Elevated magnetic resonance imaging measures of adipose tissue deposition in women with breast cancer treatment-related lymphedema

Abstract

Purpose: Breast cancer treatment-related lymphedema (BCRL) is a common co-morbidity of breast cancer therapies, yet factors that contribute to BCRL progression remain incompletely characterized. We investigated whether magnetic resonance imaging (MRI) measures of subcutaneous adipose tissue were uniquely elevated in women with BCRL.

Methods: MRI at 3.0 T of upper extremity and torso anatomy, fat and muscle tissue composition, and T2 relaxometry were applied in left and right axillae of healthy control (n = 24) and symptomatic BCRL (n = 22) participants to test the primary hypothesis that fat-to-muscle volume fraction is elevated in symptomatic BCRL relative to healthy participants, and the secondary hypothesis that fat-to-muscle volume fraction is correlated with MR relaxometry of affected tissues and BCRL stage (significance criterion: two-sided p < 0.05).

Results: Fat-to-muscle volume fraction in healthy participants was symmetric in the right and left sides (p = 0.51); in BCRL participants matched for age, sex, and BMI, fat-to-muscle volume fraction was elevated on the affected side (fraction = 0.732 ± 0.184) versus right and left side in controls (fraction = 0.545 ± 0.221, p < 0.001). Fat-to-muscle volume fraction directly correlated with muscle T2 (p = 0.046) and increased with increasing level of BCRL stage (p = 0.041).

Conclusion: Adiposity quantified by MRI is elevated in the affected upper extremity of women with BCRL and may provide a surrogate marker of condition onset or severity.

Clinical trial: NCT02611557.

Keywords: Adipose tissue; Breast cancer; Edema; Lymphedema; MR relaxometry; MRI.

Conflict of interest statement

Conflicts of interest: P.C.M.D. is a paid consultant for PureTech Health and Tactile Medical and has received clinical and imaging grants from LymphaTouch Inc. M.J.D. receives research related support from Philips North America; is a paid consultant for Pfizer Inc, Global Blood Therapeutics, and LymphaTouch; is a paid advisory board member for Novartis and bluebird bio; receives research funding from Pfizer Inc; and is the CEO of Biosight, LLC which provides healthcare technology consulting services. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Figures

Figure 1.. Anatomical imaging and segmentation procedure from 3.0T magnetic resonance fat and muscle imaging.

A T1-weighted localizer is obtained for slice planning; lymph nodes are subsequently visualized on Diffusion Weighted Imaging with Background Subtraction (DWIBS; white arrows) and adipose and fluid are visualized on high spatial resolution T1-weighted and T2-weighted MRI, respectively. Red arrows demarcate nodular adipose and yellow arrows depict subcutaneous edema and fibrosis on this participant with Stage 2 lymphedema. The upper extremities and axillary tissues are subsequently scanned using a bilateral field of view with Dixon imaging, as shown in the coronal (separate fat and water shown) and axial planes (B). Lung and central cavities (green circle) are removed and image analysis is restricted to central regions (orange box) to reduce artifact from lateral arm regions. Images were separated centrally (yellow line) and fat-water fraction was calculated separately on the right and left. (C) Regions of interest in the water-weighted tissues (blue voxels) including the skin, muscle, and lymph node cortex and in the adipose-weighted tissues (magenta voxels) are segmented a semi-automated manner (see Methods). The final segmentation included only fat and non-fat tissue, excluding breast tissue, and the ratio of the fat-water was preserved as the fat-to-muscle fraction.

Figure 2.. Anatomical imaging.

(A) Orthogonal representations of a fat (T1-weighted without fat saturation) and fluid weighted (T2-weighted with fat saturation) MRI in a 35 year female (BMI=19.6 kg/m2) without and a 44 year female (BMI=21.2 kg/m2) with secondary lymphedema. Imaging parameters for all sequences used to visualize and quantify fat and water microenvironment are summarized in Table 1. (B) Examples of fat and muscle profiles in a healthy participant and participants with secondary lymphedema. Fat-to-muscle fraction are frequently observed to be elevated in lymphedema compared to healthy participants, and regions of nodular adipose on T1-weighted MRI with fluid and fibrosis are frequently present in advanced lymphedema stages.

Figure 3.. Violin plots depicting summary statistics for healthy and symptomatic lymphedema participants.

On average, participants were matched for age (A) and BMI (B). Muscle T2 (C) is similar between groups on average, but fat-to-muscle fraction was significantly elevated on the affected side of lymphedema participants relative to the healthy participants (D). The shape of the violin plot depicts the probability distribution of the data, with whiskers extending to the extremes of data. *two-sided p<0.05 significance criteria.

Figure 4.. Relationship between the MRI-measured fat-to-muscle fraction and body-mass-index (BMI).

Across all volunteers (A), a significant and positive correlation is observed (pT2 (p<0.05), a marker of tissue microenvironment.

Figure 5.. Fat-to-muscle limb asymmetry in healthy participants, as well as breast cancer treatment related lymphedema (BCRL) intermediate (Stage 0-1) and advanced (Stage 2) stage participants.

The fat-to-muscle limb asymmetry is calculated as the fractional difference in the fat-to-muscle ratio in the involved vs. uninvolved arms of BCRL participants, or right vs. left arms in healthy participants. Mean values and standard errors are reported on the graph. *ANOVA significance p