LYMPHEDEMA

 

Lymphedema occurs when disruption of normal lymphatic drainage leads to accumulation of protein-rich lymph fluid in the interstitial space. Cancer survivors who experience lymphedema report poor physical functioning, impaired ability to engage in normal activities of daily living, and increased psychological distress.

 

Estimates of the prevalence of lymphedema vary widely due to differences in the type of cancer, measurement methods, diagnostic criteria, and timing of evaluations relative to cancer diagnosis and treatment. In a survey conducted in 2006 and 2010, 6,593 cancer survivors were asked to identify ongoing concerns. Approximately 20% of respondents reported concerns related to lymphedema. Of these individuals, 50% to 60% reported receiving care for lymphedema. These results align reasonably well with a survey study of women survivors of ovarian, endometrial, and colorectal cancers, who met criteria for lymphedema based on a validated survey that demonstrated a point prevalence of 37%, 33%, and 31%, respectively. Similarly, a randomized intervention study in women with breast cancer demonstrated, by limb volume measurements or physician diagnosis, that 42% of subjects had lymphedema at 18 months after surgery.

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Lymphedema is a common delayed effect of cancer treatment that negatively impacts survivors' quality of life. This summary reviews the anatomy of the lymphatic system, the pathophysiology of lymphedema secondary to cancer, and epidemiology. The summary also provides clinicians with information related to risk factors, diagnosis, prevention, and treatment. The summary does not deal with congenital lymphedema or lymphedema not related to cancer.

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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.

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Epidemiology and Risk Factors

Accurate estimates of the incidence and prevalence of lymphedema are difficult to provide, due in part to differences in the definition of lymphedema (e.g., patient self-reports vs. objective volume measurements) and the timing of assessment for lymphedema relative to cancer treatment. Other factors are differences in surgical techniques related to the type of lymph node dissection or the total dose, fractions, and field of radiation administered.

Common risk factors for developing lymphedema include the following:

• Extent of local surgery.

• Anatomical location of lymph node dissection.

• Radiation to lymph nodes.

• Localized infection or delayed wound healing.

• Tumor causing lymphatic obstruction 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.

• Having a higher disease stage.

• Overweight (body mass index [BMI] ≥25 kg/m2) or obesity (BMI ≥30 kg/m2).

• Black race and Hispanic ethnicity.

• Rurality.

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Signs, Symptoms, and Physical Examination

Lymphedema is typically evident by clinical findings such as unilateral, nonpitting edema, usually with involvement of the digits, in a patient with known risk factors (e.g., a breast cancer patient with 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.

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Lymphedema in patients with head and neck cancer can present slightly differently. External lymphedema does show swelling in the head and neck area, but internal lymphedema does not. Instead, patients with lymphedema related to internal head and neck cancer can present with complaints of voice changes, dysphagia, and possible difficulty breathing.

 

Diagnostic Testing

Limb measurements

The wide variety of methods for evaluating limb volume and lack of standardization make it difficult for the clinician to assess the at-risk limb. Options include water displacement, tape measurement, infrared scanning, and bioelectrical impedance measures.

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The most common method for diagnosing upper-extremity lymphedema is circumferential upper-extremity measurement using specific anatomical landmarks. Arm circumference measurements 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 unaffected arm are considered by some experts to be clinically significant. However, measuring specific differences between arms may have limited clinical relevance because of implications, such as a 3-cm difference between the arm of an obese woman and the arm of a thin woman. In addition, there can be inherent anatomical variations in circumference between the dominant and nondominant limb related to differences in muscle mass. In addition, variations after breast cancer treatment 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 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.

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Magnetic resonance lymphography (MRL)

This technique involves the intracutaneous injection of a paramagnetic contrast agent, followed by imaging of the lymphatic anatomy, dermal flow patterns, and adjacent fatty tissue. One study of 50 women with breast cancer–related lymphedema compared the lymphatic vessel morphology in their affected and unaffected arms. The lymphedema was staged according to the ISL's 2016 staging system. In all patients, the lymph fluid was in the subcutis but not the subfascial compartment of the affected arm. In stage I patients, the lymphatics were tortuous and dilated, but there was no dermal backflow or regeneration of the lymphatics. In stage II patients, there was soft tissue fibrosis and adipose tissue hypertrophy. The lymphatics were tortuous and dilated, with areas of dermal backflow and regeneration. In stage III patients, the lymphatics were unrecognizable, and there was confluent dermal backflow. The soft tissue fibrosis was more advanced. MRL is safe, feasible, and provides high anatomical detail. However, its role in lymphedema diagnosis remains to be determined.

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Staging and grading of severity

The staging system of the ISL reflects likely changes over time based on the pathophysiology of lymphedema. The stages include the following:

• Stage 0: This stage, referred to as subclinical lymphedema, is characterized by impaired lymph flow.

• Stage I: This stage is spontaneously reversible and typically marked by pitting edema, an increase in upper-extremity girth, and heaviness.

• Stage II: This moderate stage 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. The swelling at this stage is mostly fluid.

• Stage III: In the most advanced stage, swelling is mostly secondary to fat hypertrophy, so there is no pitting edema.

 

The severity of lymphedema may be evaluated using the Common Terminology Criteria for Adverse Events (CTCAE), which was 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 approach allows the clinician to address troublesome signs and symptoms that may occur without significant interlimb discrepancy. The CTCAE volume 3 criteria are:

• Grade 1: 5% to 10% interlimb discrepancy in volume or circumference at point of greatest visible difference; swelling or obscuration of anatomical 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 anatomical architecture; obliteration of skin folds; readily apparent deviation from normal anatomical contour.

• Grade 3: More than 30% interlimb discrepancy in volume; lymphorrhea; gross deviation from normal anatomical contour; interference with activities of daily living (ADL).

• Grade 4: Progression to malignancy (e.g., lymphangiosarcoma); amputation indicated; disabling lymphedema.

The fifth version of the CTCAE is more streamlined and does not include limb volumes:

• Grade 1: Trace thickening or faint discoloration.

• Grade 2: Marked discoloration; leathery skin texture; papillary formation; limitation in instrumental ADL.

• Grade 3: Severe symptoms; limitation in self-care ADL.

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Prevention and Treatment Options Overview for Lymphedema

Nonsurgical Options

Compression garments

Compression garments are used to prevent and treat lymphedema by helping to decrease excess formation of interstitial fluid, prevent reflux of lymphatic fluid, and give a barrier to help muscle pumping of fluid up the lymphatic system. Use of flat knit (inelastic) compression garments is better than elastic compression in both the reduction and maintenance phase of stages II and III lymphedema. Inelastic compression garments allow the lymph fluid to be better propelled through the impaired lymphatic system via skeletal muscles. Flat knit garments also have the advantage of applying pressure to firm and soften edema. This pressure is applied at a uniform gradient over a large area. Circular knit garments deliver more pressure in the distal (narrow) part of the garment and are better for venous insufficiency than lymphedema.

Elastic garments are best used for stage I lymphedema and lymphedema that has been converted to stage II after complete decongestive therapy (CDT).

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Intermittent external pneumatic compression

This approach should be used in conjunction with compression garments and only if compression is not enough to prevent or treat lymphedema. Concerns regarding the use of intermittent pneumatic compression include the optimum amount of pressure, treatment schedule, and the need for maintenance therapy after the initial reduction in edema. There is a theoretical concern that pressures higher than 60 mm Hg and long-term use may injure lymphatic vessels.

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Intermittent external pneumatic compression may improve lymphedema management when used adjunctively with decongestive lymphatic therapy. A small randomized trial of 23 women with new breast cancer–associated lymphedema found an additional significant volume reduction, compared with manual lymphatic drainage alone (45% vs. 26%). Similarly, improvements were also found in the maintenance phase of therapy.

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There are several barriers to multidisciplinary decongestive therapy, including cost, inadequate number of trained therapists, and time commitment. In response to these barriers, a group of researchers conducted a trial of a garment under commercial development. The device was fit to patients, who were instructed to use it twice daily for 8 weeks. The investigators randomly assigned subjects to the device group or a wait-list control group. Use of the device was feasible, although most subjects found twice a day too burdensome. The treated subjects reported greater perceived ability to control lymphedema and subjectively had less swelling. There were no serious adverse events related to device usage. The economic costs of advanced compressive devices in lymphedema related to venous insufficiency compared favorably with other compressive techniques in a study of claims data.

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Complete decongestive therapy (CDT)

CDT is the standard of care for stage II lymphedema. However, the optimal program has not been established.

CDT has two phases:

• Phase 1—Decongestion/reduction: Skin/wound care, exercise, manual lymphatic drainage, and compression bandages, performed daily for an average of 15 days.

• Phase 2—Maintenance: Skin/wound care, exercise, manual lymphatic drainage as needed, and compression garments.

One study compared manual lymphatic drainage with exercise to treat lymphedema in 39 people with oral cavity cancer. Exercise and manual lymphatic drainage each improved neck range of motion and controlled lymphedema, but they appeared to have a better effect when done together.

A systematic review of manual lymphatic drainage in patients with breast cancer reported on ten studies. Four of the studies reported that manual lymphatic drainage could reduce the incidence of lymphedema (risk ratio, 0.58; 95% confidence interval [CI], 0.37–0.93). However, seven of the studies did not show a statistical difference in volumetric changes. They did see a statistical difference in pain control, but not in quality of life.

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Physical exercise

Physical exercise may be valuable in the treatment of lymphedema for several reasons, including improvement in lymph flow from muscle contractions and overall cardiovascular function. Conversely, early concerns that exercise may cause harm have not been confirmed. Results from a small randomized study suggest that resistance exercise may be offered concurrently with CDT.

A systematic review and meta-analysis reported on 12 prevention and 36 treatment studies of exercise to either prevent or treat cancer-related lymphedema. Most studies (11 of 12 and 32 of 36) enrolled patients with breast cancer. In addition, while most studies investigated some form of resistance training, a few used aerobic exercise alone. The relative risk of developing lymphedema after exercise was 0.90 (95% CI, 0.72–1.13), which was not significant. However, there was a suggested benefit in patients who had more than five lymph nodes removed. In this case, the relative risk was 0.49 (95% CI, 0.28–0.85). For patients in the treatment studies, the standardized mean difference (SMD) in measured outcomes was −0.11 (95% CI, −0.22 to 0.01). The difference compared with the control condition was −0.10 (95% CI, −0.24 to 0.04). Significant differences were detected for discrete outcomes such as pain, upper-body function and strength, lower-body strength, fatigue, and quality of life for those in the exercise group (SMD, 0.3–0.8; P < .05).

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The American College of Sports Medicine advises that a supervised, progressive resistance exercise program is safe for patients with or at risk for lymphedema after breast cancer. There is not adequate data about the safety of unsupervised exercise. The safety of exercise in other cancers is unknown.

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Pharmacological therapy

 

Nonsteroidal anti-inflammatory drugs (NSAIDs)

The potential benefit of the NSAID ketoprofen on lymphedema was demonstrated in a pair of small trials. The rationale for the use of NSAIDs rests on observations of histopathological inflammatory changes in the affected tissue and a possible relationship between persistent inflammation and impaired lymphangiogenesis. The authors reported an open-label trial, followed by a small placebo-controlled trial. In the latter, 18 patients were treated with placebo and 16 patients were treated with ketoprofen for 4 months. In both trials, ketoprofen treatment led to a significant reduction in skin thickness and an improvement in the histopathological appearance of the skin. In neither trial, however, were there changes in limb volume or skin impedance. These promising early results require verification, given the potential gastrointestinal and cardiovascular risks of NSAIDs.

 

Surgical Options

The surgical options for the treatment of lymphedema include lymphatico-venous anastomoses (LVA), vascularized lymph node transplantation (VLNT), and reduction of excess tissue volume by excision of liposuction. Several informative reviews describe the surgical decision making involved in selecting patients and the type of operation.

There are limited data to guide the choice between liposuction and microsurgical techniques, and some investigators propose a combined approach. The choice of microsurgical techniques may be aided by imaging and clinical grading of lymphedema severity. One proposal suggests that patients are candidates for LVA if they have partial obstruction seen on lymphoscintigraphy and grade 1 or 2 lymphedema with patent lymphatic ducts observed on indocyanine green lymphography . On the other hand, VLNT may be better for patients exhibiting a total obstruction seen on lymphoscintigraphy and grade 3 or 4 lymphedema without patent lymphatic ducts observed on indocyanine green lymphography.

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Lymphatico-venous anastomosis

LVA surgery is typically used in patients with early-grade lymphedema due to difficulties in finding lymphatic vessels. One study reported results for 42 patients with later-grade, lower-extremity lymphedema who underwent preoperative magnetic resonance lymphangiography and ultrasound. The imaging allowed patients to have an average of five successful anastomoses per limb. Clinical outcomes were favorable, raising the possibility of expanded indications for this surgery.

Immediate lymphatic reconstruction at the time of cancer surgery is under active investigation.

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Vascularized lymph node transfer

VLNT involves harvesting healthy lymph nodes and their relevant venous and arterial vessels from a donor site and transferring them to the nodal basin of the affected extremity. The proposed mechanisms of action include providing alternative routes of lymphatic drainage and encouraging lymphangiogenesis to provide new lymph vessels to the extremity. At present, there is scant but promising clinical data on the efficacy of VLNT.

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A systematic review and summary of patients with breast cancer–related lymphedema who underwent CDT or VLNT examined the evidence that both interventions favorably impact health-related quality of life measures. As anticipated, the data for VLNT was more limited (two studies, 65 patients) than for CDT (14 studies, 569 patients). However, within these limits, the data for VLNT indicated that improvements were commonly seen. The data for CDT were more heterogenous, and the improvement was often less significant. These data give clinicians a reason to consider surgical intervention, although at present the standard practice seems to be CDT.

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In a retrospective study of 124 patients with breast cancer–related lymphedema, the degree of improvement in limb circumference and reduction in episodes of cellulitis appeared to be greater in patients who underwent VLNT than in those who underwent LVA. In addition to the usual caution in interpreting retrospective data, the patients who underwent VLNT were ineligible for LVA based on lymphography results. This finding seems to support the use of imaging to guide patient selection. Two small cohort studies of VLNT in patients with breast cancer demonstrated apparent improvements in objective limb measurements and subjective measures of patients’ health-related quality of life.

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Liposuction

Nonpitting chronic lymphedema may be due to adipose tissue hypertrophy. In this case, liposuction to remove the excess adipose tissue is an option. Compression garments are still needed after the liposuction. In addition, excision of the redundant skin after liposuction may be required.

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One retrospective study compared the frequency of documented episodes of erysipelas in 130 patients before and after they underwent liposuction. As anticipated, the mean excess arm volume decreased from 1,607 mL to negative 43 mL, and the ratio of affected to normal arm decreased from 1.5 to 1.0. The recorded occurrence of erysipelas decreased from 0.47 to 0.06 attacks per year. Similar results were reported in another study, in which the authors reviewed the charts of 105 women with breast cancer–related lymphedema refractory to compressive therapies who underwent liposuction between 1993 and 2012. Notably, patients had to have nonpitting edema. All women benefited, and the benefit persisted for at least 5 years by measurement.

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Laser therapy

Low-level laser therapy (LLT) is a noninvasive technique in which affected tissues receive phototherapy of various wavelengths within 650 to 1,000 nanometers. The role of LLT in the care of people with lymphedema is not established, although a 2017 systematic review found promising evidence. The proposed mechanisms of action include cellular proliferation of macrophages with reduction in fibrosis, reduced inflammatory mediators, lymphangiogenesis, and improved lymphatic flow. In addition, carbon dioxide laser treatment may also lead to clinical improvements, though the data are currently only from small case series. The carbon dioxide laser stimulates remodeling of abnormal collagen by matrix metalloproteinases and dermal neocollagenesis by fibroblasts and supports generation of new lymphatic vessels.