The n e w e ng l a n d j o u r na l of m e dic i n e

Clinical Practice

Caren G. Solomon, M.D., M.P.H., Editor

Lymphedema after Breast Cancer Treatment

Stanley G. Rockson, M.D.​​

This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence
­supporting various strategies is then presented, followed by a review of formal guidelines, when they exist.
The article ends with the author’s clinical recommendations.

A 43-year-old perimenopausal woman who recently received a diagnosis of breast From Stanford University School of
cancer visited her physician for follow-up after lumpectomy and axillary-node dissec- ­Medicine, Stanford, CA. Address reprint
requests to Dr. Rockson at the Falk Car-
tion, in which specimens of 12 lymph nodes were obtained. There was a positive diovascular Research Center, Stanford Uni-
finding only in the sentinel node. She is undergoing adjuvant radiotherapy. The pa- versity School of Medicine, 300 Pasteur
tient is concerned about the development of lymphedema. She wonders what she can Dr., Stanford, CA 94305, or at ­rockson@​
­stanford​.­edu.
do to minimize the risk of this complication and how it would be managed if it were
to develop. She has no coexisting conditions and no symptoms related to the arms. N Engl J Med 2018;379:1937-44.
DOI: 10.1056/NEJMcp1803290
Her body-mass index (BMI, the weight in kilograms divided by the square of the Copyright © 2018 Massachusetts Medical Society.
height in meters) is 29. There is no detectable swelling on physical examination.
How would you advise this patient?

The Cl inic a l Probl em

L
ymphedema is the clinical expression of an impaired lymphatic
circulation. Acquired lymphedema is most often the consequence of region-
alized injury to a previously normal vasculature and is usually a consequence
of trauma, infection, neoplasia, radiation damage, or surgical interventions, espe-
cially those that include lymphadenectomy.
Because lymphedema is underrecognized and underdocumented, it is highly
likely that the currently accepted rates of incidence and prevalence underestimate
An audio version
its magnitude. The problem is further compounded by variability in the objectively of this article is
defined threshold of volume excess required for diagnosis and by the uncertainty available at
regarding what tools are the most efficient for disease detection.1 Breast cancer– NEJM.org
related lymphedema is the most common form of lymphedema in the United
States and other developed nations. Axillary lymph-node dissection and adjuvant
radiation therapy contribute most heavily to risk.2,3 Other than breast cancer, the
most common neoplasms for which therapy is associated with lymphedema in-
clude sarcoma, gynecologic cancers, and malignant melanoma.4 Estimates of the
risk of lymphedema after breast cancer treatment vary widely,5 from 14 to 40%.
Increasingly conservative approaches to surgery and radiotherapy have driven the
estimated incidence closer to the lower limits of this range6; sentinel-node sam-
pling techniques reduce the estimated risk of breast cancer–associated lymph-
edema to 6 to 10%.7 Approximately 90% of the expected cases occur during the
first 24 months after treatment,8 but the remainder occur years to decades later.
Although there are no clinical features that reliably distinguish the minority of
patients in whom lymphedema will develop from those in whom it will not, several

n engl j med 379;20 nejm.org  November 15, 2018 1937

The New England Journal of Medicine
Downloaded from nejm.org at KAOHSIUNG MEDICAL UNIVERSITY on November 14, 2018. For personal use only. No other uses without permission.
Copyright © 2018 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

Key Clinical Points

Lymphedema after Breast Cancer Treatment

• Breast cancer–related lymphedema is the most common form of lymphedema in the United States
and other developed nations.
• Axillary lymph-node dissection and adjuvant radiation therapy are major risk factors.
• The diagnosis of lymphedema is generally based on the patient’s risk status and physical findings.
• Early or subclinical lymphedema can be objectively detected and serially assessed, and surveillance is
associated with earlier diagnosis and better outcomes.
• Treatment generally involves manual lymphatic drainage (a massage technique that stimulates
lymphatic contractility), skin care, serial application of multilayer bandaging, and exercise.
• Exercise does not exacerbate and may ameliorate symptoms in patients with established lymphedema.
For patients with an elevated body-mass index, weight reduction and maintenance strategies are
indicated.
• Debulking surgeries appear to be helpful in the later, advanced stages of disease; there is also some
evidence for benefit from microsurgery, but more data are needed regarding its effectiveness.

factors have been associated with increased risk.9
These include dissection of the axillary nodes,
with or without extensive breast surgery; radio-
therapy to the breast or the axillary, subclavicular,
or internal mammary lymph nodes; infection or
postoperative complications related to surgical
wounds or drains; ipsilateral venous compro-
mise (which may result from an indwelling
venous port, pacemaker, or dialysis catheter or
from thrombosis); advanced or recurrent cancer;
traumatic insult to the arm; taxane-based chemo-
therapy; the number of positive lymph nodes,
especially more than eight10; and capsular inva-
sion by a tumor.10 In addition — and unrelated
to cancer or cancer therapeutics — obesity pre-
disposes patients to increased risk.11,12 Hyperten-
sion has also been reported to be a risk factor in
some studies,2 but not all.8
In the earliest stages of lymphedema, the pa-
tient may report subtle changes in the surface
architecture of the arm or hand or may have
vague sensations of limb heaviness, discomfort,
or both. The clinical signs vary with the duration
and severity of the lymphedema. The earliest
perceptible swelling is typically soft (Fig. 1) and
easily displaced by the application of external
pressure (known as pitting edema). The forearm
is the most common site of initial swelling; para-
doxically, the hand is often spared even when
there is substantial edema of the more proximal
segments of the forearm. There can also be
swelling in the axilla, scapular region, and breast.
Eventually, the arm is likely to acquire a woody
texture as the skin and subdermis become indu-
rated and fibrotic (Fig. 2). In more advanced
stages, elevation of the limb and external com-
pression no longer effectively reduce limb vol-
ume; the affected limb can become grossly
enlarged and exhibit peau d’orange (Fig. 3). Pro-
liferation of subcutaneous connective tissue and
adipose hypertrophy13 lead to thickening of the
skin and loss of elasticity. The progression from
pitting edema to progressive structural distor-
tion characterizes the natural history of lymph-
edema, which often extends over the course of
weeks to months but in some cases years.14
In rare instances, isolated lymphedema of the
breast or chest wall can occur without accom-
panying lymphedema of the arm. In addition to
axillary lymph-node dissection, risk factors for
lymphedema of the breast include elevated BMI,
location and length of the breast incision, and a
history of biopsy or radiotherapy of the breast.15
In addition to swollen breast tissue, typical find-
ings include skin thickening, erythema, and dis-
comfort.
S t r ategie s a nd E v idence
Diagnosis
The diagnosis of lymphedema can be reliably
based on the patient’s risk status and the objec-
tive physical findings. Self-reported symptoms
should be thoroughly investigated. Alternate
causes of edema should be considered and ad-
dressed.
Between 10% and 18% of patients referred to
a lymphedema clinic have lipedema.16 Although
the edematous limbs characteristic of lipedema
superficially resemble those in patients with

1938 n engl j med 379;20 nejm.org  November 15, 2018

The New England Journal of Medicine

Downloaded from nejm.org at KAOHSIUNG MEDICAL UNIVERSITY on November 14, 2018. For personal use only. No other uses without permission.
Copyright © 2018 Massachusetts Medical Society. All rights reserved.
 Clinical Pr actice

Figure 2. Advanced Lymphedema.

Figure 1. Stage II Breast Cancer–Associated Lymphedema.

lymphedema, lipedema is unlikely to occur in a

single arm. In addition, the results of lymphatic
imaging are normal in patients with lipedema.
Myxedema can also resemble lymphedema, but
presentation is typically symmetric in the lower
limbs and is associated with other features of
hypothyroidism and a markedly elevated level of
thyrotropin. Another cause of edema to be consid-
ered in cancer survivors is occult veno-occlusive
disease, which is typified by a prominent, dilated Figure 3. Peau d’Orange.
superficial venous pattern and is often accompa- The dimpling of the skin known as peau d’orange can
be seen in the upper arm of this patient with advanced
nied by pain; patients frequently present with lymphedema.
mixed lymphaticovenous signs and symptoms.17
Computed tomography (CT) is indicated if veno-
occlusive disease is suspected. the axillary lymph nodes. In lymphedema, delayed
Generally, the diagnosis of lymphedema is axillary visualization accompanies accumulation
made clinically on the basis of an assessment in the dilated dermal lymphatics (i.e., “dermal
of the disproportionate size of the affected arm. backflow”). Magnetic resonance imaging is in-
In most cases, imaging is not needed to confirm creasingly used in diagnosis and is reported to
the diagnosis. If there is uncertainty, the stan- have greater specificity (85.7%) for the detection
dard approach to diagnosis is radionuclide lym- of delayed lymphatic drainage and greater sensi-
phoscintigraphy, in which the subcutaneous in- tivity (100%) for the delineation of lymph vessels
jection of radiolabeled sulfur colloid into the hand than radionuclide lymphoscintigraphy (which has
permits visualization of lymphatic drainage into rates of detection of 66.7% and 83.3%, respec-

n engl j med 379;20 nejm.org November 15, 2018 1939

The New England Journal of Medicine
Downloaded from nejm.org at KAOHSIUNG MEDICAL UNIVERSITY on November 14, 2018. For personal use only. No other uses without permission.
Copyright © 2018 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l
tively) when a reference standard based on clini-
cal presentation and combined imaging results
is used.18 Ultrasonography and CT have low sen-
sitivity for detection and are not recommended.19
Near-infrared fluorescent lymphography is a
newer means of assessing lymphedema. The tran-
sit of dermally injected indocyanine green is
monitored with fluorescent spectroscopy. Al-
though this test is more sensitive than radionu-
clide lymphoscintigraphy in the early stages of
lymphedema,19 quantitative analysis is not pos-
sible. Near-infrared fluorescent lymphography is
generally not used as a diagnostic test but rather
as an adjunctive tool in lymphatic microsurger-
ies, in which accurate visualization of the lym-
phatic drainage pathways is mandatory to achieve
a successful surgical outcome.
Surveillance
Although randomized, controlled trials (RCTs)
of surveillance are lacking, there is a growing
belief that surveillance leads to earlier diagnosis
and to treatment strategies that are both more
effective and more cost-effective than was the
case before the introduction of surveillance
practices.20 In one prospective study, surveillance
(with aggressive risk-reduction measures taken
as indicated) was associated with a lower ob-
served incidence of lymphedema (36.4% in the
control group vs. 4.4% with surveillance).21
Early or subclinical lymphedema can be ob-
jectively detected and serially assessed. Limb-
volume assessment can be performed by means
of volumetric measurement with the use of water-
displacement or by means of extrapolation from
circumferential dimensions, but these techniques
are laborious and time-consuming and therefore
not well-suited to large-scale, serial surveillance.
Optic volumetric assessment (perometry) is less
time-consuming, but it is more expensive than
most other surveillance measures. Perometry is
practiced in some centers but requires an infra-
red, optical electronic scanner to calculate the
volume of both arms. Newer techniques, includ-
ing tonometry, and measurement of the tissue
dielectric constant (to assess the water content
of local tissue) allow for noninvasive detection of
subclinical interstitial edema.22 Bioimpedance
spectroscopy, which also detects subclinical alter­
ations in the water content of tissue, is perhaps
the most commonly used approach for wide-
1940 n engl j med 379;20 nejm.org  November 15, 2018
The New England Journal of Medicine
Downloaded from nejm.org at KAOHSIUNG MEDICAL UNIVERSITY on November 14, 2018. For personal use only. No other uses without permission.
Copyright © 2018 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
spread clinical surveillance; this approach is sen-
sitive but may lack specificity.23 Currently, there
is no broadly accepted methodologic approach
to the surveillance of breast cancer–associated
lymphedema.3
S t r ategie s for R isk R educ t ion
The clinical appearance of breast cancer–associ-
ated lymphedema is thought to require both a
causal lymphatic injury and one or more initi-
ating factors that convert the latent injury into
overt edema.2 Clinical experience suggests that
infection, inflammation, skin injury, or any state
that increases capillary filtration are initiating
factors.
There is controversy regarding what interven-
tions are appropriate for the reduction of risk.9
Common recommendations include the avoid-
ance of high environmental temperatures as well
as venipuncture, injection, and measurement of
blood pressure on the side of the body on which
breast surgery was performed. However, RCTs are
needed to assess the efficacy of these approaches,
and a recent observational study showed no sig-
nificant associations between lymphedema and
change in arm volume in women who had been
treated for breast cancer and had a history of
blood draws or injections.24 Moreover, prospec-
tive studies have not consistently supported any
relationship between phlebotomy,25,26 venipunc-
ture,25 blood pressure assessment,25 or air travel25
and risk of lymphedema. Given the association
between BMI and the risk of lymphedema,
weight loss is commonly recommended in pa-
tients who are overweight or obese, but the ef-
fect of weight loss on risk in such patients has
not been formally studied.
T r e atmen t
Historically, no medications have been shown to
alleviate lymphedema. Instead, treatment involves
various physiotherapeutic interventions. Decon-
gestive lymphatic therapy relies heavily on man-
ual lymphatic drainage, a massage technique that
stimulates lymphatic contractility through gentle,
directed stretching of the skin. In addition, de-
congestive lymphatic therapy includes skin care,
serial application of multilayer bandaging, and
exercise (gentle, repetitive contraction of the
 Clinical Pr actice
musculature beneath the bandages). Typically,
the patient participates in 15 to 30 sessions over
4 to 6 weeks. Once a nadir of limb volume is
attained, the patient can be transitioned to self-
care. A cohort study in which patient condition
was assessed before and after the implementa-
tion of a program involving comprehensive lym-
phatic therapy showed lower edema volume,
enhanced lymphatic function, fewer symptoms,
improved function and quality of life, and a
lower incidence of cellulitis after implementation
of the program than at baseline before treatment
was initiated.27 A meta-analysis of seven RCTs
showed no significant reduction in arm edema
with manual lymphatic drainage as compared
with standard treatment, but many of these trials
were small and had other methodologic limita-
tions.28 A Cochrane review of trials that assessed
the effect of manual lymphatic drainage sug-
gested a benefit when manual lymphatic drain-
age was combined with compression bandaging
as compared with the use of bandaging alone,
specifically among women with mild-to-moder-
ate disease. However, the review also highlighted
inconsistencies in and limitations of the avail-
able data.29
Once initial limb-volume reduction has been
achieved, the treatment benefit is maintained
through long-term use of elasticized, properly
fitted compression garments.30 Adherence to long-
term compressive measures is considered to be
crucial, although evidence of their benefit is pri-
marily derived from observational studies involv-
ing patients with leg edema. Use of intermittent
pneumatic compression devices is associated with
a reduction in edema, both during active therapy
and in the maintenance phase of self-care. A
retrospective analysis of an insurance database
showed significantly lower rates of cellulitis,
lymphedema-related manual therapy, and outpa-
tient visits, along with lower costs, within the
year after initiation of treatment with an inter-
mittent pneumatic compression device for lymph-
edema than within the year before device use.31
Small RCTs have not shown significant benefit
from the addition of this strategy to routine
care,32 but more data are needed.
There is no evidence to suggest an association
between increased incidence of lymphedema and
exercise. In RCTs, a program of slowly progres-
sive weight lifting did not exacerbate and ap-
n engl j med 379;20 nejm.org  November 15, 2018
The New England Journal of Medicine
Downloaded from nejm.org at KAOHSIUNG MEDICAL UNIVERSITY on November 14, 2018. For personal use only. No other uses without permission.
Copyright © 2018 Massachusetts Medical Society. All rights reserved.
peared to ameliorate symptoms in patients with
established lymphedema33 and did not increase
the risk of lymphedema or symptoms in the arm
in women with a history of breast cancer and
lymph-node dissection.34,35 Aerobic exercise is also
considered to be safe.36
In some cases, microsurgical techniques are
used in an attempt to restore lymphatic function,
although these techniques should be viewed as
alternatives to the standard physical interventions
for the treatment of lymphedema. Creation of
lymphatic-to-venous anastomosis is the most
common procedure. Among 15 small observa-
tional studies included in a recent review, 13 re-
ported reduction of limb volume or circumference
after this surgery.37 An increasingly used alter-
native approach involves orthotopic tissue trans-
fer: autotransplantation of vascularized lymph
nodes into the edematous limb to facilitate
restoration of function.9 Data on outcomes for
this procedure are fairly sparse, but reported
case series suggest subjective improvement in
many recipients of the surgery; donor-site lymph-
edema in lymph-node transplantation is report-
ed to be uncommon.38 Microsurgery is now also
being used in preventive efforts: the Lymphatic
Microsurgical Preventive Healing Approach entails
performing a preemptive lymphatic-to-venous
anastomosis at the time of axillary lymph-node
dissection to reduce the likelihood of subse-
quent breast cancer–related lymphedema.39 A
recent prospective study showed a significantly
lower risk of lymphedema with this strategy
than with standard axillary lymph-node dissec-
tion (3% vs. 19% over a median follow-up of 15
months).40
For patients with advanced-stage lymphedema,
debulking interventions can be used. Since lymph-
edema entails the early and progressive deposi-
tion of subcutaneous adipose tissue, removal of
nearly 100% of the excess limb volume can be
accomplished through surgical liposuction per-
formed with the use of specialized cannulas
while the patient is under general anesthesia.41
Case series have shown sustained volume reduc-
tion over more than 15 years after this proce-
dure.41 Reductions in the frequency of soft-tissue
infection have also been reported, as compared
with the presurgical baseline.42 Continued, assid-
uous use of compression garments is needed
after liposuction.43
1941
 The n e w e ng l a n d j o u r na l
A r e a s of Uncer ta in t y
Although it is hypothesized that early interven-
tion can prevent progression to established lymph-
edema,44-46 data on long-term outcomes are not
available. It remains unclear whether recom-
mended strategies to reduce the risk of lymph-
edema after surgery for breast cancer (e.g.,
avoiding phlebotomy, venipuncture, and blood
pressure measurement in the affected arm and
minimizing air travel) are effective.
It has been proposed that axillary reverse
mapping (injection of technetium-99 into the
breast and blue dye into the arm at risk) may
reduce the incidence of lymphedema by facilitat-
ing presurgical differentiation of axillary lymph
drainage of the breast from that of the ipsilat-
eral arm. Data are lacking to directly compare
outcomes between women who have undergone
this technique together with sentinel-node biopsy
and women who have undergone sentinel-node
biopsy alone. A review of available studies re-
ported rates of lymphedema after the combined
approach that ranged from 0 to 4% and rates of
lymphedema after sentinel-node biopsy alone
that ranged from 0 to 63%.47 RCTs are needed to
assess the effects of axillary reverse mapping
on the incidence of lymphedema and on cancer
outcomes.
Microsurgical techniques require further
study.38,48 With regard to vascularized lymph-node
transfer, mechanistic preclinical studies suggest
that surgical failures may be attributable to inad-
equate lymphatic vascular engraftment of the
transplanted nodes. Studies are in progress to
determine whether engraftment can be facilitated
through the use of biologic scaffolds that poten-
tiate the growth and migration of lymphatic
endothelial cells (e.g., Prospective Evaluation of
the Biobridge Scaffold as an Adjunct to Lymph
Node Transfer for Upper Extremity Lymphedema
[ClinicalTrials.gov number, NCT02734979]).
Guidel ine s
Major professional guidelines (from the Interna-
tional Society of Lymphology,14 the American
1942 n engl j med 379;20 nejm.org  November 15, 2018
The New England Journal of Medicine
Downloaded from nejm.org at KAOHSIUNG MEDICAL UNIVERSITY on November 14, 2018. For personal use only. No other uses without permission.
Copyright © 2018 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
Society of Breast Surgeons,3 and the National
Cancer Care Network49) all emphasize the im-
portance of surveillance for lymphedema in sur-
vivors of breast cancer, exercise to reduce risk,
strategies for weight reduction and mainte-
nance in patients with an elevated baseline
BMI, and decongestive lymphatic therapy for the
management of active disease. Although the
National Cancer Care Network does not address
risk-reduction strategies, the American Society
of Breast Surgeons3 and the International Soci-
ety of Lymphology14 recommend the use of these
strategies on an individualized basis. All three
guidelines support the use of debulking lipo-
suction for advanced disease but note the un-
certainty regarding the benefits of microvas­
cular surgery. The recommendations in this
review are generally concordant with these guide-
lines.
C onclusions a nd
R ec om mendat ions
The patient described in the vignette is at in-
creased risk for the development of lymphedema
owing to her elevated BMI and her history of
axillary lymph-node dissection, nodal metasta-
sis, and radiotherapy. I would recommend a
surveillance program that includes quarterly as-
sessment of bioimpedance during this first year
after treatment, which is when the majority of
cases appear. There should also be prompt use
of compression garments and, as necessary, use
of decongestive physiotherapy for symptoms or
for worrisome changes in bioimpedance. The pa-
tient should be encouraged to attain and maintain
an ideal body weight through diet and regular
exercise. The uncertain merits of conventional
risk-reduction behaviors, including the use of a
prophylactic compression sleeve, should be ex-
plained to the patient so that she can make
informed, personalized decisions as to whether
she should incorporate these strategies into her
plans for aftercare.
Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.

References
1. Dylke ES, Schembri GP, Bailey DL, et al.
Diagnosis of upper limb lymphedema: de-
velopment of an evidence-based approach.
Acta Oncol 2016;​55:​1477-83.
2. Rockson SG. Precipitating factors in
lymphedema: myths and realities. Cancer
1998;​83:​12 Suppl American:​2814-6.
3. McLaughlin SA, Staley AC, Vicini F,
et al. Considerations for clinicians in the
diagnosis, prevention, and treatment of
breast cancer-related lymphedema: recom-
mendations from a multidisciplinary ex-
pert ASBrS panel — Part 1: definitions,
assessments, education, and future direc-
tions. Ann Surg Oncol 2017;​24:​2818-26.
4. Cormier JN, Askew RL, Mungovan KS,
Xing Y, Ross MI, Armer JM. Lymphedema
beyond breast cancer: a systematic review
and meta-analysis of cancer-related sec-
ondary lymphedema. Cancer 2010;​ 116:​
5138-49.
5. Rockson SG, Rivera KK. Estimating
the population burden of lymphedema.
Ann N Y Acad Sci 2008;​1131:​147-54.
6. Wernicke AG, Goodman RL, Turner
BC, et al. A 10-year follow-up of treatment
outcomes in patients with early stage
breast cancer and clinically negative axil-
lary nodes treated with tangential breast
irradiation following sentinel lymph node
dissection or axillary clearance. Breast
Cancer Res Treat 2011;​125:​893-902.
7. Hayes S, Cornish B, Newman B. Com-
parison of methods to diagnose lympho­
edema among breast cancer survivors:
6-month follow-up. Breast Cancer Res
Treat 2005;​89:​221-6.
8. DiSipio T, Rye S, Newman B, Hayes S.
Incidence of unilateral arm lymphoedema
after breast cancer: a systematic review
and meta-analysis. Lancet Oncol 2013;​14:​
500-15.
9. McLaughlin SA, DeSnyder SM, Klim-
berg S, et al. Considerations for clinicians
in the diagnosis, prevention, and treat-
ment of breast cancer-related lymphedema:
recommendations from an expert panel
— Part 2: preventive and therapeutic op-
tions. Ann Surg Oncol 2017;​24:​2827-35.
10. Iyigun ZE, Duymaz T, Ilgun AS, et al.
Preoperative lymphedema-related risk fac-
tors in early-stage breast cancer. Lymphat
Res Biol 2018;​16:​28-35.
11. Vieira RA, da Costa AM, de Souza JL,
et al. Risk factors for arm lymphedema in
a cohort of breast cancer patients fol-
lowed up for 10 years. Breast Care (Basel)
2016;​11:​45-50.
12. Wetzig N, Gill PG, Espinoza D, et al.
Sentinel-lymph-node-based management
or routine axillary clearance? Five-year
outcomes of the RACS Sentinel Node Bi-
n engl j med 379;20 nejm.org  November 15, 2018
The New England Journal of Medicine
Downloaded from nejm.org at KAOHSIUNG MEDICAL UNIVERSITY on November 14, 2018. For personal use only. No other uses without permission.
Copyright © 2018 Massachusetts Medical Society. All rights reserved.
Clinical Pr actice
opsy Versus Axillary Clearance (SNAC) 1
trial: assessment and incidence of true
lymphedema. Ann Surg Oncol 2017;​24:​
1064-70.
13. Brorson H, Ohlin K, Olsson G, Karls-
son MK. Breast cancer-related chronic arm
lymphedema is associated with excess
adipose and muscle tissue. Lymphat Res
Biol 2009;​7:​3-10.
14. International Society of Lymphology.
The diagnosis and treatment of peripheral
lymphedema: 2009 consensus document
of the International Society of Lymphology.
Lymphology 2009;​42:​51-60.
15. Boughey JC, Hoskin TL, Cheville AL,
et al. Risk factors associated with breast
lymphedema. Ann Surg Oncol 2014;​21:​
1202-8.
16. Szolnoky G. Differential diagnosis:​
lipedema. In:​Lee BB, Rockson SG, Ber-
gan J, eds. Lymphedema:​a concise com-
pendium of theory and practice. 2nd ed.
London:​ Springer, 2018:​239-49.
17. Szuba A, Razavi M, Rockson SG. Diag-
nosis and treatment of concomitant ve-
nous obstruction in patients with second-
ary lymphedema. J Vasc Interv Radiol
2002;​13:​799-803.
18. Bae JS, Yoo RE, Choi SH, et al. Evalua-
tion of lymphedema in upper extremities
by MR lymphangiography: comparison
with lymphoscintigraphy. Magn Reson
Imaging 2018;​49:​63-70.
19. Mihara M, Hara H, Araki J, et al. Indo-
cyanine green (ICG) lymphography is su-
perior to lymphoscintigraphy for diagnos-
tic imaging of early lymphedema of the
upper limbs. PLoS One 2012;​7(6):​e38182.
20. Stout NL, Pfalzer LA, Springer B, et al.
Breast cancer-related lymphedema: com-
paring direct costs of a prospective sur-
veillance model and a traditional model
of care. Phys Ther 2012;​92:​152-63.
21. Soran A, Ozmen T, McGuire KP, et al.
The importance of detection of subclini-
cal lymphedema for the prevention of
breast cancer-related clinical lymphede-
ma after axillary lymph node dissection;
a prospective observational study. Lymphat
Res Biol 2014;​12:​289-94.
22. Czerniec SA, Ward LC, Kilbreath SL.
Assessment of breast cancer-related lymph-
edema: a comparison of moisture meter
and spot bioimpedance measurement.
Lymphat Res Biol 2015;​13:​10-9.
23. Qin ES, Bowen MJ, Chen WF. Diag-
nostic accuracy of bioimpedance spectros-
copy in patients with lymphedema: a retro-
spective cohort analysis. J Plast Reconstr
Aesthet Surg 2018;​71:​1041-50.
24. Ferguson CM, Swaroop MN, Horick
N, et al. Impact of ipsilateral blood draws,
injections, blood pressure measurements,
and air travel on the risk of lymphedema
for patients treated for breast cancer. J Clin
Oncol 2016;​34:​691-8.
25. Basta MN, Fox JP, Kanchwala SK,
et al. Complicated breast cancer-related
lymphedema: evaluating health care re-
source utilization and associated costs of
management. Am J Surg 2016;​211:​133-41.
26. Boyages J, Kalfa S, Xu Y, et al. Worse
and worse off: the impact of lymphedema
on work and career after breast cancer.
Springerplus 2016;​5:​657.
27. Moffatt CJ, Doherty DC, Franks PJ,
Mortimer PS. Community-based treatment
for chronic edema: an effective service
model. Lymphat Res Biol 2018;​16:​92-9.
28. Huang TW, Tseng SH, Lin CC, et al.
Effects of manual lymphatic drainage on
breast cancer-related lymphedema: a sys-
tematic review and meta-analysis of ran-
domized controlled trials. World J Surg
Oncol 2013;​11:​15.
29. Ezzo J, Manheimer E, McNeely ML, et
al. Manual lymphatic drainage for lymph-
edema following breast cancer treat-
ment. Cochrane Database Syst Rev 2015;​
5:​CD003475.
30. Rockson SG. Current concepts and fu-
ture directions in the diagnosis and man-
agement of lymphatic vascular disease.
Vasc Med 2010;​15:​223-31.
31. Karaca-Mandic P, Hirsch AT, Rockson
SG, Ridner SH. The cutaneous, net clini-
cal, and health economic benefits of ad-
vanced pneumatic compression devices in
patients with lymphedema. JAMA Derma-
tol 2015;​151:​1187-93.
32. Shao Y, Qi K, Zhou QH, Zhong DS.
Intermittent pneumatic compression pump
for breast cancer-related lymphedema:
a systematic review and meta-analysis of
randomized controlled trials. Oncol Res
Treat 2014;​37:​170-4.
33. Schmitz KH, Ahmed RL, Troxel A, et
al. Weight lifting in women with breast-
cancer–related lymphedema. N Engl J Med
2009;​361:​664-73.
34. Schmitz KH, Ahmed RL, Troxel AB,
et al. Weight lifting for women at risk for
breast cancer-related lymphedema: a ran-
domized trial. JAMA 2010;​304:​2699-705.
35. Kilbreath SL, Refshauge KM, Beith JM,
et al. Upper limb progressive resistance
training and stretching exercises follow-
ing surgery for early breast cancer: a ran-
domized controlled trial. Breast Cancer
Res Treat 2012;​133:​667-76.
36. Hayes SC, Reul-Hirche H, Turner J.
Exercise and secondary lymphedema: safe-
ty, potential benefits, and research issues.
Med Sci Sports Exerc 2009;​41:​483-9.
1943
 Clinical Pr actice

37. Cornelissen AJM, Beugels J, Ewalds L,
et al. The effect of lymphaticovenous anas-
tomosis in breast cancer-related lymph-
edema: a review of the literature. Lymphat
Res Biol 2018 January 22 (Epub ahead of
print).
38. Pappalardo M, Patel K, Cheng MH.
Vascularized lymph node transfer for treat-
ment of extremity lymphedema: an over-
view of current controversies regarding
donor sites, recipient sites and outcomes.
J Surg Oncol 2018;​117:​1420-31.
39. Boccardo F, Casabona F, De Cian F,
et al. Lymphatic microsurgical preventing
healing approach (LYMPHA) for primary
surgical prevention of breast cancer-related
lymphedema: over 4 years follow-up. Micro-
surgery 2014;​34:​421-4.
40. Ozmen T, Lazaro M, Zhou Y, Vinyard
A, Avisar E. Evaluation of Simplified Lym-
phatic Microsurgical Preventing Healing
Approach (S-LYMPHA) for the prevention
of breast cancer-related clinical lymph-
edema after axillary lymph node dissec-
tion. Ann Surg 2018 May 23 (Epub ahead
of print).
41. Brorson H. Liposuction in lymphede-
ma treatment. J Reconstr Microsurg 2016;​
32:​56-65.
42. Lee D, Piller N, Hoffner M, Manjer J,
Brorson H. Liposuction of postmastec-
tomy arm lymphedema decreases the in-
cidence of erysipelas. Lymphology 2016;​
49:​85-92.
43. Schaverien MV, Munnoch DA, Brorson
H. Liposuction treatment of lymphedema.
Semin Plast Surg 2018;​32:​42-7.
44. Kilbreath SL, Lee MJ, Refshauge KM,
et al. Transient swelling versus lympho­
edema in the first year following surgery
for breast cancer. Support Care Cancer
2013;​21:​2207-15.
45. Specht MC, Miller CL, Russell TA, et
al. Defining a threshold for intervention
in breast cancer-related lymphedema: what
level of arm volume increase predicts pro-
gression? Breast Cancer Res Treat 2013;​
140:​485-94.
46. Laidley A, Anglin B. The impact of
L-Dex(®) measurements in assessing breast
cancer-related lymphedema as part of rou-
tine clinical practice. Front Oncol 2016;​6:​
192.
47. Parks RM, Cheung KL. Axillary re-
verse mapping in N0 patients requiring
sentinel lymph node biopsy — a system-
atic review of the literature and necessity
of a randomised study. Breast 2017;​33:​57-
70.
48. Scaglioni MF, Fontein DBY, Arvanita-
kis M, Giovanoli P. Systematic review of
lymphovenous anastomosis (LVA) for the
treatment of lymphedema. Microsurgery
2017;​37:​947-53.
49. National Comprehensive Cancer Net-
work Breast cancer. 2018 (https://www​
.nccn​.org/​professionals/​physician_gls/​pdf/​
breast​.pdf).
Copyright © 2018 Massachusetts Medical Society.

1944 n engl j med 379;20 nejm.org  November 15, 2018

The New England Journal of Medicine

Downloaded from nejm.org at KAOHSIUNG MEDICAL UNIVERSITY on November 14, 2018. For personal use only. No other uses without permission.
Copyright © 2018 Massachusetts Medical Society. All rights reserved.