The Prevalence of Lymphedema and Changes in Practice

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The Prevalence of Lymphedema and Changes
in Practice to
Reduce its Occurrence in Women with Breast
Cancer
Sarah A McLaughlin and Kimberly J Van Zee
Affiliation: Breast Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, Evelyn H Lauder Breast
Center, New York, NY, USA
ABSTRACT
Lymphedema is a chronic debilitating condition affecting many long-term breast cancer survivors. The incidence of
lymphedema is
reported to range from 6% to 70% after axillary surgery for breast cancer; however, its true incidence has been difficult to
quantify because of
the lack of standard diagnostic and universal assessment criteria. Extent of nodal dissection, axillary radiation, injury, and
infection in the
ipsilateral upper extremity remain significant risk factors for the development of lymphedema. Current changes in
axillary management,
including the adoption of sentinel node biopsy, the selective omission of completion axillary dissection after a positive
sentinel node, and the
elimination of axillary staging, have been proposed to further reduce axillary morbidity. Early research on lymphedema
risk reduction focuses
on supervised weight training after axillary surgery, axillary reverse mapping to avoid removal of lymph nodes draining
the upper extremity,
and incorporation of fused single photon emission computed tomography (SPECT)-CT axillary nodal images to better
plan adjuvant radiation
treatments.
Keywords: lymphedema, axillary dissection, sentinel node biopsy, breast cancer, survivorship, patient perceptions
Correspondence: Kimberly J Van Zee, Breast Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center,
and Weill Medical
College of Cornell University, Evelyn H Lauder Breast Center, 300 E. 66th St., New York, NY, 10065, USA. Tel:
(1)-646-888-5362; Fax: (1)-646-
888-4920; e-mail: vanzeek@mskcc.org
INTRODUCTION
According to the National Cancer Institute and the
Surveillance Epidemiology and End Results (SEER) database,
the mortality rate for breast cancer has been in significant
decline [1, 2], resulting in more than 2.5 million breast cancer
survivors. Today, issues of survivorship are the focus of much
research in an effort to improve the overall quality of life in
these women. Lymphedema remains a focus of survivorship
research as it is a commonly feared and potentially long-term
complication of breast cancer therapy for which no cure exists.
Lymphedema is a chronic, disfiguring, and potentially
disabling accumulation of protein-rich fluid in the interstitial
tissues resulting in edema, hypertrophy, and eventually
fibrosis of the extremity tissues. In breast cancer, the term
lymphedema classically refers to swelling of the upper
extremity and will be the focus of this review; however, it is
recognized that it can be associated with a constellation of
other symptoms including musculoskeletal pain, paresthe-
sias, and loss of shoulder mobility, especially in the most
advanced stages. The physical changes in the upper extremity
due to lymphedema may be difficult to conceal and may
impair one from performing activities of daily living. Owing
to the fear of developing lymphedema, many women alter
their lifestyles, avoiding recreational activities and practicing
risk-reducing behaviors in an effort to keep symptoms from
worsening [3]. Furthermore, despite the lack of supportive
data, the majority of women avoid having blood pressures
obtained, blood draws taken, and intravenous needles placed
in the ipsilateral arm because of the risk of developing
lymphedema [3]. Clearly, lymphedema or the risk of
developing lymphedema remains a constant reminder of a
woman’s lifelong struggle with breast cancer.
METRICS AND DEFINITIONS
The true incidence of lymphedema has been difficult to
determine accurately. The reasons for this are twofold. First,
no standardized definition of what constitutes lymphedema
exists. Both objective and subjective measures have been used.
However, the objective measure used—volume displacement,
truncated cone volumes, or simple circumferential upper
extremity arm measurements—is left to the discretion of the
investigator, who may use varying thresholds for diagnosing
lymphedema. To be meaningful, objective measures must
include baseline pretreatment values and both ipsilateral and
contralateral upper extremity measurements.
Subjective assessments of lymphedema give insight into the
patient’s perception of lymphedema, which may arguably be
the most important definition, but rarely are these subjective
findings correlated with objective measures. The dilemma
remains that measurement changes alone may not capture all
patients suffering from clinically significant lymphedema and
may overdiagnose those who are unaffected by their
measurement change.
Second, lymphedema may have a delayed onset of up to
20 years after breast cancer treatment [4]. Most series report
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only short-term follow-up of 1–3 years, thereby potentially
missing those with delayed presentation. Although 75–90%
of women affected with lymphedema present with swelling
within 3 years of treatment, the remaining women affected
with lymphedema will present with swelling at a rate of 1%
per year to 20 years [4, 5]. Therefore, it is likely that
lymphedema is more common than generally reported.
INCIDENCE
Historical estimates demonstrate wide variations in the
incidence of lymphedema, ranging from 6% to 70% [6–18].
Most attribute this wide range to differences in surgery in
both the breast and the axilla, as well as to variations in
postoperative radiation usage. In the 1990s, Petrek and
Heelan reported the lymphedema rate after axillary lymph
node dissection (ALND) was 6–30% [12], but in a study in
2001 evaluating the presence of lymphedema in 20-year breast
cancer survivors, the incidence of lymphedema was nearly
50% [4]. More recent studies confirm these findings and
underscore the necessity of long-term follow-up for detection
of lymphedema. Using a standardized telephone question-
naire validated against arm measurements, Norman et al [5,
19] conducted a 5-year population-based prospective study of
631 women who were treated for breast cancer between 1999
and 2001. They report a cumulative incidence of lymphedema
of 42%, with 89% of these patients having their first
lymphedema occurrence within 3 years of cancer diagnosis.
The adoption of sentinel lymph node biopsy (SLNB) as
standard of care for axillary staging has significantly reduced
the rate of lymphedema (Table 1). The results of three
prospective randomized trials and several non-randomized
trials conclude that rates of lymphedema after SLNB range
from 0% to 7% [3, 10, 14, 20–29]. However, these trials are
limited by the lack of long-term follow-up as most are
reported between 6 and 36 months post surgery. The largest
prospective series to date with 5 years of follow-up comparing
rates of lymphedema after SLNB and ALND followed nearly
1000 patients. All patients had baseline ipsilateral and
contralateral circumferential arm measurements, and all
patients completed a standardized interview process to
evaluate subjective findings of lymphedema [3, 24]. Overall,
5% of women undergoing SLNB had objective measurements
consistent with lymphedema, compared with 16% of patients
undergoing ALND (P,0.001). Interestingly, however, lym-
phedema was subjectively reported less frequently than it was
measured in women having SLNB, but more frequently than it
was measured in women having ALND, at 3% and 27%,
respectively. Furthermore, only 41% of women reporting arm
swelling had measured lymphedema. This finding suggests
that the most accurate diagnostic criteria for lymphedema
should include correlation of objective and subjective
measures, as reporting only one aspect may incorrectly
estimate the actual incidence of clinically significant lymphe-
dema.
CAUSATIVE FACTORS
Numerous published series have examined the associations
between breast cancer treatment factors and the development
of lymphedema. Unfortunately, the strength of each risk
factor is inconsistent across all series. The most commonly
cited contributing factors are extent of axillary surgery and the
use of axillary radiation.
Although some studies have found no relation between the
number of nodes removed and the incidence of lymphedema
Table 1. Select Series reporting Measured or Patient-Perceived Lymphedema after Sentinel Lymph Node Biopsy

Author, year [ref]

N

Follow-up (months)

Lymphedema by measurement or

patient perception

Proportion with lymphedema

Sener, 2001 [27]

303

Median 24

Measurements

3%

Veronesi, 2003 [28]

100

Median 24
Measurements

0%

Golshan, 2003 [20]

77

Minimum 12

Measurements

2.6%

Leidenius, 2005 [10]

92

Median 36

Measurements

0%

Ronka, 2005 [14]

43

Median 12

Measurements

2%

Purushotham, 2005 [25]

86

Median 12

Measurements

OR 0.3

Barranger, 2005 [75]

54

Mean 20

Patient perception

0%

Mansel, 2006 [23]

478

Median 12

Measurements

5%

Wilke, 2006 [29]

4069

Median 6

Measurements

7%

Langer, 2007 [21]

449

Median 30

Patient perception

3.5%

Lucci, 2007 [22]

446
Median 12

Measurements

2%

McLaughlin, 2008 [24]

600

Median 60

Measurements

5%

McLaughlin, 2008 [3]

600

Median 60

Patient perception

3%

Ferreira, 2008 [76]

35

Mean 24

Measurements

8%

Yen, 2009 [77]

319

Median 48

Patient perception

7%

OR, odds ratio.

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after either SLNB or ALND [22], or after ALND alone [30],
others have suggested that the number of nodes removed is
related to the risk of lymphedema. Kiel and Rademacker [31]
found an odds ratio of 13 (95% CI 2–103) for more than 16
nodes removed. Similarly, Herd-Smith et al [32] found a
hazard ratio of 1.6 (95% CI 1–2.7) for patients having more
than 30 nodes removed compared with those having less than
20 removed. Paskett et al [33] found that the risk of arm
swelling increased by 3% with the removal of each
subsequent lymph node. Furthermore, the finding of lower
rates of lymphedema after SLNB compared with ALND
supports the concept that the risk of lymphedema is
proportional to the extent of axillary surgery.
Axillary radiation has also been used as a primary treatment
modality. Although fewer data exist regarding long-term
risks, it is associated with a 2.0- to 4.5-fold increased risk of
lymphedema, in addition to other long-term morbidities,
including brachial plexopathy [34]. The synergistic combina-
tion of ALND and axillary radiation appears to have the
highest morbidity, with a 3.5- to 10.0-fold increased risk for
lymphedema [35–39] when compared with surgery alone.
Current treatment strategies generally avoid direct axillary
radiation unless more than 10 lymph nodes are involved with
metastatic disease. Despite technical advances in radiation
planning, the amount and effect of scattered radiation
tangents to the axilla on lymphedema risk is unclear, but
must be considered as more patients are completing radiation
therapy after breast-conserving surgery and, more recently,
after mastectomy [40].
Other frequently reported risk factors include patient age,
body mass index (BMI), injury or infection in the ipsilateral
arm, and the presence of positive lymph nodes. Although data
both support and refute age as a risk factor for lymphedema
[33, 41, 42], a patient’s age may influence one’s perception of
lymphedema, with younger patients reporting lymphedema
more frequently than older patients [3, 24]. Increased BMI or
weight gain since surgery has been associated with a higher
risk for lymphedema [4, 18, 24, 33, 38]. Infection and injury
are also associated with significant increased risk for
lymphedema, but both are difficult to rigorously evaluate as
each is influenced by recall bias [3, 4, 22, 24, 29].
The most recent meta-analysis on lymphedema risk factors
reviewed 98 studies conducted in the United States and
Canada through January 2008 [43]. The authors report a
significant increased risk of lymphedema for women under-
going mastectomy compared with lumpectomy (RR 1.42; 95%
CI 1.15–1.76), axillary dissection compared with no dissection
(RR 3.47; 95% CI 2.34–5.15), ALND compared with SLNB
(RR 3.07; 95% CI 2.20–4.29), radiation therapy vs no
radiation therapy (RR 1.92; 95% CI 1.61–2.28), and for
positive vs negative axillary lymph nodes (RR 1.54; 95% CI
1.32–1.80). Although this analysis demonstrates the most
comprehensive review of lymphedema risk factors, the
heterogeneity of the data must be recognized, as 11 different
definitions for lymphedema were used and follow-up ranged
between 1 month and 30 years among the 98 studies reviewed.
LYMPHEDEMA PROGRESSION
Data are beginning to accumulate regarding lymphedema
progression, of which little was previously known. At first
occurrence, lymphedema is generally mild, and the data
suggest that it tends to remain mild over time. The authors’
experience is that, at 5 years post surgery, the majority of
women with lymphedema after SLNB or ALND have only mild
swelling (measurement difference of less than 2 cm between
affected and unaffected upper extremities) involving only the
upper arm, not the forearm or hand. Severe lymphedema
(greater than 5 cm difference) was rare and documented in only
3% of women after ALND and 0.5% after SLNB [24]. These
data support previously published documented rates of severe
lymphedema [4]. Contemporary studies find that the majority
of women with lymphedema have only mild lymphedema
(definitions vary) and further suggest that mild lymphedema is
an independent risk factor for the future development of severe
lymphedema. Although this concept is intuitive, little pro-
spective documentation exists to support this theory. Recently,
Norman et al [5] found that, although the majority of patients
had only mild lymphedema, defined subjectively as swelling
noticeable only to themselves, these patients were three times
more likely to develop moderate or severe lymphedema,
defined subjectively as swelling noticeable to close relatives
or others. Additionally, patients reporting symptoms of tight
clothing or jewelry were more likely to develop lymphedema at
a later date (HR 7.37; 95% CI 4.26–12.76). Similarly, Bar Ad et
al [44] found that 48% of patients with mild lymphedema at the
time of first occurrence progressed to more severe lymphe-
dema at 5 years. The influence of treatment interventions is not
recorded in these analyses, but likely slow progression from
mild to severe lymphedema. Nonetheless, the presence of mild
subjective or objective lymphedema should be viewed as a risk
factor for future debilitating lymphedema.
CHANGES IN AXILLARY MANAGEMENT
The adoption of SLNB as the standard method of axillary
staging has markedly reduced the incidence of lymphedema. It
is documented to have low short-term rates of axillary
recurrence (0.0–1.4%), even when disease is identified within
the sentinel node [45, 46]. Currently, further efforts to reduce
lymphedema and axillary surgery morbidity focus on reducing
the number of patients undergoing completion ALND after
positive SLNB. Some argue that SLNB is both diagnostic and
therapeutic as 50–80% of patients have no additional positive
non-sentinel lymph nodes at completion ALND, and that it
therefore brings into question the value of completion ALND
[47, 48]. As a result, numerous studies have evaluated tumor
and nodal characteristics associated with additional positive
non-sentinel lymph nodes [47–51], and have prompted the
development and usage of multiple nomograms in clinical
practice to predict the likelihood of positive non-sentinel nodes
[52, 53]. The risk estimated by the nomogram acts as an aid to
the clinician and patient to assess the risk of residual axillary
disease if completion ALND is omitted. It is therefore not
surprising that current trends in axillary surgery evaluated by
Bilimoria et al [54] demonstrate that 45% of patients with
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micrometastatic disease in the sentinel node did not complete
ALND in 2005 compared with only 24% in 1998 (P,0.001). At
5 years of follow-up, the authors found that this trend resulted
in no change in either axillary recurrence or survival rates in this
population. Others have proposed forgoing axillary evaluation
altogether in certain populations. Martelli et al [55] completed a
randomized trial comparing ALND with no ALND in patients
aged 65–80 years with T1N0 estrogen receptor-positive breast
cancer. All patients were given tamoxifen. With 5 years of
follow-up, they concluded that older patients with T1N0 breast
cancer can be treated with breast surgery alone without
adversely affecting breast cancer mortality or overall survival,
arguing that even SLNB can be avoided in these patients.
At least two prospective randomized trials have been
designed comparing observation vs completion ALND for
patients with positive SLNB, including the International
Breast Cancer Study Group 23-01, which is open and
ongoing, and the American College of Surgeons Z-0011 trial,
which closed due to poor accrual. Results from both are
pending. Additionally, the European Organization for
Research and Treatment of Cancer (EORTC) cooperative
group is conducting a phase III trial named the AMAROS trial
(10981) comparing axillary radiation with completion ALND
for patients with positive SLNB. If these trials demonstrate
acceptable outcomes for the groups without completion
ALND, it is likely that the number of patients with a positive
SLNB pursuing completion ALND will continue to decrease,
which in turn will result in an overall lower incidence of
lymphedema. Long-term follow-up (.5 years) of these
populations is imperative to document such a trend.
MONITORING
No standard monitoring exists for the diagnosis of lymphe-
dema after breast cancer treatment. More rigorous lymphedema
monitoring may be of benefit if early intervention strategies are
proven successful. Recent data suggest that patients complain-
ing of arm symptoms such as heaviness, swelling, or tight
jewelry are more likely to develop lymphedema [5, 19]. Data
from a 5-year National Institutes of Health study support the
view that early assessment and intervention may prevent the
progression of lymphedema [56]. The authors used a simple,
portable, cost-effective, and easily interpretable bioimpedance
device to measure changes in arm fluid. It compares the
ipsilateral and contralateral arms, generating a lymphedema
index (L-DexTM) value [56, 57]. The procedure is performed
preoperatively and at 3-month, 6-month, 12-month, and annual
time points. A score increase of more than 10, or one that
registers outside the normal range, prompts intervention. After
4 weeks of compression therapy, patients demonstrated a
significant reduction in mean arm volume of 48 mL (¡103 mL;
P,0.0001) and maintained the reduction for 4.8 (¡4.1) months.
Validation of these findings, ease of adoption into clinical
practice, and longer follow-up are needed.
MAINTENANCE
Once the diagnosis of lymphedema is made, many options
exist for maintenance and treatment of symptoms.
Therapeutic interventions include counseling on skin and
nail care, massage, manual lymphatic drainage, and com-
pression garments, bandages, or devices. Although the
Lymphology Association of North America has standardized
examinations to certify lymphedema therapists, treatment
approaches are not standardized among therapists [58].
Manual lymphatic drainage is a gentle massage technique that
includes lightly stroking the arm to stretch the superficial
lymphatic vessels and promote contraction of the underlying
deep lymphatics. Multiple trials demonstrate extremity
volume reductions of 130–400 mL per arm after 2–4 weeks
of therapy, but acknowledge that effective maintenance
therapy is required to sustain this initial reduction [59–63].
Multilayer compression bandages serve to increase tissue
pressure, promoting lymphatic and venous fluid return to
reshape the extremity. Although effective at reducing limb
volume, proper application of the bandages is difficult for
patients to learn and time-consuming to apply. Compression
sleeves and garments are easier to apply, but their mechanism
of action remains unclear. They are helpful in maintaining
tissue–fluid balance, preventing skin stretching, and protect-
ing skin from trauma. Because of their elasticity, compression
garments are not recommended for overnight use.
In addition to these standard treatment recommendations,
renewed interest exists in the role of exercise for lymphedema
treatment and risk reduction. Ahmed et al [64] randomized 78
women without lymphedema to weight training or standard
care for 6 months after ALND or SLNB and found no evidence
of increased incidence of lymphedema in the intervention
group. Sagen et al [65] found similar results with 2 years of
follow-up. Recently, Schmitz et al [66] completed a rando-
mized controlled trial of supervised twice-weekly progressive
weight lifting in 141 breast cancer survivors with stable
lymphedema. All patients were required to wear a well-fitted
compression garment. They found that 11% of women in the
weight lifting group and 12% of those in the control group
had an increase of more than 5% in arm swelling (cumulative
incidence ratio 1.0; 95% CI 0.88–1.13), and concluded that
slow progressive weight lifting had no significant impact on
arm swelling and actually decreased episodes of lymphedema
exacerbation (P50.04). These findings by Schmitz et al mirror
the findings of others previously demonstrating that exercise
may not exacerbate existing symptoms of lymphedema [61].
Collectively, these four studies suggest that, contrary to prior
teachings, supervised activity and exercise should be encour-
aged in breast cancer survivors.
RISK REDUCTION
A new surgical technique, called axillary reverse mapping
(ARM), was introduced in 2007 in an attempt to further
reduce the incidence of lymphedema. ARM is based on the
concept that the arm and breast each have separate primary
drainage pathways. By injecting blue dye into the arm and
radioisotope into the breast, one can distinguish between the
two pathways and spare lymphatics draining the upper
extremity. Successful mapping of the upper extremity path-
way has been demonstrated in 40–90% of cases; however, a
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fraction of women have overlapping arm and breast drainage
pathways, making salvage of the upper extremity pathways
difficult [67–71]. No lymphedema is reported in patients
completing the ARM procedure, but follow-up is short at only
6 months [67]. Although promising in concept, clinicians
have been cautious in adopting ARM into clinical practice
because mapping may be altered in women with significant
axillary tumor nodal burden (.four positive nodes) [69].
Overlapping breast and upper extremity drainage patterns are
seen in up to 20% of women [72], and the ARM node has
been involved by breast cancer in 9–18% of patients [72, 73].
Further study of and indications for this technique are
needed.
Finally, Cheville et al [74] have explored the possibility of
being able to map lymph nodes draining the upper extremity
using 99mTc-sulfur. Using a dual-head single photon
emission computed tomography (SPECT) camera and low-
dose, single-slice computed tomography (CT) images, they
are able to develop fusion images which serve as a map of
upper extremity lymph node coordinates. Ideally, these nodes
can be avoided in three-dimensional radiation treatment
planning, limiting the radiation dose to lymph nodes draining
the upper extremity. Although merely a feasibility study, this
concept adds to the potential possibilities for further risk
reduction of lymphedema, but clearly more study is needed as
it is likely to be subject to similar limitations as the ARM
procedure.
SUMMARY
The number of breast cancer survivors is continuing to
increase, and issues of survivorship are being pushed to the
forefront of breast cancer research. Lymphedema is a feared
complication of breast cancer treatment because it is
unpredictable and chronic. Although lymphedema is primar-
ily defined as swelling of the upper extremity due to the
accumulation of protein-rich fluids, other symptoms, includ-
ing musculoskeletal pain, paresthesias, and decreased
shoulder range of motion may exist concurrently. It is
difficult to accurately determine the incidence of lymphe-
dema; however, contemporary literature would suggest that it
ranges from 15% to 25% within 5 years after ALND and that it
is likely to rise to 40% or higher with longer follow-up. In
current series, most cases of lymphedema are mild. The
technique of SLNB has certainly reduced the morbidity
associated with axillary staging for breast cancer; however,
there remains a small but significant risk of measured
lymphedema ranging from 0% to 7%.
Risk factors associated with lymphedema are inconsistent
across studies, but most are related to the extent of axillary
surgery, axillary radiation, injury, or infection in the ipsilateral
upper extremity, and body weight. New data are accumulating
on lymphedema progression, suggesting that patients with
mild lymphedema (noticeable only to themselves) are three
times more likely to develop moderate or severe lymphedema.
In an effort to further reduce axillary morbidities, many have
proposed further changes to axillary management.
Nomograms predicting residual disease in non-sentinel
nodes are frequently used in clinical practice to determine
the need for completion ALND. Furthermore, reported trends
in axillary surgery demonstrate decreased rates of completion
ALND after positive SLNB for micrometastatic or isolated
tumor cell disease. Finally, current surgical research focuses
on risk-reducing techniques that may allow for more selective
nodal treatments, sparing the drainage pathways of the upper
extremity. However, all patients remain at risk for lymphe-
dema if axillary radiation is used.
Disclosure: The authors report no conflict of interest.
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