Clinical Measurements of Lymphedema

Abstract

Patients, health care providers, and payers depend on practical, efficient, and useful tests that can be performed in a clinical setting in order to measure accurately and to diagnose lymphedema. Accurate measures are also necessary to monitor progression or regression of the disease, as well as treatment effects. This article reviews clinical measures of lymphedema that are currently being utilized. In addition, this article proposes an alternative objective measure, different from limb volume, that quantifies tissue texture.

Introduction

The American Cancer Society estimated 250,000 new cases of breast cancer in 2011.¹ With increasing survivorship, 2.5 million people are estimated to be living after breast cancer treatment. Each survivor is at risk of developing lymphedema during her lifetime. Lymphedema is a persistent swelling that occurs when protein-rich fluid accumulates in the subcutaneous space due to a poor or injured lymph transport system.² Onset of lymphedema can occur immediately post-surgery, during radiation, and/or several years after such treatments. Lymphedema of the breast, trunk, or arm after cancer surgery is a chronic problem for individuals to manage after their cancer treatment and can adversely affect their quality of life.^3,4

Incidence of lymphedema in the arm ranges from 2%–83%.^5–8 Variable incidence ranges may be due to inaccurate diagnosis, duration of edema without treatment, poorly defined definitions of lymphedema, poor measurement techniques, and variable timing of clinical measurement. Overall, lymphedema is under-reported and unrecognized due to inaccurate diagnosis with current measures.^9–12 Improved measurement techniques and diagnostic criteria may improve treatment outcomes and patient quality of life. The purpose of this article is to provide a brief overview of lymphedema physiology, diagnosis, and staging, and to review current clinical measurements that are typically used in lymphedema therapy practice in order to diagnose lymphedema and monitor treatment progression or regression.

Lymphedema Physiology

The lymphatic system is a one way transport system that begins with the initial lymphatics, or pre-collectors, which are located in the dermis of the skin. The initial lymphatics transport lymph fluid absorbed from the subcutaneous space deeper to lymphatic trunks, located at the muscular level.¹³ Ultimately lymph fluid will filter through lymph nodes, lymph ducts, and finally to the subclavian vein, which completes the lymph fluid's final destination to the heart. Lymphedema results as fluid pools in the subcutaneous tissue from injured or defective lymphatic systems. Understanding lymphedema soft tissue consequences is essential because the strong inflammatory stimulus that accompanies lymphedema results in abnormal collagen deposition that is unique to this chronic swelling condition.^13,14

Lymphedema can result due to an insufficient transport system causing inadequate return of lymphatic fluid back to the heart.^2,13,15 The lymphatic fluid can have an accumulation of fibroblasts, which trigger an increase in connective tissue and collagen formation that manifests as fibrosis, or hardening of the tissues.^2,15–17 External insult to the lymphatic system can occur from surgical scarring, radiation, or even repeated trauma, and can result in tissue pathology of the skin and subcutaneous space due to interruption of normal lymphatic function.¹⁴ Histology samples from induced lymphedema in a mouse model confirmed an increase of fibroblast cells, hyperkeratosis and edema of the epidermis, irregular dermal papillae, and dilated lymphatics in the dermis and subdermis.¹⁸ Research studies on humans report similar tissue alterations, given that chronic inflammation persists in the skin of lymphedematous limbs.¹⁹

Breast cancer treatment such as surgery and radiation typically targets the breast and axilla on one side. Because the human body is mapped by quadrant with specific lymphatic drainage pathways, the treatment site for breast cancer puts that quadrant at risk for inflammation and therefore lymphedema. For example, the right axillary lymph nodes are responsible for draining the right arm, right breast, and chest wall, as well as the right upper back. Each of these areas is at risk for development of lymphedema if the lymphatics in this quadrant are damaged, altered, or removed. Therefore, each area needs an objective measurement tool to quantify lymphedema.

Lymphedema Diagnosis/Staging

Diagnosis of lymphedema can be challenging in the early stages of the disease because the tissue changes are not always obvious. Current diagnostic and staging criteria are dependent on volume changes in limbs that may make early detection of edema difficult; therefore, patients may not get diagnosed properly or early enough for optimal outcomes.

Lymphedema has been described as transient, or persistent/chronic. Transient edema can be detected in the breast, axilla, trunk, or arm during the acute healing phase or postoperative period. Transient edema is defined as a single episode of swelling that lasts less than 3 months and resolves without intervention.²⁰ An Australian study of 287 breast cancer survivors revealed transient edema in 20% of the cohort, whereas 13% were considered to have chronic lymphedema.¹² If fluid persists greater than 3 months, and infection, seroma, flap necrosis, cellulitis, deep vein thrombosis, and/or recurrent tumor have been ruled out, one can assume the diagnosis of persistent or chronic lymphedema.^17,21

Persistent lymphedema has been defined by limb volume differences. There are a variety of limb volume differences described in the literature; however, there is not agreement on this definition. For example, definitions include: a ≥3% volume increase of the operated limb compared to the non-involved limb,²² or a limb volume difference of 200 mL, >5%, or 10% volume increase on the affected side defines clinical lymphedema.^23–26 In addition, when the difference in the sum of arm circumferences, taken at five sites is greater than 5 centimeters,^26,27 or if any difference in circumference is greater than 2 centimeters,²⁷ such criteria are used to delineate a lymphedema diagnosis.

The foregoing definitions of lymphedema depend on detectable volume and circumference differences between the involved and uninvolved limb. But it is important to realize that volume and girth measurements quantify more than just fluid changes; volume cannot delineate fluid, muscle mass, bone, fat, or other tissue compositional changes. Furthermore, volume measures cannot detect hypertrophy or atrophy that can occur due to increased use or disuse of an extremity. Hand dominance, surgical treatment, limb favoring, or disuse also obscure true limb differences. Therefore, it is optimal to have preoperative volume measures of both involved and uninvolved extremities.⁹ Overall, a lymphedema diagnosis based entirely on volume can potentially overlook skin and deep tissue changes, such as fibrosis within the subcutaneous space.

Lymphedema can also be defined by alterations in tissue texture that can occur with the progression of disease. During stage I lymphedema, the tissue presents as “pitting edema.” Pitting edema is graded on a 0 to 3+ scale.²⁸ In order to assess for pitting, firm pressure is applied into the tissue for 5 seconds. If an impression or indentation remains after release of pressure, pitting edema is evident and can be graded. Zero indicates that there is no indention in the tissue, 1+ is minimal indention in the tissue, 2+ is moderate, and 3+ is severe.²⁹ Over time, as the protein-rich edema persists, there is an overgrowth of connective and adipose tissue in the subcutaneous space accompanied by collagen deposition.^15,30,31 The clinical interpretation of this tissue cascade is labeled “fibrosis.” Fibrosis has been described as: none, soft, moderate, harm, firm, or brawny. As fibrosis develops, “pitting edema” decreases. Increased fibrosis changes the stage or rating of lymphedema, which may affect treatment choices (Table 1). Stage II lymphedema is chronic or persistent edema. It is described as swelling that does not resolve overnight. The tissue texture is firm, does not pit with digital pressure, and limb volume differences have increased (>2 cm measured at one site, >200 mL,≥3%, >5%, >10%, etc.^{9,17,22,24,27}). Stage III edema is considered to be severe with tissue and limb distortion due to large volume changes.^2,13,17

Table 1.

Stages of Lymphedema

	A	B	C	D
Stages	Volume/circumference measures	Pitting	Palpation/Fibrosis	Subjective reports
0 “latent”	Undetectable or <1 cm	No	No change	Yes/No
I “mild”	<2 cm	Yes	Soft, none or slight fibrosis	Resolves overnight
II “moderate”	>2 cm	No	Firm, moderate to severe fibrosis	Yes, does not reduce with elevation
III “severe”	>5 cm	No	Hard, may have papillomatous outgrowths, hyperkeratosis, “elephantiasis”	Severe discomfort and immobility

Armer JM, Radina ME, Porock D, Culbertson SD, 2003⁴⁷; Foldi M, Foldi E, 1989¹⁵; Harris SR, Hugi MR, Olivotto IA, Levin M, 2001⁴⁸; O'Brien P, 1999.⁴⁹

Columns A, B, C, are practitioner measurements; Column D is patient subjective report.

Cheville et al.¹⁷ comprised a criteria grading system, the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0) which includes: edema volume changes of the limb, dermal changes, fibrotic grading, and multiple other complicating factors from lymphedema of the head, neck, limbs, trunk, and genitalia. The CTCAE v3.0 is a detailed list of parameters that attempts to differentiate each grade of lymphedema beyond reliance on volume measure; however, this tool consists of multiple subjective measures. The CTCAE v3.0 divides lymphedema stages into four categories. The objective measure for each stage is primarily distinguished by limb volume differences: 5%–10% equal to grade 1, >10%–30% equal to grade 2, >30% equal to grade 3, and grade 4 described as progression to malignancy. Fibrosis is a categorical measure with subjective assessment. Although the CTCAE v3.0 appears to be the most descriptive list of lymphedema measures, early grade 1 and latent stage edemas (when early treatment may interrupt progression of disease) still have the potential to be overlooked. Current clinical measures, especially at the early stages of the disease, rely on limb volume difference (which may be skewed without pre-treatment measurement) and subjective interpretation of tissue texture.

Current Clinical Measures of Lymphedema

Clinically, lymphedema is currently measured utilizing a combination of measures: patient history, patient self-report of symptoms, visual inspection of the affected extremity, palpation of the affected extremity to evaluate tissue texture changes, digital pressure to detect pitting edema, and circumferential measurement of the affected extremity to calculate volume. Research or large cancer centers may have access to larger and more expensive measuring devices such as perometry, tonometry, or bioimpedance (Table 2). However, patients are usually initially evaluated by an experienced clinician who utilizes subjective history, inspection, palpation, and circumferential limb measurement. Widespread incidence of lymphedema may be under reported due to the lack of reliable techniques listed above to quantify lymphedema or inability to accurately diagnose early stage or latent disease.

Table 2.

Current Lymphedema Measures

Clinical tool	Tissue evaluated	Facility	Type of measure
Visual Inspection	Skin condition Shape of limb	Clinic	Subjective
Circumferential tape measure	Volume	Clinic	Objective
Palpation	Pitting edema Tissue firmness/fibrosis Skin temperature	Clinic	Subjective
Tonometry^*	Tissue firmness	RC	Objective
Perometry^*	Volume	RC	Objective
Bio-Impedance^*	Water content	RC	Objective
Ultrasound^*	Tissue depth Echogenictiy Visualize tissues Average pixel intensity Entropy	RC	Objective
Self-report	Tissue/size	Clinic	Subjective

Not routinely available in the clinical setting. R, research center.

Volume

Circumferential measurements

Circumferential measurement using a measuring tape along designated points on the limb, later converted to volume, is the most widely used calculation of lymphedema for common clinical practice. Sitzia (1995)³² evaluated the accuracy of mathematical formulas used to convert circumference to volume. The frustrum method demonstrated more accurate “true” volume calculations versus the cylinder formulas, which overestimated volume by 1.5%. However, the cylindrical formulas are considered “easier” formulas for calculation purposes.³²

In a study conducted by Taylor et al. (2006),³³ the authors compared volume taken by water displacement (considered the gold standard—but not routinely used in the clinic) to circumferential measurements. They found that circumferential measurements were reliable but overestimated actual volume by 110 mL.³³ They also found that a difference up to 150 mL was considered measurement error, therefore defining the minimal detectable change. Measures less than 150 mL should be treated as no change in clinical status by clinicians, as this can be attributed to chance variation or measurement error.³³ However, it is conceivable that individuals who present with stage 1 lymphedema, with limb volume differences that measure less than 100 mL, are being overlooked by current measurement and volume diagnostic standards. Therefore, diagnostics that rely on volume may be dismissing this low grade edema group. In addition, these individuals with low volume changes may benefit from treatment before obvious larger volumes have distorted their limbs.

Palpation

Lymphedema evaluation also includes assessment by the clinician of the patient's skin and subcutaneous texture. Using palpation, clinicians judge the patient's skin mobility, rate tissue fibrosis, and grade pitting edema.^28,34 However, there is insufficient clinical guidance for the interpretation of fibrosis palpation. In addition, there is a paucity of evidence about the reliability of measures that quantify pitting edema. Finally, there is a lack of comparison as to how pitting and fibrosis relate to each other throughout progression of disease. All of these tests are quantified by “clinical impression,” and the rating lacks consistency amongst clinicians. The Textbook of Lymphology includes an evaluation form for clinicians to use, but does not explain or standardize the palpation techniques.¹³ Specifically, the form contains a section to comment on skin changes such as pitting edema and fibrosis, but the text lacks operational definitions and explanations for standardizing palpation assessments. In an attempt to quantify tissue tension objectively, particularly firmer tissue that has advanced disease, tonometry was developed.³⁵

Tonometry

As discussed above, several studies have “focused” lymphedema definitions and measures by change in volume. Very few have concentrated on tissue texture “changes.” Tonometry claims to measure “softness or fibrosis” in tissue (tissue tonicity).³⁵ Tonometry measures tissue tension or tissue resistance to compression. A tonometer produces a known force upon a plunger that causes tissue deformation. Softer tissue results in greater indentation. Studies have shown good correlation of tonometry to subjective report, yet traditional volume measures such as water displacement and circumferential measurement are more precise than tissue tonometry for determining outcomes of lymphedema treatment.³⁵

Perometry

Perometry has been used more recently in lymphedema-related research.^36,37 Perometry measures have been shown to have good reliability for volume calculations. Once the limb is placed correctly in a frame, infrared light emitting diodes are cast upon the limb, emitting shadows from which volume can be calculated.²⁴ Although the perometer is becoming the new gold standard for volume measurement,²⁴ it has its limitations. When using perometry, assessing the entire limb is difficult, the device is not mobile, the assessment is limited to an arm or leg calculation, and the machine is costly.

Bioelectrical Impedance

As an alternative to volume measure of lymphedema, bioelectrical impedance (BIA) has been used to measure fluid or water content in limbs.³⁸ Electrodes on the skin pass an alternating current through the limb and the impedance to the flow of current is measured.³⁹ Many studies have validated BIA as an effective tool in the measurement of fluid content in a limb.^36,40 A prospective 3-year study evaluated the effectiveness of BIA versus circumferential measurement. Of the 102 subjects at risk, 20 developed lymphedema and BIA predicted the onset of lymphedema 10 months prior to clinical diagnosis.³⁹ Bioelectric impedance appears to be a promising measure or predictor of early stage lymphedema disease. However, this instrument is limited to limbs and water content and is unable to measure fibrotic change.

Ultrasound

An emerging technology in the measure of lymphedema, ultrasound (US) imaging is a noninvasive, safe, and economically feasible tool to view lymphedetamous tissue texture changes in the skin, subcutaneous space, fluid changes, fibrous tissue, adipose tissue, subfascial layers, and skeletal muscle. The mobile US transducer can be used on a limb, as well as on more awkward surfaces such as the hand, trunk, breast, or face—all areas that are susceptible to lymphedema. In contrast to other measuring techniques, this modality may be more versatile. If reliable, US imaging may be a safe and inexpensive modality to quantify lymphedema and tissue texture changes throughout the body.

Researchers have been studying the use of US imaging on lymphedema for the past several years. Reliable measures of tissue texture changes including dermal thickening, fibrosis, and increased adipose tissue have been demonstrated in limbs with lymphedema.^41–44 Tissue texture changes measured with US imaging were observed in cadavers that had unilateral breast cancer treatment without prior subjective report of lymphedema.⁴⁵ This suggests that although tissue texture changes exist, they were undetected by patients as well as clinicians. Thus, US imaging may have the capacity to detect early stage lymphedema disease in living individuals.

Some US studies have examined subcutaneous tissue texture changes including fibrosis. Significant findings have been found in skinfold, dermis (dermal thickness), and subcutis between involved and uninvolved extremities in women post-mastectomy.⁴⁶ The same study also reported that the fascial subcutaneous layer was significantly hyperechoic (higher density of tissue) on the edematous extremity and the subcutaneous tissue was more echogenic; however this finding was not significant.

Although previous US studies have measured depth and thickness of lymphedema in the limbs, there is a lack of research that quantifies tissue texture or fibrosis associated with lymphedema. There is also a lack of research that correlates US measures with clinical assessments or patient self-report. If US imaging proves to be a reliable measure of tissue texture changes in the limb, it may have the potential to measure more difficult areas such as the trunk, breast, face, or genitalia.

Subjective Report

Patients who have lymphedema may present with symptoms such as tingling, pain, heaviness, reports of poor clothing fit, or with minimal complaints other than the limb “feels different.”⁴⁷ Understanding patient perception is an important contribution to lymphedema measurements because changes in patient's sensation have been reported as an early indicator of volume and pressure changes in the interstitial space, prior to clinical observation or measurable volume changes.⁴⁸ Authors have reported that patient self-report of early lymphedema symptoms have been correlated with their changes in volume measures.^47,49

Patients are often the first to describe changes in their arm prior to detectable volume changes, visual distortions, and/or changes in skin integrity. The Lymphedema and Breast Cancer Questionnaire has shown that changes in self-reported sensations may be indicators of early lymphedema.⁴⁷ This questionnaire was well correlated with upper limb volume measures including circumferential limb measures, perometry, and bioelectrical impedance.

The Visual Analog Scale (VAS), rating 0 to 10 on a 10 cm line, can quantify edema by severity. In 2010, Czerniec et al.²³ used a VAS compared to other physical measurements (BIA, circumferential measure, and perometry). The 10 cm scale was labeled “not at all” at the zero anchor and “extremely so” at the 10 cm anchor. Although the authors found high correlation with physical measures, there was less correlation with subjective report. However, they concluded that self-report correlated highly with BIA, both of which may detect early changes in edema, before actual volume differences can be detected.²³

Diagnosis of lymphedema at 6 months post breast cancer treatment was assessed in a 2005 Australian study. The authors compared arm circumference, BIA, and self-report.²⁶ Prevalence of lymphedema was greatest for self-report (27.8%) as these subjects answered “yes” to having arm swelling in the last 6 months. The other physical measures, arm circumference, and BIA, were measured at one point in time, versus subjective recall over the previous 6 months. If 30% of the subjects reported having lymphedema, it cannot be confirmed if any of those individuals had a transient swelling event and yet still reported “yes” to having swelling in the last 6 months. Patients are good reporters of their condition, but accurate, objective measures need to compliment patient perception and be used for monitoring progress or regression of the disease.

Conclusion

We have reviewed several options for lymphedema measurement. Lymphedema is a complex condition that can be chronic and progressive. Throughout the course of disease, lymphedema is variable as the tissue continuously changes with progression or regression of the disease process. The disease necessitates multiple measurement strategies because several variables of importance exist: subject perception, visual skin inspection, volume/limb distortion, and firmness/fibrosis of subcutaneous texture. Most studies tend to focus on volume change. Although volume is important and is the most objective current clinical measure, using only volume may overlook important tissue texture changes, as well as latent stage lymphedema disease. Lastly, of the measurement options presented in this article, objective options that are clinically feasible are desired because these measurements are used on a routine basis.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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