Optical Imaging of Primary Tumors



The rapidly emerging field of optical imaging of tumors is an exciting area of translational research. A search in PubMed for “clinical optical imaging in cancer” reveals that the first article published was in 1964 and almost half of all the articles have been published in the last 5 years. Fluorescent probes and mechanisms to target them to cancer cells were developed for in vitro experiments and rodent models of cancer. However, with improvements in hardware, targeting agents, and fluorescent agents, optical imaging is rapidly gaining new and expanded applications in preclinical and clinical research. At the forefront of this field is the discovery of monoclonal antibodies as targeting agents and fluorescent markers that can reliably be conjugated to proteins, while minimizing interference from background fluorescence. Further sophistication and flexibility of imaging systems have and will allow these techniques to move further into the clinical realm. In this chapter, we will review the basic aspects of cancer optical imaging, including therapeutic, diagnostic, and surgical applications.


Single Photon Emission Compute Tomography Optical Imaging Photodynamic Therapy Cervical Intraepithelial Neoplasia Parathyroid Tissue 


  1. Barnett AA, Haller JC, Cairnduff F, Lane G, Brown SB, Roberts DJ: A randomised, double-blind, placebo-controlled trial of photodynamic therapy using 5-aminolaevulinic acid for the treatment of cervical intraepithelial neoplasia. Int J Cancer 2003, 103:829–832.CrossRefPubMedGoogle Scholar
  2. Barrett T, Koyama Y, Hama Y, Ravizzini G, Shin IS, Jang BS, Paik CH, Urano Y, Choyke PL, Kobayashi H: In vivo diagnosis of epidermal growth factor receptor expression using molecular imaging with a cocktail of optically labeled monoclonal antibodies. Clin Cancer Res 2007, 13:6639–6648.CrossRefPubMedGoogle Scholar
  3. Benya R, Quintana J, Brundage B: Adverse reactions to indocyanine green: a case report and a review of the literature. Cathet Cardiovasc Diagn 1989, 17:231–233.CrossRefPubMedGoogle Scholar
  4. Berg K, Selbo PK, Weyergang A, Dietze A, Prasmickaite L, Bonsted A, Engesaeter BO, Angell-Petersen E, Warloe T, Frandsen N, Hogset A: Porphyrin-related photosensitizers for cancer imaging and therapeutic applications. J Microsc 2005, 218:133–147.CrossRefPubMedGoogle Scholar
  5. Berger DP, Herbstritt L, Dengler WA, Marme D, Mertelsmann R, Fiebig HH: Vascular endothelial growth factor (VEGF) mRNA expression in human tumor models of different histologies. Ann Oncol 1995, 6:817–825.PubMedGoogle Scholar
  6. Bonner JA, De Los Santos J, Waksal HW, Needle MN, Trummel HQ, Raisch KP: Epidermal growth factor receptor as a therapeutic target in head and neck cancer. Semin Radiat Oncol 2002, 12:11–20.CrossRefPubMedGoogle Scholar
  7. Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J, et al.: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006, 354:567–578.CrossRefPubMedGoogle Scholar
  8. Braakhuis BJ, Tabor MP, Leemans CR, van der Waal I, Snow GB, Brakenhoff RH: Second primary tumors and field cancerization in oral and oropharyngeal cancer: molecular techniques provide new insights and definitions. Head Neck 2002, 24:198–206.CrossRefPubMedGoogle Scholar
  9. Casas A, Perotti C, Fukuda H, Rogers L, Butler AR, Batlle A: ALA and ALA hexyl ester-induced porphyrin synthesis in chemically induced skin tumours: the role of different vehicles on improving photosensitization. Br J Cancer 2001, 85:1794–1800.CrossRefPubMedGoogle Scholar
  10. Chang CJ, Wilder-Smith P: Topical application of photofrin for photodynamic diagnosis of oral neoplasms. Plast Reconstr Surg 2005, 115:1877–1886.CrossRefPubMedGoogle Scholar
  11. Cook JA, Jones AS, Phillips DE, Soler Lluch E: Implications of tumour in resection margins following surgical treatment of squamous cell carcinoma of the head and neck. Clin Otolaryngol Allied Sci 1993, 18:37–41.CrossRefPubMedGoogle Scholar
  12. Fradet Y, Grossman HB, Gomella L, Lerner S, Cookson M, Albala D, Droller MJ: A comparison of hexaminolevulinate fluorescence cystoscopy and white light cystoscopy for the detection of carcinoma in situ in patients with bladder cancer: a phase III, multicenter study. J Urol 2007, 178 :68–73; discussion 73.CrossRefPubMedGoogle Scholar
  13. Garanger E, Boturyn D, Dumy P: Tumor targeting with RGD peptide ligands-design of new molecular conjugates for imaging and therapy of cancers. Anticancer Agents Med Chem 2007, 7:552–558.PubMedGoogle Scholar
  14. Giusti RM, Shastri KA, Cohen MH, Keegan P, Pazdur R: FDA drug approval summary: panitumumab (Vectibix). Oncologist 2007, 12:577–583.CrossRefPubMedGoogle Scholar
  15. Giusti RM, Shastri K, Pilaro AM, Fuchs C, Cordoba-Rodriguez R, Koti K, Rothmann M, Men AY, Zhao H, Hughes M, et al.: U.S. Food and drug administration approval: panitumumab for epidermal growth factor receptor-expressing metastatic colorectal carcinoma with progression following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens. Clin Cancer Res 2008, 14:1296–1302.CrossRefPubMedGoogle Scholar
  16. Gleysteen JP, Duncan RD, Magnuson JS, Skipper JB, Zinn K, Rosenthal EL: Fluorescently labeled cetuximab to evaluate head and neck cancer response to treatment. Cancer Biol Ther 2007, 6: 1181–1185.Google Scholar
  17. Gleysteen JP, Newman JR, Chhieng D, Frost A, Zinn KR, Rosenthal EL: Fluorescent labeled anti-EGFR antibody for identification of regional and distant metastasis in a preclinical xenograft model. Head Neck 2008, 30(6):782–789.CrossRefPubMedGoogle Scholar
  18. De Grand AM, Frangioni JV: An operational near-infrared fluorescence imaging system prototype for large animal surgery. Technol Cancer Res Treat 2003, 2:553–562.PubMedGoogle Scholar
  19. Eljamel MS, Goodman C, Moseley H: ALA and Photofrin(R) Fluorescence-guided resection and repetitive PDT in glioblastoma multiforme: a single centre Phase III randomised controlled trial. Lasers Med Sci 2007, 23(4):361–367.CrossRefPubMedGoogle Scholar
  20. Hillemanns P, Korell M, Schmitt-Sody M, Baumgartner R, Beyer W, Kimmig R, Untch M, Hepp H: Photodynamic therapy in women with cervical intraepithelial neoplasia using topically applied 5-aminolevulinic acid. Int J Cancer 1999, 81:34–38.CrossRefPubMedGoogle Scholar
  21. Hillemanns P, Wang X, Hertel H, Andikyan V, Hillemanns M, Stepp H, Soergel P: Pharmacokinetics and selectivity of porphyrin synthesis after topical application of hexaminolevulinate in patients with cervical intraepithelial neoplasia. Am J Obstet Gynecol 2008, 198 :300.e1–300.e7.CrossRefGoogle Scholar
  22. Hirschberg H, Sorensen DR, Angell-Petersen E, Peng Q, Tromberg B, Sun CH, Spetalen S, Madsen S: Repetitive photodynamic therapy of malignant brain tumors. J Environ Pathol Toxicol Oncol 2006, 25:261–279.PubMedGoogle Scholar
  23. Hirschberg H, Sun CH, Tromberg BJ, Yeh AT, Madsen SJ: Enhanced cytotoxic effects of 5-aminolevulinic acid-mediated photodynamic therapy by concurrent hyperthermia in glioma spheroids. J Neurooncol 2004, 70:289–299.CrossRefPubMedGoogle Scholar
  24. Hockaday DC, Shen S, Fiveash J, Raubitschek A, Colcher D, Liu A, Alvarez V, Mamelak AN: Imaging glioma extent with 131I-TM-601. J Nucl Med 2005, 46:580–586.PubMedGoogle Scholar
  25. Hsu AR, Hou LC, Veeravagu A, Greve JM, Vogel H, Tse V, Chen X: In vivo near-infrared fluorescence imaging of integrin alphavbeta3 in an orthotopic glioblastoma model. Mol Imaging Biol 2006, 8:315–323.CrossRefPubMedGoogle Scholar
  26. Jin ZH, Josserand V, Foillard S, Boturyn D, Dumy P, Favrot MC, Coll JL: In vivo optical imaging of integrin alphaV-beta3 in mice using multivalent or monovalent cRGD targeting vectors. Mol Cancer 2007, 6:41.CrossRefPubMedGoogle Scholar
  27. Ke S, Wen X, Gurfinkel M, Charnsangavej C, Wallace S, Sevick-Muraca EM, Li C: Near-infrared optical imaging of epidermal growth factor receptor in breast cancer xenografts. Cancer Res 2003, 63:7870–7875.PubMedGoogle Scholar
  28. Kennedy JC, Pottier RH: Endogenous protoporphyrin IX, a clinically useful photosensitizer for photodynamic therapy. J Photochem Photobiol B 1992, 14:275–292.CrossRefPubMedGoogle Scholar
  29. Koyama Y, Barrett T, Hama Y, Ravizzini G, Choyke PL, Kobayashi H: In vivo molecular imaging to diagnose and subtype tumors through receptor-targeted optically labeled monoclonal antibodies. Neoplasia 2007a, 9:1021–1029.CrossRefPubMedGoogle Scholar
  30. Koyama Y, Hama Y, Urano Y, Nguyen DM, Choyke PL, Kobayashi H: Spectral fluorescence molecular imaging of lung metastases targeting HER2/neu. Clin Cancer Res 2007b, 13:2936–2945.CrossRefPubMedGoogle Scholar
  31. Kulbersh BD, Duncan RD, Magnuson JS, Skipper JB, Zinn K, Rosenthal EL: Sensitivity and specificity of fluorescent immunoguided neoplasm detection in head and neck cancer xenografts. Arch Otolaryngol Head Neck Surg 2007, 133:511–515.CrossRefPubMedGoogle Scholar
  32. Leunig A, Betz CS, Mehlmann M, Stepp H, Arbogast S, Grevers G, Baumgartner R: Detection of squamous cell carcinoma of the oral cavity by imaging 5-aminolevulinic acid-induced protoporphyrin IX fluorescence. Laryngoscope 2000, 110:78–83.CrossRefPubMedGoogle Scholar
  33. Liu J, Li J, Rosol TJ, Pan X, Voorhees JL: Biodegradable nanoparticles for targeted ultrasound imaging of breast cancer cells in vitro. Phys Med Biol 2007, 52:4739–4747.CrossRefPubMedGoogle Scholar
  34. Mamelak AN, Rosenfeld S, Bucholz R, Raubitschek A, Nabors LB, Fiveash JB, Shen S, Khazaeli MB, Colcher D, Liu A, et al.: Phase I single-dose study of intracavitary-administered iodine-131-TM-601 in adults with recurrent high-grade glioma. J Clin Oncol 2006, 24:3644–3650.CrossRefPubMedGoogle Scholar
  35. Marti A, Lange N, van den Bergh H, Sedmera D, Jichlinski P, Kucera P: Optimisation of the formation and distribution of protoporphyrin IX in the urothelium: an in vitro approach. J Urol 1999, 162:546–552.CrossRefPubMedGoogle Scholar
  36. Mayinger B, Neumann F, Kastner C, Degitz K, Hahn EG, Schwab D: Early detection of premalignant conditions in the colon by fluorescence endoscopy using local sensitization with hexaminolevulinate. Endoscopy 2008, 40:106–109.CrossRefPubMedGoogle Scholar
  37. McCarron PA, Ma LW, Juzenas P, Lani V, Woolfson A, Zawislak AA, Moan J: Facilitated delivery of ALA to inaccessible regions via bioadhesive patch systems. J Environ Pathol Toxicol Oncol 2006, 25:389–402.PubMedGoogle Scholar
  38. McMahon J, O'Brien CJ, Pathak I, Hamill R, McNeil E, Hammersley N, Gardiner S, Junor E: Influence of condition of surgical margins on local recurrence and disease-specific survival in oral and oropharyngeal cancer. Br J Oral Maxillofac Surg 2003, 41:224–231.CrossRefPubMedGoogle Scholar
  39. Mume E, Orlova A, Malmstrom PU, Lundqvist H, Sjoberg S, Tolmachev V: Radiobromination of humanized anti-HER2 monoclonal antibody trastuzumab using N-succinimidyl 5-bromo-3-pyridinecarboxylate, a potential label for immunoPET: Nucl Med Biol 2005, 32:613–622.CrossRefPubMedGoogle Scholar
  40. Newman JR, Gleysteen JP, Baranano CF, Bremser JR, Zhang W, Zinn KR, Rosenthal EL: Stereomicroscopic fluorescence imaging of head and neck cancer xenografts targeting CD147. Cancer Biol Ther 2008, 7:1063–1070.Google Scholar
  41. Overholt BF, Wang KK, Burdick JS, Lightdale CJ, Kimmey M, Nava HR, Sivak MV, Jr., Nishioka N, Barr H, Marcon N, et al.: Five-year efficacy and safety of photodynamic therapy with Photofrin in Barrett's high-grade dysplasia. Gastrointest Endosc 2007, 66:460–468.CrossRefPubMedGoogle Scholar
  42. Patrice T, Olivier D, Bourre L: PDT in clinics: indications, results, and markets. J Environ Pathol Toxicol Oncol 2006, 25:467–485.PubMedGoogle Scholar
  43. Pech O, Gossner L, May A, Rabenstein T, Vieth M, Stolte M, Berres M, Ell C: Long-term results of photodynamic therapy with 5-aminolevulinic acid for superficial Barrett's cancer and high-grade intraepithelial neoplasia. Gastrointest Endosc 2005, 62:24–30.CrossRefPubMedGoogle Scholar
  44. Prosst RL, Gahlen J, Schnuelle P, Post S, Willeke F: Fluorescence-guided minimally invasive parathyroidectomy: a novel surgical therapy for secondary hyperparathyroidism. Am J Kidney Dis 2006, 48:327–331.CrossRefPubMedGoogle Scholar
  45. Prosst RL, Schroeter L, Gahlen J: Kinetics of intraoperative fluorescence diagnosis of parathyroid glands. Eur J Endocrinol 2004, 150:743–747.CrossRefPubMedGoogle Scholar
  46. Prosst RL, Schroeter L, Gahlen J: Enhanced ALA-induced fluorescence in hyperparathyroidism. J Photochem Photobiol B 2005, 79:79–82.CrossRefPubMedGoogle Scholar
  47. Prosst RL, Willeke F, Schroeter L, Post S, Gahlen J: Fluorescence-guided minimally invasive parathyroidectomy: a novel detection technique for parathyroid glands. Surg Endosc 2006, 20:1488–1492.CrossRefPubMedGoogle Scholar
  48. Ravasz LA, Slootweg PJ, Hordijk GJ, Smit F, van der Tweel I: The status of the resection margin as a prognostic factor in the treatment of head and neck carcinoma. J Craniomaxillofac Surg 1991, 19:314–318.PubMedGoogle Scholar
  49. Regula J, MacRobert AJ, Gorchein A, Buonaccorsi GA, Thorpe SM, Spencer GM, Hatfield AR, Bown SG: Photosensitisation and photodynamic therapy of oesophageal, duodenal, and colorectal tumours using 5 aminolaevulinic acid induced protoporphyrin IX–a pilot study. Gut 1995, 36:67–75.CrossRefPubMedGoogle Scholar
  50. Rivera F, Vega-Villegas ME, Lopez-Brea MF: Cetuximab, its clinical use and future perspectives. Anticancer Drugs 2008, 19:99–113.CrossRefPubMedGoogle Scholar
  51. Rosenthal EL, Kulbersh BD, Duncan RD, Zhang W, Magnuson JS, Carroll WR, Zinn K: In vivo detection of head and neck cancer orthotopic xenografts by immunofluorescence. Laryngoscope 2006, 116:1636–1641.CrossRefPubMedGoogle Scholar
  52. Rosenthal EL, Kulbersh BD, King T, Chaudhuri TR, Zinn KR: Use of fluorescent labeled anti-epidermal growth factor receptor antibody to image head and neck squamous cell carcinoma xenografts. Mol Cancer Ther 2007, 6:1230–1238.CrossRefPubMedGoogle Scholar
  53. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL: Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987, 235:177–182.CrossRefPubMedGoogle Scholar
  54. Spaulding DC, Spaulding BO: Epidermal growth factor receptor expression and measurement in solid tumors. Semin Oncol 2002, 29:45–54.PubMedGoogle Scholar
  55. Speich R, Saesseli B, Hoffmann U, Neftel KA, Reichen J: Anaphylactoid reactions after indocyanine-green administration. Ann Intern Med 1988, 109:345–346.PubMedGoogle Scholar
  56. Stepp H, Beck T, Pongratz T, Meinel T, Kreth FW, Tonn J, Stummer W: ALA and malignant glioma: fluorescence-guided resection and photodynamic treatment. J Environ Pathol Toxicol Oncol 2007, 26:157–164.PubMedGoogle Scholar
  57. Stollman TH, Scheer MG, Leenders WP, Verrijp KC, Soede AC, Oyen WJ, Ruers TJ, Boerman OC: Specific imaging of VEGF-A expression with radiolabeled anti-VEGF monoclonal antibody. Int J Cancer 2008, 122:2310–2314.CrossRefPubMedGoogle Scholar
  58. 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 2006, 7:392–401.CrossRefPubMedGoogle Scholar
  59. Upadhyay R, Sheth RA, Weissleder R, Mahmood U: Quantitative real-time catheter-based fluorescence molecular imaging in mice. Radiology 2007, 245:523–531.CrossRefPubMedGoogle Scholar
  60. Utsuki S, Oka H, Sato S, Shimizu S, Suzuki S, Tanizaki Y, Kondo K, Miyajima Y, Fujii K: Histological examination of false positive tissue resection using 5-aminolevulinic acid-induced fluorescence guidance. Neurol Med Chir (Tokyo) 2007, 47 :210–213; discussion 213-214.CrossRefGoogle Scholar
  61. Vallbohmer D, Zhang W, Gordon M, Yang DY, Yun J, Press OA, Rhodes KE, Sherrod AE, Iqbal S, Danenberg KD, et al.: Molecular determinants of cetuximab efficacy. J Clin Oncol 2005, 23:3536–3544.CrossRefPubMedGoogle Scholar
  62. Veiseh M, Gabikian P, Bahrami SB, Veiseh O, Zhang M, Hackman RC, Ravanpay AC, Stroud MR, Kusuma Y, Hansen SJ, et al.: Tumor paint: a chlorotoxin:Cy5.5 bioconjugate for intraoperative visualization of cancer foci. Cancer Res 2007, 67:6882–6888.CrossRefPubMedGoogle Scholar
  63. Withrow KP, Gleysteen JP, Safavy A, Skipper J, Desmond RA, Zinn K, Rosenthal EL: Assessment of indocyanine green-labeled cetuximab to detect xenografted head and neck cancer cell lines. Otolaryngol Head Neck Surg 2007, 137:729–734.CrossRefPubMedGoogle Scholar
  64. Withrow KP, Newman JR, Skipper JB, Gleysteen JP, Magnuson JS, Zinn K, Rosenthal EL: Assessment of bevacizumab conjugated to Cy5.5 for detection of head and neck cancer xenografts. Technol Cancer Res Treat 2008, 7:61–66.PubMedGoogle Scholar
  65. Witjes JA, Douglass J: The role of hexaminolevulinate fluorescence cystoscopy in bladder cancer. Nat Clin Pract Urol 2007, 4:542–549.CrossRefPubMedGoogle Scholar
  66. Woolgar JA, Triantafyllou A: A histopathological appraisal of surgical margins in oral and oropharyngeal cancer resection specimens. Oral Oncol 2005, 41:1034–1043.CrossRefPubMedGoogle Scholar
  67. Wu Y, Cai W, Chen X: Near-infrared fluorescence imaging of tumor integrin alpha v beta 3 expression with Cy7-labeled RGD multimers. Mol Imaging Biol 2006, 8:226–236.CrossRefPubMedGoogle Scholar
  68. Wu SM, Ren QG, Zhou MO, Wei Y, Chen JY: Photodynamic effects of 5-aminolevulinic acid and its hexylester on several cell lines. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai) 2003, 35:655–660.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Division of Otolaryngology – Head and Neck Surgery, Department of SurgeryUniversity of Alabama at BirminghamBirminghamUSA

Personalised recommendations