1 | P a g e

Critical Review and Assessment of Noninvasive Methods to Evaluate or Characterize Breast

Cancer Related Lymphedema Features Catherine Xu and HN Mayrovitz (Mentor) 2018

Lymphedema

Lymphedema is a condition characterized by persistent swelling of certain parts of the

body caused by an impaired lymphatic

system due to lymphatic injury or

congenital and anatomical defects [1].

The lymphatic system is comprised of a

network of vessels and nodes as shown in

figure 1 that extend throughout the body

to remove toxins, waste, and other

unwanted materials. Lymph fluid

containing white blood cells and other

substances including proteins, fats, and

salts, circulate throughout lymph vessels

to collect bacteria, viruses, and waste

products. The waste is then filtered

through lymph nodes (figure 2) and

emptied back into the venous system to be

delivered to the subclavian veins at the

base of the neck and expelled through the

skin, lungs, and kidneys. When the lymphatic

system is compromised due to obstruction or

underdevelopment of the lymphatic vessels,

lymphatic fluid can collect in subcutaneous

tissues and cause the affected area to swell.

Swelling often occurs in an arm when injury

occurs to axillary nodes, or in the leg when

injury occurs to groin nodes but can be

present in other body parts as well.

2 | P a g e

Primary and Secondary Lymphedema

Lymphedema can be classified as primary or secondary. Primary lymphedema is a rare

genetic developmental disorder characterized by swelling of certain parts of the body not caused

by other health conditions. It has been classified based on the age of onset into congenital,

peripubertal, and late-onset lymphedema [2]. The most common form of primary lymphedema is

lymphedema praecox, also known as Meige disease, which usually affects adolescent women

with a female : male ratio of approximately 2:1 [3], and is typically unilateral [4]. Lymphedema

tarda occurs in individuals who have congenitally weakened lymphatics so that trauma or

inflammatory reaction can result in lymphedema [4]. Due to the complexity of the lymphatic

system, there are many genes involved in its development which makes it difficult to determine

which gene could cause primary lymphedema. Lymphedema can also occur as part of a

syndrome with other clinical signs. Genetic insights point toward VEGF-C/VEGFR-3 signaling

as a target for lymphedema treatment by the 23 mutated human genes reported presently [2].

Secondary lymphedema causes can be numerous but in most Western countries most

likely occurs as a result of lymphatic obstruction or lymphatic interruption from surgery, trauma,

radiation, or infection. It is most commonly caused by removal of or damage to lymph nodes

during cancer surgery or radiation treatments. Particularly after cancer treatment, secondary

lymphedema may develop during or months to years later. Radiation therapy can damage healthy

lymph nodes and vessels or cause scarring and diminish lymph flow. In developing countries, the

most common cause of lymphedema is lymphatic filariasis, a disease caused by microscopic

thread-like worms that live in the human lymph system. People with the disease can suffer from

lymphedema and is a leading cause of permanent disability.

3 | P a g e

Lymphedema from Breast Cancer

Lymphedema of the arm continues to be a harrowing problem for a significant number of

breast cancer survivors (figure 3).

After breast cancer treatment,

incidence of upper extremity

lymphedema, also referred to as

breast cancer treatment-related

lymphedema (BCRL), ranges from

2% - 83% [5]. The large incidence

range may be due to inaccurate

diagnosis, poorly defined definitions of lymphedema, or poor measurement techniques [6]. When

cancer cells break away from a tumor, they can get stuck in adjacent lymph nodes. A normal part

of breast cancer surgery is the removal of at least two or three lymph nodes to determine whether

the cancer has spread into the surrounding lymph nodes. If the cancer traveled away from the

breast tumor and into the lymphatic system, the node nearest the tumor, would be the first to

show evidence of breast cancer. An axillary node dissection, in which some of the lymph nodes

located in the underarm are removed, would then be required to check for the presence of cancer

cells [7]. Removal of the lymph nodes may cause disruption or damage to the normal drainage

pattern in the nodes and increases the risk of developing lymphedema [8]. As a result, breast

cancer surgery may damage lymph vessels due to their close proximity which can lead to

scarring and reduced efficiency of the lymphatic system in its removal of lymph [9]. The

overwhelmed lymphatic system would then have an abnormal buildup of fluid which can cause

swelling in areas of the arm, breast, or chest.

4 | P a g e

Lower Extremity Lymphedema

As upper extremity lymphedema can occur due to damage of axillary nodes, lower

extremity lymphedema (figure 4) can occur from damage to groin nodes. Lymphedema can

occur from an inguinal lymph

node dissection which is the

removal of lymph nodes in the

groin region to check for the

presence of cancer cells.

Radiation therapy can also

increase the risk of lymphedema

development. Due to the low

number of alternate lymph

pathways for drainage in the lower extremities, lymphedema can often occur in the legs. The

drainage pathway at the groin is also narrowed by the lacunar ligament and further accumulation

of lymph fluid results in decreased oxygen tension and fibrosis [4].

Non-invasive Diagnostic and Measuring Techniques

Lymphedema, is a potential side effect of cancer surgery or radiation treatment that can

appear in some people during or after months or years of treatment. The rate of development is

different for all women and tissue changes are not always apparent which is why detection of

early lymphedema can be challenging and the numerous measurement techniques makes it

difficult to know which is best. To detect the presence of lymphedema, clinicians must be able to

accurately measure the volume or circumference of the affected area. Early identification of

5 | P a g e

lymphedema before significant fluid buildup allows for early intervention that may prevent or

slow the progression of lymphedema to a chronic stage.

Many methods may be used to diagnose lymphedema. Some methods used in measuring

upper limb volume are direct manual measurements such as water displacement and

circumferential tape measurements [10]. Water displacement has been known to be the most

widely accepted measurement

technique by comparing the limb

volume with that of the unaffected

limb using a various type of

containers of water [9, 11, 12] as

illustrated for hand and foot volume

measurements in figure 5. Upon insertion of part of the limb, the volume of water displaced is

measured and compared to the unaffected limb or to prior measurements. In a study to test the

validity of this technique, an intraclass correlation coefficient of 0.99 was found for the

reliability of water displacement volumes [12]. In recent years, circumferential measurement has

become the most commonly used test for lymphedema, replacing water displacement

measurements for a few reasons [11].

The least expensive method is the use

of a tape measure to measure at various

locations along the affected limb (arm, leg) at

regular intervals and in the same places during

each subsequent follow-up (figure 6).

6 | P a g e

Volumes of the limb can be derived from circumference measure by using a geometric formula

[13] as schematically illustrated in figure

7. Compared to circumferential

measurements, water displacement

techniques can be time-consuming,

nonhygienic, and not portable [11, 12].

However, both techniques in measuring

limb volume contain a few

disadvantages. In water displacement, it is not easy to guarantee that the limbs are submerged to

the same level and circumferential measurements collected could be affected by the positions

chosen on the limb to measure circumferences using anatomic landmarks [12]. Even with these

possible sources of error, a study conducted by Taylor et al. to test the validity of the

measurements of arm circumference and volumes obtained a high intraclass correlation

coefficient of mostly ≥.98 which indicates high reliability [12]. They found that circumferential

measurements were reliable but overestimated actual volume by 100 mL and a difference up to

150 mL was considered measurement error [12]. The study also concluded that volumes

calculated from anatomic landmarks are more reliable and accurate than those obtained from

circumferential measurements based on distance from fingertips [12]. They reasoned that

because the length of the arm differs for each woman, fixed distances from fingertips would be

in different positions relative to the anatomy of each woman [12]. Water displacement is too

messy and cumbersome to be used to assess methods for the treatment of lymphedema which

requires accurate measurements of limb volumes [12]. It also does not isolate the site of swelling

and requires a strict protocol [14].

7 | P a g e

In addition to water displacement and circumferential measurements, another method for

assessing volume change is the infrared optoelectronic device (Perometer) which is illustrated in

figure 8 shown measuring legs but is also used to measure arm rcumferences. This device uses

infrared light transmitters and

projects light inside a square frame

to create an electronic image of the

limb. As the limb is placed inside

the frame it blocks light

transmission and creates an

electronic limb image to produce

measurements of limb circumference [10, 14] from which volume is clculated. Adriaenssens et

al. [10] conducted a comparative study between water displacement, circumferential

measurement, and Perometer methods for evaluating arm volume in patients with BCRL.The

Perometer measurements were found to be between values obtained from the other methods,

especially for larger arm volumes, producing values above and below the estimated arm volumes

obtained by water displacement and circumferential measurements [10]. In another study,

Seward et al. [15] found evidence that supporting the accuracy of perometry as equal to that of

water displacement. However, they reasoned that volume measurements may be of little value

when diagnosing mild lymphedema. Changes in fat or muscle composition can drastically affect

arm volume and mimic changes in lymph accumulation. Although the Perometer has good

reliability for volume calculations it has its limitations. When using the Perometer, assessment of

the entire limb can be difficult, it is not mobile, usage is limited to an arm or leg measurement,

and the machine is costly [5].

8 | P a g e

Diagnosis of lymphedema depends on volume and circumference differences between the

involved and uninvolved limb. However, volume measurements quantify more than just fluid

changes. It cannot delineate fluid, muscle mass, bone, fat of other changes in tissue composition

[5]. It also cannot detect hypertrophy or atrophy that may occur due to increased use or disuse of

the limb [5]. Overall, a lymphedema diagnosis based only on volume can potentially overlook

skin and deep tissue changes within the subcutaneous space.

An alternative to volume measurement of lymphedema, Bioimpedance spectroscopy, has

been used to measure fluid content in the limbs. The process sends a painless electrical current

through the body and measures the body’s resistance and response to the current to find

information about tissue and water content without the involvement of invasive procedures as

illustrated in figure 9. Body tissues have different electrical conductivities and will produce

different resistances to electric current. Bone and adipose have high impedance as they are

insulators while

skeletal muscle

and interstitial

fluid have high

conductivity

[15]. The more

water present,

the less

resistance there

will be to the electric current which will provide the measurement of water content without

including adipose or fibrous tissue [15].

9 | P a g e

The multi frequency bioimpedance analysis (BIA) is a method that uses a range of

frequencies to calculate resistance when the current is extrapolated back to 0 Hz [15]. This

method is performed by placing electrodes on the surface of the skin to calculate the amount of

body fluid the affected limb contains [16]. To examine the reliability of bioimpedance, a small

study was conducted in comparison to perometry with several women who developed

lymphedema post breast cancer treatment. Followed by a control study, bioimpedance was

compared to perometry as well as tape volume. The results indicate that the bioimpedance

analysis was able to detect a difference in fluid that was not reflected by volume [16]. Another

study used bioimpedance to determine the prevalence of lymphedema 6 years post breast cancer

surgery [15]. Of the 166 patients in the cohort, 34% showed evidence of lymphedema at one or

more testing phases, and only 6.5% were detected by bioimpedance [15]. They concluded that

the bioimpedance measurements are best read as resistance ratios and are less accurate than other

measurement methods when converted to volume and they must be taken while the patient is

positioned supine [15]. The change in impedance accurately quantifies accumulation of lymph

fluid and can detect early edema changes [17]. The BIA is quick and inexpensive and offers

quantification of lymph fluid. However, it does not measure skin thickness and may be affected

by skin temperature. Tissue fluid can accumulate during pregnancy or menstruation and altered

electrolyte balance in malnourished states. The BIA should be cautiously interpreted when used

on lymphedema patients because it measure changes in fluid resistance only [17].

Another technique developed for the detection of edema, the tissue dielectric constant

(TDC), could be the most efficient and accurate method in the detection of early lymphedema

[18]. Measurement of TDC uses an open-ended coaxial probe to quantitate the dielectric

properties of the examined tissues which correlate to tissue water content [19] and is illustrated

10 | P a g e

in figure 10. A comparison study between bioimpedance spectroscopy and TDC methods,

suggested greater sensitivity for TDC which could detect early, superficial accumulation of

tissue water [18]. Studies suggest that this method might be the preferable method in early

detection of breast cancer related lymphedema in patients in a latent phase [18, 19].

TDC measurements are sensitive to skin-to-fat tissue water and can possibly be used to detect

changes in local tissue water in patients with breast cancer related lymphedema (BCRL) [20]. A

study conducted to distinguish TDC measurements of local tissue water in the arms of women

with and without breast cancer related lymphedema found that a TDC ratio of 1.26 and above

could define an at-risk arm [20]. A study by Bakar et al. was conducted to confirm this value in

determining clinical lymphedema after breast cancer surgery. Sixty-three participants were

11 | P a g e

recruited in two groups: the lymphedema group (n=32) who had BCRL after breast cancer

surgery, and the latent group (n=31) who had breast cancer surgery yet no lymphedema [18].

Local tissue water (LTW) measurements were conducted with Moisture Meter-D compact at

sites 8 cm proximal, 6 cm distal from the antecubital fossa, and 10 cm inferior from the axilla in

2.5 mm depth [18]. Sensitivity of the TDC method was analyzed based on a reference of 1.2 or

higher interarm LTW ratio in both groups. The results show that absolute LTW values were

significantly different (p

12 | P a g e

treatment study of lower-limb lymphedema [18]. A total of 17 patients with lower-limb

lymphedema were recruited in the study and complex decongestive physiotherapy was applied

for 5 days a week for 4 weeks [23]. Circumferential tape measurement of both limbs was

performed at nine sites using a tape measure and percentage skin water (PWC) content of the

thigh, calf, and ankle were measured [23]. The results reflected a positive effect of complex

decongestive physiotherapy (CDP) in patients with lower-limb lymphedema as there was

significant reduction of circumference at all nine measurement sites along the lower limb

(p

13 | P a g e

[24]. Five ultrasound images were taken at each site and captured information in the superficial

tissue layers up to a 4-mm depth [24]. The results indicated that the therapists were not

consistent with each other when rating edema but were consistent when measuring limb volume

differences (p < 0.01) [24]. Ultrasound imaging is concluded to be a safe, mobile, and effective

method to measure lymphedema tissue texture and changes in tissue at the subdermal level [14,

24]. However, future studies are needed to continue to evaluate this potential method and should

be repeated on cohorts with different degrees of lymphedema to determine the usefulness of

ultrasound measures in evaluating and managing this condition. If US imaging is proven to be a

reliable measurement method, it may have the potential to measure more difficult areas of the

body.

Magnetic Resonance Imaging (MRI) provides a more precise anatomical information. It

can identify enlarged lymph vessels and cause of lymphatic obstruction [17]. The MRI also

semi-quantitate the degree of fat and liquid in the affected limb when compared to the unaffected

limb [17]. Computed tomography (CT) provides cross-sectional image and displays the density

of the subcutaneous and muscle compartments, but is not a useful screen method [17]. Both

methods are expensive and are used as additional diagnostic tools.

Conclusions

Due to the numerous variables contributing to this condition such as genetics, patient

anatomy, and cancer treatments, it can be difficult to predict the risk of acquiring lymphedema.

Patients and clinicians depend on practical and efficient techniques that can accurately measure

and diagnose lymphedema. Accurate measurements are necessary to monitor the progression or

regression of swelling and a consistent guideline is needed for evaluation of lymphedema along

with a comprehensive history and physical examination [17]. Clinically, lymphedema is initially

14 | P a g e

evaluated using subjective history, inspection, palpation, and circumferential limb measurement

[5]. Since lymphedema is a complex condition with continuous changes in tissue with

progression or regression of swelling, objective measurement methods are favored because they

are used routinely. As each method has its own advantages and disadvantages, the consistent use

of one method for measurements should be reliable in detecting swelling. With the reviewal of

measurement methods for lymphedema, it may be beneficial to use multiple methods to combat

several existing variables such as subject perception, visual skin inspection, volume distortion,

and firmness of subcutaneous texture [5]. Volume measurement alone may overlook important

tissue texture changes [5] and decreased limb volume is not always an indicator of successful

limb reduction [17]. Detection of mild lymphedema may benefit from the usage of both volume

measurement and local tissue water measurements as either forms of measurement conducted

alone may not be accurate. The easiest method in assessing volume in asymmetrical limbs is by

use of circumferential measurements. Tape measurement is simple and inexpensive and it can be

easily converted into volume. To measure tissue water content, the BIA and TDC methods show

promising results, however, further development of these methods is needed before use in

routine clinical practice.

15 | P a g e

References

1. Damstra, R.J. and P.S. Mortimer, Diagnosis and therapy in children with lymphoedema.

Phlebology, 2008. 23(6): p. 276-86.

2. Brouillard, P., L. Boon, and M. Vikkula, Genetics of lymphatic anomalies. J Clin Invest,

2014. 124(3): p. 898-904.

3. Pandey, S. and S. Sharma, Meige's syndrome: History, epidemiology, clinical features,

pathogenesis and treatment. J Neurol Sci, 2017. 372: p. 162-170.

4. Kerchner, K., A. Fleischer, and G. Yosipovitch, Lower extremity lymphedema update:

pathophysiology, diagnosis, and treatment guidelines. J Am Acad Dermatol, 2008. 59(2):

p. 324-31.

5. Johnson, K.C., A.G. Kennedy, and S.M. Henry, Clinical measurements of lymphedema.

Lymphat Res Biol, 2014. 12(4): p. 216-21.

6. Deutsch, M., et al., The incidence of arm edema in women with breast cancer randomized

on the National Surgical Adjuvant Breast and Bowel Project study B-04 to radical

mastectomy versus total mastectomy and radiotherapy versus total mastectomy alone. Int

J Radiat Oncol Biol Phys, 2008. 70(4): p. 1020-4.

7. Ugur, S., et al., Risk factors of breast cancer-related lymphedema. Lymphat Res Biol,

2013. 11(2): p. 72-5.

8. Fu, M.R., Breast cancer-related lymphedema: Symptoms, diagnosis, risk reduction, and

management. World J Clin Oncol, 2014. 5(3): p. 241-7.

9. Megens, A.M., et al., Measurement of upper extremity volume in women after axillary

dissection for breast cancer. Arch Phys Med Rehabil, 2001. 82(12): p. 1639-44.

10. Adriaenssens, N., et al., Comparative study between mobile infrared optoelectronic

volumetry with a Perometer and two commonly used methods for the evaluation of arm

volume in patients with breast cancer related lymphedema of the arm. Lymphology,

2013. 46(3): p. 132-43.

11. Ridner, S.H., et al., Comparison of upper limb volume measurement techniques and arm

symptoms between healthy volunteers and individuals with known lymphedema.

Lymphology, 2007. 40(1): p. 35-46.

16 | P a g e

12. Taylor, R., et al., Reliability and validity of arm volume measurements for assessment of

lymphedema. Phys Ther, 2006. 86(2): p. 205-14.

13. Czerniec, S.A., et al., Assessment of breast cancer-related arm lymphedema--comparison

of physical measurement methods and self-report. Cancer Invest, 2010. 28(1): p. 54-62.

14. McLaughlin, S.A., et al., Considerations for Clinicians in the Diagnosis, Prevention, and

Treatment of Breast Cancer-Related Lymphedema: Recommendations from a

Multidisciplinary Expert ASBrS Panel : Part 1: Definitions, Assessments, Education, and

Future Directions. Ann Surg Oncol, 2017. 24(10): p. 2818-2826.

15. Seward, C., et al., A comprehensive review of bioimpedance spectroscopy as a diagnostic

tool for the detection and measurement of breast cancer-related lymphedema. J Surg

Oncol, 2016. 114(5): p. 537-542.

16. Whitworth, P.W. and A. Cooper, Reducing chronic breast cancer-related lymphedema

utilizing a program of prospective surveillance with bioimpedance spectroscopy. Breast

J, 2018. 24(1): p. 62-65.

17. Caban, M.E., Trends in the evaluation of lymphedema. Lymphology, 2002. 35(1): p. 28-

38.

18. Bakar, Y., A. Tugral, and U. Uyeturk, Measurement of Local Tissue Water in Patients

with Breast Cancer-Related Lymphedema. Lymphat Res Biol, 2017.

19. Rockson, S.G., Detecting Lymphedema: Bioimpedance Spectroscopy and the Tissue

Dielectric Constant. Lymphat Res Biol, 2015. 13(3): p. 169.

20. Mayrovitz, H.N., D.N. Weingrad, and S. Davey, Tissue dielectric constant (TDC)

measurements as a means of characterizing localized tissue water in arms of women with

and without breast cancer treatment related lymphedema. Lymphology, 2014. 47(3): p.

142-50.

21. Mayrovitz, H.N., D.N. Weingrad, and S. Davey, Local tissue water in at-risk and

contralateral forearms of women with and without breast cancer treatment-related

lymphedema. Lymphat Res Biol, 2009. 7(3): p. 153-8.

22. Czerniec, S.A., L.C. Ward, and S.L. Kilbreath, Assessment of breast cancer-related

lymphedema: a comparison of moisture meter and spot bioimpedance measurement.

Lymphat Res Biol, 2015. 13(1): p. 10-9.

17 | P a g e

23. Tugral, A., T. Viren, and Y. Bakar, Tissue dielectric constant and circumference

measurement in the follow-up of treatment-related changes in lower-limb lymphedema.

Int Angiol, 2018. 37(1): p. 26-31.

24. Johnson, K.C., et al., Ultrasound and Clinical Measures for Lymphedema. Lymphat Res

Biol, 2016. 14(1): p. 8-17.