Bilateral Changes in Deep Tissue Environment After Manual Lymphatic Drainage in Patients with Breast Cancer Treatment-Related Lymphedema

Abstract

Background: Breast cancer treatment-related lymphedema (BCRL) arises from a mechanical insufficiency following cancer therapies. Early BCRL detection and personalized intervention require an improved understanding of the physiological processes that initiate lymphatic impairment. Here, internal magnetic resonance imaging (MRI) measures of the tissue microenvironment were paired with clinical measures of tissue structure to test fundamental hypotheses regarding structural tissue and muscle changes after the commonly used therapeutic intervention of manual lymphatic drainage (MLD).

Methods and results: Measurements to identify lymphatic dysfunction in healthy volunteers (n = 29) and patients with BCRL (n = 16) consisted of (1) limb volume, tissue dielectric constant, and bioelectrical impedance (i.e., non-MRI measures); (2) qualitative 3 Tesla diffusion-weighted, T1-weighted and T2-weighted MRI; and (3) quantitative multi-echo T2 MRI of the axilla. Measurements were repeated in patients immediately following MLD. Normative control and BCRL T2 values were quantified and a signed Wilcoxon Rank-Sum test was applied (significance: two-sided p < 0.05). Non-MRI measures yielded significant capacity for discriminating between arms with versus without clinical signs of BCRL, yet yielded no change in response to MLD. Alternatively, a significant increase in deep tissue T2 on the involved (pre T2 = 0.0371 ± 0.003 seconds; post T2 = 0.0389 ± 0.003; p = 0.029) and contralateral (pre T2 = 0.0365 ± 0.002; post T2 = 0.0395 ± 0.002; p < 0.01) arms was observed. Trends for larger T2 increases on the involved side after MLD in patients with stage 2 BCRL relative to earlier stages 0 and 1 BCRL were observed, consistent with tissue composition changes in later stages of BCRL manifesting as breakdown of fibrotic tissue after MLD in the involved arm. Contrast consistent with relocation of fluid to the contralateral quadrant was observed in all stages.

Conclusion: Quantitative deep tissue T2 MRI values yielded significant changes following MLD treatment, whereas non-MRI measurements did not vary. These findings highlight that internal imaging measures of tissue composition may be useful for evaluating how current and emerging therapies impact tissue function.

Keywords: MLD; MRI; cancer; lymphatic; lymphedema; manual lymphatic drainage; therapy.

Conflict of interest statement

No competing financial interests exist.

Figures

FIG. 1.

Anatomical imaging and tissue regions that were the focus of the quantitative superficial and deep T2 MRI measurements. Lymph nodes were identified on DWIBS images (A) (bilateral; warm colors) and surrounding tissue and fat structure were visualized on T1-weighted mDIXON scans (B). The yellow box denotes the approximate location of the bilateral quantitative T2 measures. High spatial resolution T2-weighted (C) and T1-weighted (D and E) MRI were also used for identification of axillary regions and surrounding anatomy. Blue arrows denote lymph nodes. DWIBS, diffusion-weighted-inversion-with-background-suppression; mDIXON, multipoint DIXON; MRI, magnetic resonance imaging.

FIG. 2.

Control and BCRL values of TDC (A), BIS L-DEX measure (B), limb volume ratio (C), and deep tissue T2 values (D). TDCs are mean values including right and left arms in controls. Limb volume ratios are right:left in control volunteers and involved:contralateral in patients with BCRL. All non-MRI measures were significantly different between control and BCRL participants with the exception of limb volume ratio (#p = 0.055), which was only significantly different when patients with stage 0 BCRL were excluded (*p = 0.015). Neither deep nor superficial (not shown) T2 values were different between control and BCRL participants. p-Values denote two-sided p-values from a Wilcoxon Rank-Sum test. Central lines denote median, upper and bottom solid lines denote 75th and 25th percentile of data, and whiskers extend to all data not considered outliers defined as 2.5 SDs beyond the mean (black cross). Actual data points are overlaid as red circles. (E) One representative slice of a quantitative T2 map (seconds) in a control participant scanned at two time points (separated by ∼1 month) demonstrates the range of consistency in T2 values, which are quantified (F) between right and left arms across all healthy control volunteers (n = 29) and (G) across the six control participants enrolled for reproducibility and ICC assessment. (H) A weak (Spearman's ρ = 0.46) but significant (p = 0.013) positive relationship between deep tissue T2 and age was observed, highlighting the need to control for age in population studies that incorporate quantitative T2 mapping of upper bodies. BCRL, breast cancer treatment-related lymphedema; BIS-L-DEX, bioimpedance spectroscopy L-DEX; ICC, intraclass correlation coefficient; TDC, tissue dielectric constant. SD, standard deviation.

FIG. 3.

Changes in study parameters pre- and post-MLD intervention in patient participants. (A–C) No significant change was observed in non-MRI measures pre- versus post-MLD. TDC shown is for the involved side only, however, no trend was found on the contralateral side. (D and E) In deep tissue, T2 increases significantly on both involved and contralateral sides, whereas superficial T2 does not change significantly on average. p-Values reflect two-sided results from a paired Wilcoxon Rank-Sum test. The larger range of values found in patients may provide a basis for evaluating personalized responses and is addressed in Figure 4 and the Discussion section. Central lines denote median, upper and bottom solid lines denote 75th and 25th percentile of data, and whiskers extend to all data not considered outliers defined as 2.5 SDs beyond the mean (black cross). Actual data points are overlaid as red circles. MLD, manual lymphatic drainage.

FIG. 4.

A single slice taken from three patients before and after MLD intervention. All images are in radiological orientation, with the involved side on radiological right. For control reproducibility (Figs. 2 and 5). (A) A 58-year-old female with right-sided BCRL scanned ∼5 years after 19 lymph nodes were removed when undergoing a mastectomy with lymph node dissection. Clear, focal increases in deep (white arrows) and superficial (yellow arrows) T2 are observed after MLD. (B) A 57-year-old female with right-sided stage 1 BCRL scanned ∼3 years after 24 lymph nodes were removed during a mastectomy with lymph node dissection. Similar as in (A), clear regions of deep and superficial T2 increases are observed in both quadrants. (C) A 59-year-old female with right-sided subclinical BCRL scanned ∼14 years after 19 lymph nodes were removed during a mastectomy with lymph node dissection. Here, clear reductions in T2 are observed in deep and superficial tissue T2 on the involved side, and tissue composition changes from bilateral asymmetry pre-MLD to bilateral symmetry post-MLD. These images highlight the spatial heterogeneity of changes in MRI contrast occurring after MLD, which may not be detectable using more conventional measurements of total limb volume or emerging measurements of extracellular fluid composition. These images also are consistent with early stages of BCRL, the response to MLD is largely consistent with relocation of fluid from the involved to contralateral quadrant (T2 lengthening). In more advanced stages of BCRL, this effect competes in a spatially dependent manner with changes in fibrosis on the involved side from pre-MLD (T2 shortening) to post-MLD fibrosis reductions (T2 lengthening). Heterogeneity of deep (D and E) and superficial (F and G)T2 relaxation times in control and BCRL participants are shown. Values are SD of the quantitative T2 over the designated region and thus reflect the heterogeneity in the measure across the region. In control participants (D and F), deep and superficial T2 are largely symmetric and vary by on average 0.01–0.02 seconds across the region. In patients with BCRL (E and G), similar heterogeneity is observed in contralateral regions, however, much higher variation is observed both before and after MLD in the involved regions. These data suggest that there is a large and heterogeneous response of T2 to MLD in the involved hemisphere. Bars denote the SD of values across all control (n = 29) and BCRL (n = 16) participants.

FIG. 5.

(A) A Bland–Altman plot showing the difference (vertical axis) versus mean (horizontal axis) of T2 values calculated in right and left arms of control volunteers, showing a mean negligible difference between right and left arm T2. Solid lines signify the mean difference and dashed lines signify ±95% CIs. (B) A Bland–Altman plot showing the difference in deep tissue T2 values before and after MLD therapy in BCRL and subset of healthy control volunteers scanned twice for reproducibility assessment. In patients with BCRL, the vertical axis depicts the difference in T2 after MLD (post-MLD T2 minus pre-MLD T2) and the horizontal axis depicts the mean of pre- and post-MLD T2 values. In controls, the vertical axis depicts the difference in T2 values between the two scan sessions and the horizontal axis depicts the mean of the T2 values for the two scans. The control volunteers exhibit only a small difference in quantified T2 values between time points with relatively small CIs. In patient volunteers, the T2 difference is larger and the 95% CIs increase, with both affected and contralateral arms exhibiting increases in T2 after MLD therapy. 95% CI, confidence interval.