Lymphedema Assessment Modalities at Bedside or OfficeHistory and physical examination

Clinical H&P encompasses numerous domains including symptoms, time course, underlying risk factors, such as infectious history and other medical comorbidities, mobility, positioning, family and social history, cutaneous and soft tissue effects, motor-sensory and musculoskeletal abnormalities, and body weight. A varied taxonomy of descriptive terms may apply to skin and soft tissue characteristics, including basic characteristics as pitting, firmness, fibrosis, thickening, or erythema, to more elaborate descriptors including, but not limited to hyperkeratosis, lipodermatosclerosis, papillomatosis, nodular fibrosis, lymphedema rubra, phlebolymphedema, lymphangiomas (blisters containing lymph fluid), sausage digits, and elephantiasis verrucosa nostra [13,14,15,16]. Associated observations may include evidence of cellulitis, lymphorrhea, or wounds [5]. Palpation is employed to assess fibrosis, including skin and deeper tissue mobility, and extent of pitting, but reliable grading criteria for fibrosis are needed [17]. In the lower extremities, Stemmer’s sign (inability to pinch a skinfold at the dorsum of the second toe) is a classic observation [13, 18], and individuals with history of axillary lymph node dissection may exhibit axillary cording especially early in the posttreatment course.

Various staging or grading paradigms exist, most notably the International society of lymphology (ISL) system ranging from subclinical lymphedema to lymphostatic elephantiasis, and which contains morphologic as well as size criteria [5, 19]. The ISL stages include subclinical (0 or Ia), early accumulation with pitting (I), increased fat and fibrosis infiltration (II) and lymphostatic elephantiasis (III). Other paradigms have also been employed. The Campisi scale delineates 5 stages including, in order of severity, initial/irregular edema, persistent lymphedema, persistent lymphedema with lymphangitis, fibrolymphedema, and elephantiasis [13, 20]. The National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) 5.0 (Grades 1–3), emphasizes soft tissue and skin characteristics, and in the severe category this scale incorporates limitation of self care as a criterion [21]. An earlier version, NCI-CTCAE 3.0 incorporates multiple lymphedema-related contexts including limb, head and neck, trunk/genital, lymphocele, cording and lymphedema-related fibrosis [22]. While not specific to lymphedema, the Pitting Edema Scale (1–4) has also been applied to lymphedema evaluation though reliability is likely limited [23].

Despite its ubiquity and importance to clinical care, studies are lacking with regard to accuracy and intra/interrater reliability of the physical examination for either clinical or research settings [4]. Lymphedema staging has value as a conceptual shorthand, and high feasibility to be incorporated into office visits. Limitations of clinical staging include imprecision regarding severity, that features of more than one stage may be present in the same individual, and that mixed etiologies of swelling may be present.

Bedside and office measures: general statement

An understanding of how to use and interpret the results of the bedside or office-based tools for surveillance and monitoring can greatly enhance the earliest diagnosis and treatment of lymphedema as well as give objective measures of change related to therapeutic intervention. A word of caution: no one device to-date can adequately measure all elements of therapeutic change given the heterogeneity of lymphedema. Furthermore, utility may break down in the absence of a reliable benchmark for comparison, such as a baseline measurement or unaffected contralateral limb. This requires a clinician to contextualize clinical interpretation.

Volume measurement

Volume measurement is an extension of the physical examination that can be undertaken with varying levels of technological sophistication. While parameters for detection exist, none are universally agreed upon, but volumetric thresholds of 3%, 5% or 10% change from baseline or in comparison to a normal contralateral side have been employed [5, 24], as well as absolute value of 150-200 ml difference in volume [25]. ISL 2020 guidelines define severity as minimal (> 5 < 20% increase in limb volume), moderate (20–40% increase), or severe (> 40% increase), with some clinics preferring to use > 5–10% as minimal and > 10– < 20% as mild. The variability in limb volumes between different individuals limits utility of using absolute volume change as a severity parameter for breast cancer-related lymphedema [24, 26]. Good reliability and validity have been found with numerous techniques including the traditional objective measures of water volumetry and tape measurement, as well as with more advanced approaches including perometry and (the nonvolumetric technique of) bioimpedance spectroscopy [27]. While most research has been conducted for breast cancer-related lymphedema, these principles apply to all types of lymphedema, including patients at risk for secondary lymphedema of the lower limbs who have had central operations with nodal sampling or resection.

Tape measurement

Tape measure-derived circumferential and volumetric measurements remain the most common clinical method [5, 10, 13, 28, 29] as well as the most extensively researched with regard to its reliability, validity and diagnostic accuracy [2, 27, 30, 31]. Tape measurement has been employed in multiple trials, but there is potential for interrater variability, and likely low sensitivity for subclinical disease [24].

A difference or change of 2 cm or more at any one measurement site has been described as significant, (though of questionable reliability, especially in the setting of higher limb girths)[19] versus a combined difference of 5 cm or more summed over 5 sites along the limb [17]. Volumetric conversions may be performed by fulstrum or truncated cone calculations, with the former considered more accurate and less likely to overestimate volumes [31]. Formulaic adjustments also exist which account for dynamic factors such as body weight [32].

There is not universal agreement on measurement paradigms between fixed intervals or landmark-based. Taylor et al., examining the arms of breast cancer survivors with lymphedema, found volumes calculated from anatomic landmarks to be reliable, valid, and more accurate than those obtained from circumferential measurements based on distance from fingertips [30]. Sun et al. concurred with these findings, in a volumetric study of breast cancer patients assessed serially postoperatively, comparing landmark versus fixed-interval derived tape measurements to perometry as the gold standard. In the Sun study, the landmark-based measurements had better sensitivity and specificity than the fixed interval measures (93.1%/63.1% overall for landmark-based and 81.9%/16% for 4 cm intervals) though the landmark technique underestimated upper arm volumes and had only 63.2–66.7% sensitivity for the lower (5–10%) relative volume change subcategory [33].

Tape measurement and water displacement are highly correlated but can yield different values, with between 5% and 15–19% variation reported, so these techniques cannot be used interchangeably [30, 31]. While reported diagnostic thresholds for treatment initiation vary, a clinical practice guideline on upper quadrant lymphedema yielded Grade B recommendations for tape measure use including volume ratio of 1.04 from the unaffected limb, volume differential > / = 200 ml between sides, and 5% or greater increase from baseline, but recommended against using a single site 2 cm difference as a diagnostic criterion [2].

Tape measurement has excellent feasibility regarding expense and accessibility. Concerns include the need for standardized protocols, training, and time to complete and compute measurements. Tape measurement is most applicable for limb rather than axial lymphedema, and like most volumetric measures it does not capture tissue composition.

Water displacement

Water displacement tanks for volumetric assessment have a limited role in most clinical settings due to feasibility barriers, though can be advantageous in research settings due to high degree of precision, with upper limb standard error of measurement of 3.6% compared to 6.6% for tape measurement [27]. However, error may be introduced if the limb is not submerged to a consistent level [30].

While water displacement is valid, accurate and reliable, disadvantages include being cumbersome, non-portable, requiring space, time and with risk of cross contamination [10, 30, 34]. Additionally, water displacement indicates the totality of volume but does not provide geometric detail on focal areas of enlargement. Measurement of lymphedema involvement near the root of the limb may be limited [5]. The Clinical Practice Guideline developed by the Oncology Section of the American Physical Therapy Association gave water displacement a Grade B recommendation, with criteria of > 200 ml or > 10% interlimb difference [2].

Perometry

Perometry provides a quick measure of limb circumference measures and calculated summed volume using an infrared scanner frame that slides over the body region in seconds. The device measures arms, legs, torso, hands and feet depending on the perometer model. The advantages of using perometry are reliability of repeat measurements, rapid measurements with ease of repeating measurements and ability to evaluate limb circumference at 0.5 cm increments. Additionally, measures can be used for compression garment fitting, though some additional measurements may be necessary with custom garment fitting. In breast cancer-related lymphedema, perometry has good correlation with circumferential measures and good correction with bioimpedance spectroscopy [35, 36]. Disadvantages include potential awkward patient positioning, expense of device, not easily transported requiring designated space, and limited centers with access to the equipment mostly found in research centers [35, 37]. Additionally, there is difficulty with hand and foot measurements and positioning can be problematic for some patients to get accurate reproducible arm and leg volume results where consistency in measurement technique needs to be maintained for repeated measures over time [35, 38]. Although considered a reliable measure of limb size and offers potential earlier detection of swelling compared to tape measure and palpation, as with other volume and circumference measurements, perometry is unable to discern extracellular fluid accumulation directly, rather volume changes could be related to muscle and fat changes as well within the area of interest. Therefore, similar to other devices of water displacement and tape measurements, perometry is not recommended as the sole method to measure and monitor lymphedema.

Bioimpedance

Bioimpedance technology is a method that measures biological impedance at different frequencies permitting clinicians to assess fluid compartments and body composition. This potentially provides clinicians a variety of information to help with making a clinical diagnosis of lymphedema and tailoring patient care treatment. Multiple frequency bioelectrical impedance analysis (MFBIA) and bioimpedance spectroscopy (BIS) provide a more comprehensive analysis compared with single frequency bioelectrical impedance analysis (SFBIA) by obtaining bioimpedance data at several different frequencies (MFBIA at different points from 1 to 1000 kHz and BIS continually from 0 to 1000 kHz) where BIS includes the crucial 0 kHz frequency [39] as part of its assessment. Impedance comprises resistance and reactance, indicating opposition from body fluids and cell membranes, respectively [40]. The inverse relationship between impedance and tissue fluid volume is a key principle [41]. The frequency of the current determines what is being measured, with zero frequency current unable to penetrate cell membranes [42]. Additionally, bioimpedance measures provide body composition data and phase angle data where a growing body of research is promising to inform oncology clinicians on changes to lean body mass and a prognostic factor in the advanced cancer setting, respectively [43, 44].

Bioimpedance devices gage resistance to electrical current flow, especially in the extracellular fluid compartment at low frequencies. More specifically for bioimpedance spectroscopy (BIS) devices, an “impedance ratio” methodology is utilized for assessing unilateral arm or leglymphedema. This involves comparing the resistance at 0 kHz in the affected/at-risk limb to that in the unaffected limb, expressed as a ratio [45]. Alternatively, this ratio can be linearized into an L-Dex score, where abnormal values indicate deviations from the normal range (− 10 to + 10 L-Dex units) and a change exceeding 6.5 L-Dex units from baseline signifies subclinical lymphedema [46]. While this is currently a manufacturer-specific paradigm, similar scoring systems exist for other available bioimpedance devices. BIS is recognized for its non invasive effectiveness in measuring extracellular fluid and detecting subclinical changes indicative of lymphedema onset [42, 47]. It offers high sensitivity, standardized cut-off measurements, and excellent inter-observer variability [48, 49]. Moreover, BIS can assess intra and extracellular fluid as well as total body water [50], and is now eligible for insurance reimbursement in the United States.

Stand-on devices are available for BIS and MFBIA which incorporate stainless steel contact electrodes within hand and foot plates, with values graphically displayed over time. At this time, BIS has a larger body of research, as well as greater clinical penetration, however the extent to which BIS or MFBIA may be more advantageous than the other is unknown. Although BIS and MFBIA offer fluid and body composition measurements and are relatively quick to use, there is an expense to obtaining the technology which may also be on a subscription basis, and the information obtained in the severely obese population remains questionable [51].

Tissue dielectric constant—percent water content

Tissue dielectric constant (TDC) are focal measures of skin-to-fat water providing a quantified measure of tissue water within the skin and subcutis to aid a clinician’s assessment of local edema detection [52]. Advantages to TDC is its portable and focal assessment of superficial tissue water content for suspicious tissue allowing for comparison to contralateral focal body region. Focal measurements can be obtained on any skin region where newer devices provide user feedback on force and have the option of calculating the percent water ratio to “spot” scan for impairment. This portable tool provides rapid localized information on superficial water content on any skin region including torso, breast, top of hand and foot, and head and neck. TDC readings can be converted to percentage water content (PWC) for ease with comparing involved or at-risk with contralateral body regions [53]. Growing evidence reveals its use in early detection of breast lymphedema and the use of percent water content [52,53,54,55,56,57]. Disadvantages include the analysis of fluid is superficial to the skin and subdermis, depth assessment varies with the probe used typically ranging from 0.5 to 5.0 mm, focal measurement does not allow for efficient whole limb surveillance for edema, normative values appear to vary across body regions and are sparsely reported to-date, and evidence is lacking in how measures may change with advancing stages of lymphedema. Though this device also cannot be used without clinical examination, it offers promising use for focal swelling and comparison of contralateral sites on the trunk, breast, head, neck, feet and hands to provide clinicians an objective noninvasive measure of superficial fluid levels.

Tonometry

Tissue tonometry evaluates the resistance to pressure exerted on the skin providing an output of tissue induration in Newtons (N). Measurements assess local tissue areas and newer devices provide user feedback on speed and pressure for measurement accuracy. Some models require repeat measures and automatically compute the measurement average. The local skin measurement takes less than one minute to assess for an experienced clinician using the tool. Advantages to tonometry device are its ability to provide a measurement of tissue firmness and its portability and inter reliability [58]. Disadvantages are that measures may be influenced by ambient fluctuations, there are challenges with repeat measurement, device expense, limited literature on normative and impaired values, and uncertainty as to how the measures will vary across the stages of lymphedema [35, 58], as fibrotic areas may soften with treatment while overly soft and edematous regions may harden with treatment. Research suggests potential for tonometry to inform on tissue fibrosis and treatment efficacy [59,60,61,62]. Further research is essential for a more in-depth understanding of this technology’s utility toward clinical assessment and treatment allocation in lymphedema.

Three-dimensional (3D) imaging

In the setting of lymphedema, 3D imaging technology advancements offer fast, noninvasive anthropometric body measurements of volume and circumference for baseline and longitudinal uses. The technology may involve scanners or a camera sensor attachment to a device with software subscription to obtain the images, in which currently limb and torso measurements are the most commonly measured. There is also the option for measurements of the hands, feet along with potential for the head and neck, necessitating further research to optimize the options across all body regions for clinical use. The 3D imaging outputs typically involve a silhouette of the body image captured providing total volume and circumferential measurements currently up to every 4 mm along the torso and limbs (arms and legs). The speed of obtaining circumferential and volumetric measures through 3D imaging offer a fast and portable opportunity for clinics to obtain a substantial amount of anthropometric data illustrating the change of volume and circumference over time [63, 64]. Though this technology is efficient and reliable for certain body regions to use for the trained user, ongoing research is necessary to optimize model fitting and measurement extraction for entire body regions. Compared to the tape measure, the technology offers more promise with speed and interrater accuracy, yet this technology is more costly potentially involving a software subscription. Similar to perometry, 3D imaging currently cannot provide proficient data for “tight” circumferential measurements needed in particular regions when fitting for custom compression garments.

Patient reported outcome measures

Patient reported outcome measures (PROMs) assess latent constructs such as symptoms, quality of life (QoL), and self-efficacy that could not be otherwise quantified. PROMs typically measure defining, yet subjective, dimensions of a patient’s experience, and may be condition-specific or generic. In the case of lymphedema-specific PROMs, tools have been developed and validated to evaluate the impact of lymphedema on the physical, psychoemotional, functional, and social aspects of a patient’s life [65,66,67,68,69,