REVIEW

Lymphedema
Stanley G. Rockson, MD
Lymphedema is a set of pathologic conditions that are charac-
terized by the regional accumulation of excessive amounts of
interstitial protein-rich uid. These occur as a result of an im-
balance between the demand for lymphatic ow and the capac-
ity of the lymphatic circulation. Lymphedema can result from
either primary or acquired (secondary) disorders. In this
review, the pathophysiology, classication, natural history,
differential diagnosis, and treatment of lymphedema are
discussed. Am J Med. 2001;110:288295. 2001 by Excerpta
Medica, Inc.
L
ymphedema is the general term for a set of patho-
logic conditions in which there is excessive, re-
gional interstitial accumulation of protein-rich
uid. It can be either a primary or acquired (secondary)
condition. Lymphedema usually involves abnormalities
in the regional lymphatic drainage of the extremities (ei-
ther upper or lower, or both), althoughvisceral lymphatic
abnormalities can also occur. Generalized developmental
insufciency of the lymphatic circulation is not compat-
ible with life (1).
Inadditiontothe chronic changes inthe size andstruc-
ture of the subcutaneous and integumentary structures,
lymphedema may have a substantial effect on quality of
life and the perception of well-being (2). Patients with
lymphedema manifest anxiety, depression, adjustment
problems, and difculty in vocational, domestic, social,
and sexual domains (35). Among women who develop
postmastectomy lymphedema, psychological factors may
reduce compliance with available treatments (6,7).
PATHOPHYSIOLOGY OF LYMPHEDEMA
In contrast with venous edema, in which enhanced cap-
illary pressure can indirectly stimulate lymph produc-
tion, lymphedema is caused by a reduction in lymphatic
transport. Several anatomic problems can lead to lym-
phatic stasis, including lymphatic hypoplasia and func-
tional insufciency or absence of lymphatic valves (8).
Some patients may have an impairment in the intrinsic
contractility of the lymphangion (the segmentally con-
tracting, functional vascular unit of the lymphatic circu-
lation) (8). Secondary lymphedema, which is much more
common than the primary form, can develop as a conse-
quence of any surgical, traumatic, inammatory, or neo-
plastic disruption or obstruction of lymphatic pathways.
Much of the current understanding of the pathophys-
iology of lymphedema derives from the experimental
work of Olszewski (9) in dogs. In this experimental
model, mechanical interruption of lymph vessels of the
limb was sufcient to produce lymphedema after a period
of months to years. Before overt edema occurred, marked
lymphangiographic changes were observed in the ab-
sence of detectable accumulation of interstitial uid.
Eventually, lymph collectors became brotic and lost
their normal permeability. In addition, electron micro-
graphs of skin lymph capillaries disclosed permanent in-
competence of the interendothelial junctions. In contrast
to the pattern observed in other edematous states that
occasion venous hypertension, like congestive heart fail-
ure and thrombotic venous disorders, the advent of
chronic lymphedema in these limbs was not accompa-
nied by the lymphatic hypertension that might otherwise
have been theoretically predicted.
Once established, lymphatic stasis fosters the accumu-
lation of protein and cellular metabolites, such as macro-
molecular protein and hyaluronian, within the extracel-
lular space. Impaired lymphatic transport produces accu-
mulation of both macromolecular protein and of
hyaluronian (10). This is followed by an increase in the
tissue colloid osmotic pressure, which leads to water ac-
cumulation and increased interstitial hydraulic pressure.
Chronic lymph stasis often produces an increase in the
number of broblasts, adipocytes, and keratinocytes in
the edematous tissues. Mononuclear cells (chiey macro-
phages) often demarcate the chronic inammatory re-
sponse (11,12). In most patients, there is an increase in
collagen deposition, with adipose and connective tissue
overgrowth in the edematous skin and subcutaneous tis-
sues (13). Histopathologic ndings in chronic lymphed-
From the Division of Cardiovascular Medicine, Stanford University
School of Medicine, Falk Cardiovascular Research Center, Stanford,
California.
Requests for reprints should be addressed to Stanley G. Rockson,
MD, Division of Cardiovascular Medicine, Stanford University School
of Medicine, Falk Cardiovascular Research Center, Stanford, California
94305.
Manuscript submitted January 3, 2000, and accepted in revised form
November 9, 2000.
288 2001 by Excerpta Medica, Inc. 0002-9343/01/$see front matter
All rights reserved. PII S0002-9343(00)00727-0
ema include thickening of the basement membrane of
lymphatic vessels, fragmentation and degeneration of
elastic bers, increased numbers of broblasts and in-
ammatory cells, and increased amounts of ground sub-
stance and pathological collagen bers (14). Ultimately,
these processes lead to progressive subcutaneous brosis.
CLASSIFICATIONOF LYMPHEDEMA
The simplest classication of lymphedema relies upon a
differentiation between primary and secondary causes
(15). Primary lymphedemas are often classied accord-
ing to the age at which the edema rst appeared. Congen-
ital lymphedema is apparent at birth or becomes recog-
nized withinthe rst 2 years of life. Lymphedema praecox
is most commonly detected at the time of puberty, but
may appear as late as the third decade of life. Lymphed-
ema tarda typically appears after age 35 years. Recent ad-
vances within the genetic investigation of hereditary
lymphedemas have permitted the identication of possi-
ble candidate genes for lymphedema-distachiasis (16).
Linkage analysis of family cohorts with cholestasis-
lymphedema syndrome has similarly resulted in success-
ful chromosomal mapping of the disease locus (17). Ge-
netic mapping of the autosomal dominant formof hered-
itary primary lymphedema (Milroys disease) (18)
suggests that the disease can be ascribed to a mutation
that inactivates the VEGFR3 tyrosine kinase signaling
mechanism that is felt to be specic to lymphatic vessels
(19).
In congenital lymphedema, the swelling can involve
only a single lower extremity, but edema of multiple
limbs, the genitalia, and even the face can be seen. Bilat-
eral leg swelling and involvement of the entire lower ex-
tremity is more likely in congenital cases than in other
forms of primary lymphedema (20).
When cases of congenital lymphedema cluster in fam-
ilies, an autosomal dominant pattern of transmission is
most frequently described. However, isolatedinstances of
lymphedema are much more common (21). There is a
strong association between intrauterine and congenital
lymphatic dysfunction and several heritable chromo-
somal abnormalities (15).
Lymphedema praecox, the most common form of pri-
mary lymphedema, is responsible for as many as 94% of
the cases in large reported series. The estimated 10:1 ratio
of females to males suggests that estrogenic hormones are
involved (21). The edema is usually unilateral and is lim-
ited to the foot and calf in the majority of patients (21).
Lymphedema tarda is relatively uncommon, and ac-
counts for fewer than 10% of cases of primary lymphed-
ema.
An alternative classication for primary lymphedema
relies upon morphologic characteristics (20). Distal hyp-
oplasia of the lymphatics is typically associated with bi-
lateral peripheral edema of the lower extremities. There is
usually a family history of similar symptoms, a female
predominance, and a tendency for indolent progression.
When isolated proximal obstructive hypoplasia is ob-
served, clinical involvement of the entire limb is more
likely, usually accompaniedby relentless worsening of the
edema. Patients who have unilateral edema involving the
entire lower extremity are likely to have lymphatic hyper-
plasia with megalymphatics, although this syndrome is
uncommon.
Secondary lymphedema develops after disruption or
obstruction of lymphatic pathways by other disease pro-
cesses, or as a consequence of surgery or radiotherapy.
Secondary lymphedema is much more common than the
primary form. Edema of the arm after axillary lymph
node dissection is probably the most common cause of
lymphedema inthe UnitedStates (22), althoughits global
incidence is overshadowed by lariasis, which affects
more than 90 million people (23).
The reported incidence of edema after mastectomy
varies substantially, from 6% to 80% among published
series (22). Differences in the incidence estimates may
reect variations in the denition of edema. A recently
published series suggests that, with up to 13 years of
follow-up, a 14% late incidence of postmastectomy
lymphedema can be expected in surgically treated pa-
tients with adjuvant postoperative irradiation (24). Fur-
thermore, in a second recent series, 21 of 110 patients
treated with breast-conserving techniques also developed
chronic postsurgical armswelling (25). Thus, despite im-
provements in surgical and radiotherapeutic techniques,
lymphedematous complications cannot be obviated and
are, infact, not uncommon(26,27). Edema of the leg may
occur after pelvic or genital cancer surgeries, particularly
when there has been inguinal and pelvic lymph node dis-
section or irradiation. Its reported frequency varies be-
tween 1% and 47% (28,29). Pelvic irradiation increases
the frequency of leg lymphedema after cancer surgery
(30).
NATURAL HISTORY OF LYMPHEDEMA
The natural history of lymphedema is uncertain, partic-
ularly as it may be asymptomatic. For example, as late as 3
years after radical mastectomy and axillary node dissec-
tion, more than20%of womenremainfree of any clinical
evidence of lymphatic impairment, despite the extensive
iatrogenic destruction of the lymphatic architecture in
these patients (31,32). Similarly, in many forms of pri-
mary lymphedema, there may be a protracted phase of
apparently normal lymphatic function, despite an inher-
ited anatomic or functional disturbance of this microcir-
culation. This latent phase of lymphedema may represent
Lymphedema/Rockson
March 2001 THE AMERICAN JOURNAL OF MEDICINE Volume 110 289
a balance between the existing increased lymph load and
a reduced outow capacity (32). Lymphedema may be-
come manifest when compensatory mechanisms, which
may include lymphatic regeneration, become inadequate
to withstand the requirement for lymphatic ow.
The precipitating factors for the appearance of overt
lymphedema are not known (33). At the onset of clinical
lymphedema, swelling of the involved extremity is typi-
cally described as puffy, and the disturbance may be in-
termittent. With chronicity, the involved structures de-
velop the characteristic features of induration and bro-
sis (13), which may be substantial (Figure 1).
In many patients, the maximal increase in girth of the
involved limb is determined within the rst year after
onset, unless there are supervening complications like re-
current cellulitis. The propensity to recurrent soft-tissue
infection is one of the most troublesome aspects of long-
standing lymphedema. Microbial growth is encouraged
by the surplus of uid and accumulated proteins. Lym-
phatic dysfunction also impairs local immune responses
(34). The impaired regional immunosurveillance of
lymphedema is supported by the observed impairments
inthe cutaneous immune responses inpatients withpost-
mastetomy lymphedema (34). With recurrent infections,
there is progressive damage of lymphatic capillaries. In
one reported series, acute cellulitis in the arm was ob-
served in 6%of patients during 42 months of surveillance
after breast cancer therapy (35).
The clinical presentation of soft-tissue infection in
lymphedema can be variable, from very subtle exacerba-
tions of lymphedema characterized by skin changes with-
out fever, to rapidly progressive soft tissue infection with
high fever and systemic toxicity. Recurrent attacks of cel-
lulitis further damage the cutaneous lymphatics, worsen
the skin quality, and aggravate the edema.
In very rare cases, chronic lymphedema may be com-
plicated by the local development of malignant tumors
such as lymphangiosarcomata, which can be either scle-
rotic plaques or multicentric lesions with blue-tinged
nodules or bullous changes (36). Other cutaneous malig-
nancies that have been observed in association with
chronic lymphedema (37) include lymphoma, mela-
noma (38), squamous cell carcinoma (39), and Kaposis
sarcoma (40).
DIAGNOSIS OF LYMPHEDEMA
In most patients with advanced lymphedema, the charac-
teristic clinical presentation and physical ndings estab-
Figure 1. Severe, advanced primary lymphedema with brosis, hyperpigmentation, and excoriation of the skin.
Lymphedema/Rockson
290 March 2001 THE AMERICAN JOURNAL OF MEDICINE Volume 110
lish the diagnosis with near certainty (41). However, early
in the natural history, or with presentations of mild or
intermittent swelling, it may be more difcult to distin-
guish lymphedema from other edematous states. Several
physical features distinguish lymphedema from other
causes of chronic edema of the extremities. Among these
are the classic changes of cutaneous and subcutaneous
brosis (peau dorange), and the Stemmer sign, which is
an inability to tent the skin on the dorsum of the digits of
the feet. Although the Stemmer sign has not been vali-
dated, it was initially reported to discriminate patients
with lymphedema (42). Lymphedema in the legs often
produces preferential swelling of the dorsum of the foot,
as well as the characteristic blunt, squared-off appear-
ance of the digits in the involved extremity.
When the physical examination does not conclusively
support the diagnosis of lymphedema, additional evi-
dence may be necessary to conrm impaired lymphatic
function. Available tests include isotopic lymphoscintig-
raphy, indirect and direct lymphography, lymphatic cap-
illaroscopy, magnetic resonance imaging (MRI), axial to-
mography, and ultrasonography. Direct lymphography is
generally limited to the evaluation of candidates for lym-
phatic surgery. Isotopic lymphoscintigraphy is the most
commonly used test and is generally considered to be the
gold standard for the diagnosis of lymphedema. A radio-
labeled macromolecular tracer (eg, sulfur colloid) is ad-
ministered into the subdermal, interdigital region of the
affected limb. The lymphatic transport of the radiola-
beled macromolecule can be monitored in a semiquanti-
tative fashion with a gamma camera. Major lymphatic
trunks andlymphnodes canbe visualized. Typical abnor-
malities in lymphedema include absent or delayed trans-
port of tracer, absent or delayed visualization of lymph
nodes, crossover lling with retrograde backow, and
dermal backow (4345). In a series of more than 700
patients, peripheral lymphatics were visualized readily
(46). These imaging techniques can also be used to mon-
itor the effects of therapy and to facilitate invasive thera-
pies for chylous reux (the reux of intestinal lymph to
the skin as a consequence of lymphatic valvular incom-
petence) (47).
Magnetic resonance imaging and computerized tomo-
graphic (CT) imaging allowthe objective documentation
of structural changes attributable to lymphedema (48).
The characteristic absence of edema within the muscular
compartment helps to distinguish lymphedema radio-
graphically from other forms of edema. In addition, the
honeycomb distribution of edema within the epifascial
plane, along with thickening of the skin, is characteristic
of lymphedema. The anatomic delineation of lymphatic
and nodal architecture derived from MR imaging can
complement the functional assessment provided by lym-
phoscintigraphy (45,49).
Less commonly employed techniques include tissue
tonometry (50,51) and bioelectric impedance analysis
(5255). These techniques allow detection of small
changes in tissue turgor and may have utility in the detec-
tion of subclinical states of lymphatic impairment, as well
as in the serial assessment of the response to treatment.
DIFFERENTIAL DIAGNOSIS
Chronic Venous Insufciency and Postphlebitic
Syndrome
This common condition is often confused with lymphed-
ema of the legs. Its distinguishing clinical features include
aching discomfort in the lower extremities during sitting
or standing and chronic pruritus, particularly overlying
the incompetent communicating veins (56). Physical
ndings include cutaneous deposits of hemosiderin,
dusky discoloration and venous engorgement with de-
pendence, cutaneous varicosities, and if advanced, ulcer-
ation of the skin.
Myxedema
This special form of edema arises when abnormal depos-
its of mucinous substances accumulate in the skin as a
result of thyroid disease (57). Hyaluronic acid-rich pro-
tein deposition in the dermis produces edema that, in
turn, disrupts structural integrity and reduces the elastic-
ity of the skin. Inthyrotoxicosis, this process is focal inthe
pretibial region (58); in hypothyroidism, the myxedema
is more generalized. Myxedema is characterized by
roughening of the skin of the palms, soles, elbows and
knees; brittle, uneven nails; dull, thinning hair; yellow-
orange discoloration of the skin; and reduced sweat pro-
duction. However, it may be difcult to distinguish from
lymphedema.
Lipedema
This condition affects women, or men with a feminizing
disorder. The edema is caused by the abnormal accumu-
lation of fatty substances in the subcutaneous regions,
typically between the pelvis and the ankle, with sparing of
the feet. Although the pathophysiology of this disorder is
uncertain, it does involve an excess of subcutaneous adi-
pocytes with structural alterations in the small vascular
structures within the skin. Indeed, regional abnormalities
of the circulation may cause the initial accumulation of
fat in the affected regions (59). The characteristic distri-
bution, withsparing of the feet, shouldsuggest the correct
diagnosis. The absence of a Stemmers sign is an addi-
tional clue. Most often, lipedema arises within1 to 2 years
after the onset of puberty. In addition to the near lifelong
history of heavy thighs and hips, affected patients often
complain of painful swelling. In addition, there is com-
monly a propensity to bruising, perhaps a result of in-
creased fragility of capillaries within the adipose tissue.
Lymphedema/Rockson
March 2001 THE AMERICAN JOURNAL OF MEDICINE Volume 110 291
Malignant Lymphedema
In the United States, the leading cause of lymphedema of
both upper and lower extremities is neoplastic disease
and related therapies. Thus, in the differential diagnosis
of new or worsening lymphedema, recurrence of cancer,
leading to intrinsic or extrinsic obstruction of lymph
ow, must be considered. Malignant lymphedema often
develops rapidly and progresses relentlessly (60). In addi-
tion, pain, which is generally absent in benign lymphed-
ema, may be present. The malignant form of lymphed-
ema tends to begin centrally. Often, the tissue is quite
rm from the outset, without the soft consistency seen in
the early stages of benign lymphedema.
LYMPHEDEMA TREATMENT
General Therapeutic Measures
Lymphedema is a chronic conditionthat requires lifelong
attention. Meticulous attention to control of edema may
reduce the likelihood of disease progression and limit the
incidence of soft-tissue infections (41). Aggressive imple-
mentation of decongestive lymphatic therapy is the
mainstay of most therapeutic recommendations
(6163). This complex form of physical therapy inte-
grates meticulous skin care, massage, exercise, and use of
compressive elastic garments. Decongestive lymphatic
therapy canacutely reduce limb volume as well as provide
long-term benets owing to the acceleration of lymph
transport in the edematous limb and the dispersal of ac-
cumulated protein (63).
The specialized massage technique for these patients
(manual lymphatic drainage or therapy) is intended to
enhance lymphatic contractility and to augment and re-
direct lymph ow through the nonobstructed cutaneous
lymphatics. Manual lymphatic drainage should not be
confused with other forms of therapeutic massage that
have no effect on lymphatic contractility. The mild tissue
compression during manual lymphatic drainage pro-
duces better lling of the initial lymphatics and enhances
transport capacity, through the cutaneous lymphatic di-
latation and development of accessory lymph collectors
(64).
During the acute approach to volume reduction, non-
elastic, compressive wrappings should be applied after
each session of manual lymphatic drainage and worn
during exercise to prevent reaccumulation of uid and to
promote lymph ow during exertion. Complete decon-
gestive physiotherapy, including manual lymphatic
drainage, compression bandaging, garments and skin
care, is an effective treatment modality for many patients
with primary and secondary lymphedema (Figure 2). In a
recent series of 299 patients, with an average follow-up of
9 months, there were average reductions of 59%in upper
extremity volume, and 68% in lower extremity volume,
withmaintenance of 90%of this benet during follow-up
in compliant patients (65). In another, subsequent pro-
spective analysis of therapeutic responses in chronic
lymphedema, short-term decongestive lymphatic ther-
apy, when coupled with focused patient instruction in
long-term self-care, was documented to be efcacious,
with sustainable long-term therapeutic responses (66).
The use of intermittent pneumatic compression with
single or multichamber pumps removes excess uid from
the extremity and should be considered as an adjunctive
approach (41). Pneumatic compression techniques,
however, cannot clear edema uid from the adjacent
trunk. Consequently, as uid shifts occur during pneu-
matic compression, the root of the limb must be decom-
pressed with manual techniques. The use of any form of
compressive therapy requires a sufcient arterial blood
supply to the limb. Incases of limb ischemia, compressive
therapy, which can compromise arterial blood ow and
promote severe ischemia and necrosis, is contraindi-
cated.
The prescription of compressive garments is a neces-
sary adjunct to all other forms of lymphedema therapy.
Relatively inelastic sleeves and underwear that transmit
high-grade compression (40 to 80 mm Hg) will prevent
reaccumulation of uid after successful decongestive
treatments. Garments must be tted properly and re-
placed when they lose their elasticity (every 3 to 6
months).
Other treatments are under investigation. Low-level
laser therapy may be effective in postmastectomy
lymphedema; in a series of 10 patients, subjective im-
provement was accompanied by objective documenta-
tion of improved bioimpedance and reduced extracellu-
lar and intracellular uid accumulation (67). In addition,
some promising responses have been reported after local
hyperthermia (68) and the intra-arterial injection of au-
tologous lymphocytes (69). In the latter approach, it is
postulated that regression of edema is linked to the ex-
pression of L-selectin, a lymphocyte-specic adhesion
molecule (69).
Pharmacotherapy and Diet
The reported benet of coumarin (5,6-benzo-[a]-py-
rone) in lymphedema (70) is ascribed to its stimulatory
effect upon cutaneous macrophages and, thereby, upon
local proteolysis. Coumarin also stimulates other cellular
elements of the immune system and may promote pro-
tein reabsorption. Efcacy has been demonstrated in
lymphedema of the arms and legs (70), as well as inlarial
elephantiasis (71). A meta-analysis of 50 clinical trials
suggests that these slow-acting compounds can provide a
mean decrease in edema volume of about 55% (72).
However, coumarin administered orally may cause idio-
syncratic hepatitis. Topical coumarins are under investi-
gation; none is available for clinical use in the United
Lymphedema/Rockson
292 March 2001 THE AMERICAN JOURNAL OF MEDICINE Volume 110
States. There are scant, but provocative, data concerning
the therapeutic benet of augmenting dietary avenoids
(73). These naturally-occurring compounds, particularly
the rutin derivatives, are thought to benet lymphedema
through protective effects on vascular endothelium and
general improvement in the microcirculation. In addi-
tion, there is one report that suggests that dietary restric-
tion of long-chain triglycerides provides some relief of
edema in these patients (74).
Surgical Therapy
Invasive approaches may be necessary in patients with
unacceptable subcutaneous adipose hypertrophy and -
brosis (7577). Two main surgical approaches have
been utilized. In excisional procedures, part or all of the
lymphedematous epifascial tissue is removed, whereas
microsurgical interventions involve the creation of
lymphaticolymphatic, lymphaticoveno-lymphatic, lym-
phaticovenous, or lymph node-venous anastomoses
(78). Although lymphaticovenous anastomosis (79,80)
and transplantation of lymph collectors have been advo-
cated (8183) for chronic lymphedema, the long-term
results of such interventions have not been uniformly en-
couraging (81,84). Debulking surgical procedures are de-
signed to remove redundant skin and subcutaneous tis-
sue (85), often with wide excision and split skin grafting
(86). The procedures do not improve lymphatic drain-
age. Other surgical techniques include treatment with
transfer of an omental pedicle (87) or interposition of a
vascular pedicle ap to serve as a lymphatic wick (88).
Surgical approaches, however, may cause further damage
to cutaneous lymphatics and may lead to skin necrosis,
papillomatosis, ulceration, stula formation, and edema
exacerbation (75,89). Additional surgical risks include
sensorineural damage, hypertrophic scarring, ulceration,
graft necrosis, and exophytic keratosis. Nevertheless, par-
tial excision may be indicated for cases of advanced bro-
sis or frank elephantiasis.
Suction techniques may also be used to remove excess
subcutaneous tissue. Surgical liposuction of chronic
postmastectomy lymphedema has been reported to pro-
duce excellent results, with sustained reduction of excess
volume (89,90). In one series, an average long-term re-
duction of edema volume of 106% (in some patients,
there is actually surgical overcorrection so that, when
comparedwiththe normal limb, the therapeutic response
is actually 100%) was observed in 28 patients with an
average edema volume of 1,845 mL (89). Liposuction
with long-term decongestive compression therapy re-
Figure 2. Results of intensive decongestive lymphatic physiotherapy for severe, advanced primary lymphedema (see Figure 1).
Lymphedema/Rockson
March 2001 THE AMERICAN JOURNAL OF MEDICINE Volume 110 293
duces edema volume more successfully than does com-
pression therapy alone. However, the volume reduction
will not be successful unless compression therapy is
maintained after the surgical intervention (91).
ACKNOWLEDGMENT
The assistance of Dr. Andrzej Szuba in the preparation of the
gures is gratefully ackowledged.
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