Current diagnostic and quantitative techniques in the field of lymphedema management: a critical review

Abstract

Lymphedema evaluation entails multifaceted considerations for which options continue to evolve and emerge. This paper provides a critical review of the current status of diagnostic and quantitative measures for lymphedema, from traditional and novel bedside assessment tools for volumetric and fluid assessment, to advanced imaging modalities. Modalities are contrasted with regard to empirical support and feasibility of clinical implementation. The manuscript proposes a grid framework for comparing the ability of each modality to quantify specific lymphedema characteristics, including distribution, dysmorphism, tissue composition and fluid content, lymphatic anatomy and function, metaplasia, clinical symptoms, and quality of life and function. This review additionally applies a similar framework approach to consider how well assessment tools support important clinical needs, including: (1) screening, (2) diagnosis and differential diagnosis, (3) individualization of treatment, and (4) monitoring treatment response. The framework highlights which clinical needs are served by an abundance of assessment tools and identifies others that have problematically few. The framework clarifies which tools have greater or lesser empirical support. The framework is designed to assist stakeholders in selecting appropriate diagnostic and surveillance modalities, gauging levels of confidence when applying tools to specific clinical needs, elucidating overarching patterns of diagnostic and quantitative strengths and weaknesses, and informing future investigation.

Keywords: Cancer; Diagnosis; Imaging; Lymphedema; Measurement; Monitoring; Screening.

Fig. 1

Lymphoscintigraphy for assessment of lymphatic function. a Lower extremity lymphedema showing pooling of lymphatic fluid in left calf and decreased left pelvic lymph node activity. b Postmastectomy lymphedema with pooling in distal left upper limb and markedly reduced axillary lymph node activity

Fig. 2

Ultrasound to distinguish normal, lymphedema and lipedema. Lymphedema is associated with increased dermal thickness and with subcutaneous tissue hyperechogenicity, whereas lipedema is associated with increased thickness and hypoechogenicity of the subcutaneous fat (dermis marked in upper arrows, subcutaneous tissues in lower arrows)

Fig. 3

Breast Cancer-Related Lymphedema seen by Near-Infrared Fluorescence Lymphatic Imaging (NIRF-LI). Example images of (left) healthy lymphatics with well defined, linear lymphatic structure and contractile function, and (right) diseased lymphatics with fluorescent network of tortuous lymphatic vessels and dermal backflow

Fig. 4

Breast Cancer-Related Lymphedema seen by Near-Infrared Fluorescence Lymphatic Imaging (NIRF-LI) in the setting of normal arm volumes. Dermal backflow (top images) is evident in three different breast cancer patients’ affected arms. White-light (bottom) images were also collected with a white-light camera mounted on the imager arm. Relative volume changes (RVC) for all three patients were negative, well below 5-10% used to clinically diagnose breast cancer-related lymphedema

Fig. 5

Noninvasive MRI methods for structural and physiologic lymphedema assessment. Noninvasive MRI methods provide structural and physiologic imaging measures for upper-extremity lymphedema (top row) and lower-extremity lymphedema (bottom row). A Optimized image contrast at 3T MRI provided lymph node anatomical imaging sensitive to the afferent and efferent vessel and lymph node substructures. Structural MRI of soft tissue anatomy demonstrates tissue remodeling in disease such as skin and adipose tissue thickening, and fibrosis deposition. B MR lymphangiography visualizes deep lymphatic vessel morphology, such as in the thoracic duct anterior to the spinal cord. Edema is also visualized as hyper-intense signal on non-tracer MR lymphangiography to localize dependent edema and response to manual therapies. C Tissue composition in lymphedema can be quantified with 3T MR relaxometry (e.g. T₂ relaxation time map in upper-extremity unilateral lymphedema), and Dixon fat-fraction mapping. These measures indicate edematous and heterogeneous tissue in lymphedema, which responds to manual lymphatic drainage therapy. D Molecular imaging methods relevant for lymphedema include CEST-MRI of proteins (e.g. magnetization transfer ratio, MTR of amide proteins) and sodium MRI of endogenous tissue sodium content (mmol/L). Molecular imaging is being investigated for early biomarkers of edema formation and objective, localized measures of lymphatic disease severity. Together, MRI is a versatile modality to investigate lymphatic physiology and disease with high potential for clinical translation.