Anatomy and Pathophysiology of the Lymphatic System
Axillary node removal
Sentinel node biopsy
Exercise does not increase risk of lymphedema onset
Diagnosis and Evaluation
Lymphedema is swelling that occurs when protein-rich lymph fluid accumulates in the interstitial tissue. This lymph fluid may contain plasma proteins, extravascular blood cells, excess water, and parenchymal products. Lymphedema is one of the most poorly understood, relatively underestimated, and least researched complications of cancer or its treatment. The Institute of Medicine of the National Academies published a report in 2006 recommending a “survivorship care plan” for cancer patients that incorporates information about late effects of treatment, health management behaviors, disease management, and recurrence monitoring. The Institute of Medicine also highlighted critical shortfalls in the transition to survivorship, particularly in providing education about late effects of treatment.
Lymphedema is an important consideration for clinicians who care for cancer patients because of its relatively high frequency and significant functional and quality of life implications for patients. Lymphedema is an independent predictor of decreased quality of life, even when other predictive factors such as socioeconomic status, decreased range of motion, age, and obesity are taken into account.
This summary will review issues related to anatomy and pathophysiology of lymphedema related to cancer, its clinical manifestations, diagnosis, and treatment. Primary (congenital) lymphedema and non–cancer-related lymphedema (e.g., recurrent cellulitis, connective tissue disease, and infection) will not be reviewed here.
In this summary, unless otherwise stated, evidence and practice issues as they relate to adults are discussed. The evidence and application to practice related to children may differ significantly from information related to adults. When specific information about the care of children is available, it is summarized under its own heading.Anatomy and Pathophysiology of the Lymphatic System
The human lymphatic system generally includes superficial or primary lymphatic vessels that form a complex dermal network of capillarylike 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 deeper third 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. The superficial and deep lymphatic systems probably function independently, except in abnormal states, although there is evidence that they communicate near lymph nodes. 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. Lymph channels of the right arm 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. Because 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.
The onset of secondary lymphedema is often insidious. However, it may be suddenly provoked by local inflammation from causes such as infection or limb injury. Therefore, patients should be evaluated for evidence of cellulitis. Classically, lymphedema is characterized by nonpitting swelling of an extremity, usually with involvement of the digits. Early stages of lymphedema manifest with pitting edema until fibrosis develops. The distribution of the swelling may be restricted only in the proximal or distal portion of the limb. Lymphedema may also predispose to recurrent skin infections.
Lymphedema can and does occur in the trunk, in addition to the limbs. For example, radiation therapy to the chest wall is associated with the development of edema specifically in the irradiated breast.[6,7]
Patients with lymphedema may report a wide variety of complaints, including heaviness or fullness related to the weight of the limb, a tight sensation of the skin, or decreased flexibility of the affected joint. The texture of the skin may become hyperkeratotic, with verrucous and vesicular skin lesions. With upper-extremity involvement, the patient may have difficulty fitting the affected area into clothing or wearing previously well-fitting rings, watches, or bracelets. Similar difficulties with lower-extremity lymphedema include a sensation of tightness or difficulty wearing shoes, itching of the legs or toes, burning sensation in the legs, or sleep disturbance and loss of hair. Ambulation can be affected because of the increased size and weight of the affected limb. Activities of daily living, hobbies, and the ability to perform previous work tasks may also be affected.Psychological symptoms
Breast cancer survivors with arm lymphedema have been found to be more disabled, experience a poorer quality of life, and have more psychological distress than do survivors without lymphedema.[8,9] In addition, women reporting swelling have reported significantly lower quality of life with multiple functional assessments.Epidemiology
Lymphedema can occur after any cancer or its treatment that affects lymph node drainage. It has been reported to occur within days and up to 30 years after treatment for breast cancer. Eighty percent of patients experience onset within 3 years of surgery; the remainder develop edema at a rate of 1% per year. Upper-extremity lymphedema most often occurs after breast cancer; lower-extremity lymphedema most often occurs with uterine cancer, prostate cancer, lymphoma, or melanoma. A large population-based study supports the evidence that lower-limb lymphedema is experienced by a significant proportion of women after treatment for gynecological cancer, with the highest prevalence (36%) among vulvar cancer survivors and the lowest prevalence (5%) among ovarian cancer survivors.
There is no consistency in the data on the incidence and prevalence of lymphedema after breast cancer, probably because of differences in diagnosis, the different characteristics of the patients studied, and inadequate follow-up to capture delayed development of the disorder. The overall incidence of arm lymphedema can range from 8% to 56% at 2 years postsurgery.
It is important to diagnose and treat lymphedema when it is mild because those with mild lymphedema make up the cohort that gives rise to preventable severe, debilitating lymphedema. Women with mild lymphedema are more than three times as likely to develop severe lymphedema than are women with no lymphedema.Risk Factors
Patients undergoing axillary surgery and/or axillary radiation therapy for breast cancer are at higher risk for developing lymphedema of the arm. Previous convention suggested that nodal positivity was a predisposing factor for the development of lymphedema in breast cancer patients. Controlling for axillary radiation, one study actually found an inverse relationship between nodal positivity and arm volume.Axillary node removal
Compared with axillary sampling alone, partial or total mastectomy followed by full axillary lymph node dissection significantly increases a patient’s chance of developing arm edema. For example, in one series of 100 women who underwent partial or total mastectomy and then full axillary lymph node dissection or axillary sampling, arm edema developed in more patients who underwent axillary lymph node dissection compared with sampling alone (30% vs. none). In addition, the extent of axillary lymph node dissection increases the risk for developing arm edema. For example, in one series involving 381 women undergoing segmental mastectomy and axillary lymph node dissection, women who had ten or more lymph nodes removed were more likely than women who had few lymph nodes in the specimen to develop arm symptoms within the first year (53% vs. 33%) and within the next 2 years (33% vs. 20%).Sentinel node biopsy
For patients with breast cancer, sentinel lymph node dissection has gained favor over axillary lymph node dissection for the axillary staging of early disease because of decreased morbidity and because of the questionable survival benefits of axillary lymph node dissection, as shown in a phase III randomized study (ACOSOG-Z0011) of axillary lymph node dissection in women who had stage I or IIA breast cancer and a positive sentinel node.[Level of evidence: I] Several studies have shown that lymphedema is more prevalent in breast cancer patients who undergo axillary lymph node dissection than in those who undergo sentinel lymph node biopsy.[Level of evidence: II] One study evaluated 30 patients with unilateral invasive breast carcinoma who underwent sentinel lymph node biopsy and 30 patients who underwent axillary lymph node dissection. This study found a 20% rate of developing lymphedema in the axillary lymph node dissection group compared with none in the sentinel lymph node biopsy group. Rates of lymphedema among women who undergo sentinel lymph node biopsy have been reported to be between 5% and 17%, depending on the diagnostic threshold and length of follow-up.[20-22] The majority of diagnosed lymphedema is mild.[Level of evidence: II]Obesity
Among all breast cancer patients, being obese or overweight may predispose women to developing lymphedema after treatment for breast cancer.[11,23][Level of evidence: I] A well-conducted prospective study followed 138 breast cancer patients for 30 months postdiagnosis. Individuals with body mass indices of 30 or higher at the time of diagnosis were 3.6 times more likely to develop lymphedema, but weight gain after diagnosis was not related.
Some studies have correlated the degree of lymphedema with the level of obesity.[Level of evidence: I] Similarly, among young breast cancer survivors, persistent swelling was related to having more lymph nodes removed and being obese.
The dose-response relationship between obesity and risk for lymphedema onset is not known. There have also been no studies to determine whether weight loss among patients at risk for developing lymphedema would reduce risk. At this time, it is not possible to advise patients regarding the dose-response relationship of weight loss and risk reduction or the body weight associated with lowest risk of incident lymphedema.Other risks
Other risk factors for developing lymphedema include the following:
- Extent of local surgery.
- Local radiation (axillary, inguinal, pelvic, or supraclavicular regions).
- Delayed wound healing.
- Tumor causing lymphatic obstruction of the anterior cervical, thoracic, axillary, pelvic, or abdominal nodes.
- Scarring of the left or right subclavian lymphatic ducts by either surgery or radiation.
- Intrapelvic or intra-abdominal tumors that involve or directly compress lymphatic vessels and/or the cisterna chyli and thoracic duct.
Roughly one-third of breast cancer patients (and a majority of African Americans with breast cancer) present with regional disease and positive lymph nodes, thus requiring complete axillary lymph node dissection; many undergo further irradiation of their axillary and supraclavicular lymph node beds. Lymphedema is a persistent adverse effect of breast cancer treatment that will continue to occur long into the future, despite increasing use of sentinel lymph node biopsy procedures.Exercise does not increase risk of lymphedema onset
Historically, those at risk for lymphedema have been advised to avoid using the affected limb. The reasoning for this clinical advice seems to arise from the notion that the removal of lymph nodes altered the response of the affected area to inflammation, infection, injury, and trauma—therefore, it would be wise to avoid stressing the limb. However, exercise has a different effect on the body at lower doses than it does at higher doses; extreme exercise would promote inflammation and injury and should be avoided in patients at risk for lymphedema. By contrast, slowly progressive, carefully controlled increases in physiologic stress on a limb at risk for lymphedema may actually provide protection for real-life situations that require taxing that body part (e.g., carrying grocery bags, doing holiday shopping, or lifting a child). Therefore, physiologic evidence exists to question the historic advice to restrict use of the affected limb.
Furthermore, there is empirical evidence that upper-body exercise does NOT result in increased onset of lymphedema among breast cancer survivors.[27,28];[23,29,30] The largest of these studies (N = 204) [Level of evidence: I] measured the arms of women before breast surgery with axillary node dissection and randomly assigned participants to one of two rehabilitation programs:
- No activity restrictions (NAR). The women in this group (N = 104) had no restrictions on physical activities that used the affected limb for 6 months postsurgery. The NAR patients followed a supervised program of moderate, progressive resistance exercise training 2 to 3 times per week. The resistance exercises (total exercise time = 45 minutes) included a minimum of 15 repetitions for each exercise, using low resistance (0.5 kg) during the first 2 weeks. The resistance was increased individually for each patient (no upper limit), with the aim of enhancing muscular strength and endurance but always using 15 repetitions per set for each exercise.
- Activity restrictions (AR). The women in this group (N = 100) were instructed to restrict the activity of the affected limb for 6 months postsurgery. The patients were told to avoid heavy or strenuous physical activities such as aerobic or other types of exercise classes that included heavy upper-limb physical activity or work, and to avoid carrying or lifting groceries or other items weighing more than 3 kg.
At the end of 2 years of postsurgical follow-up, the incidence of new lymphedema was 13% in both groups. Of note, the single most important predictor of lymphedema onset in this large study was obesity.
Another large (N = 134 completers) randomized study compared a 1-year weight-lifting intervention with a no-exercise control group for breast cancer survivors who had unilateral disease and at least two lymph nodes removed. No patients had evidence of lymphedema at baseline. A progressive weight-lifting program did not result in an increased incidence of lymphedema. The study was designed as an equivalence trial but noted a lower incidence of lymphedema in the weight-training group (11% vs. 17%, with a significant difference of 7% vs. 22%, for those with five or more lymph nodes removed).
Patients with and at risk for lymphedema should be evaluated by a certified lymphedema therapist to ensure it is safe to proceed with exercise of the affected body part. (See the Lymphology Association of North America Web site for referrals to certified lymphedema therapists in locations across the United States.)
Patients who have lymphedema should wear a well-fitting compression garment during all exercise that uses the affected limb or body part. If there are questions regarding whether lymphedema is present, there is no evidence as to whether use of a garment will be helpful or harmful. Garments must be well fitted to be useful, are costly, may not be covered by insurance without a clear diagnosis, and must be replaced every 6 months. Among women with an unclear diagnosis, it is likely that the risk of avoiding upper-body activity outweighs the risk of engaging in slowly progressive upper-body activity without a garment. Patients without lymphedema do NOT need to wear a garment while doing exercise with the at-risk limb.
Evidence from studies with breast cancer survivors suggests that upper-body exercise among women with and at risk for lymphedema should start at a very low intensity and progress slowly and according to symptom response.;[Level of evidence: I] There should be a certified lymphedema specialist to whom these women can be referred if there is a need for evaluation of possible flare-ups or onsets. If there is a break in exercise of a week or longer, it is strongly recommended that women decrease the intensity of activity with the upper body and then increase it again gradually. Changes in symptoms (increased heaviness, achiness, puffiness, swelling) that last a week or longer should be evaluated for possible onsets or flare-ups. It is likely that starting at low intensity and progressing slowly is better for the affected limb than is avoiding activity.Diagnosis and Evaluation
Lymphedema is typically evident by clinical findings such as nonpitting edema, usually with involvement of the digits, in a patient with known risk factors such as previous axillary dissection. Other causes of limb swelling, including deep venous thrombosis, malignancy, and infection, should be considered in the differential diagnosis and excluded with appropriate studies, if indicated.
If the diagnosis is not evident on the basis of clinical assessment, imaging of the lymphatic system with lymphoscintigraphy (radionuclide imaging) may be necessary. Lymphangiography is generally no longer a favored diagnostic test and may be contraindicated in patients with malignancy because of concern that it may contribute to metastatic spread of tumor. Additional imaging techniques such as magnetic resonance imaging may complement information obtained via lymphoscintigraphy by providing anatomic and nodal detail.
The wide variety of methods described in the literature for evaluating limb volume and lack of standardization makes it difficult for the clinician to assess the at-risk limb. Options include water displacement, tape measurement, infrared scanning, and bioelectrical impedance measures.
The most widely used method to diagnose upper-extremity lymphedema is circumferential upper-extremity measurement using specific anatomical landmarks. Arm circumference measures are used to estimate volume differences between the affected and unaffected arms. Sequential measurements are taken at four points on both arms: the metacarpal-phalangeal joints, the wrist, 10 cm distal to the lateral epicondyles, and 15 cm proximal to the lateral epicondyles. Differences of 2 cm or more at any point compared with the contralateral arm are considered by some experts to be clinically significant. However, measuring specific differences between arms may have limited clinical relevance because of implications, for example, of a 3-cm difference between the arm of an obese woman and the arm of a thin woman. In addition, there can be inherent anatomic variations in circumference between the dominant and nondominant limb related to differences in muscle mass and variations after breast cancer treatment that may occur with atrophy of the ipsilateral arm or hypertrophy of the contralateral arm. A small study comparing various methods of assessing upper-limb lymphedema did not show any superiority of any one method. Sequential measurements over time, including pretreatment measurements, may prove to be more clinically meaningful.
The water displacement method is another way to evaluate arm edema. A volume difference of 200 mL or more between the affected and opposite arms is typically considered to be a cutoff point to define lymphedema.
One common method of lymphedema classification uses three stages based on severity. Stage I is spontaneously reversible and typically is marked by pitting edema, increase in upper-extremity girth, and heaviness. Stage II is characterized by a spongy consistency of the tissue without signs of pitting edema. Tissue fibrosis can then cause the limbs to harden and increase in size. Stage III, also called lymphostatic elephantiasis, is the most advanced stage, but is rarely seen following breast cancer treatment.
Another commonly used approach to classifying lymphedema is the Common Terminology Criteria for Adverse Events v3.0 (CTCAE), which were developed for grading adverse events in the context of clinical trials. A key advantage of the CTCAE approach is that it includes both objective measures (interlimb discrepancy) and subjective, clinical assessments in diagnosing lymphedema. This allows for the very real possibility that a patient could have clinically meaningful, treatable lymphedema isolated to a segment of his or her limb that would not meet objective interlimb discrepancy criteria, but which could still be graded according to severity by signs and symptoms, as follows:
- Grade 1: 5% to 10% interlimb discrepancy in volume or circumference at point of greatest visible difference; swelling or obscuration of anatomic architecture on close inspection; pitting edema.
- Grade 2: More than 10% to 30% interlimb discrepancy in volume or circumference at point of greatest visible difference; readily apparent obscuration of anatomic architecture; obliteration of skin folds; readily apparent deviation from normal anatomic contour.
- Grade 3: More than 30% interlimb discrepancy in volume; lymphorrhea; gross deviation from normal anatomic contour; interfering with activities of daily living.
- Grade 4: Progression to malignancy (e.g., lymphangiosarcoma); amputation indicated; disabling lymphedema.
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