Breast cancer-related chronic arm lymphedema is associated with excess adipose and muscle tissue.

Abstract

Arm lymphedema is a common complication after breast cancer treatment. Although conservative treatment can be used to reduce swelling, treatment often fails, possibly due to chronic edema being transformed from lymph fluid to subcutaneous fat, a condition called nonpitting lymphedema. It is currently unknown if the excess volume is solely due to excess in fat. This study evaluated whether dual energy X-ray absorptiometry (DXA) could be used to estimate the excess fat, muscle, and bone tissue in patients with arm lymphedema.
Eighteen women with arm lymphedema were investigated. Measurements were converted to volume values and compared with values obtained using plethysmography (PG). Linear regression equations and correlation equations were used to compare the DXA and the PG techniques in regard to total volume and excess volume in the lymphedematous arm. DXA was used to estimate excess fat, muscle, and bone volume in the lymphedematous arm. Both DXA and PG provided similar total arm volume and excess volume measurements for the lymphedematous arm. The lymphedematous arm showed 73% more fat, 47% more muscle, and 7% more bone by volume in the lymphedematous arm.
Both excess fat and muscle volume contributed to the total excess volume in nonpitting arm lymphedema; excess soft tissue developed the first few years after breast cancer surgery. DXA can be used to identify patients with excess fat in their arms and thus unsuitable for conservative treatment and may be useful in estimating the amount of fat to remove in patients scheduled for liposuction.

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LYMPHATIC RESEARCH AND BIOLOGY
Volume 7, Number 1, 2009
© Mary Ann Liebert, Inc.
DOI: 10.1089/lrb.2008.1022
Breast Cancer-Related Chronic Arm Lymphedema
Is Associated with Excess Adipose and Muscle Tissue
Håkan Brorson, M.D., Ph.D.,1Karin Ohlin, O.T.R.,1 Gaby Olsson, R.P.T., L.T.,1
and Magnus K. Karlsson, M.D., Ph.D.2
Abstract
Background: Arm lymphedema is a common complication after breast cancer treatment. Although conserva-
tive treatment can be used to reduce swelling, treatment often fails, possibly due to chronic edema being trans-
formed from lymph fluid to subcutaneous fat, a condition called nonpitting lymphedema. It is currently un-
known if the excess volume is solely due to excess in fat. This study evaluated whether dual energy X-ray
absorptiometry (DXA) could be used to estimate the excess fat, muscle, and bone tissue in patients with arm
lymphedema.
Methods and Results: Eighteen women with arm lymphedema were investigated. Measurements were con-
verted to volume values and compared with values obtained using plethysmography (PG). Linear regression
equations and correlation equations were used to compare the DXA and the PG techniques in regard to total
volume and excess volume in the lymphedematous arm. DXA was used to estimate excess fat, muscle, and
bone volume in the lymphedematous arm. Both DXA and PG provided similar total arm volume and excess
volume measurements for the lymphedematous arm. The lymphedematous arm showed 73% more fat, 47%
more muscle, and 7% more bone by volume in the lymphedematous arm.
Conclusions: Both excess fat and muscle volume contributed to the total excess volume in nonpitting arm lymph-
edema; excess soft tissue developed the first few years after breast cancer surgery. DXA can be used to iden-
tify patients with excess fat in their arms and thus unsuitable for conservative treatment and may be useful in
estimating the amount of fat to remove in patients scheduled for liposuction.
3
Introduction
B
juvant irradiation and chemotherapy. One common compli-
cation following surgery is arm lymphedema. The incidence
of lymphedema after breast cancer treatment varies between
8% and 80%, depending on whether axillary lymph nodes
have been removed and whether postoperative irradiation
has been given.1,2Lymph node removal and irradiation can
lead to tissue scarring and to the destruction of lymphatic
vessels; the remaining lymphatic vessels become unable to
transport the lymph, with the result that the lymph collec-
tors become dilated and overloaded. The valves become in-
sufficient, preventing them from performing their function.
This failure spreads distally until even the most peripheral
REAST CANCER IS THE MOST COMMON CANCER IN WOMEN. In
most cases it is treated with surgery with or without ad-
lymph vessels that drain into the affected system become di-
lated.3
In parallel with lymphatic vessel dilation, mononuclear
phagocytic cells in the mesenchymal tissues begin to lose
their ability to remove accumulating proteins. The intersti-
tial proteins that accumulate are osmotically active mole-
cules that attract fluid to the area. This accumulation of pro-
tein and fluid usually occurs after surgery during a 1- to
3-week transitory phase.3
There may be no clinical signs of lymphedema in the la-
tent phase that follows the transitory phase and can occur
from 4 months to 10 years after surgery. At the end of the
latent phase, pressure in the edematous arm usually leads to
‘pitting’: When the edematous tissue is pushed with a fin-
gertip, a depression is formed as the lymph is squeezed into
the surroundings. This condition can involve both excess
Department of Clinical Sciences Malmö, Lund University, 1Plastic and Reconstructive Surgery and 2Clinical and Molecular Osteoporo-
sis Research Unit, Department of Orthopaedics, Malmö University Hospital, Malmö, Sweden.
The project was supported by the Tegger Foundation, the Swedish Society of Medicine, the Lundgren Foundation, the Swedish Cancer
Society, Stockholm, the Foundation Against Cancer at Malmö University Hospital, the Thureus Foundation at Uppsala University, and
Skane County Council’s Research and Development Foundation.

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fluid and adipose tissue, and can be objectively measured
using a tissue tonometer to detect decreased tissue com-
pressibility.3,4
Traditionally, the swelling of a lymphedematous arm has
been thought to be solely due to an accumulation of lymph
fluid. Noninvasive conservative regimens such as physio-
therapy, involving manual lymph drainage, skin care,
remedial exercises, and compression bandaging comple-
mented with compression garments have been the treat-
ments of choice.5However, noninvasive treatment often fails
in patients with chronic edema, as does microsurgery using
lympho-venous shunts or lymph vessel transplantation.6,7In
such patients, liposuction has been used with good re-
sults.8–10Aspirate analysis during liposuction has shown
that this technique removes excess adipose tissue in the
swollen arm; further, swelling of the arm does not recur af-
ter liposuction.8–10However, even though liposuction has
been reported to be successful in treating arm lymphedema,
currently there is no consensus as to whether the increase in
volume is due entirely to excess fat or whether there is also
an increase in muscle and bone tissue. Furthermore, there is
no consensus about why this condition can develop either
right after the operation or up to many years afterwards.
We wished to determine which tissue or tissues comprise
the excess tissue or volume in patients with unilateral post-
mastectomy, nonpitting arm lymphedema. The aim of this
study was to evaluate whether measurements using dual en-
ergy X-ray absorptiometry (DXA) were similar to those ob-
tained using plethysmography (PG), which is the gold stan-
dard for estimating lymphedematous arm volume. We also
wanted to determine whether DXA could be used to com-
pare unaffected and lymphedematous arm volumes. Our re-
sults showed that DXA can be used as a method to estimate
arm volume, and that the increased volume in nonpitting
arm lymphedema is predominantly due to fat.
Materials and Methods
Eighteen female patients with secondary upper limb
lymphedema participated in the study (Table 1). All had un-
dergone mastectomies with lymph node excision: 16 patients
had unilateral modified radical mastectomies and 2 patients
had partial mastectomies. Radiotherapy was given to 15 pa-
tients and chemotherapy to 4. None of the patients had a
generalized disease or any local wound problems after the
operation. All the lymphedemas were of the nonpitting type.
Previous treatment of the patients’ lymphedema included
a variety of conservative therapies such as manual lymph
drainage, compression pumping, bandaging with semi-elas-
tic rolls, and home exercises. None of the 18 patients felt that
the previous conservative treatments had been successful, as
the treatment had not completely reduced the excess volume
in their arms.
The volume of both arms was measured by a water dis-
placement technique called plethysmography (PG), which
has been thoroughly described in previous reports.11,12The
hand and the whole arm up to the axilla, equivalent to the
area measured by DXA, were included in the PG measure-
ment.8The contralateral arm was also measured for com-
parison. The displaced water was weighed on a balance to
the nearest 5 grams, corresponding to a volume of 5 ml. The
excess arm volume or ‘edema volume’ was defined as the
difference in volume between the lymphedematous and the
normal arm.
Dual-energy X-ray absorptiometry (DXA; DPX-L version
3.2, Lunar, Madison, WI) accurately estimates soft tissue com-
position.13–15We used DXA to measure the soft tissue com-
position of both the lymphedematous and the normal arm of
each patient; the hand and the whole arm up to the axilla,
which is equivalent to the area measured by PG, were included
in the DXA estimation. Using the standard LUNAR total body
soft ware, the fat mass, lean mass, and bone mineral content
(BMC) were determined for each arm.13,14The measured tis-
sue weight was then transformed into an estimated volume
using the known densities of fat (0.9167 g/ml ? 0.92 g/cm3),16
muscle (1.0615 g/ml ? 1.06 g/cm3),17,18and bone (3.15 g/
cm3).19The coefficient of variation (CV%) was estimated by
repeating the DXA measurements twice in 16 arms. The CV
was 2.5% for total arm tissue, 1.2% for fat tissue, 4.2% for lean
body mass, and 4.9% for BMC.
Each patient was examined while dressed in short arm and
short leg underwear in a recumbent position with her arms
slightly abducted. Foam rubber was placed between the up-
per arms and the torso to prevent direct contact. A region of
BRORSON ET AL.4
TABLE 1.CHARACTERISTICS OF 18 WOMEN WITH UNILATERAL NONPITTING ARM LYMPHEDEMA AFTER
BREAST CANCER TREATMENT IN WHOM CONSERVATIVE TREATMENT WAS UNSUCCESSFUL
Number of patients
Age at cancer operation
Mean
Range
Interval between breast cancer
operation and onset of lymphedema (years)
Mean
Range
Duration of lymphedema (years)
Mean
Range
Age at investigation (years)
Mean
Range
18
49
34–77
1.8
0–6
11
2–38
62
41–80
Interval between breast cancer
operation and investigation
(years)
Mean
Range
Height (cm)
Mean
Range
Weight (kg)
Mean
Range
BMI (kg/m2)
Mean
Range
13
2–38
165
153–177
79
63–114
29
24–39

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interest (ROI) was defined that included the upper extremi-
ties from the armpit and distally. This region corresponded to
the region measured by PG, and is the same region that is gen-
erally included when liposuction is performed on the arm.
All PG measurements were performed by two investiga-
tors, a physiotherapist (GO) and an occupational therapist
(KO). DXA was performed according to the manufacturer’s
recommendations. A single technician performed all the
BCRL AND ADIPOSE TISSUE5
FIG. 1.
and by dual-energy X-ray absorptiometry (DXA). [? ? 1.015 (95% CI: 0.970–1.061), r ? 0.996, p ? 0.0001].
Regression analysis of the mean total volume of the lymphedematous arms as measured by plethysmography (PG)
FIG. 2.
X-ray absorptiometry (DXA) [? ? 0.884 (95% CI: 0.814–0.955), r ? 0.988, p ? 0.0001].
Regression analysis of the mean excess arm volume as measured by plethysmography (PG) and by dual-energy

Page 4

measurements, and a single researcher (HB) conducted the
software analyses. During the study period, daily calibration
of the PG machine was performed using the Lunar phantom.
Statistics
Data are presented as mean and range or mean and stan-
dard deviation (SD). The Student’s t-test was used to com-
pare the values for the lymphedematous and the normal arm
of each patient. Linear regression analysis was performed to
obtain the coefficient of correlation (r) and the coefficient of
regression (?) with a 95% confidence interval (95% CI); the
constant was set to zero when volumes were analyzed. A p
value of ? 0.05 was considered statistically significant.
Ethics
The study was approved by the Ethics of Human Investi-
gation Committee at Lund University, Sweden, and by the
Radiation Protection Committee of Malmö University Hos-
pital, Sweden. Written informed consent was obtained from
the patients. The study was performed in accordance with
the principles set forth in the Helsinki declaration.
Results
The total mean volume of the lymphedematous arms was
estimated by DXA to be 3873 ml (range, 2809–5802) and by
PG to be 3962 ml (range, 2780–5365). There was a high cor-
relation between the methods [? ?1.015 (95% CI: 0.970–
1.061), r ? 0.996, p ? 0.0001] (Fig. 1).
The mean excess arm volume of the lymphedematous
arms was estimated by DXA to be 1422 ml (range, 735–2603)
and by PG to be 1275 ml (range, 620–1920). This corresponds
to a mean increase of 58% (range, 30–83) as measured by
DXA and 47% (range, 29–66) as measured by PG. There was
a high correlation between the methods when estimating the
excess arm volume [? ? 0.884 (95% CI: 0.814–0.955); r ?
0.988, p ? 0.0001] (Fig. 2, Table 2).
DXA analysis of the specific tissues showed that there was
73% (range, 43–111) greater volume due to fat, 47% (range,
13–81) greater volume due to muscle, and 7% (range,
?12–32) more bone volume in the lymphedematous arm
compared to the healthy arm (Fig. 3).
The excess volume in the lymphedematous arm comprised
55% fat (range, 32–81), 45% muscle (range, 18–68), and 0.2%
bone (range, ?0.4–1.1) (Fig. 4).
BRORSON ET AL.6
TABLE 2.DUAL-ENERGY X-RAY ABSORPTIOMETRY (DXA) ESTIMATION OF TOTAL ARM VOLUME
AND VOLUME OF FAT, MUSCLE, AND BONE IN LYMPHEDEMATOUS
AND NORMAL ARMS OF 18 WOMEN WITH UNILATERAL NONPITTING ARM LYMPHEDEMA
VolumesTotal arm FatMuscle Bone Plethysmography
Normal arm (ml)
Swollen arm (ml)
Excess volume
(ml)
Increased volume
in the diseased
arm (%)
2452 (1820–3603)
3873 (2809–5802)
1422 (735–2603)
1040 (632–1452)
1810 (1090–2998)
770 (421–1579)
1377 (1054–2108)
2027 (1551–3236)
650 (186–1127)
35 (24–43)
37 (28–51)
2 (?4–11)
2687 (2135–3560)
3962 (777–2780)
1275 (620–1920)
58 (30–83)
p ? 0.0001
73 (43–111)
p ? 0.0001
47 (13–81)
p ? 0.0001
7 (?12–32)
p ? 0.05
47 (29–66)
p ? 0.0001
The total arm volume was measured by plethysmography (PG). Data is given as mean (range).
FIG. 3.
and healthy arms (Normal) as estimated by dual-energy X-ray absorptiometry (DXA).
The mean (SD) volume of the arm and of fat, lean body mass (muscle), and bone in the lymphedematous (Lymph)

Page 5

The duration of the lymphedema did not correlate with
the excess volume of the arm as measured by PG [? ?
?10.1 (95% CI: ?33.5- 13.3); r ? 0.222, p ? 0.375] or by
DXA [? ? ?12.5 (95% CI: ?39.1–14.0); r ? 0.242, p ?
0.333]. There was also no correlation between the duration
of the lymphedema and the DXA-estimated excess in terms
of fat volume [? ? ?6.08 (95% CI: ?24.1–11.9); r ? 0.176,
p ? 0.485] (Fig. 5), muscle volume [? ? ?6.27 (95% CI:
?22.0–9.46); r ? 0.207, p ? 0.410)] (Fig. 6) or bone volume
[? ? ?0.172 (95% CI: ?0.358–0.014); r ? 0.440, p ? 0.067]
(Fig. 7).
There was a significant correlation between the total ex-
cess volume of the lymphedematous arm and the excess
muscle volume, both when total excess volume was esti-
mated by PG [? ? 0.507 (95% CI: 0.437–0.577); r ? 0.966,
p ? 0.0001] and by DXA [? ? 0.456 (95% CI: 0.397–0.515);
r ? 0.970, p ? 0.0001]. There was also a significant corre-
lation between the total excess volume of the lymphede-
BCRL AND ADIPOSE TISSUE7
FIG. 4.
X-ray absorptiometry (DXA). The percentage values indicate the increased volume in the lymphedematous arm compared
to the unaffected arm.
The total mean (SD) excess arm volume and the proportion of fat, muscle, and bone as estimated by dual-energy
FIG. 5.
arm as measured by DXA.
No correlation was found between the duration of the lymphedema and the excess fat in the lymphedematous

Page 6

matous arm and the excess fat volume, both when total ex-
cess volume was estimated by PG [? ? 0.595 (95% CI:
0.507–0.683); r ? 0.961, p ? 0.0001) and by DXA (? ? 0.542
(95% CI: 0.484–0.601); r ? 0.979, p ? 0.0001]. In addition,
there was a significant correlation between the total excess
volume of the lymphedematous arm and the excess bone
volume, both when the total excess volume was estimated
by PG [? ? 0.0017 (95% CI: 0.0005–0.0030); r ? 0.572, p ?
BRORSON ET AL.8
FIG. 6.
tous arm as measured by DXA.
No correlation was found between the duration of the lymphedema and the excess muscle in the lymphedema-
FIG. 7.
arm as measured by DXA.
No correlation was found between the duration of the lymphedema and the excess bone in the lymphedematous

Page 7

0.05] and by DXA [? ? 0.0016 (95% CI: 0.0005–0.0027); r ?
0.593, p ? 0.05].
Conclusions
Clinical findings of hypertrophy of adipose tissue in a lym-
phedematous arm following breast cancer treatment has long
been neglected.20,21Previous reports in patients with nonpit-
ting lymphedema treated with liposuction have indicted that,
on average, the aspirate consisted of 68% to 93% fat, 32% in-
terstitial fluid, and 7% lymph, depending on whether a tourni-
quet was used.8,22A study using computed tomography re-
ported excess of fat volume of 81%.22This is similar to the 73%
greater fat volume in the lymphedematous arm compared to
the healthy arm that we found in this study.
This study was performed to evaluate whether DXA could
be used to estimate the excess fat, muscle, and bone tissue in
the diseased lymphedematous arm. The high correlation of
DXA with the PG technique, usually regarded as the gold stan-
dard for arm volume measurements, suggests that DXA can
be used to estimate the excess volume. However, the DXA
measurements must first be transformed into volume values
using known tissue densities. Compared to PG, which can
only estimate volume, DXA measurements can also estimate
the volumes of the various tissues in the arm. This could be
of great clinical relevance in order to objectively evaluate dif-
ferent treatment strategies. Excess adipose tissue, for exam-
ple, could also indicate a higher risk of treatment failure when
using conservative treatment strategies; liposuction might be
indicated in such a case. DXA measurements could also be
used preoperatively to estimate the amount of excess adipose
tissue that should be emoved by liposuction.
The DXA measurements also showed that the increased
volume of lymphedematous arms was not only the result of
excess adipose tissue. We also found that there was a sub-
stantially greater volume due to increased lean body mass
(predominantly muscle) and, to some part, bone in the af-
fected arm compared to the healthy arm. In addition, the in-
crease in arm volume correlated with the excess volumes of
all three compartments (i.e., fat, muscle, and bone). No other
studies have reported increased amounts of muscle and bone
tissue in a lymphedematous arm. One hypothesis that could
explain this is that the greater weight of the affected arm
leads to a higher mechanical load on both the muscle and
the skeleton, resulting in increased muscle and bone
mass.23–25It is also interesting to note that in individuals with
lymphedema for 2–38 years (Table 1), there was no correla-
tion between the duration of lymphedema and the amount
of excess adipose (Fig. 5), muscle (Fig. 6), or bone tissue (Fig.
7). This indicates that the increase in soft tissue volume de-
velops when the lymphedema appears or soon thereafter.
Most of the increased soft tissue volume in the affected
arm was due to increased fat. This explains the clinical find-
ing that liposuction can be used to effectively treat long-
standing nonpitting arm edema. Furthermore, DXA seems
to be an excellent method for preoperatively evaluating the
amount of fat tissue to remove during liposuction. Future
prospective studies are needed to evaluate whether the pre-
operative DXA estimation of excess fat volume correlates
with the amount of fat actually removed during surgery.
In summary, this study indicates that the excess volume
in breast cancer-related chronic arm lymphedema is due to
both excess fat and muscle tissue. The excess soft tissue can
develop either when the lymphedema becomes clinically sig-
nificant or can occur within a year or two. The DXA tech-
nique can be used to objectively monitor soft tissue increases
and may identify individuals who have a poor prognosis
with conservative treatment. DXA may also be used to esti-
mate the amount of fat that should be removed in patients
subjected to liposuction.
Acknowledgments
The authors thank Jan-Åke Nilsson, statistician at the Clin-
ical and Molecular Osteoporosis Research Unit, Department
of Orthopaedics, Malmö University Hospital, who super-
vised the statistical analyses.
Disclosure Statement
No competing financial interests exist
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Address reprint requests to:
Håkan Brorson, M.D., Ph.D.,
Department of Plastic and Reconstructive Surgery
Lund University
Malmö University Hospital
SE-205 02 Malmö, Sweden
E-mail: hakan.brorson@med.lu.se
BRORSON ET AL.10