Chen TY, Emrich LJ, Driscoll DL (1987) The clinical significance of pathological findings in surgically resected margins of the primary tumor in head and neck carcinoma. Int J Radiat Oncol Biol Phys 13: 833–837

    CAS  PubMed  Google Scholar 

  11. D’Hallewin MA, de Witte PA, Waelkens E, Merlevede W, Baert L (2000) Fluorescence detection of flat bladder carcinoma in situ after intravesical instillation of hypericin. J Urol 164: 349–351

    CAS  PubMed  Google Scholar 

  12. Delank W, Khanavkar B, Nakhosteen JA, Stoll W (2000) A pilot study of autofluorescent endoscopy for the in vivo detection of laryngeal cancer. Laryngoscope 110: 368–373

    CAS  PubMed  Google Scholar 

  13. Dhingra JK, Perrault DF Jr, McMillan K et al. (1996) Early diagnosis of upper aerodigestive tract cancer by autofluorescence. Arch Otolaryngol Head Neck Surg 122: 1181–1186

    CAS  PubMed  Google Scholar 

  14. Dhingra JK, Zhang X, McMillan K et al. (1998) Diagnosis of head and neck precancerous lesions in an animal model using fluorescence spectroscopy. Laryngoscope 108: 471–475

    CAS  PubMed  Google Scholar 

  15. Dunn RJ, Devine KD (1972) Tetracycline-induced fluorescence of laryngeal, pharyngeal, and oral cancer. Laryngoscope 82: 189–198

    CAS  PubMed  Google Scholar 

  16. Dunsche A, Harle F (2000) Die Krebsvorstufen der Mundschleimhaut—eine Übersicht. Laryngorhinootologie 79: 423–427

    Article  CAS  PubMed  Google Scholar 

  17. Ebihara A, Krasieva TB, Liaw LH et al. (2003) Detection and diagnosis of oral cancer by light-induced fluorescence. Lasers Surg Med 32: 17–24

    Article  PubMed  Google Scholar 

  18. Figge FHJ, Weiland GS, Manganiello LOJ (1948) Cancer detection and therapy: Affinity of neoplastic, embryonic and traumatized tissues for porphyrins and metalloporphyrins. Proc Soc Exp Biol Med 68: 640–641

    CAS  Google Scholar 

  19. Firenzuoli F, Gori L (1999) Toxicity of Hypericum perforatum. Forsch Komplementarmed 6: 271

    Article  CAS  PubMed  Google Scholar 

  20. Fryen A, Glanz H, Lohmann W, Dreyer T, Bohle RM (1997) Significance of autofluorescence for the optical demarcation of field cancerisation in the upper aerodigestive tract. Acta Otolaryngol Stockh 117: 316–319

    CAS  PubMed  Google Scholar 

  21. Ghadially FN (1960) Red fluorescence of experimentally induced and human tumors. J Pathol Bacteriol 80: 345–351

    CAS  PubMed  Google Scholar 

  22. Ghadially FN, Neish WJP (1960) Porphyrin fluorescence of experimentally produced squamous cell carcinoma. Nature 188: 1124–1124

    CAS  PubMed  Google Scholar 

  23. Ghadially FN, Neish WJP, Dawkins HC (1963) Mechanisms involved in the production of red fluorescence of human and experimental tumours. J Path Bact 85: 77–90

    CAS  PubMed  Google Scholar 

  24. Harries ML, Lam S, MacAulay C, Qu J, Palcic B (1995) Diagnostic imaging of the larynx: autofluorescence of laryngeal tumours using the helium-cadmium laser. J Laryngol Otol 109: 108–110

    PubMed  Google Scholar 

  25. Harris DM, Werkhaven J (1987) Endogenous porphyrin fluorescence in tumors. Lasers Surg Med 7: 467–472

    CAS  PubMed  Google Scholar 

  26. Hölzel D, Klamert A, Schmidt M (1996) Übersichtstabellen. In: Krebs: Häufigkeiten, Befunde und Behandlungsergebnisse. W. Zuckschwerdt, Germering/München, S 491–534

  27. Inaguma M, Hashimoto K (1999) Porphyrin-like fluorescence in oral cancer: In vivo fluorescence spectral characterization of lesions by use of a near-ultraviolet excited autofluorescence diagnosis system and separation of fluorescent extracts by capillary electrophoresis. Cancer 86: 2201–2211

    Article  CAS  PubMed  Google Scholar 

  28. Ingrams DR, Dhingra JK, Roy K et al. (1997) Autofluorescence characteristics of oral mucosa. Head Neck 19: 27–32

    Article  CAS  PubMed  Google Scholar 

  29. Jacobson EL, Jacobson MK (1976) Pyridine nucleotide levels as a function of growth in normal and transformed 3T3 cells. Arch Biochem Biophys 175: 627–634

    CAS  PubMed  Google Scholar 

  30. Kennedy JC, Pottier RH (1992) Endogenous Protoporphyrin IX, a clinically useful photosensitizer for photodynamic therapy. J Photochem Photobiol B 14: 275–292

    CAS  PubMed  Google Scholar 

  31. Kennedy JC, Pottier RH, Pross DC (1990) Photodynamic therapy with endogenous Protoporphyrin IX: basic principles and present clinical experience. J Photochem Photobiol B 6: 143–148

    CAS  PubMed  Google Scholar 

  32. Kluftinger AM, Davis NL, Quenville NF et al. (1992) Detection of squamous cell cancer and pre-cancerous lesions by imaging of tissue autofluorescence in the hamster cheek pouch model. Surg Oncol 1: 183–188

    CAS  PubMed  Google Scholar 

  33. König F, McGovern FJ, Althausen AF, Deutsch TF, Schomacker KT (1996) Laser induced autofluorescence diagnosis of bladder cancer. J Urol 156: 1597–1601

    PubMed  Google Scholar 

  34. Kolli VR, Savage HE, Yao TJ, Schantz SP (1995) Native cellular fluorescence of neoplastic upper aerodigestive mucosa. Arch Otolaryngol Head Neck Surg 121: 1287–1292

    CAS  PubMed  Google Scholar 

  35. Kolli VR, Shaha AR, Savage HE et al. (1995) Native cellular fluorescence can identify changes in epithelial thickness in-vivo in the upper aerodigestive tract. Am J Surg 170: 495–498

    Article  CAS  PubMed  Google Scholar 

  36. Kulapaditharom B, Boonkitticharoen V (1998) Laser-induced fluorescence imaging in localization of head and neck cancers. Ann Otol Rhinol Laryngol 107: 241–246

    CAS  PubMed  Google Scholar 

  37. Lam S, MacAulay C, Hung J et al. (1993) Detection of dysplasia and carcinoma in situ with a lung imaging fluorescence endoscope device. J Thorac Cardiovasc Surg 105: 1035–1040

    CAS  PubMed  Google Scholar 

  38. Langer S, Abels C, Botzlar A et al. (1999) Active and higher intracellular uptake of 5-aminolevulinic acid in tumors may be inhibited by glycine. J Invest Dermatol 112: 723–728

    Article  CAS  PubMed  Google Scholar 

  39. Leonard JR, Beck W (1971) Hematoporphyrin fluorescence: an aid in diagnosis of malignant neoplasms. Laryngoscope 81: 365–372

    CAS  PubMed  Google Scholar 

  40. Leunig A, Betz CS (2003) Fluoreszenzdiagnostik in der HNO-Heilkunde. In: Szeimies R-M, Jocham D, Landthaler M (Hrsg) Klinische Fluoreszenzdiagnostik und Photodynamische Therapie. Blackwell, Berlin, S 106–119

  41. Leunig A, Betz CS, Mehlmann M et al. (2000) Detection of squamous cell carcinoma of the oral cavity by imaging 5-aminolevulinic acid-induced Protoporphyrin IX fluorescence. Laryngoscope 110: 78–83

    CAS  PubMed  Google Scholar 

  42. Leunig A, Rick K, Stepp H et al. (1996) Photodynamische Diagnostik von Neoplasien der Mundhöhle nach lokaler Applikation von 5-Aminolävulinsäure. Laryngol Rhinol Otol Stuttg 75: 459–464

    CAS  Google Scholar 

  43. Leunig A, Rick K, Stepp H et al. (1996) Fluorescence imaging and spectroscopy of 5-aminolevulinic acid induced protoporphyrin IX for the detection of neoplastic lesions in the oral cavity. Am J Surg 172: 674–677

    Article  CAS  PubMed  Google Scholar 

  44. Lippert BM, Külkens C, Klahr N, Folz BJ, Werner JA (2000) 5-Delta-Aminolävulinsäure induzierte Fluoreszenzdiagnostik bei Karzinomen der oberen Luft- und Speisewege—erste Ergebnisse. In: Lippert BM, Schmidt S, Werner JA (Hrsg) Fluoreszenzdiagnostik und Photodynamische Therapie. Shaker, Aachen, S 65–73

  45. Lipson RL, Baldes EJ, Olsen AM (1961) The use of a derivative of hematoporphyrin in tumor detection. J Natl Cancer Inst 26: 1–11

    CAS  PubMed  Google Scholar 

  46. Malzahn K, Dreyer T, Glanz H, Arens C (2002) Autofluorescence endoscopy in the diagnosis of early laryngeal cancer and its precursor lesions. Laryngoscope 112: 488–493

    PubMed  Google Scholar 

  47. Mehlmann M, Betz CS, Stepp H et al. (1999) Fluorescence staining of laryngeal neoplasms after topical application of 5-aminolevulinic acid: preliminary results. Lasers Surg Med 25: 414–420

    Article  CAS  PubMed  Google Scholar 

  48. Monnier P, Savary M, Fontolliet C et al. (1990) Photodetection and photodynamic therapy of „early“ squamous cell carcinomas of the pharynx, oesophagus and tracheo-bronchial tree. Lasers Med Sci 5: 149–169

    Google Scholar 

  49. Navone NM, Polo CF, Frisardi AL, Andrade NE, del C.Batlle AM (1990) Heme biosynthesis in human breast cancer--mimetic „in vitro“ studies and some heme enzymic activity levels. Int J Biochem 22: 1407–1411

    Article  CAS  PubMed  Google Scholar 

  50. Okpanyi SN, Lidzba H, Scholl BC, Miltenburger HG (1990) Genotoxizität eines standardisierten Hypericum-Extraktes. Arzneimittelforschung 40: 851–855

    CAS  PubMed  Google Scholar 

  51. Onizawa K, Okamura N, Saginoya H et al. (2002) Analysis of fluorescence in oral squamous cell carcinoma. Oral Oncol 38: 343–348

    Article  PubMed  Google Scholar 

  52. Onizawa K, Saginoya H, Furuya Y, Yoshida H (1996) Fluorescence photography as a diagnostic method for oral cancer. Cancer Lett 108: 61–66

    Article  CAS  PubMed  Google Scholar 

  53. Onizawa K, Saginoya H, Furuya Y, Yoshida H, Fukuda H (1999) Usefulness of fluorescence photography for diagnosis of oral cancer. Int J Oral Maxillofac Surg 28: 206–210

    Article  CAS  PubMed  Google Scholar 

  54. Onizawa K, Yoshida H, Saginoya H (2000) Chromatic analysis of autofluorescence emitted from squamous cell carcinomas arising in the oral cavity: a preliminary study. Int J Oral Maxillofac Surg 29: 42–46

    Article  CAS  PubMed  Google Scholar 

  55. Ortel B, Chen N, Brissette J et al. (1998) Differentiation-specific increase in ALA-induced protoporphyrin IX accumulation in primary mouse keratinocytes. Br J Cancer 77: 1744–1751

    CAS  PubMed  Google Scholar 

  56. Policard A (1924) Etude sur les aspects offerts par des tumeurs experimentales examinées à la lumière de Wood. Compte-rendus Soc Biol 91: 1423–1424

    Google Scholar 

  57. Pollack MA, Taylor A, Taylor J, Williams RJ (1942) B vitamins in cancerous tissues. I. Riboflavins. Cancer Res 2: 739–743

    CAS  Google Scholar 

  58. Rasetti L, Rubino GF, Drago W (1967) Ferrochelatase, ALA-dehydrase and ALA-synthetase activity in human tumor tissues. Panminerva Med 57: 2834–2837

    Google Scholar 

  59. Rassmussen-Taxdal DS, Ward GE, Figge FHJ (1955) Fluorescence of human lymphatic and cancer tissues following high doses of intravenous hematoporphyrin. Cancer 8: 78–81

    PubMed  Google Scholar 

  60. Richards-Kortum R, Sevick-Muraca E (1996) Quantitative optical spectroscopy for tissue diagnosis. Annu Rev Phys Chem 47: 555–606

    Article  CAS  PubMed  Google Scholar 

  61. Ronchese F (1954) The fluorescence of cancer under the Wood light. Oral Surg 7: 967–971

    PubMed  Google Scholar 

  62. Ronchese F, Walker BS, Young RM (1954) The reddish-orange fluorescence of necrotic cancerous surfaces under the Wood light. Arch Derm Syph N Y 69: 31–42

    Google Scholar 

  63. Rubino GF, Rasetti L (1966) Porphyrin metabolism in human neoplastic tissues. Panminerva Med 8: 290–292

    CAS  PubMed  Google Scholar 

  64. Schantz SP, Kolli V, Savage HE et al. (1998) In vivo native cellular fluorescence and histological characteristics of head and neck cancer. Clin Cancer Res 4: 1177–1182

    CAS  PubMed  Google Scholar 

  65. Schneckenburger H, Gschwend M, Paul R-J et al. (1994) Time-gated spectroscopy of intrinsic fluorophores in cells and tissues. In: Chubeddu R, Marchesini R, Mordon SR et al. (eds) Optical biopsy and fluorescence spectroscopy and imaging. Proc SPIE 2324: 187–195

    CAS  Google Scholar 

  66. Schomacker KT, Frisoli JK, Compton CC et al. (1992) Ultraviolet laser-induced fluorescence of colonic tissue: basic biology and diagnostic potenzial. Lasers Surg Med 12: 63–78

    CAS  PubMed  Google Scholar 

  67. Schwartz JP, Passonneau JV, Johnson GS, Pastan I (1974) The effect of growth conditions on NAD+ and NADH concentrations and the NAD+: NADH ratio in normal and transformed fibroblasts. J Biol Chem 249: 4138–4143

    CAS  PubMed  Google Scholar 

  68. Silverman S Jr (1988) Early diagnosis of oral cancer. Cancer 62: 1796–1799

    PubMed  Google Scholar 

  69. Sommer K, Diddens H, Hüttmann G, Remmert S (1995) Experimentelle Untersuchungen zur Fluoreszenzdiagnostik von Plattenepithelkarzinomen der Zunge und in der Mundhöhle mit lokal applizierter 5-Aminolävulinsäure (ALA). HNO-Informationen 20: 147

    Google Scholar 

  70. Statistisches Bundesamt (2000) Gesundheitsberichterstattung des Bundes. Statistisches Bundesamt/Robotron Datenbank-Software GmbH

  71. van Hillegersberg R, van den Berg JW, Kort WJ, Terpstra OT, Wilson JH (1992) Selective accumulation of endogenously produced porphyrins in a liver metastasis model in rats. Gastroenterology 103: 647–651

    PubMed  Google Scholar 

  72. van Staveren HJ, van Veen RL, Speelman OC et al. (2000) Classification of clinical autofluorescence spectra of oral leukoplakia using an artificial neural network: a pilot study. Oral Oncol 36: 286–293

    Article  PubMed  Google Scholar 

  73. Vandenbogaerde AL, Geboes KR, Cuveele JF et al. (1996) Antitumour activity of photosensitized hypericin on A431 cell xenografts. Anticancer Res 16: 1619–1625

    CAS  PubMed  Google Scholar 

  74. Wagnieres GA, Studzinski AP, Braichotte DR et al. (1997) Clinical imaging fluorescence apparatus for the endoscopic photodetection of early cancers by the use of Photofrin II. Applied-Optics 36: 5608–5620

  75. Wang CY, Chen CT, Chiang CP et al. (1999) A probability-based multivariate statistical algorithm for autofluorescence spectroscopic identification of oral carcinogenesis. Photochem Photobiol 69: 471–477

    CAS  PubMed  Google Scholar 

  76. Wang CY, Chiang HK, Chen CT et al. (1999) Diagnosis of oral cancer by light-induced autofluorescence spectroscopy using double excitation wavelengths. Oral Oncol 35: 144–150

    Article  CAS  PubMed  Google Scholar 

  77. Xie X, Hudson JB, Guns ES (2001) Tumor-specific and photodependent cytotoxicity of hypericin in the human LNCaP prostate tumor model. Photochem Photobiol 74: 221–225

    CAS  PubMed  Google Scholar 

  78. Yang YL, Ye YM, Li FM, Li YF, Ma PZ (1987) Characteristic autofluorescence for cancer diagnosis and its origin. Lasers Surg Med 7: 528–532

    CAS  PubMed  Google Scholar 

  79. Zargi M, Fajdiga I, Smid L (2000) Autofluorescence imaging in the diagnosis of laryngeal cancer. Eur Arch Otorhinolaryngol 257: 17–23

    CAS  PubMed  Google Scholar 

  80. Zargi M, Fajdiga I, Smid L (2002) From microlaryngoscopy to fluorescence laryngeal endoscopy. Zdrav Vestn 71-III: 65–68

    Google Scholar 

  81. Zargi M, Smid L, Fajdiga I et al. (1997) Detection and localization of early laryngeal cancer with laser- induced fluorescence: preliminary report. Eur Arch Otorhinolaryngol Suppl 254: S113–6

    Google Scholar 

  82. Zargi M, Smid L, Fajdiga I et al. (1997) Laser induced fluorescence in diagnostics of laryngeal cancer. Acta Otolaryngol Suppl Stockh 125–127

  83. Zenk W, Dietel W, Schleier P, Gunzel S (1999) Visualisierung von Karzinomen der Mundhohle durch Stimulierung der Synthese von fluoreszierendem Protoporphyrin IX. Mund Kiefer Gesichtschir 3: 205–209

    Article  CAS  PubMed  Google Scholar 

  84. Zhang JC, Savage HE, Sacks PG et al. (1997) Innate cellular fluorescence reflects alterations in cellular proliferation. Lasers Surg Med 20: 319–331

    Article  CAS  PubMed  Google Scholar 

Download references

Danksagung

Die Untersuchungen der eigenen Arbeitsgruppe wurden unterstützt durch die Wilhelm-Sander-Stiftung, Förderkennzeichen 96.080.1/2.

Author information

Authors and Affiliations

  1. Klinik für Hals-, Nasen- und Ohrenheilkunde der Ludwig-Maximilians-Universität, Klinikum Großhadern, München

    C. S. Betz & A. Leunig

  2. Hals-Nasen-Ohren-Klinik der Ludwig-Maximilians-Universität, Klinikum Großhadern, Marchionistraße 15, 81366 , München

    C. S. Betz

Authors
  1. C. S. Betz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Leunig
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C. S. Betz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Betz, C.S., Leunig, A. Möglichkeiten und Grenzen der Fluoreszenzdiagnostik und photodynamischen Therapie. HNO 51, 1019–1035 (2003). https://doi.org/10.1007/s00106-003-0960-5

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00106-003-0960-5

Schlüsselwörter

Keywords

Search

Navigation