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Review
. 2000 Jan-Apr;2(1-2):26-40.
doi: 10.1038/sj.neo.7900082.

Non-invasive in vivo characterization of breast tumors using photon migration spectroscopy

B J Tromberg  1 , N Shah, R Lanning, A Cerussi, J Espinoza, T Pham, L Svaasand, J Butler
Affiliations
Review

Non-invasive in vivo characterization of breast tumors using photon migration spectroscopy

B J Tromberg et al. Neoplasia. 2000 Jan-Apr.

Abstract

Frequency-domain photon migration (FDPM) is a non-invasive optical technique that utilizes intensity-modulated, near-infrared (NIR) light to quantitatively measure optical properties in thick tissues. Optical properties (absorption, mu(a), and scattering, mu(s)', parameters) derived from FDPM measurements can be used to construct low-resolution (0.5 to 1 cm) functional images of tissue hemoglobin (total, oxy-, and deoxy-forms), oxygen saturation, blood volume fraction, water content, fat content and cellular structure. Unlike conventional NIR transillumination, FDPM enables quantitative analysis of tissue absorption and scattering parameters in a single non-invasive measurement. The unique functional information provided by FDPM makes it well-suited to characterizing tumors in thick tissues. In order to test the sensitivity of FDPM for cancer diagnosis, we have initiated clinical studies to quantitatively determine normal and malignant breast tissue optical and physiological properties in human subjects. Measurements are performed using a non-invasive, multi-wavelength, diode-laser FDPM device optimized for clinical studies. Results show that ductal carcinomas (invasive and in situ) and benign fibroadenomas exhibit 1.25 to 3-fold higher absorption than normal breast tissue. Within this group, absorption is greatest for measurements obtained from sites of invasive cancer. Optical scattering is approximately 20% greater in pre-menopausal versus post-menopausal subjects due to differences in gland/cell proliferation and collagen/fat content. Spatial variations in tissue scattering reveal the loss of differentiation associated with breast disease progression. Overall, the metabolic demands of hormonal stimulation and tumor growth are detectable using photon migration techniques. Measurements provide quantitative optical property values that reflect changes in tissue perfusion, oxygen consumption, and cell/matrix development.

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Figures

Figure 1
Figure 1
Upper panels: Spectral dependence of tissue chromophore absorption. A tissue optical “window” exists in the red/NIR between 600 and 1300 nm (from J.L. Boulnois, Lasers in Medical Science, 1986:1:47–66). Lower panels: Spectral dependence of light transmission through rabbit ear with implanted tumor model.
Figure 2
Figure 2
Red/NIR light launched into tissue propagates with directional changes (scattering) until captured by an absorber (molecule). Multiple scattering increases the mean photon path length. A short, e.g., picosecond, light pulse launched into tissue spreads out in proportion to the number of available photon paths. Absorption is a loss mechanism that reduces the number of available photon paths and hence limits the temporal dispersion of the pulse. Under low absorption conditions, a light pulse will experience maximal dispersion. The photon density, or fluence rate (ϕ) decays exponentially with distance from the source. The 1/e exponential decay constant, or optical penetration depth (δ) is a function of the absorption, µa, and scattering, µs′, properties of the medium.
Figure 3
Figure 3
Numerical simulation showing time-dependent propagation of ultrashort light pulse in tissue with optical properties similar to human breast (µa = 0.1 cm-1, µs′= 10 cm-1). Two-dimensional x–z views (40x25 mm2) of detected photon density are shown. Time-gating of the detector provides control over depth and volume of tissue probed.
Figure 4
Figure 4
One-gigahertz, multi-frequency, multi-wavelength FDPM instrument. See text for complete description.
Figure 5
Figure 5
FDPM measurement overview: intensity-modulated light is launched into tissue, resulting in the propagation of diffuse photon density waves. The frequency-dependent experimental response (phase, phi, and amplitude, A vs. frequency, ω) is compared to a theoretical model. Model-data fits provide calculated values for absorption, µa, and reduced scattering, µs′, coefficients at each optical wavelength. Absorption and scattering spectra are generated. Absorption spectra are used to calculate concentration of principal tissue chromophores.
Figure 6
Figure 6
(A) Structural and functional components of the optical signal in normal and transformed tissue. (B) Absorption spectra of tissue with composition similar to human post-menopausal breast: 10 µM deoxyhemoglobin [Hb], 15 µM oxyhemoglobin [HbO2], fat (80% volume fraction), and water (15% volume fraction).
Figure 7
Figure 7
FDPM measurements in PRE (•) and POST (○) menopausal normal breast (four subjects). (A) Calculated values of absorption coefficients, µa, vs. wavelength. (B) Calculated values of reduced scattering coefficients, µs′, vs. wavelength.
Figure 8
Figure 8
FDPM measurements of phase (A) and amplitude (B) vs. source modulation frequency obtained from normal and tumor sites on patient 1 (ductal carcinoma in situ, DCIS). Source-detector distance = 2.5 cm; λ = 674 nm. Solid lines are best simultaneous fits to phase and amplitude data from tumor (•) and normal (○) data points, respectively. Ten percent of 200 frequency-domain data points is shown for clarity.
Figure 9
Figure 9
(A) Ratio of absorption coefficients (tumor/normal) acquired in medial-lateral and superior-inferior scans at 674 nm for patient 1 (ductal carcinoma in situ, DCIS). Normal side represents average of 11 multiple site measurements. Contrast of approximately three-fold is observed for tumor vs. normal sites when the probe is placed 5 mm lateral of the estimated tumor center. (B) Wavelength dependence of optical properties acquired from the peak contrast location (5 mm lateral, medial-lateral axis) and symmetric location on normal side.
Figure 10
Figure 10
(A) Hemoglobin concentration (µM) in deoxy- [Hb], oxy- [HbO2], and total forms; %oxygen saturation (100x[HbO2]/[Hb(tot)]), and water content (%) for normal and tumor breast, patient 1. Values calculated from wavelength dependence of absorption (Figure 9B). (B) The ratio µs′ RSD values for normal/tumor tissues at each measurement wavelength for patients 1 (DCIS), 2 (invasive ductal carcinoma), and 3 (benign fibroadenoma). RSD is determined from the mean and standard deviation of 11 measurements and nine discrete locations on normal and tumor sides. A RSD ratio of 1 implies that tumor and normal tissue have equivalent structural variation.
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