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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


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

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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


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

tively) when a reference standard based on clini- spread clinical surveillance; this approach is sen-
cal presentation and combined imaging results sitive but may lack specificity.23 Currently, there
is used.18 Ultrasonography and CT have low sen- is no broadly accepted methodologic approach
sitivity for detection and are not recommended.19 to the surveillance of breast cancer–associated
Near-infrared fluorescent lymphography is a lymphedema.3
newer means of assessing lymphedema. The tran-
sit of dermally injected indocyanine green is S t r ategie s for R isk R educ t ion
monitored with fluorescent spectroscopy. Al-
though this test is more sensitive than radionu- The clinical appearance of breast cancer–associ-
clide lymphoscintigraphy in the early stages of ated lymphedema is thought to require both a
lymphedema,19 quantitative analysis is not pos- causal lymphatic injury and one or more initi-
sible. Near-infrared fluorescent lymphography is ating factors that convert the latent injury into
generally not used as a diagnostic test but rather overt edema.2 Clinical experience suggests that
as an adjunctive tool in lymphatic microsurger- infection, inflammation, skin injury, or any state
ies, in which accurate visualization of the lym- that increases capillary filtration are initiating
phatic drainage pathways is mandatory to achieve factors.
a successful surgical outcome. There is controversy regarding what interven-
tions are appropriate for the reduction of risk.9
Surveillance Common recommendations include the avoid-
Although randomized, controlled trials (RCTs) ance of high environmental temperatures as well
of surveillance are lacking, there is a growing as venipuncture, injection, and measurement of
belief that surveillance leads to earlier diagnosis blood pressure on the side of the body on which
and to treatment strategies that are both more breast surgery was performed. However, RCTs are
effective and more cost-effective than was the needed to assess the efficacy of these approaches,
case before the introduction of surveillance and a recent observational study showed no sig-
practices.20 In one prospective study, surveillance nificant associations between lymphedema and
(with aggressive risk-reduction measures taken change in arm volume in women who had been
as indicated) was associated with a lower ob- treated for breast cancer and had a history of
served incidence of lymphedema (36.4% in the blood draws or injections.24 Moreover, prospec-
control group vs. 4.4% with surveillance).21 tive studies have not consistently supported any
Early or subclinical lymphedema can be ob- relationship between phlebotomy,25,26 venipunc-
jectively detected and serially assessed. Limb- ture,25 blood pressure assessment,25 or air travel25
volume assessment can be performed by means and risk of lymphedema. Given the association
of volumetric measurement with the use of water- between BMI and the risk of lymphedema,
displacement or by means of extrapolation from weight loss is commonly recommended in pa-
circumferential dimensions, but these techniques tients who are overweight or obese, but the ef-
are laborious and time-consuming and therefore fect of weight loss on risk in such patients has
not well-suited to large-scale, serial surveillance. not been formally studied.
Optic volumetric assessment (perometry) is less
time-consuming, but it is more expensive than T r e atmen t
most other surveillance measures. Perometry is
practiced in some centers but requires an infra- Historically, no medications have been shown to
red, optical electronic scanner to calculate the alleviate lymphedema. Instead, treatment involves
volume of both arms. Newer techniques, includ- various physiotherapeutic interventions. Decon-
ing tonometry, and measurement of the tissue gestive lymphatic therapy relies heavily on man-
dielectric constant (to assess the water content ual lymphatic drainage, a massage technique that
of local tissue) allow for noninvasive detection of stimulates lymphatic contractility through gentle,
subclinical interstitial edema.22 Bioimpedance directed stretching of the skin. In addition, de-
spectroscopy, which also detects subclinical alter­ congestive lymphatic therapy includes skin care,
ations in the water content of tissue, is perhaps serial application of multilayer bandaging, and
the most commonly used approach for wide- exercise (gentle, repetitive contraction of the

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Clinical Pr actice

musculature beneath the bandages). Typically, peared to ameliorate symptoms in patients with
the patient participates in 15 to 30 sessions over established lymphedema33 and did not increase
4 to 6 weeks. Once a nadir of limb volume is the risk of lymphedema or symptoms in the arm
attained, the patient can be transitioned to self- in women with a history of breast cancer and
care. A cohort study in which patient condition lymph-node dissection.34,35 Aerobic exercise is also
was assessed before and after the implementa- considered to be safe.36
tion of a program involving comprehensive lym- In some cases, microsurgical techniques are
phatic therapy showed lower edema volume, used in an attempt to restore lymphatic function,
enhanced lymphatic function, fewer symptoms, although these techniques should be viewed as
improved function and quality of life, and a alternatives to the standard physical interventions
lower incidence of cellulitis after implementation for the treatment of lymphedema. Creation of
of the program than at baseline before treatment lymphatic-to-venous anastomosis is the most
was initiated.27 A meta-analysis of seven RCTs common procedure. Among 15 small observa-
showed no significant reduction in arm edema tional studies included in a recent review, 13 re-
with manual lymphatic drainage as compared ported reduction of limb volume or circumference
with standard treatment, but many of these trials after this surgery.37 An increasingly used alter-
were small and had other methodologic limita- native approach involves orthotopic tissue trans-
tions.28 A Cochrane review of trials that assessed fer: autotransplantation of vascularized lymph
the effect of manual lymphatic drainage sug- nodes into the edematous limb to facilitate
gested a benefit when manual lymphatic drain- restoration of function.9 Data on outcomes for
age was combined with compression bandaging this procedure are fairly sparse, but reported
as compared with the use of bandaging alone, case series suggest subjective improvement in
specifically among women with mild-to-moder- many recipients of the surgery; donor-site lymph-
ate disease. However, the review also highlighted edema in lymph-node transplantation is report-
inconsistencies in and limitations of the avail- ed to be uncommon.38 Microsurgery is now also
able data.29 being used in preventive efforts: the Lymphatic
Once initial limb-volume reduction has been Microsurgical Preventive Healing Approach entails
achieved, the treatment benefit is maintained performing a preemptive lymphatic-to-venous
through long-term use of elasticized, properly anastomosis at the time of axillary lymph-node
fitted compression garments.30 Adherence to long- dissection to reduce the likelihood of subse-
term compressive measures is considered to be quent breast cancer–related lymphedema.39 A
crucial, although evidence of their benefit is pri- recent prospective study showed a significantly
marily derived from observational studies involv- lower risk of lymphedema with this strategy
ing patients with leg edema. Use of intermittent than with standard axillary lymph-node dissec-
pneumatic compression devices is associated with tion (3% vs. 19% over a median follow-up of 15
a reduction in edema, both during active therapy months).40
and in the maintenance phase of self-care. A For patients with advanced-stage lymphedema,
retrospective analysis of an insurance database debulking interventions can be used. Since lymph-
showed significantly lower rates of cellulitis, edema entails the early and progressive deposi-
lymphedema-related manual therapy, and outpa- tion of subcutaneous adipose tissue, removal of
tient visits, along with lower costs, within the nearly 100% of the excess limb volume can be
year after initiation of treatment with an inter- accomplished through surgical liposuction per-
mittent pneumatic compression device for lymph- formed with the use of specialized cannulas
edema than within the year before device use.31 while the patient is under general anesthesia.41
Small RCTs have not shown significant benefit Case series have shown sustained volume reduc-
from the addition of this strategy to routine tion over more than 15 years after this proce-
care,32 but more data are needed. dure.41 Reductions in the frequency of soft-tissue
There is no evidence to suggest an association infection have also been reported, as compared
between increased incidence of lymphedema and with the presurgical baseline.42 Continued, assid-
exercise. In RCTs, a program of slowly progres- uous use of compression garments is needed
sive weight lifting did not exacerbate and ap- after liposuction.43

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

A r e a s of Uncer ta in t y Society of Breast Surgeons,3 and the National


Cancer Care Network49) all emphasize the im-
Although it is hypothesized that early interven- portance of surveillance for lymphedema in sur-
tion can prevent progression to established lymph- vivors of breast cancer, exercise to reduce risk,
edema,44-46 data on long-term outcomes are not strategies for weight reduction and mainte-
available. It remains unclear whether recom- nance in patients with an elevated baseline
mended strategies to reduce the risk of lymph- BMI, and decongestive lymphatic therapy for the
edema after surgery for breast cancer (e.g., management of active disease. Although the
avoiding phlebotomy, venipuncture, and blood National Cancer Care Network does not address
pressure measurement in the affected arm and risk-reduction strategies, the American Society
minimizing air travel) are effective. of Breast Surgeons3 and the International Soci-
It has been proposed that axillary reverse ety of Lymphology14 recommend the use of these
mapping (injection of technetium-99 into the strategies on an individualized basis. All three
breast and blue dye into the arm at risk) may guidelines support the use of debulking lipo-
reduce the incidence of lymphedema by facilitat- suction for advanced disease but note the un-
ing presurgical differentiation of axillary lymph certainty regarding the benefits of microvas­
drainage of the breast from that of the ipsilat- cular surgery. The recommendations in this
eral arm. Data are lacking to directly compare review are generally concordant with these guide-
outcomes between women who have undergone lines.
this technique together with sentinel-node biopsy
and women who have undergone sentinel-node
C onclusions a nd
biopsy alone. A review of available studies re- R ec om mendat ions
ported rates of lymphedema after the combined
approach that ranged from 0 to 4% and rates of The patient described in the vignette is at in-
lymphedema after sentinel-node biopsy alone creased risk for the development of lymphedema
that ranged from 0 to 63%.47 RCTs are needed to owing to her elevated BMI and her history of
assess the effects of axillary reverse mapping axillary lymph-node dissection, nodal metasta-
on the incidence of lymphedema and on cancer sis, and radiotherapy. I would recommend a
outcomes. surveillance program that includes quarterly as-
Microsurgical techniques require further sessment of bioimpedance during this first year
study.38,48 With regard to vascularized lymph-node after treatment, which is when the majority of
transfer, mechanistic preclinical studies suggest cases appear. There should also be prompt use
that surgical failures may be attributable to inad- of compression garments and, as necessary, use
equate lymphatic vascular engraftment of the of decongestive physiotherapy for symptoms or
transplanted nodes. Studies are in progress to for worrisome changes in bioimpedance. The pa-
determine whether engraftment can be facilitated tient should be encouraged to attain and maintain
through the use of biologic scaffolds that poten- an ideal body weight through diet and regular
tiate the growth and migration of lymphatic exercise. The uncertain merits of conventional
endothelial cells (e.g., Prospective Evaluation of risk-reduction behaviors, including the use of a
the Biobridge Scaffold as an Adjunct to Lymph prophylactic compression sleeve, should be ex-
Node Transfer for Upper Extremity Lymphedema plained to the patient so that she can make
[ClinicalTrials.gov number, NCT02734979]). informed, personalized decisions as to whether
she should incorporate these strategies into her
plans for aftercare.
Guidel ine s
Major professional guidelines (from the Interna- Disclosure forms provided by the author are available with the
tional Society of Lymphology,14 the American full text of this article at NEJM.org.

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Clinical Pr actice

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Clinical Pr actice

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