Imaging of Lymph Flow in Breast Cancer Patients after Microdose Administration of a Near-Infrared Fluorophore: Feasibility Study

Purpose: To prospectively demonstrate the feasibility of using indocyanine green, a near-infrared (NIR) fluorophore at the minimum dose needed for noninvasive optical imaging of lymph nodes (LNs) in breast cancer patients undergoing sentinel lymph node mapping (SLNM).

Materials and Methods: Informed consent was obtained from 24 women (age range, 30–85 years) who received intradermal subcutaneous injections of 0.31–100 μg indocyanine green in the breast in this IRB-approved, HIPAA-compliant, dose escalation study to find the minimum microdose for imaging. The breast, axilla, and sternum were illuminated with NIR light and the fluorescence generated in the tissue was collected with an NIR-sensitive intensified charged-coupled device. Lymphoscintigraphy was also performed. Resected LNs were evaluated for the presence of radioactivity, blue dye accumulation, and fluorescence. The associations between the resected LNs that were fluorescent and (a) the time elapsed between NIR fluorophore administration and resection and (b) the dosage of NIR fluorophores were tested with the Spearman rank and Pearson product moment correlation tests, respectively.

Results: Lymph imaging consistently failed with indocyanine green microdosages between 0.31 and 0.77 μg. When indocyanine green dosages were 10 μg or higher, lymph drainage pathways from the injection site to LNs were imaged in eight of nine women; lymph propulsion was observed in seven of those eight. When propulsion in the breast and axilla regions was present, the mean apparent velocities ranged from 0.08 to 0.32 cm/sec, the time elapsed between “packets” of propelled fluid varied from 14 to 92 seconds. In patients who received 10 μg of indocyanine green or more, a weak negative correlation between the fluorescence status of resected LNs and the time between NIR fluorophore administration and LN resection was found. No statistical association was found between the fluorescence status of resected LNs and the dose of NIR fluorophore.

Conclusion: NIR fluorescence imaging of lymph function and LNs is feasible in humans at microdoses that would be needed for future molecular imaging of cancer-positive LNs.

Supplemental material: http://radiology.rsnajnls.org/cgi/content/full/2463070962/DC1

© RSNA, 2008

References

  • 1 Krag D, Weaver D, Ashikaga T, et al. The sentinel node in breast cancer: a multicenter validation study. N Engl J Med 1998; 339: 941–946.
  • 2 Querzoli P, Pedriali M, Rinaldi R, et al. Axillary lymph node nanometastases are prognostic factors for disease-free survival and metastatic relapse in breast cancer patients. Clin Cancer Res 2006;12:6696–6701.
  • 3 Cummings MC, Walsh MD, Hohn BG, Bennett IC, Wright RG, McGuckin MA. Occult axillary lymph node metastases in breast cancer do matter results of 10-year survival analysis. Am J Surg Pathol 2002;26:1286–1295.
  • 4 Clare SE, Sener SF, Wilkens W, Goldschmidt R, Merkel D, Winchester DJ. Prognostic significance of occult lymph node metastases in node-negative breast cancer. Ann Surg Oncol 1997;4:447–451.
  • 5 Cote RJ, Peterson HF, Chaiwun B, et al. Role of immunohistochemical detection of lymph-node metastases in management of breast cancer. Lancet 1999;354:896–900.
  • 6 Adams KE, Ke S, Kwon S, et al. Comparison of visible and near-infrared wavelength-excitable fluorescent dyes for molecular imaging of cancer. J Biomed Opt 2007;12:(2)024017.
  • 7 U.S. Department of Health and Human Services, Center for Drug Evaluation and Research. Guidance for industry, investigators, and reviewers exploratory IND studies. Rockville, Md: U.S. Department of Health and Human Services, 2006.
  • 8 Reynolds JS, Troy TL, Sevick-Muraca EM. Multipixel techniques for frequency-domain photon migration imaging. Biotechnol Prog 1997;13:669–680.
  • 9 Glantz SA. Primer of biostatistics. New York, NY: McGraw-Hill, 2005.
  • 10 Sharma R, Wang W, Rasmussen JC, et al. Quantitative imaging of lymph function. Am J Physiol Heart Circ Physiol 2007;292:H3109–H3118.
  • 11 Motomura K, Inaji H, Komoike Y, Kasugai T, Noguchi S, Koyama H. Sentinel node biopsy guided by indocyanin green dye in breast cancer patients. Jpn J Clin Oncol 1999;29:604–607.
  • 12 Kitai T, Inomoto T, Miwa M, Shikayama T. Fluorescence navigation with indocyanine green for detecting sentinel lymph nodes in breast cancer. Breast Cancer 2005;12:211–215.
  • 13 McMasters KM, Tuttle TM, Carlson DJ, et al. Sentinel lymph node biopsy for breast cancer: a suitable alternative to routine axillary dissection in multi-institutional practice when optimal technique is used. J Clin Oncol 2000;18:2560–2566.
  • 14 Achilefu S, Dorshow RB, Bugaj JE, Rajagopalan R. Novel receptor-targeted fluorescent contrast agents for in vivo tumor imaging. Invest Radiol 2000;35:479–485.
  • 15 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.
  • 16 Li C, Wang W, Wu QP, et al. Dual optical and nuclear imaging in human melanoma xenografts using a single targeted imaging probe. Nucl Med Biol 2006;33:349–358.
  • 17 Hwang K, Houston JP, Rasmussen JC, Ke S, Li C, Sevick-Muraca EM. Enhanced fluorescence optical imaging with improved excitation light rejection. J Mol Imaging 2005;4:194–204.
  • 18 Joshi A, Bangerth W, Sevick-Muraca EM. Adaptive finite element based tomography for fluorescence optical imaging in tissue. Opt Express 2004;12:5402–5417.
  • 19 Rusznyak I, Foldi M, Szabo G. Lymphatics and lymph circulation. London, England: Pergamon, 1967.

Article History

Published in print: 2008