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Three-dimensional in vivo fluorescence diffuse optical tomography of breast cancer in humans

Alper Corlu, Regine Choe, Turgut Durduran, Mark A. Rosen, Martin Schweiger, Simon R. Arridge, Mitchell D. Schnall, and Arjun G. Yodh

Open Access Open Access

Abstract

We present three-dimensional (3D) in vivo images of human breast cancer based on fluorescence diffuse optical tomography (FDOT). To our knowledge, this work represents the first reported 3D fluorescence tomography of human breast cancer in vivo. In our protocol, the fluorophore Indocyanine Green (ICG) is injected intravenously. Fluorescence excitation and detection are accomplished in the soft-compression, parallel-plane, transmission geometry using laser sources at 786 nm and spectrally filtered CCD detection. Phantom and in vivo studies confirm the signals are due to ICG fluorescence, rather than tissue autofluorescence and excitation light leakage. Fluorescence images of breast tumors were in good agreement with those of MRI, and with DOT based on endogenous contrast. Tumor-to-normal tissue contrast based on ICG fluorescence was two-to-four-fold higher than contrast based on hemoglobin and scattering parameters. In total the measurements demonstrate that FDOT of breast cancer is feasible and promising.

©2007 Optical Society of America

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Figures (16)
Fig. 1.
Fig. 1. Schematic of parallel plate DOT instrument. (a) The subject lies in prone position with breasts suspended in the breast box. Continuous wave (CW) transmission and frequency-domain (FD) remission measurements are performed simultaneously. Spectral filters are introduced in front of the detectors for fluorescence measurements. 45 sources and 9 FD detectors are positioned on the compression plate in a 9×5 and 3×3 grid arrangement. A diode laser at 786 nm is utilized for excitation of ICG and fluorescence detection (b) Excitation and emission spectra of whole blood containing 0.05 mg/ml of sterile ICG [58] are shown together with the 785 nm notch filter (blue line) and 830 nm (red shading, FWHM = 10 nm) bandpass filter.

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Fig. 2.
Fig. 2. (a) Illustration of the phantom (CCD view). The tube ends are attached to a pump (not shown) in order to titrate the phantom with different ICG concentrations. (b) Timetable for the phantom measurement protocol.

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Fig. 3.
Fig. 3. Time-table for the in vivo measurements.

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Fig. 4.
Fig. 4. Reconstruction flowchart.

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Fig. 5.
Fig. 5. Outline of the phantom is drawn in pink color and white mark (*) shows the projection of the 43 rd source location onto the detector plane. The phantom has 1μM ICG concentration. (a) Transmission intensity at the excitation wavelength is centered at the source position. (b) Fluorescence signal originates within the object.

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Fig. 6.
Fig. 6. Image slices from 3D reconstructions of the phantom’s ICG concentration (a) and absorption at 786nm (b). Object location and size correlate well with both fluorescence and absorption images.

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Fig. 7.
Fig. 7. The different origin of excitation transmission and fluorescence signals are demonstrated with data acquired from a patient (case 2). The breast outline is drawn with red, and the white mark (*) shows the projection of the excitation source location onto the detector plane. Transmitted excitation light appears to come from the source position as shown in (a) and (b) for source 23 and 36, respectively. The fluorescence signal, on the other hand, is clearly contained inside the breast boundary, as demonstrated for sources 23 and 36 in (c) and (d), respectively.

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Fig. 8.
Fig. 8. Fluorescence intensity (blue line) versus time, obtained from images acquired while excitation light at 786nm illuminates the medium from the 15 th source position. The green line shows the exponential fit to the fluorescence peak intensity values acquired after the 3 rd minute. The full fluorescence scan starts at t = 6.6 min and at t = 10.2 min, fluorescence intensity is recorded with the 15 th source. This data point serves as a reference to correct the full scan data.

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Fig. 9.
Fig. 9. Images acquired at different time points in a patient scan (case 2) while the excitation light at 786 nm illuminated the tissue from 15 th source position (marked with a white *). (a) At t = 0, before ICG injection, the detected intensity is essentially the system noise. (b) t = 2 min, fluorescence signal reaches its peak. (c) At later times the signal decreases as the ICG clears out of the tissue.

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Fig. 10.
Fig. 10. (a) Illustration of the tumor location for Case 1. (b) According to the gadolinium enhanced sagittal MR image slice the tumor is located around y = 5 cm position in the DOT configuration. (c) Fluorescence transillumination image obtained from patient (case 1).

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Fig. 11.
Fig. 11. Patient Case 1: Total hemoglobin concentration, blood oxygen saturation, μ′s (786nm) and fluorescence image slices at y = 5 cm are displayed (a) with their values along a horizontal line passing through the center of tumor (b).

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Fig. 12.
Fig. 12. Iso-surface plot of THC, μ′s (786nm) and fluorescence at iso-values of three standard deviations above their respective means correspond to tumor location. Outline designates the border of the breast modeled as an ellipsoid using the breast photo taken with the CCD camera.

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Fig. 13.
Fig. 13. (a) Illustration of the tumor location for Case 2. (b) Sagittal slice from gadolinium enhanced MR image shows a bright spot below the nipple area corresponding to the y = 4 cm axial slice in the DOT configuration. (c) Fluorescence transillumination picture obtained from patient (case 2).

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Fig. 14.
Fig. 14. Patient Case 2: Total hemoglobin concentration, blood oxygen saturation, μ′s (786nm) and fluorescence image slices at y = 4 cm are displayed (a) with their values along a horizontal line passing through the center of tumor location (b).

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Fig. 15.
Fig. 15. (a) Illustration of the tumor location for Case 3. (b) According to the gadolinium enhanced sagittal MR image slice the tumor is located around y = 5 cm position in the DOT configuration. (c) Fluorescence transillumination picture obtained from patient (case 3).

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Fig. 16.
Fig. 16. Patient Case 3: Total hemoglobin concentration, blood oxygen saturation, μ′s (786nm) and fluorescence image slices at y = 5 cm are displayed (a) with their values along a horizontal line passing through the center of tumor location (b).

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Equations (11)

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− ∇ ∙ D ( λ ex , r ) ∇ Φ ( λ ex , ω , r ) + ( μ a ( λ ex , r ) + iω v ) Φ ( λ ex , ω , r ) = q 0 ( λ ex , ω , r s ) ,
− ∇ ∙ D ( λ fl , r ) ∇ Φ ( λ fl , ω , r ) + ( μ a ( λ fl , r ) + iω v ) Φ ( λ fl , ω , r ) = n ( r ) 1 − iωτ ( r ) Φ ( λ ex , ω , r ) .
n ( r ) = [ C ] × ε ( λ ex ) × η ,
Φ + D ( λ ) α d Φ d v ̂ = 0 ,
Φ c ( λ fl , r s , r d ) = ∫ d 3 r n ( r ) Φ c ( λ ex , r s , r ) G ( λ fl , r d , r ) ,
Φ m ( λ fl , r s , r d ) Φ m ( λ ex , r s , r d ) = Θ ( r s , r d , λ fl ) Φ c ( λ fl , r s , r d ) Θ ( r s , r d , λ ex ) Φ c ( λ ex , r s , r d ) ,
= 1 Φ c ( λ ex , r s , r d ) ∫ d 3 r n ( r ) Φ c ( λ ex , r s , r ) G ( λ fl , r d , r ) .
Φ m ( λ fl , r s , r d ) Φ m ( λ ex , r s , r d ) ≡ 1 Φ c ( λ ex , r s , r d ) ∑ j = 1 N h 3 n j Φ c ( λ ex , r s , r j ) G ( λ fl , r s , r j ) .
( J T J + Λ L ) n = J T y .
J i , j = h 3 Φ c ( λ ex , r si , r j ) G ( λ fl , r di , r j ) Φ c ( λ ex , r si , r di ) ,
T ( r d ) = − log ( ∑ s N s Φ m fl ( r s , r d ) ∑ s N s Φ m ex ( r s , r d ) ) .
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