Overview
Introduction
Physiology
Acute-Onset versus Insidious-Onset Lymphedema
Transient versus Chronic Lymphedema
Incidence and Prevalence
Risk Factors
Diagnosis
Introduction
Lymphedema is the accumulation of lymph in the interstitial spaces, principally
in the subcutaneous fatty tissues, caused by a defect in the lymphatic system.
It is marked by an abnormal collection of excess tissue proteins, edema,
chronic inflammation, and fibrosis.[1] Lymphedema is a frequent complication
of cancer and its therapies, and can have long-term physical and psychosocial
consequences for patients.
Physiology
The human lymphatic system generally includes superficial or primary lymphatic
vessels that form a complex dermal network of capillary-like channels that
drain into larger, secondary lymphatic vessels located in the subdermal space.
These primary and secondary lymphatic vessels parallel the superficial veins
and drain into a third, deeper layer of lymphatic vessels located in the
subcutaneous fat adjacent to the fascia. A muscular wall and numerous valves aid active, unidirectional lymphatic flow
in secondary and subcutaneous lymphatic vessels. Primary lymphatic vessels lack a muscular wall and do not
have valves. An intramuscular system of lymphatic vessels that parallels the
deep arteries and drains the muscular compartment, joints, and synovium also
exists. While there is evidence that the superficial and deep lymphatic
systems communicate near lymph nodes, they probably function independently
except in abnormal states.[2] Lymph drains from the lower limbs into the
lumbar lymphatic trunk, which joins the intestinal lymphatic trunk and cisterna
chyli to form the thoracic duct that empties into the left subclavian vein.
The lymphatic vessels of the left arm drain into the left subclavian lymphatic
trunk and then into the left subclavian vein. Right arm lymph channels drain
into the right subclavian lymphatic trunk and then into the right subclavian
vein.
One function of the lymphatic system is to return excess fluid and protein from
interstitial spaces to the blood vascular system. Since lymphatic vessels
often lack a basement membrane, they can resorb molecules too large for venous
uptake. Mechanisms of clinical edema include increased arteriovenous capillary
filtration and reduced interstitial fluid absorption. Causes of increased
capillary filtration include increased hydrostatic pressure in capillaries,
decreased tissue pressure, and increased membrane permeability. Reduced
interstitial fluid resorption can be caused by decreased plasma oncotic
pressure, increased oncotic pressure of tissue fluid, and lymphatic
obstruction.
Lymphedema is categorized as either primary or secondary. Primary lymphedema
is caused by congenital absence or abnormalities of lymphatic tissue and is
relatively rare. Secondary lymphedema is generally caused by obstruction or
interruption of the lymphatic system, which usually occurs at proximal limb
segments (i.e., lymph nodes) due to infection, malignancy, or scar tissue (see
table below).[1] The pelvic and inguinal groups of nodes in the lower extremities
and the axillary nodes of the upper extremities are the primary sites of
obstruction.
Lymph Drainage Failure* *Adapted from Mortimer PS: The pathophysiology of lymphedema. Cancer 83(12
suppl 2): 2798-2802, 1998. | Mechanism | Reduced lymph-conducting
pathways | Hypertrophy or hyperplasia of lymphatic vessels | Functional failure | Obstructed lymphatics | Possible causes | Aplasia or hypoplasia
of whole vessel | Lymphangiomatosis, lymphatic malformations | Valvular failure | Lymph node abnormalities (e.g., fibrosis) | Acquired obliteration
of lymphatic lumen
(e.g., lymphangio-thrombosis, lymphangitis) | Megalymphatics | Disordered contractility | Scarring from lymphadenectomy, radiation
therapy, or
infection |
It has been assumed that lymphedematous limbs contain interstitial fluids with
higher protein concentrations than plasma. A recent report, however, found a
negative correlation between protein concentration and arm edema.[3]
Concomitant venous obstruction has also been observed in patients with
lymphedematous limbs. An investigation of venous outflow using duplex Doppler
ultrasound revealed venous abnormalities in more than 60% of cases.[4]
Additional studies suggest that local vasodilatory control may be altered,
although not on a sustained basis.[5] Further work in this area is needed to
better discern the pathophysiology of lymphedema.
Acute-Onset versus Insidious-Onset Lymphedema
Secondary lymphedema may be categorized by its chronicity. Four patterns of
acute lymphedema have been identified. The first occurs within a few days
after surgery as a result of the cutting of lymphatic channels or injury to or
manipulation of the subclavian lymphatic trunks or the associated subclavian
veins. It is usually transient and mild, responding to limb elevation and
muscle pumping of the associated limbs (e.g., making a fist and releasing it)
within 1 week of onset. The affected area may be warm and slightly
erythematous, but it is generally not painful.
A second type of acute lymphedema may occur within 6 to 8 weeks
postoperatively, possibly as a result of acute lymphangitis or phlebitis.
There is no associated venous thrombosis in these cases. This pattern of
lymphedema may also be seen during the course of radiation treatment of a limb
or its associated lymphatic drainage route. The affected area is tender, warm
or hot, and erythematous. This type of lymphedema can usually be successfully
treated with limb elevation and anti-inflammatory medication, although more
involved treatments may be necessary. The first 2 acute forms do not
necessarily portend chronic swelling after their resolution.
A third type of acute lymphedema is an erysipeloid form, occurring after an
insect bite, or minor injury or burn. It is often superimposed on a chronic
edematous limb. The affected area is erythematous, very tender and hot. This
form of edema often requires limb elevation and antibiotics. Compression
pumping or wrapping is contraindicated during acute stages of infection. Many
clinicians will permit treatment once severe erythema or blistering has
resolved. Mild erythema can persist following an infection.
The fourth and most common type of lymphedema is usually insidious and is not
always associated with erythema. Discomfort of the skin or aching in the
proximal segments (neck/shoulders for upper extremity, lumbar spine/hips for
lower extremity) may be noted due to stretch of the soft tissues or muscular
overuse and postural changes caused by increased limb weight. This type has a
variable onset and is frequently apparent 18 to 24 months after surgery. It
may appear a few months or many years after cancer treatment.
Transient versus Chronic Lymphedema
Transient lymphedema is a temporary condition that lasts less than 6 months and
is associated with pitting edema with tactile pressure and lack of brawny skin
changes.[1] The following factors may place the patient at risk for
acute-onset, transient lymphedema:
- Surgical drains with extravasation of
protein into the surgical site.
- Inflammation following injury, radiation, or
infection leading to increased capillary permeability.
- Immobility of the
limb(s) that results in decreased external compression by the musculature.
-
Temporary absence of collateral lymphatics.
- Proximal venous occlusion by
thrombosis or phlebitis.
- Reversal of equilibrium at the capillary bed that
results in accumulation of third-space fluid.
Chronic lymphedema is the most difficult of all types of edema to reverse, due
to the nature of its pathophysiology. A cycle is started, in which the
deficient lymphatic system of the limb is incapable of compensating for the
increased demand for fluid drainage. This condition may occur subsequent to
any of the following:
- Tumor recurrence or progression in the nodal area.
-
Infection and/or injury of lymphatic vessels.
- Immobility.
- Radiation injury to
lymphatic structures.
- Surgery.
- Unsuccessful management of early lymphedema.
- Venous obstruction due to thrombosis.
Early in the course of developing lymphedema, the patient experiences soft,
pitting edema that may be easily improved by limb elevation, gentle exercise,
and elastic support. Continual and progressive lymphostasis, however, causes
dilation of the lymph vessels and backflow of fluid to the tissue beds.
Collagen proteins accumulate, further increasing colloid osmotic tissue
pressure, leading to enhanced fluid flow from the vascular capillaries into the
interstitial space. The stasis of fluid and protein stimulates inflammation
and macrophage activity as the body attempts to degrade the excess proteins.
Fibrosis of the interstitial connective tissue by fibrinogen and fibroblasts
causes the development of the brawny, stiff, nonpitting lymphedema that no
longer responds to elevation, gentle exercise, or elastic compression garments.
Chronic lymphedema gradually becomes nonpitting.
Lymphedematous tissues have lower oxygen content, a greater distance between
lymph vessels due to fluid accumulation and swelling, impaired lymphatic
clearance, and depressed macrophage function, rendering patients at increased
risk of infection and cellulitis. Since there is no other route for tissue
protein transport, treatment for patients with advanced lymphedema with chronic
fibrosis is more difficult than when treated earlier. Additionally, once these
tissues are stretched, edema recurs more readily.
Generalized lymphedema may also occur subsequent to hypoalbuminemia with low
plasma oncotic pressure due to the following:
- Inadequate oral nutrition (secondary to
anorexia, nausea, vomiting, depression, chemotherapy).
- Decreased intestinal
absorption of protein or abnormal protein synthesis/anabolism.
- Protein loss
due to leakage of blood, ascites, effusions, or surgical drains.
- Contributing medical conditions leading to hypoalbuminemia (e.g., diabetes,
kidney malfunction, hypertension, congestive heart failure, liver disease).
Incidence and Prevalence
The reported incidence of lymphedema varies, being subject to discrepancies in
its definition and measurement, and differing time points since treatment in
which subjects are assessed for this complication. The incidence also varies
depending upon the treatment and limb involved. With these caveats understood,
there appears to be an overall incidence of arm edema after breast cancer
therapy of 26%.[6] A survey of 1151 women treated with radiation for breast
cancer reported lymphedema in 23% of subjects at 0 to 2 years after treatment
and 45% at 15 or more years after treatment. Among breast cancer patients
treated with surgery alone, prevalence increased from 20% at 0 to 2 years to
30% at 15 or more years since surgery.[7]
A study of 744 breast cancer patients found that patients with lymphedema had impaired quality of life (QOL) using the European Organization for Research and Treatment of Cancer (EORTC) QOL Questionnaire C-30.[8]
Risk Factors
Factors that contribute to the development of lymphedema are irradiation of the
dissected nodal basin, postoperative wound complications and subsequent
cellulitis of the limb, the extent of node dissection, and advanced age.
The following are risk factors for the development of lymphedema:
- Breast cancer, if they have received radiation therapy or had node
dissection. Radiation therapy to the axilla following axillary node
dissection increases the incidence of lymphedema. A review of several
studies reports lymphedema in approximately 41% (range, 21%-51%) of patients
who underwent axillary radiation and surgery, compared with 17% (range,
6%-39%) of those receiving axillary surgery without radiation.[6] The
extent of axillary dissection also increases the risk of lymphedema.
- Nodal dissection of axillary, inguinal, or pelvic regions.
- Radiation therapy of axillary, inguinal, or pelvic regions, or
supraclavicular (mantle field) radiation.
- Scarring of the left or right subclavian lymphatic ducts and veins by
either surgical or radiation procedures.
- Advanced cancer causing bulky lymphadenopathy of the anterior cervical,
thoracic, axillary, pelvic, or abdominal nodes.
- Intrapelvic or intra-abdominal tumors that involve or directly compress
lymphatic vessels and/or the cisterna chyli and thoracic duct.
- Other factors, such as poor nutritional status and obesity, that may
lead to delayed wound healing, which in turn is an important risk factor
for the development of lymphedema.[9-11]
Diagnosis
There are disparate reports concerning the incidence of lymphedema, especially
involving the upper extremities, due largely to a lack of uniform diagnostic
criteria. Objective criteria are based on circumferential or volumetric
measurements, but there is no agreement on the diagnostic criteria for
lymphedema. Some studies utilize differences in the affected limb compared to
the unaffected limb of 1 to 2 cm. Anatomical variation, handedness, and body
habitus may make this a meaningless difference. Optimally, sequential
measurements over time, including pretreatment measurements, should be made.
Water displacement measurement 15 cm above the epicondyle has been suggested as
the best objective criterion with which to judge lymphedema; a displacement
value of 200 mL included 96.4% of patients with subjective lymphedema.[12]
Some studies use 6 cm above the elbow; preferably, measurement of the upper
extremities should be at consistent points along the arm, above and below the
antecubital fossa, and across the hand or wrist. The lower extremities do not
offer as precise a point, but may be measured at consistent points.[13,14]
Approximately 50% of patients with minimal edema report a feeling of heaviness
or fullness of the extremity. Assessment of the patient with edema includes a
history and physical examination. The history should include information
regarding past surgeries, postoperative complications, prior radiation
treatments, the time interval from radiation or surgery to the onset of
symptoms, and intervening variables in the presence or severity of symptoms.
The quality and behavior of the edema (fluctuation with position, progression
over time) should be assessed. History of trauma or infection should be
determined. In addition, information concerning current medications may be
important.[1] Edema is not detectable clinically until the interstitial volume
reaches 30% above normal. The following scale may be clinically useful:
- 1+ = Edema that is barely detectable.
- 2+ = A slight indentation is visible when the skin is depressed.
-
3+ = A deeper fingerprint returns to normal in 5 to 30 seconds.
- 4+ = The extremity may be 1.5 to 2 times normal size.
References
- Brennan MJ: Lymphedema following the surgical treatment of breast cancer: a review of pathophysiology and treatment. J Pain Symptom Manage 7 (2): 110-6, 1992.
[PUBMED Abstract]
- Horsley JS, Styblo T: Lymphedema in the postmastectomy patient. In: Bland KI, Copeland EM, eds.: The Breast: Comprehensive Management of Benign and Malignant Diseases. Philadelphia, Pa: Saunders, 1991, pp 701-6.
- Bates DO, Levick JR, Mortimer PS: Change in macromolecular composition of interstitial fluid from swollen arms after breast cancer treatment, and its implications. Clin Sci (Lond) 85 (6): 737-46, 1993.
[PUBMED Abstract]
- Svensson WE, Mortimer PS, Tohno E, et al.: Colour Doppler demonstrates venous flow abnormalities in breast cancer patients with chronic arm swelling. Eur J Cancer 30A (5): 657-60, 1994.
[PUBMED Abstract]
- Stanton AW, Levick JR, Mortimer PS: Cutaneous vascular control in the arms of women with postmastectomy oedema. Exp Physiol 81 (3): 447-64, 1996.
[PUBMED Abstract]
- Erickson VS, Pearson ML, Ganz PA, et al.: Arm edema in breast cancer patients. J Natl Cancer Inst 93 (2): 96-111, 2001.
[PUBMED Abstract]
- Mortimer PS, Bates DO, Brassington HD, et al.: The prevalence of arm oedema following treatment for breast cancer. Q J Med 89: 377-80, 1996.
- Kwan W, Jackson J, Weir LM, et al.: Chronic arm morbidity after curative breast cancer treatment: prevalence and impact on quality of life. J Clin Oncol 20 (20): 4242-8, 2002.
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- Földi E, Földi M, Weissleder H: Conservative treatment of lymphoedema of the limbs. Angiology 36 (3): 171-80, 1985.
[PUBMED Abstract]
- Petrek JA, Senie RT, Peters M, et al.: Lymphedema in a cohort of breast carcinoma survivors 20 years after diagnosis. Cancer 92 (6): 1368-77, 2001.
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- Deutsch M, Flickinger JC: Arm edema after lumpectomy and breast irradiation. Am J Clin Oncol 26 (3): 229-31, 2003.
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- Kissin MW, Querci della Rovere G, Easton D, et al.: Risk of lymphoedema following the treatment of breast cancer. Br J Surg 73 (7): 580-4, 1986.
[PUBMED Abstract]
- Guyton AC: The lymphatic system, interstitial fluid dynamics, edema, and pulmonary fluid. In: Guyton AC: Textbook of Medical Physiology. 7th ed. Philadelphia, Pa : WB Saunders, 1986, pp 361-73.
- Getz DH: The primary, secondary, and tertiary nursing interventions of lymphedema. Cancer Nurs 8 (3): 177-84, 1985.
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