Response to “Comments on ‘Subcutaneous Adipose Tissue Edema in Lipedema Revealed by Noninvasive 3T MR Lymphangiography’”

On behalf of the authors of Crescenzi et al,¹ where the authors provided evidence for subcutaneous adipose tissue edema in women with lipedema using a novel magnetic resonance (MR) lymphangiography approach, here we reply and provide clarification regarding the importance of fibrosis presence, topography of limb involvement, and disease duration as requested in the commentary by Baklacı and Eyigör.²

First, musculoskeletal tissue fibrosis is an important aspect of disease in lymphedema and the clinical staging grossly incorporates the presence of edema and fibrosis. Although histological evidence exists for fibrosis in tissues with lipedema, there is much less known about its etiology, extent, and time course in lipedema than in lymphedema.^3,4 Imaging could play a role in furthering our understanding of fibrosis, and more completely the extracellular matrix composition within adipose tissue, in each disease. However, our study was designed to test hypotheses regarding edema in the subcutaneous adipose tissue, and was inadequately powered to stratify findings by the presence and location of fibrosis. Given limited objective bedside tools for fibrosis characterization, sensitive protocols will be required and could incorporate imaging for in vivo spatial quantitation of edema and fibrosis. Radiologically evident fibrosis can be discerned from edema using contrast-enhanced T₁-weighted imaging, where early enhancement indicates developing granulation of tissue and delayed enhancement indicates mature fibrosis. While it is possible to discern and differentiate confluent fibrosis from edema on fluid sensitive sequences (fibrosis tends to be less bright), it is often difficult to distinguish interstitial fibrosis on fluid sensitive sequences. This technique provided evidence that edema was focal in patients with lymphedema, yet more diffuse in patients with lipedema. It is logical that similar patterns would manifest for fibrosis given the cyclic nature of these components in lymphedema,⁵ although this remains to be observed in lipedema. However, interstitial fibrosis is not detectable on non-contrast-enhanced MR lymphangiography owing to the long echo time sequence. Observing the presence of fibrosis or extracellular matrix changes in lipedema may require specific molecular imaging to quantify tissue composition such as sodium ²³Na-MRI.^6,7 We agree that fibrosis is an important clinical aspect and avenue of investigation in future studies of lymphedema and lipedema.

Second, we agree that clinically standard lymphedema evaluation includes limb volumetric measurements, and these data were obtained in all participants using a perometer system as we have outlined in prior work.⁶ However, these data were not specifically reported, as limb volume was not an outcome measure in this study. Rather, this information assisted with the clinical assessment of the individual and the appropriate staging of lymphedema or lipedema. We chose to perform MR lymphangiography at a standard location for all participants, in the absence of reference features across the legs for this relatively nascent imaging modality. The calf was chosen as the standard site in order to systematically evaluate the potential presence of subcutaneous adipose tissue edema involving the distal extremity in lipedema. Whole-leg MR lymphangiography is feasible, as demonstrated in a case example in fig. 2,¹ which requires less scan time than clinically standard whole-limb lymphoscintigraphy. As lymphatic imaging technologies continue to advance,⁸ comparative studiesto a clinical standard will be important to optimize our understanding of study findings and translate interpretations for clinical use.

Finally, while disease duration is often well-defined in cancer-related lymphedema, disease onset is often difficult to identify in participants with lipedema. Early symptoms of lipedema often overlap with other common conditions, and time to diagnosis is often more than 10 years in the absence of objective diagnostic tests. We agree and underscore the importance of early diagnosis and subsequent treatment, as disease chronicity will likely affect therapy response, but this was not the focus of our observational imaging study. Imaging could play a role in optimizing lymphatic therapies, and specifically, MR lymphangiography contrast was responsive to manual lymphatic drainage therapy in patients with breast cancer treatment-related lymphedema.⁹ Tissue sodium content was reduced on sodium ²³Na-MRI following physical therapy in patients with early-stage lipedema.¹⁰ Discovering imaging markers sensitive to early lymphatic insufficiency in lipedema or lymphedema, or to disease duration, remains a relevant area of research.

We thank the authors for highlighting important aspects of clinical and research assessments for leg lymphedema and lipedema. With further standardization, it is likely that imaging can play an important role in further characterizing the relevance of these issues and disease physiology to better serve the needs of patients.