Clinical feasibility of noninvasive visualization of lymphatic flow with principles of spin labeling MR imaging: implications for lymphedema assessment

Abstract

Purpose: To extend a commonly used noninvasive arterial spin labeling magnetic resonance (MR) imaging method for measuring blood flow to evaluate lymphatic flow.

Materials and methods: All volunteers (n = 12) provided informed consent in accordance with institutional review board and HIPAA regulations. Quantitative relaxation time (T1 and T2) measurements were made in extracted human lymphatic fluid at 3.0 T. Guided by these parameters, an arterial spin labeling MR imaging approach was adapted to measure lymphatic flow (flow-alternating inversion-recovery lymphatic water labeling, 3 × 3 × 5 mm) in healthy subjects (n = 6; mean age, 30 years ± 1 [standard deviation]; recruitment duration, 2 months). Lymphatic flow velocity was quantified by performing spin labeling measurements as a function of postlabeling delay time and by measuring time to peak signal intensity in axillary lymph nodes. Clinical feasibility was evaluated in patients with stage II lymphedema (three women; age range, 43-64 years) and in control subjects with unilateral cuff-induced lymphatic stenosis (one woman, two men; age range, 31-35 years).

Results: Mean T1 and T2 relaxation times of lymphatic fluid at 3.0 T were 3100 msec ± 160 (range, 2930-3210 msec; median, 3200 msec) and 610 msec ± 12 (range, 598-618 msec; median, 610 msec), respectively. Healthy lymphatic flow (afferent vessel to axillary node) velocity was 0.61 cm/min ± 0.13 (n = 6). A reduction (P < .005) in lymphatic flow velocity in the affected arms of patients and the affected arms of healthy subjects with manipulated cuff-induced flow reduction was observed. The ratio of unaffected to affected axilla lymphatic velocity (1.24 ± 0.18) was significantly (P < .005) higher than the left-to-right ratio in healthy subjects (0.91 ± 0.18).

Conclusion: This work provides a foundation for clinical investigations whereby lymphedema etiogenesis and therapies may be interrogated without exogenous agents and with clinically available imaging equipment. Online supplemental material is available for this article.

© RSNA, 2013.

Figures

Figure 1. Relaxation time measurements

(a) Inversion recovery and (b) exponential spin echo decay of a representative lymphatic fluid sample at 38C. Circles represent experimental data and the solid line the fit (Eqs. 1 and 2, respectively). In vivo image of lymph nodes on (c) the DWIBS scan, as well as (d) without and with the inversion prepulse in a basic EPI acquisition. The inversion prepulse was placed at the expected null point (TI = 1.4s at TR = 4s) of lymphatic water, calculated with the T1=3100 ms measured from the ex vivo lymphatic sample. A quantitative analysis of the signal in the nodes (e) demonstrates that signal intensity following the longitudinal nulling is not statistically different from the noise signal. This provides support for the ex vivo T1 measurements reflecting in vivo lymphatic water T1. The central red line represents the median value while the box represents the 25th and 75th percentile. ***P<0.001

Figure 1. Relaxation time measurements

(a) Inversion recovery and (b) exponential spin echo decay of a representative lymphatic fluid sample at 38C. Circles represent experimental data and the solid line the fit (Eqs. 1 and 2, respectively). In vivo image of lymph nodes on (c) the DWIBS scan, as well as (d) without and with the inversion prepulse in a basic EPI acquisition. The inversion prepulse was placed at the expected null point (TI = 1.4s at TR = 4s) of lymphatic water, calculated with the T1=3100 ms measured from the ex vivo lymphatic sample. A quantitative analysis of the signal in the nodes (e) demonstrates that signal intensity following the longitudinal nulling is not statistically different from the noise signal. This provides support for the ex vivo T1 measurements reflecting in vivo lymphatic water T1. The central red line represents the median value while the box represents the 25th and 75th percentile. ***P<0.001

Figure 1. Relaxation time measurements

(a) Inversion recovery and (b) exponential spin echo decay of a representative lymphatic fluid sample at 38C. Circles represent experimental data and the solid line the fit (Eqs. 1 and 2, respectively). In vivo image of lymph nodes on (c) the DWIBS scan, as well as (d) without and with the inversion prepulse in a basic EPI acquisition. The inversion prepulse was placed at the expected null point (TI = 1.4s at TR = 4s) of lymphatic water, calculated with the T1=3100 ms measured from the ex vivo lymphatic sample. A quantitative analysis of the signal in the nodes (e) demonstrates that signal intensity following the longitudinal nulling is not statistically different from the noise signal. This provides support for the ex vivo T1 measurements reflecting in vivo lymphatic water T1. The central red line represents the median value while the box represents the 25th and 75th percentile. ***P<0.001

Figure 1. Relaxation time measurements

(a) Inversion recovery and (b) exponential spin echo decay of a representative lymphatic fluid sample at 38C. Circles represent experimental data and the solid line the fit (Eqs. 1 and 2, respectively). In vivo image of lymph nodes on (c) the DWIBS scan, as well as (d) without and with the inversion prepulse in a basic EPI acquisition. The inversion prepulse was placed at the expected null point (TI = 1.4s at TR = 4s) of lymphatic water, calculated with the T1=3100 ms measured from the ex vivo lymphatic sample. A quantitative analysis of the signal in the nodes (e) demonstrates that signal intensity following the longitudinal nulling is not statistically different from the noise signal. This provides support for the ex vivo T1 measurements reflecting in vivo lymphatic water T1. The central red line represents the median value while the box represents the 25th and 75th percentile. ***P<0.001

Figure 1. Relaxation time measurements

(a) Inversion recovery and (b) exponential spin echo decay of a representative lymphatic fluid sample at 38C. Circles represent experimental data and the solid line the fit (Eqs. 1 and 2, respectively). In vivo image of lymph nodes on (c) the DWIBS scan, as well as (d) without and with the inversion prepulse in a basic EPI acquisition. The inversion prepulse was placed at the expected null point (TI = 1.4s at TR = 4s) of lymphatic water, calculated with the T1=3100 ms measured from the ex vivo lymphatic sample. A quantitative analysis of the signal in the nodes (e) demonstrates that signal intensity following the longitudinal nulling is not statistically different from the noise signal. This provides support for the ex vivo T1 measurements reflecting in vivo lymphatic water T1. The central red line represents the median value while the box represents the 25th and 75th percentile. ***P<0.001

Figure 2. Lymph node identification

(a,b,c) A representative DWIBS scan (30 yr/M) clearly demarcates the lymph nodes across orthogonal axes. A single axial slice, such as the one shown here (white line) is used to guide the location of the spin labeling positioning. (d) Corresponding control spin labeling image, whose location and planning was guided by the DWIBS contrast. (e) The DWIBS image overlaid on control image and thresholded to identify different structures (green=CSF; yellow = lymph) and to draw the ROIs (2 – 4 voxels) for evaluating lymph kinetic curves.

Figure 2. Lymph node identification

(a,b,c) A representative DWIBS scan (30 yr/M) clearly demarcates the lymph nodes across orthogonal axes. A single axial slice, such as the one shown here (white line) is used to guide the location of the spin labeling positioning. (d) Corresponding control spin labeling image, whose location and planning was guided by the DWIBS contrast. (e) The DWIBS image overlaid on control image and thresholded to identify different structures (green=CSF; yellow = lymph) and to draw the ROIs (2 – 4 voxels) for evaluating lymph kinetic curves.

Figure 2. Lymph node identification

(a,b,c) A representative DWIBS scan (30 yr/M) clearly demarcates the lymph nodes across orthogonal axes. A single axial slice, such as the one shown here (white line) is used to guide the location of the spin labeling positioning. (d) Corresponding control spin labeling image, whose location and planning was guided by the DWIBS contrast. (e) The DWIBS image overlaid on control image and thresholded to identify different structures (green=CSF; yellow = lymph) and to draw the ROIs (2 – 4 voxels) for evaluating lymph kinetic curves.

Figure 2. Lymph node identification

(a,b,c) A representative DWIBS scan (30 yr/M) clearly demarcates the lymph nodes across orthogonal axes. A single axial slice, such as the one shown here (white line) is used to guide the location of the spin labeling positioning. (d) Corresponding control spin labeling image, whose location and planning was guided by the DWIBS contrast. (e) The DWIBS image overlaid on control image and thresholded to identify different structures (green=CSF; yellow = lymph) and to draw the ROIs (2 – 4 voxels) for evaluating lymph kinetic curves.

Figure 2. Lymph node identification

(a,b,c) A representative DWIBS scan (30 yr/M) clearly demarcates the lymph nodes across orthogonal axes. A single axial slice, such as the one shown here (white line) is used to guide the location of the spin labeling positioning. (d) Corresponding control spin labeling image, whose location and planning was guided by the DWIBS contrast. (e) The DWIBS image overlaid on control image and thresholded to identify different structures (green=CSF; yellow = lymph) and to draw the ROIs (2 – 4 voxels) for evaluating lymph kinetic curves.

Figure 3. Unobstructed Lymphatic Flow Results

Lymphatic and blood water magnetization as a function of post-labeling delay times for six separate healthy subjects. In-plane dimensions of the lymph nodes evaluated for each subject are also reported. Note that the blood signal increases quickly owing to the short T1 of blood water and fast blood water velocity. Alternatively, the signal in the axillary lymph node increases much later, owing to the much slower velocity of lymph fluid. The relatively fast rise and fall of the lymphatic curve is consistent with mixing of lymphatic water in the node and finite node dwell times, similar to the macrovascular blood compartment in arterial spin labeling experiments (see Appendix III).

Figure 4

Obstructed Lymphatic Flow Results (a): Lymphatic flow curves for a representative healthy volunteer (M, 31 yrs) with unilateral cuff steno-occlusion of lymphatic fluid (pressure=60 mmHg) and for a patient (F, 60 yrs) with Stage II lymphedema secondary to unilateral breast cancer mastectomy. In both; healthy subjects and patients, a delay in lymphatic arrival times on the affected side relative to unaffected side is observed. Additionally, multiple arrival times are found, consistent with multiple afferent vessels delivering lymphatic water to the node. (b) The ratio of lymphatic flow velocity in the unaffected arm to the affected arm was significantly higher (P

Figure 4

Obstructed Lymphatic Flow Results (a): Lymphatic flow curves for a representative healthy volunteer (M, 31 yrs) with unilateral cuff steno-occlusion of lymphatic fluid (pressure=60 mmHg) and for a patient (F, 60 yrs) with Stage II lymphedema secondary to unilateral breast cancer mastectomy. In both; healthy subjects and patients, a delay in lymphatic arrival times on the affected side relative to unaffected side is observed. Additionally, multiple arrival times are found, consistent with multiple afferent vessels delivering lymphatic water to the node. (b) The ratio of lymphatic flow velocity in the unaffected arm to the affected arm was significantly higher (P