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Lymphology 50 (2017) 84-94

IS ULTRASONOGRAPHY A USEFUL METHOD TO EVALUATE THE EFFECTIVENESS OF COMPLEX DECONGESTIVE THERAPY

IN BREAST CANCER-RELATED LYMPHEDEMA?

D. Sezgin Ozcan, O. Oken, M. Dalyan Aras, B.F. Koseoglu

Department of Physical Medicine and Rehabilitation (DSO,MDA,BFK), Ankara Physical Medicineand Rehabilitation Training and Research Hospital, and Department of Physical Medicine andRehabilitation (OO), Liv Hospital Ankara, Ankara, Turkey

ABSTRACT

In recent years the use of ultrasonographyhas become widespread in the field of lymph-edema especially as an aid for diagnosis. Theaim of this study was to evaluate whetherultrasonography is a useful method to assessthe efficacy of complex decongestive therapy(CDT). Circumferences and ultrasonographicevaluations (cutis and subcutis thickness)were performed at 10 cm proximal and distalto the elbow and limb volume (upper andforearm) was calculated from circumferencesat six anatomic landmarks by using truncatedcone formula. Measurements were recordedbefore and after CDT on both sides. A total of twenty-six women (mean age 51.3± 10.8)with the diagnosis of breast cancer-relatedlymphedema (BCRL) were enrolled in thestudy. Significant reduction in the subcutisthickness was observed on the affected sideafter the treatment period, and the percentagechange in subcutis thickness was correlatedwith the percentage change in edema. Thisstudy also demonstrated that the soft tissuethickness was higher in the affected arm andultrasonographic findings were consistent with the other measurement methods (circum-ferences and limb volumes). Considering thatultrasound imaging is patient-friendly, non-invasive, and cost-effective, we recommend its

more widespread use for evaluating treatmentefficacy in BCRL.

Keywords: complete decongestive therapy,postmastectomy lymphedema, treatmentefficacy, ultrasound

Lymphedema is a disorder characterizedby the accumulation of protein-rich lymphaticfluid in the cutaneous and subcutaneoustissue. It is divided into primary and secon-dary lymphedema based on the underlyingcause. Primary lymphedema develops due tothe congenital abnormalities while secondarylymphedema is an acquired disorder resultingfrom alteration of lymphatic vessels or lymphnodes. Common causes of secondary lymph-edema are cancer and its treatment (surgery,radiation therapy), trauma, tumor, burn, and inflammation (1-4). Upper extremitylymphedema develops in breast cancersurvivors. The related risk factors include thenumber of removed axillary nodes, radio-therapy, presence of postoperative axillaryhematoma, seroma, or infection, overweightand reduced physical activity (5,6). Itsprevalence ranges from 10-35% after breastcancer treatment and results in a reduction in level of physical activities and functions,psychological problems, and reduced health-related quality of life (1,5,7). Although there

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is no cure for this condition, early diagnosisand initiation of treatment are required toprovide optimal benefits (1,8). Lymphedemais defined based on clinical findings inpatients with known risk factors, and whenneeded, specialized diagnostic tests are per-formed including volumetric measurement,soft tissue and lymphatic vessel imaging (9).The patient’s subjective complaints such asperceived swelling and the sensation ofheaviness or tightness are also important and require careful follow-up (10).

In lymphedema, high protein content ofthe lymphatic fluid in the interstitial spaceincreases the limb volume and activatesneutrophils, macrophages, and fibroblastsleading to tissue fibrosclerosis. Observing thepresence of these histological changes isimportant for estimating the prognosis andresponse to the lymphedema treatment (2,11).Volumetric and circumferential measure-ments are the widely used methods for thedetection and follow-up evaluation of lymph-edema but they can’t evaluate the histologicalproperties. The other less common methodsare the bioelectric impedance used for earlydetection of the lymphedema and tonometryfor assessment of elasticity. Only magneticresonance imaging (MRI), computedtomography (CT) and ultrasonography (US)can be used in both diagnosis and evaluationof the histological characteristics of theaffected soft tissues (12-15). Considering thecost, ease of use, and patient-friendlyproperties, ultrasonography seems to be moreadvantageous than CT and MRI forlymphedema patients. Ultrasonography is areliable and valid method to evaluate thethickness of the cutaneous and subcutaneouscompartments and fibrotic changes in thesubcutaneous tissue in lymphedema patients(12,16,17). In recent years, the use ofultrasonography has become widespread inthe field of lymphedema especially indiagnosis and evaluation of elastic propertiesof the tissue, but not commonly in the follow-up evaluation including treatment efficacy.

Complete decongestive therapy (CDT) is

a multicomponent therapeutic approachaccepted as a standard treatment of lymph-edema. It consists of manual lymphaticdrainage (MLD), compression therapy,therapeutic exercises, skin care, and patienteducation. The aims of the CDT are to reducethe extremity volume by moving lymph fluidfrom affected lymphotomes using residuallymphatics, reduce fibrotic tissue, and avoidthe development of complications andrecurrences. In the literature, multiple studieshave demonstrated that CDT is an effectivetreatment method for reducing limb volumeand severity of pain and in improving thequality of life in patients with breast cancer-related lymphedema (9,15,18-20). Volumetricand circumferential measurements are mostlyused to evaluate the efficacy of CDT butrecently it has been considered that US mayalso be a practical and sensitive method forassessment of the CDT response (2).

Most studies in the literature related toultrasonographic evaluation in lymphedemaare based on use for diagnosis. In thesestudies, it has been shown that the cutis andthe subcutis thickness were increased in theaffected arm compared to the contralateralarm (3,12,14,21,22). The few studies whichused ultrasonography for evaluation of theeffectiveness of CDT only showed reductionin the cutis and subcutis thickness withoutany comparisons with the other measurementmethods (2,7). In this study, we evaluated theinfluence of complex decongestive therapy onthe soft tissue thickness and the consistencyof the changes in ultrasonographic findingsalong with the circumferential measurementand the limb volume in patients with breastcancer-related lymphedema.

MATERIALS AND METHODS

Subjects

A total of 45 consecutive women with the diagnosis of breast cancer-related lymph-edema (BCRL) were evaluated in thelymphedema clinic at the Ankara Physical

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Medicine and Rehabilitation Training andResearch Hospital from April to November2013. A difference of 2 cm or more incircumferential measurements between theaffected and unaffected arms after the breastcancer treatment was accepted as sufficientfor BCRL diagnosis. Subjects with unilateralstage 2 BCRL (9,23) and who were at leastthree months post breast-cancer treatmentswere eligible for the study. Subjects withrecurrence or metastasis of breast cancer,edema due to other reasons (heart, kidney or liver diseases, primary lymphedema,filariasis), or who had contraindications forapplication of CDT (active infection, deepvein thrombosis/thrombophlebitis, cardiacedema, peripheral artery disease) wereexcluded. Considering previous medicalhistory and physical examination findings, we enrolled only 28 of 45 potential patients in the study (eight patients had stage 1 andfour patients had stage 3 lymphedema; threepatients had metastatic disease, and twopatients had cellulitis on the affected arm).During the treatment period, one subjectdeveloped cellulitis and one subject was diag-nosed with recurrence of ipsilateral breastcancer. Therefore, two subjects were droppedfrom the study. In total, 26 subjects completedthe treatment and were included the finalanalysis. Approval was obtained from thehospital Ethics Committee, and all partici-pants provided written informed consent.

Treatment Protocol

All subjects underwent CDT phase 1program including MLD, compressionbandages, remedial exercises, and skin care.MLD was applied by a physiotherapistqualified in the Vodder method five times aweek for three weeks (a total of 15, 45 minutesessions). MLD was followed by daily multi-layered short-stretch bandaging worn for 21-24 hours a day. Abdominal breathingexercise and remedial exercises wereperformed with the bandages on. Subjectswere given advice on skin and nail care.

Assessment and Outcome Measures

Baseline socio-demographic and clinicalproperties were recorded for each patient.The circumferential measurements, ultra-sonographic measurements of soft tissuethickness, and volumes of upper limbs wererecorded before and after CDT on both sides.Interlimb differences of volumes, circum-ference, and soft tissue thickness were used to evaluate the consistency of these threemeasurement methods. The percentagechange in edema and percentage change insubcutis thickness were also calculatedseparately for upper and forearm to evaluatethe effectiveness of the CDT and the correla-tion between the two assessment methods.

Circumferential Measurements

The circumferential measurements (cm)were taken horizontally at five anatomiclandmarks: the wrist, 10 cm below elbow,elbow, 10 cm above elbow, and axilla by aplastic tape using a slight pressure. Theupper limb was divided into four segments bythe mentioned anatomic landmarks, and armvolume was calculated using a formula fortruncated cone. The sum of these volumesgives the total volume of the limb (24). Limbvolume was calculated as two separatesegments (upper arm and forearm) (cm3) forboth affected and unaffected sides. Percen-tage change in edema was calculated usingthe following formula: Percentage change inedema = (Vi - Vf)/(Vi - Vn) x 100 (Vi: theinitial volume of the lymphoedematous limb,Vf: the final volume of the lymphoedematouslimb, Vn: volume of the normal limb). Thecircumferences of 10 cm proximal and distalof the elbow crease were recorded before and after the therapy on both sides and thecorrelations were evaluated with the softtissue thickness at the same landmarks.

Ultrasonographic Measurement

Ultrasonography was performed by using

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a linear array probe (7-12 MHz Logiq P5; GE Medical Systems, Wisconsin, USA). Toreduce inter-operator error, the samephysiatrist experienced in neuromuscularultra-sound performed the measurements.During each measurement, patients wereseated with their forearm supinated andextended on a pillow. The ultrasound gel wasapplied to the skin liberally and the probeplaced perpendicular to the skin surface. The position of the probe was vertical to thearm axis. No pressure was applied to theprobe to avoid affecting the soft tissue thick-ness. The ultrasound image was obtainedwhen the thickness of the gel layer was atleast 1 cm and the cutis and the subcutislayers were clearly distinguishable. The

measurements were done at the followingsites: 1) 10 cm proximal to the elbow creasealong the line parallel to arm axis from themidpoint of the medial and lateral epicondylesand 2) 10 cm distal to the elbow crease alongthe line parallel to arm axis from the midpointof the medial and lateral epicondyles.Ultrasonographic images were taken threetimes at each landmark, and mean resultswere calculated. The cutis (epidermis anddermis) thickness (between entry echo underthe gel layer and the dermis-subcutaneousboundary) and the subcutis thickness(between the cutis-subcutis and the subcutis-muscle boundary) (mm) were measured (Fig. 1). These measurements were performedbefore and after CDT for both sides.

Fig. 1: Ultrasonographic images of a patient with unilateral breast cancer-related lymphedema demonstratingcutaneous and subcutaneous thickness A: Unaffected arm B: Affected arm with increased cutis and subcutisthickness.

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Percentage change in subcutis thickness wascalculated using a corresponding formula tothat used for percentage change in edema(above) to assess the effectiveness of CDT.

Statistical Analysis

Statistical analysis was performed usingSPSS software package (version 20.0, SPSSInc., Chicago, IL). Distributions of continu-ous variables were evaluated by Shapiro-Wilktest. Descriptive statistics were expressed asmean ± standard deviation for continuousvariables, median (minimum-maximum) fordiscrete variables and number (n) andpercentage (%) for categorical variables. Thesignificances of the difference in medianvalues between the affected and unaffectedarms were analyzed with the Mann-WhitneyU test. The Wilcoxon test was applied todetermine significant changes between beforeand after CDT. Spearman correlationanalysis was performed to evaluate theconsistency of the measurement methods. A p value of <0.05 was considered significant.

RESULTS

A total of 26 female subjects (mean age51.3 ± 10.8) with the diagnosis of BCRLcompleted the treatment period. Two subjectshad ductal carcinoma in situ and 24 of 26subjects had invasive ductal carcinoma. Table 1 displays the socio-demographic andclinical properties of the subjects.

Pre-treatment comparisons betweenaffected and unaffected arms revealedsignificantly high values of limb volume,circumference, and soft tissue thickness (cutis and subcutis) in both upper and fore-arm on the affected side (p<0.01) (Table 2).Following completion of the CDT program,limb volume, circumference, and subcutisthickness were decreased signifi-cantly on theaffected side (p<0.001). But no staticallysignificant change was observed in the cutisthickness (p>0.05) (Tables 3 and 4).

Consistency between findings ofultrasonographic and circumferentialmeasurements was assessed on the affectedside before and after the therapy. Significantcorrelations of the interlimb difference ofsubcutis thickness with the interlimb differ-ence of circumferences and limb volumeswere revealed (Table 5). After treatment,

TABLE 1Socio-Demographic and Clinical Characteristics of Subjects

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TABLE 2Pre-Treatment Comparisons of Volumes, Circumferences, and Soft Tissue

Thickness Values in Affected and Unaffected Sides

TABLE 3Comparisons of Volumes and Circumferences Before and After CDT

in Both Affected and Unaffected Sides

the mean percentage change in edema in theupper and forearm were 36.9% and 40.3%and the mean percentage change in subcutisthickness in the upper and forearm were

34.6% and 37.5%. These were correlated inboth upper and forearm on the affected side(respectively r=0.530 p= 0.013 and r=0.605p= 0.006).

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DISCUSSION

Breast cancer-related lymphedema isusually not a life-threatening condition butcauses several psychosocial problems andlimitations in physical functions leading toreduced health-related quality of life. Inrecent years, use of ultrasonography hasbecome widespread in the field of lymph-edema for diagnosis and evaluation of soft

tissue structures but use for examiningresponse to treatment has not been wide-spread. The aim of this study was to evaluatewhether ultrasonography is a useful methodto assess the efficacy of CDT. In this study,significant reduction in the subcutis thicknesswas observed on the affected side after thetreatment period, and the percentage changein subcutis thickness was correlated with thepercentage change in edema. This study also

TABLE 4Comparisons of Soft Tissue Thickness Before and After CDT

in Both Affected and Unaffected Sides

TABLE 5Correlations of the Absolute Subcutis Thickness with the Absolute Circumferences

and Volumes in Upper And Forearm Before and After the CDT]

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demonstrated that the soft tissue (skin andsubcutis) thickness was higher in the affectedarm, and ultrasonographic findings wereconsistent with measurements of circum-ferences and limb volume in both the upperand forearm.

In lymphedema, increase in protein andcell debris components stimulate the activitiesof neutrophils, macrophages, and fibroblasts,and cause swelling of the affected extremity.If left untreated, lymphedema leads to chronicinflammation which stimulates fibrosis and inadvance stages, keratosis and skin papilloma(11,25). The most common measurementmethods in use for diagnosis and follow-upare circumferential and volumetric evaluation.But these methods can’t give informationabout the structure of soft tissue as CT, MR,and US. These methods may provide infor-mation for prediction of treatment efficacyand prognosis but both CT and MRI areexpensive, time-consuming, and CT has theadded risk of radiation exposure (2). Ultra-sonography is a patient-friendly, easy-to-use,time and cost effective measurement methodproviding the knowledge of soft tissuestructure and may be a useful method for alldiagnosis, assessment, and prediction of thetreatment efficacy.

Ultrasonographic evaluation of lymph-edematous tissues reveals different patternsof ultrasonographic findings caused bymorphological alterations in the dermal andsubdermal layers. In lymphedema, the dermisshows homogenous hypo-echogenic changesbecause of water accumulation in the collagentissue. The subcutaneous tissue shows differ-ent patterns of echographic findings with thefirst pattern showing more uniform hypo-echogenic reflection because of the diffuseaccumulation of protein-rich lymphatic fluidthat is seen more frequently in acute lymph-edema. The second pattern is hyperechogenicareas surrounded by hypo-echogenic tracesdue to the adipose tissue surrounded by afluid with fibrous tissue. The third pattern ishomogenous hyperechogenic appearance dueto the overgrowth of adipose tissue which is

observed in patients with chronic edema (21).Several predictive factors of the response tothe treatment were suggested. The presenceof lymph fluid spread into the extracellularmatrix of the subcutaneous layer wasproposed as a factor of better response whilethe presence of fibrosis with the formation of adipose tissue and presence of less waterwould lead to lower treatment efficacy(21,26). In this study, we didn’t evaluate thehistological properties and the relation withthe responses to the treatment. We onlyevaluated the cutis and subcutis thickness by ultrasonography.

In the literature, several studies haveshown that the cutis and the subcutis thick-ness were higher in the affected arm than thecontralateral arm (3,12,14,21,22). Mellor et alalso suggested that evaluating the skinthickness by ultrasonography may be usefulfor diagnosing lymphedema because of theuniform increase all around the arm whilesubcutis swelling varies (14). In our study, we found that both the cutis and the subcutisthickness were increased on the affected side,compatible with the previous studies. Becauselymphedema mostly affects the distal upperarm and proximal forearm, we used 10 cmabove and below of the elbow as the anatomiclandmarks. But for ease of the application,we only used the ventral side of the arm forassessment. In contrast to these studies, wealso evaluated the consistency of subcutisthickness measurement with circumferencesand limb volumes (separately for upper andforearm), and significant correlations werefound with these commonly used methods. Inthe literature, a few studies have comparedthese measurement methods for consistency.The study by Uzkeser et al demonstratedsignificant correlation of dermal thicknesswith the water immersion method andcircumferences only in the forearm region but they didn’t evaluate the correlations ofsubcutis thickness. Considering that thesubcutaneous tissue contributes more to armvolume in lymphedema, we preferred toanalyze the correlations based on subcutis

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thickness. The results of our study supportthe use of ultrasonography in the diagnosis of lymphedema as a method consistent withlimb volumes and circumferences.

Complex Decongestive Therapy (CDT),the mainstay therapy of lymphedema,consists of two phases, and this study onlyevaluated the short-term effect of the firstintensive phase on lymphedema volume.Manual Lymph Drainage (MLD) is the maincomponent of CDT and involves specifichand movements stimulating excess inter-stitial lymph fluid from congested areasamong damaged lymphatics into the residualfunctional lymph vessels and nodes.Compression bandages applying after MLDcreates an internal pump-like action betweenthe rest and action of muscles leading tomovement of the lymph fluid from thecongested areas into the blood vascularcirculation. Bandages also prevent re-accumulation of lymph fluid and help tomaintain volume reduction after MLD. MLD and compression bandages also providereduction and breaking up fibrosis of in thetissues (9). Assessment of treatment efficacyis mostly performed by comparing themeasured circumferences and limb volumebefore and after the therapy but, in recentyears, interest in the use of ultrasonographyfor this purpose has increased.

In the literature, we found a few studiesusing ultrasonography for the evaluation ofthe effects of CDT in breast cancer-relatedlymphedema. These studies only showed thereduction in the cutis and subcutis thicknessin the post-treatment evaluations without anycomparisons with the other measurementmethods as we did. Lee et al demonstratedthat after a two-week CDT program that softtissue thickness was significantly reducedonly at the elbow and 10 cm above the elbowbut not at 10 cm below the elbow while thecircumferential measurements revealed asignificant reduction in all three points (2). A second study by Ranheer et al after a CDTprogram demonstrated a significant reductionin both cutis and subcutis thickness of the

edematous limb (7). A study by Uzkeser et alevaluated the effectiveness of MLD andintermittent pneumatic compression pumpingin lymphedema treatment and found asignificant decrease in dermal thickness afterboth treatments but they didn’t evaluate thechanges in subcutis thickness (27). Ourresults showed disparity from the mentionedstudies because we found significant decreaseonly in subcutis thickness not in cutisthickness. Previously it has been suggestedthat the increase in subcutaneous tissuecontributes most to the lymphedema volume(21). Therefore, a decrease in subcutisthickness instead of cutis thickness aftervolume reduction by CDT can be explainedby the light of this information. Differentfrom previous studies, we also evaluatedconsistency of the percentage change insubcutis thickness (10 cm above and belowthe elbow) compared with percentage changein edema reduction (upper and forearm) andfound a significant correlation between thetwo assessment methods. Percentage changein edema reduction is a widely used andimportant determiner in the assessment of the response to the treatment.

The limitations of this study are thesmall sample size and not including any long-term follow-up evaluation after the three-week CDT. In addition, only patients withstage 2 lymphedema were enrolled in thestudy because this group was expected to gain the most benefits from the treatment.Therefore the results can’t be generalized to stage 1 or 3 lymphedema patients. Theother limitation is that determination of limbvolume used a calculated limb volumederived from circumferential measurementsinstead of the gold standard water immersionmethod. We preferred to use this methodbecause it is also a reliable and valid methodwhich is more practical than the waterimmersion method. It has also been demon-strated that these two methods have a strongcorrelation (28,29).

According to our results, pre- and post-treatment measurement of subcutis thickness

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using ultrasonography seems to be a usefulmethod in the assessment of the efficacy ofCDT. Moreover, we found that the ultra-sonographic measurements correlated withthe most commonly used assessment methodsof circumferential measurements and limbvolume calculated from circumferences.Considering that ultrasound imaging ispatient-friendly, non-invasive, and cost-effective, we recommend more widespreaduse for evaluating treatment efficacy inBCRL. Further long-term studies withgreater number of patients including stage 1 and 3 lymphedema are needed.

CONFLICT OF INTEREST ANDDISCLOSURE

All authors declare that no competingfinancial interests exist.

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Didem Sezgin Ozcan, MDAnkara Physical Medicine and

Rehabilitation Training and Research Hospital

Ankara, TurkeyTel: +90 (312) 310 32 30Fax: +90 (312) 311 80 54E-mail: sezgindidem@gmail.com