Pathophysiology and clinical manifestations [631989]

Lymphedema
Pathophysiology and clinical manifestations
A y m a nA .G r a d a ,M D ,a n dT a n i aJ .P h i l l i p s ,M D
Boston, Massachusetts
Lymphedema is a localized form of tissue swelling resulting from excessive retention of lymphatic fluid in the
interstitial compartment and caused by impaired lymphatic drainage. Lymphedema is classified as primary orsecondary. Primary lymphedema is caused by developmental lymphatic vascular anomalies. Secondarylymphedema is acquired and arises as a result of an underlying systemic disease, trauma, or surgery. Weperformed PubMed and Google Scholar searches of the English-language literature (1966-2017) using theterms lymphedema, cancer-related lymphedema, and lymphatic complications. Relevant publications weremanually reviewed for additional resources. This progressive chronic disease has serious implications onpatients’ quality of life. It is often misdiagnosed because it mimics other conditions of extremity swelling.
There is no definitive cure for lymphedema. However, with proper diagnosis and management, its
progression and potential complications may be limited. ( J Am Acad Dermatol 2017;77:1009-20.)
Key words: lymphedema; pathophysiology; primary; secondary; skin.
PATHOPHYSIOLOGY
Key points
dLymphedema is caused by impaired lymphatic
drainage in the presence of normal capillary
function
dLymphatic congestion induces chronic
inflammation, which leads to fibrosis andfurther lymphatic damage
dPrimary lymphedema is caused by geneticmutation or developmental abnormalitiesdFilariasis is the most common cause of sec-ondary (acquired) lymphedema worldwide
dCancer-related treatment is the most com-mon cause of secondary lymphedema in theUnited StatesAbbreviations used:
APCD: advanced pneumatic compression device
BCRL: breast cancer erelated lymphedema
ENV: elephantiasis nostras verrucosaLearning objectives
After completing this learning activity, participants should be able to identity patients who are at risk for developing lymphedema; have an underst anding of the etiology and
pathophysiology of lymphedema; and describe the dermatologic manifestations of lymphedema.
Disclosures
Editors
The editors involved with this CME activity and all content validation/peer reviewers of the journal-based CME activity have reported no relevant fin ancial relationships with
commercial interest(s).
Authors
The authors involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s).
Planners
The planners involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). The edit orial and education staff involved
with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s).
From the Department of Dermatology, Boston University School
of Medicine.
Funding sources: None.Conflicts of interest: None declared.
Accepted for publication March 6, 2017.
Reprints not available from the authors.Correspondence to: Ayman A. Grada, MD, Department of
Dermatology, Boston University School of Medicine, 609
Albany St, Ste 600B, Boston, MA 02118. E-mail: [anonimizat] .0190-9622/$36.00
/C2112017 by the American Academy of Dermatology, Inc.
http://dx.doi.org/10.1016/j.jaad.2017.03.022Date of release: December 2017
Expiration date: December 2020
1009

The lymphatic system is composed of lymphatic
organs, such as lymph nodes, tonsils, thymus, andthe spleen, all of which are connected via a networkof lymphatic vessels that run parallel to the venouscirculation. The lymphatic system has 3 main
functions: drainage of excess interstitial fluid, fat
absorption, and immune surveillance. Interstitialfluid refers to the portion of fluid that leaks fromblood capillaries into the tissue spaces. Most of theinterstitial fluid ( ;90%) is reabsorbed via the
venous microcirculation and returns to the blood-stream. The remainder ( ;10%) of the interstitial
fluid has a relatively high protein concentration
and is drained by blind-ended lymphatic capillaries
(Fig 1 ). Once this protein-rich interstitial fluid enters
the lymphatic capillaries, it is referred to as lymph.Lymph is then transported via the collectinglymphatic vessels, filtered through lymph nodes,and ultimately reenters the circulatory system nearthe point where the peripheral venous blood entersthe right heart.
1The normal lymphatic flow is 2 L to
3 L per day.2Unlike lymphatic capillaries, the
collecting lymphatic vessels have smooth musclewalls and therefore the ability to contract andpropel the lymphatic fluid forward. Impairment inthe draining capacity caused by obstruction orlymphatic hypoplasia leads to an accumulation ofinterstitial fluid and tissue swelling known aslymphedema. The subsequent decrease in oxygen
tension leads to chronic inflammation and reactive
tissue fibrosis.The lymphatic system has an important immune
surveillance function. Circulating lymph transportsvarious antigens and activated antigen-presentingcells into the lymph nodes to orchestrate the immuneresponse.
3Skin has an extensive presence of
lymphatic capillaries. Patients with lymphedema are
prone to recurrent skin infections because of theaccumulation of peripheral tissue antigens. Chronicinflammation and the subsequent soft tissue fibrosis inlymphedema has been attributed to T
H2i m m u n e
response initiated because of lymphatic stasis.4
EPIDEMIOLOGY
Key points
dLymphedema is more common in females
than males
dLower extremity lymphedema is much morecommon than upper extremity lymphedema
Incidence and prevalence
Lymphedema is a significant problem in the
United States and throughout the world. It has
been reported that lymphedema affects as many as200 million people worldwide and approximately 3million people in the United States.
5,6Lymphedema
affects females more often than males. Primarylymphedema is rare, with an estimated prevalenceof 1 in 100,000 individuals, and usually occursduring childhood, but may present at any age.
7,8
Approximately 99% of individuals with lymphedemahave a secondary disease.
5,9The prevalence of
Fig 1. Normal lymphatic circulation. A, Lymphatic drainage returns tissue fluid to the
bloodstream. B, Lymphatic capillaries collect excess fluid from the interstitial space. Around
90% of fluid filtered by blood capillaries will be reabsorbed and returned to the venousmicrocirculation. The remaining 10% is a protein-rich fluid ‘‘lymph’’ and will be drained by the
lymphatic capillaries. Lymphedema develops when there is a malfunction in the lymphatic
drainage system. (Copyright Alila Medical Media.)JAMACADDERMATOL
DECEMBER 20171010 Grada and Phillips

secondary lymphedema is 1 in 1000 individuals,
with the mean age at the time of diagnosis ranging
from 50 and 58 years.10-12In the US and
Western countries, secondary lymphedema ismost commonly reported in patients undergoinglymphadenectomy or radiation therapy for breastcancer.
6However, it may occur after any malignancy
that affects lymphatic drainage. Filariasis is the mostcommon cause of secondary lymphedema in the
world.
13
Lower extremity lymphedema is much more
common than upper extremity lymphedema andis usually associated with infection, chronicvenous insufficiency, rapamycin treatment inpatients with renal failure, obesity, and malig-nancies, such as uterine cancer, prostate cancer,lymphoma, and melanoma.
14Upper extremity
lymphedema is most commonly associated with
breast cancer. In patients undergoing post-mastectomy irradiation therapy, the incidence oflymphedema is approximately 30%.
15A systematic
review and metaanalysis of cancer-related second-ary lymphedema reported an overall incidence of15.5% after treatment of malignancy (the ratevaries by malignancy)
16and an overall incidence
of 16% after treatment of melanoma (upper
extremity, 5%; lower extremity, 28%).16The risk
of lymphedema was found to be highest inpatients receiving radiation therapy (31%).
Impact on health outcomes and costs
Lymphedema is a major burden to any health care
system because it is chronic, progressive, and re-quires lifelong treatment. Patients with primarylymphedema have a lower morbidity compared topatients with secondary lymphedema, possiblybecause they have a better ability to compensatefor lymphatic malfunction.
17Because of a lack of
epidemiologic evidence, the economic burdens of
the disease have not been studied extensively.18
Women with breast cancer erelated lymphedema
(BCRL) had a greater risk of recurrent soft tissueinfections and incurred higher medical costs whencompared to those without (matched controls).
19An
increased medical cost in patients with lymphedemais most likely the result of frequent visits tophysicians and physical therapists.
20
Etiology and classification
Lymphedema is classified according to etiology
into either primary (hereditary) or secondary(acquired).
Primary lymphedema. Primary lymphedema is
rare and results from genetic mutations that lead
to underdevelopment of lymphatic vessels andmalfunction of the lymphatic drainage capacity.
Primary lymphedema can be an isolated disease or
part of a complex syndrome. Most cases are inheritedas an autosomal dominant trait with incompletepenetrance and variable expression. Nearly 30% ofprimary lymphedema patients have identifiablegenetic mutations, often in the signaling pathwayfor vascular endothelial growth factor C.
9More than
20 genes have been linked to lymphatic anomalies in
primary lymphedema.21However, there is a high
degree of genetic heterogeneity.21Primary lymphe-
dema often occurs in the lower extremities, and onrare occasions it may affect the genitalia and arms. Ingeneral, incidence in females is twice that in males.
22
Based on age of onset, primary lymphedema issubdivided into 3 categories: congenital lymphe-dema (at or shortly after birth), lymphedema praecox
(around puberty or shortly thereafter), and
lymphedema tarda (late in life; Table I ). In Milroy
disease, mutations in the VEGFR3 gene cause
lymphatic hypoplasia, resulting in a dysfunctionalvalve system and failure of initial lymphatic fluidabsorption.
23Milroy disease is a familial (inherited)
condition, whereas the other forms of primarylymphedema are usually nonfamilial (sporadic).
Nonfamilial primary lymphedema is more common
than familial cases. Because patients with geneticmutations may develop lymphedema at puberty orlater in life, we believe that categorization accordingto age is oversimplified and can be potentiallymisleading because it is not based on specificphenotypic features or pathobiologic basis. Theideal classification should be based on robust
phenotype egenotype correlations.
Secondary lymphedema. Secondary lymphe-
dema is far more common than primary lymphe-dema. It is acquired by damage or obstruction ofpreviously normal lymphatics by disease processes,recurrent infection, trauma, surgery, obesity, or as aconsequence of malignancy and malignancy-associated therapeutic interventions, such as
radiation therapy.
24Secondary periorbital lymphe-
dema may occur with rosacea.25Both chronic
venous hypertension and venous ulcers can beassociated with impaired lymphatic function.
26In
patients with chronic venous disease, 20% will alsohave secondary lymphatic damage from fluidoverload.
26,27Phlebolymphedema refers to
lymphedema caused by chronic venous disease.
Secondary lymphedema may also be influenced by
genetic predisposition.21,28
Infection. Lymphatic filariasis (also known as
elephantiasis) is the most common cause ofsecondary lymphedema worldwide. It is anacquired infection with mosquito-borne nematodeJAMACADDERMATOL
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Table I. Categories of primary lymphedema
Phenotype Genes (protein) OMIM Inheritance Phenotypic form Clinical findings Type of mutationCytogenetic
location
Congenital lymphedema Age of onset: 0-2 years
Hereditary lymphedema type IA
(primary congenital
lymphedema/Nonne eMilroy
lymphedema)FLT4 (VEGFR3) 153100 AD, AR, de
novoIsolated
lymphedemaBilateral lymphedema Missense,
inactivating5q35.3
Hereditary lymphedema type IB LMPH1B 611944 AD Isolated
lymphedemaBilateral lymphedema Missense 6q16.2-q22.1
Hereditary lymphedema type ID
(Milroy-like lymphedema)VEGFC 615907 AD Isolated
lymphedemaBilateral lymphedema LOF 4q34.3
Microcephaly, chorioretinopathy,
lymphedema mentalretardation syndromeKIF11 (EG5) 152950 AD, de novo Syndromic Microcephaly, mental
retardation, lower extremitylymphedemaLOF 10q23.33
Fetal chylothorax ITGA9 603523 AR, de novo Syndromic Hydrops fetalis Missense 3p21.3
Oculodentodigital dysplasia/
lymphedema syndromeGJA1 (CX43) 164200 AD Syndromic Lower-extremity lymphedema,
microcephaly, microphthalmia,
complete syndactyly of the
fourth and fifth fingersMissense 6q22.31
Turner syndrome 45XO ,SHOX
gene has
been linked300582
(SHOX)Most cases
are not
inheritedSyndromic Webbed neck, low posterior
hairline, lymphedema, primary
amenorrhea, aortic coarctationIncomplete or
missing X
chromosomeX chromosome,
Xp22.33
Choanal atresia/lymphedema
syndromePTPN14 613611 AR Syndromic Bilateral bony choanal atresia
and lower extremity
lymphedemaLOF 1q32-q41
Ectodermal dysplasia, anhidrotic,
with immunodeficiency,
osteopetrosis, and
lymphedemaIKBKG 300301 X-linked Syndromic Ectodermal, dysplasia, anhidrotic,
lymphedema, and
immunodeficiencyHypomorphic Xq28
Capillary malformation d
arteriovenous malformation,
including Parkes WebersyndromeRASA1 608354 AD Syndromic Port wine stain, arteriovenous
fistula, lymphedemaLOFJAMACADDERMATOL
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Noonan syndrome 1 PTPN11 (SHP2) 163950 AD Syndromic Short stature, hypertelorism,
nuchal edema, pigmented
nevi, caf /C19e au lait macules,
keratosis pilaris atrophicans,keloid formation, coarse light-
colored curly hair, hypogo-
nadism, pulmonary stenosisGOF 12q24.13
Noonan syndrome 4 SOS1 610733 AD GOF 2p22.1
Noonan syndrome 3 KRAS 609942 AD GOF 12p12.1
Klippel-Trenaunay-Weber
syndromeKTWS 149000 Sporadic Syndromic Limb overgrowth, cutaneous
angiomas, and venous disease,
lymphedemaUnknown 8q22.3
Cholestasis lymphedema
syndrome (Aagenaes
syndrome)LCS1 214900 AR Syndromic Lymphedema and obstructive
jaundice15q
Tuberous sclerosis-1 TSC1 191100 AD, de novo Syndromic Facial angiofibromas, gingival fi-
bromas, ash-leaf macules, sei-
zures, shagreen patch, dental
enamel pits, neuropsychiatricdefects, lymphedemaLOF 9q34.13
Tuberous sclerosis-2 TSC2 613254 AD, de novo Syndromic LOF 16p13.3
Hennekam lymphangiectasia e
lymphedema syndromeCCBE1 235510 AR, de novo Syndromic Lymphedema (face and lower
extremities), intestinal lym-phangiectasia, intellectual
deficit, facial dysmorphismLOF 18q21.32
Hennekam lymphangiectasia e
lymphedema syndrome 2FAT4 616006 AR Syndromic LOF 4q28
Lymphedema praecox Age of onset: puberty to 35 years of age
Hereditary lymphedema type II
(Meige’s disease)LMPH2 153200 AD with
variable
penetranceIsolated
lymphedemaLower extremity lymphedema Unknown Not mapped
Hereditary lymphedema type IC GJC2 (CX47) 613480 AD Isolated
lymphedema4-limb late-onset lymphedema Missense 1q42.13
Lymphedema edistichiasis
syndromeFOXC2 153400 AD, de novo Syndromic Late-onset lymphedema,
secondary set of aberranteyelashes arising from the
meibomian glands, ptosis,
venous refluxLOF 16q24.1
Yellow nail syndrome FOXC2? 153300 Sporadic Syndromic Yellow nails, late-onset lower
extremity lymphedema, and
respiratory tract involvementLOF Not mapped
ContinuedJAMACADDERMATOL
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(roundworm) Wuchereria bancrofti . It infects
people who reside or who have traveled to areas
endemic with the disease, mainly in sub-SaharanAfrica and India. The adult worm’s larvae aredeposited on the skin by mosquitoes. The larvaethen migrate to the lymphatics causing blockage oflymphatic flow. According to the World HealthOrganization fact sheet
29(updated March 2017),
more than 120 million people are infected, with
about 40 million individuals disfigured and
incapacitated by the disease.
Herpesvirus infection may rarely cause
lymphedema. One case study reported acquiredlymphedema in a patient with herpetic whitlow.
30
Recurrent cellulitis and erysipelas lead to damage ofcutaneous lymphatics and can cause unilaterallymphedema.
31Lymphogranuloma venerum, a
sexually transmitted disease caused by Chlamydia
trachomatis , can cause lymphedema of the external
genitalia.32Scrofula, tuberculous lymph nodes of the
neck, is the much less common cause.33
Malignancy-related therapeutic interven-
tions. Surgical dissection or excision of lymph
nodes during mastectomy for breast cancer ormelanoma treatment leads to impaired lymphatic
drainage. Radiation therapy that follows causes
the loss of dermal lymphatic vessels and nodalfibrosis, which makes any prospect for lymphaticregeneration unlikely.
34Lymphedema caused by
malignancy-related interventions usually manifestsas chronic unilateral extremity swelling. However,surgery of the prostate and cervix may cause bilateralswelling.
35,36
Podoconiosis. Podoconiosis is a nonfilarial
elephantiasis caused by chronic exposure ofbare feet to irritant clay soil containing silicamicroparticles. It is the second most common causeof tropical lymphedema worldwide.
37When
absorbed through the skin, these mineral particlesinduce an inflammation of the lymphatics and causesubendothelial lymphatic edema and eventual
blockade of the lumen.
38Podoconiosis is endemic
in the highlands of tropical Africa, North India, andCentral America.
38,39
Morbid obesity. Morbid obesity has been
recognized as a risk factor for developing lymphe-dema. A body mass index [60 kg/m
2has been
linked to impaired lymphatic flow.12An increased
amount of adipose tissue in dependent areas causes
obstruction of lymphatic vessels.24,40-42Decreased
physical activity in obese patients is an exacerbatingfactor. Large abdominal pannus may causeobstruction to the lymphatic drainage of the lowerextremities. Massive localized lymphedema is abenign overgrowth of lymphoproliferative tissueTable I. Cont’d
Phenotype Genes (protein) OMIM Inheritance Phenotypic form Clinical findings Type of mutationCytogenetic
location
Primary lymphedema with
myelodysplasia (Emberger
syndrome)GATA2 614038 AD, de novo Syndromic Lymphedema of lower
extremities and genitalia,
immune dysfunction,cutaneous warts, deafnessLOF 3q21.3
Hypotrichosis elymphedema e
telangiectasia (renal defect)
syndromeSOX18 607823 AD, AR Syndromic Lymphedema, alopecia,
telangiectasiasLOF/D-N 20q13.33
Lymphedema tarda Late-onset
hereditary
lymphedema,triggered by
trauma
or infectionAge of
onset:
[35 years
of age
Question mark indicates unclear mutation.
AD, Autosomal dominant; AR, autosomal recessive; D-N, dominant negative; GOF, gain of function; LOF, loss of function; OMIM , Online Mendelian Inheritance in Man.JAMACADDERMATOL
DECEMBER 20171014 Grada and Phillips

manifesting as a large pedunculated mass in
morbidly obese patients.40,43-45
CLINICAL MANIFESTATIONS
Key points
dEarly-stage lymphedema mimics other
causes of tissue swelling, such as venousedema
dChronic lymphedema is characterized byskin thickening and tissue fibrosis
dElephantiasis verrucosa nostras is a severemanifestation of chronic lymphedema
dIt is important to rule out venous edema,lipedema, obesity, and drug-induced swellingbefore making a diagnosis
Skin changes
Lymphedema can be unilateral or bilateral.
Patients often complain of a sense of heaviness anddiscomfort of the affected limb, especially at the end
of the day.
46Transient nontender pitting edema
occurs in newly developed lymphedema. Overtime, the skin develops a pitted or dimpled texture(peau d’orange). As the disease progresses, the skinbecomes indurated with a leathery texture becauseof skin thickening and fibrosis. Nonpitting edemaindicates an irreversible stage of lymphedema. Aninability to pinch the fold of skin at the base
of the second toe (Kaposi eStemmer sign) is
pathognomonic for chronic lymphedema ( Fig 2 ).Over time, elephantiasis nostras verrucosa develops.
The skin over the affected area has a wartyhyperkeratotic ‘‘mossy’’ or ‘‘cobblestoned’’ appear-ance ( Fig 3 ). Skin in chronic lymphedema is prone to
fissures, ulceration, and recurrent cellulitis. Weepingand oozing of clear to light yellow fluid (lymphor-rhea) is common. Impetigo is common as well. Inmore rare cases, patients with long-standing
lymphedema develop cutaneous angiosarcoma.
This aggressive tumor usually presents with reddishpurple patches or nodules that may enlarge, ulcerate,and form satellite lesions ( Fig 4 ).
Differential diagnosis of lymphedema
Earlier stages of lymphedema can be difficult to
distinguish from other common causes of extremityswelling, such as venous disease, lipedema, andmorbid obesity. Key differences between various
causes of chronic extremity swelling are outlined in
Table ll .
Fig 2. Lymphedema. A, Swelling on the dorsal aspect of
the feet is typical for patients with lymphedema. B, The
KaposieStemmer sign is positive. (Reprinted from Ker-
chner et al,24with permission from Elsevier.)
Fig 3. Lymphedema. Elephantiasis nostras verrucosa in a
female patient with chronic lymphedema. Note the mul-tiple nodules grouped in a cobblestone fashion in bothlower extremities. Some of the nodules are ulcerated.
Fig 4. Cutaneous angiosarcoma. Right calf with 17-cm 3
8-cm violaceous ulcerated, multifocal tumor. (Reprinted
from Robinson et al, Angiosarcoma in an obese woman
with worsening lymphedema after weight-loss and skin-reduction surgeries, J Am Acad Dermatol 2011;65:448-449,
with permission from Elsevier.)JAMACADDERMATOL
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Chronic venous insufficiency. Edema caused
by chronic venous insufficiency can mimic early-stage lymphedema. Although they both exhibitpitting edema, venous edema is usually associatedwith other clinical features of venous disease, such asvaricose veins, brown to red hemosiderin skin
pigmentation, and venous leg ulcers. Moreover,
venous edema improves after leg elevation.
31In
chronic venous insufficiency, edema is caused byincreased capillary hydrostatic pressure. Inlymphedema, the capillary hydrostatic pressure isusually normal, which is why leg elevation is noteffective in reducing lymphedema.
47Limb swelling,
which does not improve with overnight elevation,
often indicates chronic lymphedema. Moreover,
higher protein content in lymphedema makes itmore prone to recurrent skin infection whencompared to venous edema. It is noteworthy thatchronic venous insufficiency may cause lymphaticmalfunction.
48
Lipedema. Lipedema, also known as lipomato-
sis of the leg, is a chronic progressive disorder of the
adipose tissue. It is often misdiagnosed as primary
lymphedema.49It occurs almost exclusively inwomen, and most commonly arises within a few
years after the onset of puberty.31It manifests as
bilateral symmetrical accumulation of subcutane-ous fat, mainly in the lower extremities, andpresents with tenderness, easy bruising, and the
tendency for leg swelling that worsens with
standing.
46,50One distinctive feature is that the
swelling stops abruptly at the level of the malleoli.Easy bruising is related to increased fragility ofcapillaries within the adipose tissue.
31Lipedema
can cause lymphatic dysfunction at a later stage.51
Key features to differentiate lipedema fromlymphedema are outlined in Table III .
Drug-induced edema. Several medications are
known to cause fluid retention and tissue swelling
through various mechanisms, such as sodiumoverload, renal dysfunction, and vascular hyper-permeability.
52Calcium channel blockers can
interfere with the pumping function of the collectinglymphatic vessels.
53These medications can worsen
swelling in patients with lymphedema. Thoroughmedication histories should be obtained from
patients presenting with chronic extremity swelling
(Table IV ).Table II. Key differences between various causes of chronic extremity swelling
Attribute Lymphedema Lipedema Venous insufficiency Cardiac/renal failure
Gender Females [males Almost always female
patientsFemales[males Males [females
Location Lower extremity, upper
extremity in BCRLLower extremities,
spares the feetAnkles and calves, feet
usually sparedLower extremity,
abdomen
Symmetry Can be unilateral or
bilateralUsually bilateral Bilateral Bilateral
KaposieStemmer
signPositive Negative Negative Negative
Pain None in the early stages.
Discomfort in late
stagesTender Occasional aching Aching can be
present
Effect of leg
elevationNo improvement in
chronic lymphedemaNo improvement Improves with elevation Improves with
elevation
Skin changes Signs of inflammation,
peau d’orange,fibrosis, and
nonpitting skin texture
in chroniclymphedema.
Hyperkeratosis and
verrucous changes insevere presentationsSoft, nonpitting Usually pitting edema,
hyperpigmentationfrom hemosiderin
deposition; visible
varicosities oftenpresentAlmost always
pitting edema
Onset Primary lymphedema can
present in childhood.
Secondarylymphedema almost
always in adulthoodAdulthood Adulthood Mostly adulthood
BCRL , Breast cancer erelated lymphedema; F, female; M, male.JAMACADDERMATOL
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Hypoalbuminemia. Low blood concentration
of albumin in protein-losing disorders, such asglomerulonephritis, nephrotic syndrome, or exten-sive burns, leads to a decrease in oncotic pressureinside the blood vessels. This leads to impairedreabsorption of interstitial fluid into the venouscapillaries and gives rise to edema, which is oftenbilateral.
Myxedema. Deposition of mucin in the dermis
promotes fluid retention and may lead tolymphedema caused by the obstruction of peripherallymphatics.
54,55In a rare form of pretibial
myxedema, nodular lesions coalesce and give awarty appearance of the skin, mimicking elephanti-asis nostras verrucosa. Pretibial myxedema is usuallyassociated with Graves’ disease.
POTENTIAL COMPLICATIONS
Key points
dChronic limb swelling causes discomfort and
functional impairment
dRecurrent bacterial and fungal infections are
common
dRecurrent cellulitis and lymphangitis contri-bute to further lymphatic damage
dUlceration is common and can be difficult totreat
dCutaneous angiosarcoma is a rare and lethal
complication; look for red-purple discoloration
dSerious psychosocial implications because of
cosmetic impairment and activity restriction
Multiple cutaneous ulcerations are common.
Patients with lymphedema are susceptible torecurrent soft tissue infections, such as cellulitisand erysipelas. The main cause of cellulitis isgroup A Streptococcus. Each episode of cellulitis
further damages the lymphatic system and
worsens the patient’s condition.
56,57Tinea pedis isextremely common because of chronic interdigital
maceration.
There is a 10% risk of developing angiosarcoma in
patients with chronic lymphedema lasting $10 years.
StewarteTreves syndrome refers to cutaneous
angiosarcoma developing in patients withpostmastectomy lymphedema.
58Angiosarcoma is a
highly aggressive malignant tumor with a poorprognosis and a 5-year survival rate \10%.
59Other
malignancies that have been reported in association
with lymphedema include squamous cell
carcinoma,60basal cell carcinoma,61cutaneous
lymphomas,62-64melanoma,65,66and Kaposi sar-
coma.67,68Although there is no clear cause and
effect relationship between lymphedema and thedevelopment of these tumors, one possibleexplanation is the impairment of local immunesurveillance in the lymphedematous extremity.
69
Psychosocial stigmatization and low self-esteem
are common among lymphedema patients becauseTable III. Key clinical differences between
lipedema and lymphedema of the lower extremity
Lipedema Lymphedema
Almost always
female patientsBoth males and females
Spares the foot Foot involved
Usually bilateral Usually unilateral
Negative Kaposi e
Stemmer signPositive Kaposi eStemmer sign
Nonpitting Nonpitting when it becomes
chronic
Tender Usually nontenderSoft FirmTable IV. List of medications that may cause tissue
swelling
Medications that cause fluid retention
Corticosteroids
Antihypertensives (ie, calcium channel blockers, minoxidil,
methyldopa, hydralazine, clonidine, and beta blockers)
Nonsteroidal antiinflammatory drugs
Estrogens and progesteroneHypoglycemics (thiazolidinediones)Cytokines (granulocyte macrophage colony-stimulating
factor, granulocyte-colony stimulating factor,
interleukin-4, interleukin-2, and interferon a-2a)
Chemotherapeutic agents (cyclophosphamide,
cyclosporine, and cytosine arabinoside)
Antivirals (acyclovir)Antidepressants (phenothiazine and trazodone)
Table V. Potential complications of lymphedema
Potential complications
Physical
Heaviness and discomfort
Decreased range of motion
Recurrent skin infectionElephantiasis verruca nostra
Recurrent skin ulcers
Cutaneous angiosarcoma
Psychological
Depression
AnxietyNegative body imageJAMACADDERMATOL
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of impaired mobility, difficulty fitting into clothing,
and deformity of limbs and genitalia.70,71A summary
of potential complications is listed in Table V .
Definition for lymphedema
There is no standardized definition of lymphe-
dema. The International Society of Lymphology72
defines lymphedema as ‘‘an abnormal collection ofexcessive tissue proteins, edema, chronic inflamma-tion, and fibrosis.’’ Edema is defined as an increase ininterstitial fluid volume that is enough to produceclinically palpable swelling.
24
Because chronic inflammation and fibrosis are
sequelae of lymph retention in the interstitialcompartment, the following definition for lymphe-
dema is proposed: a localized form of tissue swelling
caused by excessive retention of lymphatic fluid inthe interstitial compartment.
In conclusion, lymphedema is a chronic disease
with serious implications on quality of life.Impaired lymphatic draining capacity leads toextremity swelling. Primary lymphedema arisesfrom faulty lymphatic vascular development.
Secondary (acquired) lymphedema develops
because of lymphatic damage caused by otherunderlying conditions, such as cancer, surgery,and filariasis. Recurrent skin infections and ulcer-ations are common complications. Cutaneousangiosarcoma is a rare but a deadly complicationof chronic lymphedema. Although many diseaseentities may mimic lymphedema, a thorough
history and physical examination will help narrow
the differential diagnosis.
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