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Cancer related lymphedema | The BMJ

admin July 3, 2025 Conventional Medicine

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Andrea L Cheville, consultant and professor of physical medicine and rehabilitation1,
Sarah A McLaughlin, consultant and professor of surgery2,
Gretchen E Glaser, consultant and professor of obstetrics and gynecology3,
Judy C Boughey, consultant and professor of surgery4

¹Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN, USA

²Department of Surgery, Mayo Clinic, Jacksonville, FL, USA

³Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN, USA

⁴Division of Breast and Melanoma Surgical Oncology, Department of Surgery, Mayo Clinic, Rochester, MN, USA

Correspondence to: A Cheville cheville.andrea{at}mayo.edu

Abstract:

Lymphedema is a prevalent, incurable, and morbid condition with the potential to degrade the health and quality of life of patients living with cancer and beyond cancer. Effective long term control requires coordination by an interdisciplinary team to ensure that lymphedema progression, complications, and related disablement are detected and appropriately addressed. This review provides an overview of lymphatic function and lymphedema pathogenesis with focused discussion of the unique characteristics of cancer related lymphedema (CRL) including natural history, clinical presentation, and risk factors for onset and progression. Surgical practice changes and supportive evidence for lymph node sparing and lymphatic reconstruction for CRL prevention are described. The review outlines evaluations to diagnose, stage, and monitor CRL, and characterizes evidence for current CRL prevention and management practices, including surgeries to restore lymphatic function. Multimodal management with complete decongestive therapy remains first line treatment for CRL, though patient-specific customization might be required to optimize patients’ clinical response and quality of life as outlined in the review.

Introduction

Cancer related lymphedema (CRL) is a prevalent consequence of injury to lymph vessels and nodes that could be caused by cancer treatment or cancerous infiltration of lymphatic structures. CRL is chronic, progressive swelling with potential for metaplasia involving one or more body parts owing to impaired lymph removal and transport. CRL adversely impacts patients’ healthcare utilization, clinical outcomes, and quality of life, particularly their functional, financial, and psychological wellbeing.1 Once established, lymphedema is incurable, though it can be mitigated by continuous use of maintenance activities. These might be burdensome and also lessen quality of life.2 Unfortunately, most patients with CRL report diagnostic delays, inappropriate management, and clinician disinterest in their CRL.3 CRL’s negative impact, chronicity, and requirement for indefinite temporization have spurred clinical efforts to protect and repair the lymphatic system during and after cancer treatment.

Surgical lymph sparing procedures are now extensively integrated into standard cancer care. Sentinel lymph node biopsy, for example, reduces CRL in patients with melanoma, breast, gynecologic, and urologic cancers by minimizing lymph node removal.4 5 6 Procedures to restore lymphatic function also show promise. Technologies that detect incipient CRL have become clinically available, which enable earlier detection and proactive mitigation. Improved cancer care has also impacted CRL by permitting less anatomically disruptive treatments and increasing survival in the advanced stages of cancer. Together, these advances have altered the prognosis, epidemiology, and management of CRL over the past decade.

In this review, we provide an overview of lymphatic function and lymphedema pathogenesis followed by more focused discussion of unique characteristics of CRL including natural history, risk factors for onset, and progression. We review the evidence base for current practice standards about lymphedema prevention, detection, and management.

Sources and selection criteria

We identified source literature through searches of PubMed, CINAHL, Google Scholar, and Medline using the search terms “cancer” and “lymphedema,” AND one of “diagnosis,” “measurement,” “imaging,” “prevalence,” “pathophysiology,” “complications,” “sequelae,” “treatment,” “prevention,” “management,” “risk,” “decongestive therapy,” “decongestion,” “compression,” “exercise,” “manual,” or “patient reported outcome.” We prioritized randomized controlled trials (RCTs), cohort studies, meta-analyses, and systematic reviews published since 2015, with no language restrictions. Non-peer reviewed publications and opinion pieces were excluded. We reviewed the references of relevant publications for pertinent studies. For figure 5, systematic reviews and meta-analyses were included if they reported the effect of conventional, adapted and adjunctive complex or complete decongestive therapy (CDT) components on CRL prevention, reduction, and/or patient reported outcomes without application of quality criteria.

Epidemiology

Lymphedema could be characterized as primary or secondary based on the presumed cause. Primary lymphedema develops owing to endogenous compromise of the lymphatic system and could be congenital. Primary lymphedema might occur in individuals living with and beyond cancer but is not considered CRL. Secondary lymphedema develops owing to compromise of an intact lymphatic system. Iatrogenesis is the most common cause of secondary lymphedema in high income countries, in the context of cancer treatment.

The incidence of CRL has been most extensively characterized in association with breast cancer treatment affecting between 2% and 74% of survivors.16 Patients also develop CRL from treatment for other solid tumors such as melanoma, prostate, head and neck, gynecologic, and urologic cancers. The mean CRL incidence rate is 15.5% across all cancers, however, rates vary markedly by cancer type and location.17 For example, up to 40% of gynecological cancer survivors report lymphedema.18 Among melanoma survivors, lymphedema incidence varies by location of melanoma and nodal basin involved and is markedly higher in the lower extremity (28%) relative to the upper extremity (5%).17

Lymphatic system

The lymphatic system is a unidirectional network that returns filtered interstitial fluid and tissue metabolites to the blood circulation and fulfills important roles in immune cell trafficking and lipid absorption.7 8 Virtually all interstitial fluid requires lymphatic transport.9 Lymph capillaries are blind, finger-like projections of loosely adherent endothelial cells that create subpapillary and deep dermal networks. Lymph capillaries are larger than blood capillaries and lack basement membrane permitting ingress of interstitial fluid and solid debris into the lymphatic circulation. At this point, the fluid and solids become lymph and flow from the capillaries to collector vessels that converge to form larger vessels which drain into lymph nodes. Lymph vessels rely on the intrinsic contractility of smooth muscle in the collecting vessel walls, as well as contraction of adjacent, extrinsic muscles; arterial pulsations; and diaphragmatic excursion for lymph propulsion.10 11 Unidirectional valves in lymph collecting vessels prevent backflow and stasis.

Lymph nodes regulate lymph viscosity, filter recyclable debris, and support the system’s immunoregulatory functions. Lymph nodes play a vital role in triggering and modulating immune responses.12 Lymph typically flows through chains of superficial and deep nodes before re-entering the venous circulation. The lymphatic system plays a vital role in maintenance of tissue fluid homeostasis, particularly the regulation of interstitial fluid volume and composition.13 14 15 The venous system assists in maintaining fluid balance, however, physiological insights suggest that the lymphatic system transports a larger proportion of interstitial fluid than previously thought.

Pathophysiology

Understanding of CRL pathophysiology has advanced with insights into the mechanisms by which iatrogenic lymphatic injury initiates and sustains cellular, molecular, and biochemical changes.19 20 21 Initially, impaired lymphatic return and hypertension cause mismatch between lymph production and removal. Increasing mismatch exhausts the system’s reserve leading to tissue edema. Venous obstruction related to cancer and treatment effects might further increase lymphatic load and edema.22 Tumor-specific biological features, such as peritumoral lymphovascular invasion and extranodal extension, are also thought to be involved in CRL pathogenesis.23 Once lymphatic vascular dysfunction is established, a self-perpetuating cycle of local stasis, inflammation, fibrosis, adipose deposition, and metaplasia advances CRL pathophysiology.21 24

Tissue inflammation plays a causal role in CRL progression from incipient stages 0-I (International Society of Lymphology’s staging system) to more advanced stages II-III, and is attributed to chronic interstitial fluid accumulation, and impaired transit of inflammatory cells and mediators in the interstitium (fig 1).13 25 Complement activity, stress response, remodeling of the extracellular matrix, and immunologic responses are believed to mediate inflammation, yet the sequencing and interdependencies of these processes remain a focus of ongoing study.26 Research has clarified the contributory yet pleiotropic roles played by T cell and macrophage subtypes in the inflammation, fibrosis, and lymphangiogenesis that cause and exacerbate lymphedema.27 28 Studies of inflammatory expression profiles in animal models of lymphedema have implicated arachidonate 5-lipoxygenase and its metabolite, the eicosanoid leukotriene B4, as instigating the sequence of pathological changes that underlie lymphedema.13 29

Fig 1

Pathogenesis of lymphedema. The lists of cellular and molecular mediators are representative but not comprehensive

Late stage CRL is characterized by elaborate deposition of extracellular matrix components and fibrotic remodeling in the interstitial space which further impedes lymph sequestration and transport. Fibrosis contributes to stagnant interstitial fluid, and impaired nutrient and oxygen diffusion. The latter has been posited to facilitate fibrosis.30 Th2 cells play an appreciable role in tissue fibrotic remodeling by affecting the balance of profibrotic cytokines and antifibrotic cytokines, and by influencing monocyte differentiation.31 Transforming growth factor β has also been implicated.32 A further pathological hallmark of late stage lymphedema is progressive expansion of the subcutaneous adipose layer which is related to lymph vessel impairment and, potentially, Th2 activity.13

The endothelial glycocalyx, a gel-like layer that covers the luminal surface of lymph collectors and assists with endothelial function, has been implicated in CRL pathogenesis.33 Inflammation causes the lymphatic glycocalyx to remodel, leading to increased permeability, impaired regulation of fluid balance, and profibrotic conditions.34 35

Natural history

Onset

Although CRL often develops insidiously, acute swelling might occur with local inflammation or infection; hot, humid weather; or changes in the duration or intensity of physical activity. Often edema initially follows a stuttering pattern with episodes of transient swelling alternating with periods of resolution. Over time, swelling becomes chronic, and improvement with overnight elevation diminishes and eventually ceases.

Understanding of the timing of CRL onset is based on studies on breast cancer and is, therefore, restricted to the upper extremity. In general, 80% to 90% of breast cancer survivors who develop lymphedema do so within three years of cancer treatment.36 In a cohort of 2171 breast cancer survivors, lymphedema onset peaked between 12 and 30 months after treatment. Lymphedema occurring within 12 months was associated with axillary lymph node dissection (P3738

These estimates should be generalized with caution to survivors of other cancers, particularly those with or at risk for leg and axial lymphedema. The interval between cancer treatment and lymphedema onset remains under-researched in these subgroups. A single report describing 76 patients with oral cavity or oropharyngeal cancer found that external lymphedema and fibrosis severity peaked 0-3 months post-treatment and decreased gradually thereafter but did not return to baseline by 12 months post-treatment.39 Computed tomography revealed durable increases in internal tissues after multimodal therapy.

Progression

In the absence of treatment, CRL progresses through a series of stages marked by increasing tissue metaplasia of the interstitium and dermis (table 1). Progression might be more rapid in lower extremity CRL and could be accelerated in the upper and lower extremities by cellulitis.40

Table 1

Clinical presentation and evaluation of the stages of lymphedema from the International Society of Lymphology

Risk factors for the onset and progression of lymphedema

Cancer and cancer treatment

The risk of CRL is associated with the extent of lymph node resection, radiation, and receipt of systemic therapies, though many other risk factors have been identified (box 1).41

Box 1

Common risk factors for the onset and progression of lymphedema related to cancer

Increased risk (strong or causal association)

Extensive lymph node surgery
Increasing number of positive lymph nodes
Raised BMI and obesity
Radiation therapy
Chemotherapy (eg, taxanes)
Recurrent infections

Increased risk (modest to weak association)

Venous injury (eg, deep vein thrombosis, vein stripping)
Chronic venous insufficiency
Parasitic infection
Extremity trauma
Genetics

Unlikely to affect risk

Air travel (assumes use of compression garments if indicated)
Intravenous sticks or blood draws (assumes appropriate prep and monitoring for infiltration and infection)
Aerobic or resistive exercise (assumes use of compression garments if indicated)
Blood pressure measurements (assumes use of compression garments if indicated)

RETURN TO TEXT

Extent of nodal surgery

Extent of nodal surgery has long been considered the primary risk factor for CRL and removing more nodes results in higher lymphedema rates, although there is no defined cut point that triggers CRL. In breast cancer, CRL rates after axillary lymph node dissection can range from 10% to 60%, whereas rates after sentinel lymph node surgery are only 0% to 7%. Similarly, lymphadenectomies for gynecologic cancers (endometrial, cervical, and vulvar) give CRL risks of 20% to 60%.23 Fortunately, sentinel lymph node surgery reduces CRL to the extent that there is no change in risk relative to hysterectomy—only in patients with endometrial cancer.42

Radiation

Regional nodal irradiation increases the risk of CRL when performed in addition to nodal surgery.43 44 Rates in cancer survivors can be as high as 17% to 41% for breast cancer and 6% to 49% for gynecologic cancers.45 Radiation increases the risk fivefold and when combined with axillary dissection 10-fold.46 47 Increasing total dose of radiation, overlapping radiation fields, and posterior axillary boost all increase risk.48 In gynecologic malignancy, risk with external beam is higher than with brachytherapy.11 38 49 50 Radiation is presumed to mediate the onset and progression of CRL by decreased lymphatic proliferation, fibrosis, and secondary lymphatic obstruction although this mechanism is not well researched.

Systemic therapies

Chemotherapy is associated with CRL. Anthracycline drugs (particularly doxorubicin) have been associated with CRL and some studies indicate that dantrolene might be able to mitigate the impact of doxorubicin on CRL, however, more studies are needed.43 Taxane chemotherapy and longer duration chemotherapy regimens have been associated with CRL in some reports.51 52 However, the finding has not been consistent and potential mechanisms remain unclear.40 Trastuzumab has also been associated with greater risk of lymphedema.53 Other medications, not specific to cancer, have been associated with CRL including several classes of cardiovascular agents and thiazidolinedione drugs that are used to treat diabetes.39 43 54

Multimodal therapies

CRL is a multi-hit process, and multimodal therapies combine to increase lymphedema risk.55 An epidemiological study of 1794 patients with breast cancer found lymphedema rates were highest (>25%) in patients treated with axillary dissection, nodal radiation, and anthracycline/cytoxan plus taxane chemotherapy.56

Malignant compromise

Lymphedema could occur or worsen in advanced stage solid and liquid cancers due to exogenous compression, destruction, or infiltration of lymph vessels and nodes by malignant cells.57

Systemic characteristics and comorbidities

Obesity

Obesity is increasingly recognized as a risk factor for developing all types of lymphedema, including CRL.51 Excess body fat can impair lymphatic vasculature by chronic inflammation, increased lymphatic pressure, and poor lymphatic vessel function. In the setting of surgical lymph node extirpation or damage to lymphatic vessels, obesity can result in an imbalance between lymphatic load and transport capacity.52 Obesity impaired lymphatic vessels can result in increased inflammation triggering lymphedema due to abnormal dilation of lymphatic vessels and small lymph nodes.58 Studies evaluating obesity as a lymphedema risk factor have focused on BMI as a surrogate. Patients with BMI >30 and those with noticeable postoperative weight fluctuations (change of 10 pounds gained/lost per month) have demonstrated a greater risk of developing lymphedema.20 42 43 49 50 54 59 60 61 62

Genetics

By contrast with primary lymphedema, for which specific genetic mutations have been causally implicated,44 51 the field of CRL genetics is emerging. Most research has concentrated on breast CRL because many patients do not develop lymphedema despite similarities in the extent of surgery and treatment. Two systematic reviews examined genetic alterations in patients with breast CRL and identified 18 and 23 genes, respectively, that might be important for CRL development.63 64 Others have performed discovery work to evaluate if the presence of microRNAs or circulating biomarkers can predict lymphedema.52 57 65

Venous insufficiency

CRL of the lower extremities can occur at the same time as venous insufficiency. This has been demonstrated by the finding that among a cohort of 440 patients with lymphedema treated at a physical therapy department, which was affiliated with a cancer center, 42% had phlebolymphedema.66

Local lymphatic injury

The risk of CRL could be increased by premorbid lymphatic compromise due to burns, trauma, iatrogenic compromise unrelated to cancer, and recurrent infections. The extent to which local injuries could contribute to CRL is unclear. The contribution might be quite low—as reflected in the 1% lymphedema incidence detected during long term follow up of a cohort after burn injuries.62

Predictive algorithms

Algorithms and nomograms have shown varying degrees of success in predicting CRL. Most algorithms and nomograms incorporate known risk factors such as BMI, extent of nodal surgery, and nodal irradiation. Two nomograms with concordance indices of 0.79 and 0.71, respectively, have been reported for lymphedema after treatment for breast cancer.48 67 More recently, a nomogram for CRL after cervical cancer had a concordance index of 0.89.68 Predictive capabilities are improving and offer a potential means of risk-stratifying to individualize the prevention and monitoring of CRL.

Diagnosis, differential, and clinical evaluation

Diagnosis

Lymphedema could be distinguished from other causes of swelling by its discrete involvement of one or more body parts, asymmetry, insidious onset and progression, and characteristic tissue texture and skin changes. Lymphedema secondary to cancer treatments could also be identified by its confinement to the drainage territories of resected lymph nodes (fig 2). Diagnosis is often suggested by history and clinical exam findings with confirmation provided by clinical evaluations and imaging. Patient reported symptom assessments for upper quadrant CRL have high sensitivity (93% to 96%) and moderate specificity (69% to 75%).69 Reports suggest that clinical exam findings also have high sensitivity but low specificity. For example, the presence of a Stemmer sign, the inability to pinch a discrete skin fold overlying the dorsum of the second toe, has a sensitivity of 92% and specificity of 57% when compared with lymphoscintigraphy.70 An isolated report found the presence of nonpitting edema to have a specificity of 88%. However, nonpitting edema is seldom noted in early stage CRL when diagnostic uncertainty has diminished.71 In earlier lymphedema stages, nonpitting edema and increased skinfold thickness were less sensitive.72

Fig 2

Characteristics of cancer-related lymphedema associated with surgical dissection of specific lymph node beds. SLN=sentinel lymph node; CLND=completion lymph node dissection

Differential

The differential diagnosis varies with the pattern of onset, distribution, and the presence of systemic and/or local symptoms. Venous conditions lead the differential because thrombosis of upper and lower extremity veins is common in patients with cancer, treatable, and potentially morbid.73 Most diagnoses in the differential exacerbate rather than cause the asymmetrical and unilateral swelling that characterizes CRL. These include myxedema, solid organ failure (kidney, heart, or liver), obstructive sleep apnea, obesity, inactivity, malabsorption, polycystic ovarian syndrome, and hypercortisolism.74 Medication effects also feature prominently in the differential because many common drugs (NSAIDS, steroids, gabapentinoids, and calcium channel blockers) might cause or worsen edema.

Clinical evaluations

Clinical evaluations are used to identify non-lymphatic causes of edema, confirm lymphedema diagnoses, prognosticate, individualize treatment, and monitor patients with and at risk of developing CRL.75 Limb volumes are a common and pragmatic means of monitoring CRL. Bioimpedance spectroscopy offers high sensitivity and specificity for early detection of extracellular fluid in subclinical stage 0 CRL.76 77 Lymphoscintigraphy, by contrast, offers clinically useful insight about residual lymphatic function in the later stages of lymphedema.

Circumferential measurements

Circumferential measurement uses a standard tape measure to obtain the girth of a limb at specific intervals, which is then used to calculate volume. Circumferential measurements of the upper extremity demonstrate excellent inter-rater and intrarater reliability, with intraclass correlation coefficients ranging from 0.93 to 0.99 for the arm, both with and without hand measurements.69 In the leg, reliability is more difficult to obtain, with a large study demonstrating 11.3% of patients with inter-rater differences greater than 1cm.23 Measurements can be taken at various points along the upper or lower limb, such as every 4 cm, 8 cm, 10 cm, or 12 cm, with the 4 cm interval being the most common for the upper extremity and 10 cm for the lower extremity.23 The volume is then calculated, typically by using the truncated cone formula. This method has been shown to have a high correlation with water displacement, the gold standard for volume measurement, with correlation coefficients ranging from 0.93 to 0.98 for the arm.69 Correlation coefficients in the leg are less reproducible,78 with correlation coefficients ranging from 0.131 to 0.998.79 Circumferential measurements might overestimate limb volume compared with other methods (eg, computed tomography).80 Circumferential measurements in gynecologic cancer have not been shown to correlate with patients’ subjective measurements and quality of life.78

Optoelectronic volumetry

Optoelectronic volumetry (perometry) uses infrared light and sensors to indirectly measure extremity volume and has been validated for use in lymphedema.81A perometer obtains multiple measurements at extremely small intervals and then the computer calculates the volume. It uses the same principles as sum of tape circumferences but is more accurate given the multiple measurements and computer calculations. The measurements are obtained by moving a frame with multiple perpendicular light beams along the limb. Cross-sectional areas at each interval are calculated and added together by the computer and converted to a volume. Perometers do not measure hands or feet. The same positioning of the patient and their limb is essential for accuracy with this technique. Perometry has been validated and shows high intrarater (intraclass correlation coefficient 0.989) and inter-rater reliability (0.993).82 Obtaining a perometry measurement is quick and time efficient because most bilateral limb assessments can be performed in under two minutes. Frequent calibration of the machine is critical. Unfortunately, the equipment is expensive and not widely available and as a result, it is typically only used in large academic or research institutions.

Water displacement

Water displacement was previously the gold standard for indirect limb volume measurement. Water displacement is accurate but is less commonly used clinically owing to hygiene and infection control concerns, large equipment footprint, and space needs. This technique maintains value as a standard against which other measurement methods are evaluated for accuracy.69 Water displacement measurement is a form of plethysmography, which measures the amount of water displaced when the extremity is immersed in a tank. It can measure the entire limb including the hand and foot.

Three dimensional imaging and volume scanning

Three dimensional imaging and volume scanning requires circumferential movement of a smartphone or tablet around an affected body part allowing the software to capture a three dimensional model. The software calculates segmental and total circumference volumes. Studies have demonstrated that three dimensional imaging systems have high accuracy and reliability, with strong correlations to water displacement measurements (Pearson’s correlation coefficient up to 0.99).83 84 These systems also show excellent inter-rater and intrarater reliability. The approach is faster than traditional methods, generally requiring one to five minutes depending on the patient and the characteristics of their lymphedema. Three dimensional laser scans can detect subtle changes in swelling, which makes them a reasonable choice for longitudinal monitoring. Additionally, three dimensional scanning can accurately measure hand and foot volumes and enhance the design and fit of compression garments.84 85

Patient reported outcome measures (PROMs)

PROMs are assessment tools that quantify latent constructs such as patients’ mood, symptoms, and overall quality of life. PROMs have been used to characterize the subjective experiences of patients with CRL, and are an important dimension of clinical diagnosis, treatment, and research. Multiple PROMs have been developed to assess patients with primary or secondary lymphedema, and to assess patients with CRL in particular.86 87 Generic, or condition agnostic, PROMs have been reported to demonstrate acceptable to excellent discrimination in assessing function and quality of life among individuals with lymphedema.88

A subset of PROMs has been developed to screen for lymphedema, with different tools being used for the upper and lower limbs. Upper limb instruments include the Lymphedema Breast Cancer Questionnaire (area under the curve not reported),89 and a telephone screening questionnaire developed by Norman and colleagues (sensitivity 0.96, specificity 0.75).90 Lower limb instruments include the Lower Extremity Lymphedema screening questionnaire (area under the curve 0.92),91 and the Gynecological Cancer Lymphedema Questionnaire (0.95).92 In general, the instruments have higher sensitivity than specificity and their use might generate false positives if not used with other diagnostic and screening approaches. Symptom-based severity PROM scoring systems could assist when conventional assessment approaches are inaccurate or unavailable (eg, genital lymphedema).93

PROMs that assess quality of life, symptoms, function, and mood (among other constructs) are designed for use after a patient has been diagnosed with lymphedema. Several commonly used quality of life tools include the lymph quality of life measure for limb lymphedema LYMQOL,94 upper limb lymphedema 27 scale (ULL27), and the lymphedema life impact scale (LLIS).95 These tools identify patients with poor quality of life, intense symptoms, or disablement related to CRL that warrant clinical attention, and could therefore be valuable longitudinal assessment tools.

Anatomical studies

Lymphoscintigraphy

Lymphoscintigraphy involves the injection of radiolabeled tracer, most often into the interdigital web spaces of the upper or lower extremities, followed by monitoring tracer ascent by using gamma camera images. Tracer can also be injected intradermally, subcutaneously, or peritumorally, in accordance with the clinical indication. Lymphoscintigraphy has a moderate sensitivity (0.62) and high specificity (1.0) for diagnosing lymphedema when compared with the unaffected limb.69 Sensitivity in early lymphedema (stages 0-II) has not been precisely characterized, but it is generally considered to be poor.96 Therefore, a positive lymphoscintigraphy could confirm the diagnosis of lymphedema and identify areas likely to benefit from more intense decongestion and compression.97 Lymphoscintigraphy provides actionable clinical information by identifying abnormalities in lymphatic drainage, such as dermal backflow, lymphatic obstruction, and lymph node involvement.

Indocyanine green lymphography

Indocyanine green lymphography (near infrared fluorescent imaging) images subcutaneous lymphatic vessels by injection of fluorescent dye (indocyanine green) that binds to plasma proteins and highlights the lymphatic vessels when exposed to near infrared light. The dye emits near infrared fluorescence, which is captured in real time by using a specialized camera system, allowing for the visualization of lymphatic flow and patterns of lymph vessels (fig 3). One of the primary advantages of indocyanine green lymphography is its ability to provide detailed, dynamic images and identify areas of dysfunction or obstruction. This technology shows promise for use to diagnose lymphedema and to monitor the effectiveness of treatment because several patterns of enhancement abnormality have been correlated with the progression of lymphatic dysfunction.98 99 These patterns facilitate diagnosing lymphedema but also help in guiding surgical interventions, and in evaluating the effectiveness of treatments. Indocyanine green lymphography is minimally invasive and offers real time feedback, making it a valuable tool for personalized treatment planning and ongoing management.

Fig 3

Indocyanine green lymphogram contrasting the normal, upper, and lymphedematous arms of a patient with late stage II breast cancer related lymphedema

Ultrasonography

Ultrasound scanning has been used to identify the CRL stage and to map different stages and severity in an affected body part.100 Skin thickness, subcutaneous tissue thickness, and subcutaneous echogenicity all correlate with the International Society of Lymphology Stages.101 High correlation between histological and ultrasonographic characteristics was found when comparing tissue and images collected during and before lymphovenous surgery.102 Ultrasound is feasible for use in outpatient clinical practices given its relatively low cost, portability, and interpretability, though user training is required.75

Computed tomography lymphangiography

Computed tomography and computed tomography lymphangiography have a supportive role in lymphedema diagnostics. Computed tomography provides high resolution imaging of the lymphatic system and identifies obstructions, leaks, or tumors. In addition, computed tomography can provide detailed information about the relationships of the lymphatic vessels and the surrounding tissues (specifically venous anatomy), including locating perforator vessels during the preparation for lymphatic tissue transfer.103 Computed tomography can assess the degree of tissue edema, but it cannot differentiate between lymphedema and edema.104 The limitations of computed tomography lymphangiography include exposure to ionizing radiation and adverse reactions to contrast agents.

Magnetic resonance lymphography

Magnetic resonance lymphography is a non-invasive imaging technique used to visualize the lymphatic system, including its anatomy and function.105 The technique could detect abnormalities at earlier stages than lymphoscintigraphy. There are two primary types of magnetic resonance lymphography: dynamic contrast enhanced magnetic resonance lymphography and non-contrast magnetic lymphography. A gadolinium based contrast agent is injected into the lymph nodes for dynamic contrast enhanced magnetic resonance lymphography, which allows for high resolution, three dimensional imaging of the central conducting lymphatics (such as the thoracic duct and cisterna chyli). Non-contrast magnetic resonance lymphography uses T2 weighted sequences to visualize the lymphatic system without the need for contrast agents. Both types of magnetic resonance lymphography provide detailed anatomical information that is unavailable with other imaging approaches. However, access and cost constrain the use of magnetic resonance lymphography in many clinical settings.

Complications of lymphedema

Cellulitis

Cellulitis occurs when common skin bacteria, typically Staphylococcus epidermidis, enter the interstitial environment with impaired immune surveillance and sluggish pathogen removal. Methicillin resistant staphylococcus aureus accounts for fewer than 5% of cellulitis related to lymphedema.106 A recent study reported cellulitis prevalence and recurrence rates of 12.6% and 56.6%, respectively, in extremity lymphedema.106 Although cellulitis might require hospitalization, most episodes are effectively managed as outpatients with oral antibiotics. Rapid initiation of antibiotic therapy is critical because a single episode of cellulitis could cause permanent damage to an already impaired lymphatic system.40

Wounds

Stage III CRL of the legs could be complicated by non-healing wounds due to impaired interstitial homeostasis with diminished oxygen and nutrient transport. Additionally, the fibrosis characteristic of stage II and III CRL might undermine the skin’s elasticity and ability to withstand sustained pressure and traction.

Pain

Pain, characterized as persistent heaviness or aching, could afflict patients with lymphedema. Sensations might be provoked or intensified by activity; maintaining the limb in a dependent position; and hot, humid weather. Pain and heaviness generally diminish with lymphedema treatment, particularly compression and exercise.107 Topical analgesics might offer benefit, though their use is not empirically supported. Systemic analgesics could be considered.

Malignant transformation

Chronic lymphedema can create a permissive environment for certain malignancies owing, in part, to impaired cell mediated immunity. The occurrence of angiosarcomas, known as Stewart-Treves syndrome, is a very rare complication of lymphedema.108 Current understanding largely derives from case reports that lack incidence estimates. The syndrome initially manifests as violaceous skin nodules, subdermal masses, and eschar productive of serosanguinous ooze; all of which warrant scrutiny and biopsy. Other malignancies, including melanoma, non-melanoma skin cancer, Kaposi sarcoma, and cutaneous lymphomas have been reported in cases of chronic lymphedema.108 Malignant transformation rates and lymphedema characteristics associated with transformation are under studied.

Lymphorrhea

Lymphorrhea is the leakage of lymph through intact skin or a skin defect due to increased interstitial pressure. Often, lymphorrhea presents as yellowish, clear fluid (lymph) that beads up and trickles along the skin overlying affected body parts. Because lymphorrhea is protein rich, it can accumulate and create a proteinaceous coating which is conducive to microbial growth. Copious lymphorrhea can be uniquely problematic in genital lymphedema because it could contribute to recurrent cellulitis.109

Primary prevention

Behavioral approaches

Preventive behaviors, such as avoiding blood pressure measures or blood draws in body parts at risk for lymphedema, have been recommended to cancer survivors despite a lack of supportive evidence. Widespread adoption occurred without consideration of variation in lymphedema risk. 81 110 Recent prospective trials and observational cohort studies have systematically evaluated these behaviors among breast cancer survivors. A prospective subanalysis of a randomized controlled trial included 295 patients with breast cancer who reported their exposure to 30 different behaviors. Only sauna use (n=13, odds ratio 5.77, 95% confidence interval 1.00 to 33.82, P=0.05) was associated with an increased risk of CRL.111 Subsequently, a prospective limb volume monitoring program of 632 patients with self-reported risk factor exposure demonstrated that blood draws, injections, blood pressure measures, and flying were not associated with lymphedema onset.112 113 Only cellulitis significantly increased risk (95% confidence interval 1.7 to 3.8, P113 These studies have resulted in changes to recommendations and guidelines and, within the confines of a prospective screening program, routine precautionary behaviors might not be necessary.114 Guidelines are not currently available for patients at risk for lower extremity lymphedema.

Intensive primary prevention of lymphedema among patients at high risk could be available through formalized rehabilitation programs. Prospective studies suggest that standard referral for preemptive treatment of at-risk patients could be more effective than patient self-education and surveillance.115 116 A lymphedema specialist might recommend a multimodal program designed to prevent lymphedema onset and infectious complications. An observational study found that prospective surveillance of breast cancer survivors by physical therapists at three month intervals enhanced lymphedema control and reduced physical impairments one year after treatment.117 A systematic review concluded that participation in prospective surveillance with early management reduced the risk of chronic breast CRL versus usual care (relative risk 0.31, 95% confidence interval 0.10 to 0.95).118 The benefits of surveillance remain untested among patients at risk for secondary axial and leg lymphedema.

Surgical approaches

Given the association of lymphedema with lymph node removal, there has been a focus on decreasing the extensiveness of surgery, where feasible, while maintaining good oncologic outcomes. For example, use of axillary lymph node dissection in breast cancer, formerly the standard of care, has dramatically decreased in favor of sentinel lymph node surgery. By contrast with axillary dissection, sentinel lymph node surgery removes an average of two or three lymph nodes, which undergo pathological evaluation for metastatic spread. Patients with negative sentinel nodes can avoid axillary dissection.119 Further de-escalation has occurred based on the findings of the randomized controlled trials listed in table 2. The use of sentinel node surgery for axillary staging to identify patients with pathologic negative nodes and allow omission of axillary dissection has also extended to patients with node positive breast cancer treated with neoadjuvant chemotherapy.120

Table 2

Key clinical trials (publication year, no) resulting in de-escalation of nodal surgery

A similar approach, using sentinel lymph node biopsy in lieu of pelvic and para-aortic lymph node dissection, has been adopted in surgery for gynecologic cancers. Recent clinical trials, focused on de-escalation of nodal surgery, have shown equivalent oncologic outcomes and secondarily established that removing fewer lymph nodes results in less CRL.4 5 6 These trials have further driven the adoption of sentinel lymph node surgery for staging, when appropriate, in lieu of routine lymph node dissection. The robustness of outcomes in clinical trials has led to the worldwide adoption of these practices as standard clinical care. Use of radiation is also being explored as a means of limiting lymphatic compromise from nodal surgery.121

New surgical procedures have been developed to try to preserve or reconstruct the axillary lymphatics with the use of axillary reverse mapping and lymphovenous bypass to decrease the risk of CRL. Axillary reverse mapping requires injection of dye into the upper extremity to allow visualization of the lymphatics draining the arm while performing axillary surgery.122 123 Avoiding ligation of the blue lymphatics, where oncologically appropriate, can preserve lymphatic drainage from the arm and decrease the risk of lymphedema. When performing an axillary dissection, especially since now axillary dissection is generally reserved for patients with severe volume nodal disease, the arm lymphatics often cannot be preserved. Preservation of the arm lymph node is controversial because rates of nodal involvement are high—71% in a recent prospective trial.124 However, identification of the lymphatics draining the arm can allow for lymphovenous bypass, a technique that involves an anastomosis between the lymphatic to a venous branch to restore lymphatic flow. These techniques have also been used to prevent lymphedema in patients undergoing lymphadenectomy for gynecologic cancers.125 A systematic review including multiple tumor types showed a relative risk of 0.33 for postoperative lymphedema when immediate lymphatic reconstruction was performed.126 A Cochrane review comparing the efficacy of surgical interventions to prevent lymphedema identified two randomized controlled trials (95 patients) that evaluated lymphaticovenous anastomosis.127 The Cochrane review found that lymphaticovenular anastomosis reduced the incidence of lymphedema compared with nonoperative management with a risk ratio of 0.20 (95% confidence interval 0.06 to 0.63, P=0.006; 95 participants; low-certainty evidence).

Treatment of lymphedema

Manual and behavioral therapies

Manual treatments remain the mainstay of lymphedema management irrespective of the cause.98 Multicomponent manual programs that strategically combine and deliver treatments daily for a minimum period of two weeks reduce long established lymphedema. Referred to as complex or complete decongestive therapy (CDT), the program’s unprecedented effectiveness (limb volume reductions up to 70%) led to its adoption as the international standard of care.128 129 130 In addition to acute volume reduction, CDT can improve patients’ quality of life, function, and symptoms, and lessen morbidity.131 132 The distinct but overlapping treatments used to reduce (phase 1) and maintain (phase 2) CRL volume and tissue quality are depicted in figure 4. CDT was developed to manage stage I to stage III lymphedema. Some patients with stage 0 or early stage I CRL, and limited tissue swelling, could initiate treatment with phase 2 maintenance activities and bypass the requirement for phase 1 reduction.

Fig 4

Components of phases 1 and 2 complete decongestive therapy for cancer related lymphedema

Phase 1 CDT is time and human resource intensive. Additionally, lifelong adherence to phase 2 CDT maintenance activities can be challenging for patients. Consequently, efforts to streamline CDT’s requirements while preserving effectiveness have received considerable attention. Several hundred trials have tested CDT phases 1 and 2 components in isolation, and iterations that limit the number of treatment components, as well as their frequency and duration. Some approaches have modified CDT components and added adjuncts (eg, low level light therapy, Kinesio tape, and compression pumps). Figure 5 presents systematic reviews and meta-analyses identified by searching PubMed and CINAHL from 1 January 2015 to 15 February 2025.133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158

Fig 5

Summary of systematic reviews and meta-analyses since 2015 evaluating the effectiveness of manual and behavioral therapy on cancer related lymphedema prevention, reduction, and patient reported outcomes

The systematic reviews and meta-analyses concur that the evidence for manual and behavioral lymphedema therapies is of generally low quality, overwhelmingly collected from breast cancer cohorts (≈95%), and marked by persistent gaps.159 Several noteworthy exceptions are the guideline endorsed recommendations to use: conventional phase 1 CDT to reduce stages II and III lymphedema; individualized and needs matched phase 2 CDT for maintenance of all CRL stages; and resistive exercise for CRL prevention and maintenance.135 159 160

The evidence, as well as expert consensus, provides low to moderate support for several additional recommendations135 159 160: non-standard CDT elements (eg, myofascial release) might be considered as adjuncts during reductive and maintenance CDT, but should not replace conventional CDT components; multicomponent, versus single component treatments are preferred; streamlined versions of CDT could be effective, but evidence is lacking for means to individualize treatment while preserving effectiveness; and CDT modalities should be considered to enhance patient reported outcomes. A problematic knowledge gap persists regarding optimal means of managing stage 0 to I CRL while preserving patients’ quality of life. Compression garments can be effective during this interval when used to prevent or maintain but not reduce CRL. Specific considerations for selecting and using the recommended CDT modalities are discussed below.

Compression garments

Compression garments worn during waking hours are the mainstay of maintenance CDT (phase 2). Garments vary with respect to compression class, extent of coverage, fabric, and cost, with higher compression and made-to-measure flat knit garments being the more difficult to access and fit properly. Flat knit garments are relatively stiff compared with circular knit compression garments and are often prescribed at higher compression classes (eg, ≥30 mm Hg). Badly fitting garments could be poorly tolerated and cause skin irritation and breakdown. Nonetheless, patients with stage II, and most with stage III lymphedema or irregular limb contour, particularly of the lower extremities, might derive greater benefit from custom garments. Also, because of the frequently irregular contour of truncal, breast, genital, and head and neck lymphedema, custom garments are often preferred.

Many challenges to garment use (eg, bulkiness, inability to don and doff, slippage) can be effectively addressed. A few of the approaches used to comfort and convenience include matching garment characteristics with a patient’s activity (eg, reserving higher compression for activities that increase lymph load, as well as use of donning aids and techniques, roll on adhesive, and silicone banding).

Patients’ perceptions of their garments and experiences wearing them are also central treatment considerations.161 162 Breast cancer survivors with CRL who wear garments experience lower quality of life.2 More specifically, among 51 survivors with breast CRL, the 30 who wore compression sleeves reported a more negative impact on health related quality of life in the “pragmatic domain,” mean (SD) among the compression group 0.28 (0.27) versus the non-compression group 0.13 (0.22), P=0.03. Affected subdomains included work activities 23%/0% (P=0.03), embarrassment 33%/5% (P=0.02), feeling discomfort during sports and hobbies 30%/5% (P=0.03), and having to answer questions about the lymphedema 27%/0% (P=0.02). Unfortunately, patients can experience unwelcome attention from their garments.

Some patients require nighttime compression and/or are unable to wear compression garments. Although conventional garments could be used for nighttime compression, “adjunctive” or “alternative” compression devices are often preferred. These devices are of two general types—garments constructed of a thick material (eg, neoprene or canvas) with overlying cinchable velcro straps, and garments fashioned of two layers of fabric with small foam chips stitched between them. Evidence supporting use of either type of adjunctive device is sparse, apart from a randomized, controlled trial reported in 2022.163 Among 120 patients with breast CRL, adding a nighttime adjunctive device to daily use of a compression sleeve reduced limb volume to a degree greater than sleeve use alone (15.9% (22) v 1.5% (18), Pv 12.1% (16), P=0.33). Adjunctive devices could be used as first line therapy when CDT is inaccessible.

Manual lymphatic drainage

Systematic reviews and meta-analyses of manual lymphatic drainage yielded mixed results. Trials included in the systematic reviews and metanalyses were restricted to breast CRL. In this context, the systematic reviews and meta-analyses suggest that patients with mild to moderate CRL might experience greater benefit.148 Inconsistent support for manual lymphatic drainage has led providers to incorporate alternative approaches to stimulate lymph flow and normalize soft tissue (eg, fibrolytic techniques), on an individual basis.159

Exercise

Resistive exercise has been shown to reduce the risk of CRL onset and progression among breast cancer survivors.164 165 The Physical Activity in Lymphedema trial showed a 15% reduction in the incidence of new breast CRL among breast cancer survivors with five or more lymph nodes removed.166 167 Resistance exercise is empirically safe and should be considered integral to preventive and maintenance CRL treatment when it is monitored, performed with compression garments, and initiated and advanced gradually. Aerobic exercise is less studied. Limited evidence suggests that it neither benefits nor adversely affects CRL.168 Integrating diaphragmatic breathing with exercise might augment beneficial effects.135

Compression pumps

Concerns that intermittent pneumatic compression pumps cause proximal fibrosis, as well as genital and truncal edema, lack empirical support.169 The systematic reviews and meta-analyses (fig 5) do not consistently suggest that compression pumps offer benefit during phases 1 and 2 CDT. Nonetheless, most current guidelines mention intermittent pneumatic compression pumps as an adjunctive treatment option while acknowledging the low to very low quality of evidence. Reviews and guidelines do not consistently distinguish between standard intermittent pneumatic compression pumps with one or fewer chambers, advanced pneumatic compression devices with multiple chambers, and non-pneumatic wearable pumps,170 though some suggest that advanced pneumatic compression devices offer modestly improved comfort and volume reduction.135 160

Weight management and dietary approaches

Increased body mass index (BMI) is associated with an increased risk of CRL onset and progression, and diminished health related quality of life in the presence of CRL.18 171 Further, increased BMI places patients at risk for comorbidities that accelerate CRL progression (eg, venous stasis syndrome).172 Weight management is, therefore, an integral component of CRL treatment. However, a previous assumption that weight loss would reduce CRL volume has been effectively challenged. A trial of 351 overweight breast cancer survivors with CRL randomized participants to one of four cohorts: control, exercise, weight loss, or exercise and weight loss. Exercise included a 52 week home based strength and resistance training twice weekly and 180 minutes of walking weekly. The weight loss component included meal replacement therapy for 20 weeks and 52 weeks of lifestyle modifications and counseling. The trial found no evidence of arm volume reduction in any cohort (all P>0.40) at 12 months follow up.173 These results should not be generalized to lower extremity CRL given its greater tendency to rapidly progress.

Drugs

To date, there have not been good pharmacologic agents for the treatment of lymphedema. In the late 1990s, there was interest in benzopyrones, which reduce vascular permeability and decrease fluid in subcutaneous tissues. Coumarin (5,6-benzo-α pyrone) was shown in some studies to be effective in treating lymphedema, however, a prospective study of 140 patients with chronic lymphedema randomized to 200 mg oral coumarin versus placebo twice a day for six months demonstrated no difference between coumarin and placebo and reported liver toxicity in 6% of patients.174 175 A Cochrane review was not able to draw conclusions about the effectiveness of benzopyrenes for lymphedema.175

Recently there has been growing interest in ketoprofen, a unique non-steroidal anti-inflammatory drug, for the management of lymphedema. Ketoprofen possesses dual pathways of inflammatory inhibition, blocking both cyclooxygenase and 5-lipoxygenase. Two small exploratory studies have been performed that show reduced skin thickness and improvements in histopathology with use of ketoprofen.51 Ketoprofen is approved by the US Food and Drug Administration for “chronic forms of inflammation that need an aggressive approach.” Ubeminex (bestatin), a leukotriene A4 hydrolase inhibitor, is more targeted than ketoprofen and is also undergoing evaluation. The ULTRA trial, a phase 2 multicenter, placebo controlled trial of 54 participants with lower extremity lymphedema who received 150 mg bestatin three times daily for 24 weeks, did not meet its primary endpoint of skin thickness and secondary endpoints of limb volume and bioimpedance.176

Other medications in the management of lymphedema are used to treat symptoms. Oral and topical retinoids can help normalize keratinization and decrease inflammatory and fibrotic changes.177 178 Topical emollients and keratolytics (eg, ammonium lactate, urea, and salicylic acid) can be used to help with secondary epidermal changes.

Surgery

Recent advances in microsurgical techniques and surgical equipment have contributed to the renewed interest in surgery to treat lymphedema. Surgical approaches are broadly categorized as those resecting lymphedematous tissue and those reconstructing or improving lymphatic function (table 3). Historically, the Charles procedure was performed, which resects substantial portions of diseased skin and lymphatic tissue with considerable fatty deposition. Contemporary resection techniques tend to favor large bore cannula suction assisted protein liposuction for tissue resection. Suction assisted protein liposuction is effective in removing most of the excess extremity volume,179 and can improve mobility. However, post suction assisted protein liposuction treatment mandates strict lifelong compression therapy to maintain volume reductions because tissue resection does not restore lymphatic function. One study followed 67 patients with lower extremity lymphedema treated with suction assisted protein liposuction followed by continuous compression therapy.180 At five years’ follow-up, the decrease in excess volume was maintained and no major complications were identified. These data confirm the effectiveness of liposuction when patients closely adhere to post-treatment compression therapy.

Table 3

Surgery for cancer related lymphedema prevention and treatment

Functional lymphatic reconstruction options include lymphatic-lymphatic bypass, lymphovenous bypass, and lymph node transfer. These procedures are typically performed in the earlier stages of lymphedema when patients still retain some lymphatic function. The bypass techniques seek to restore or divert lymphatic flow. Lymph node transfer aims to augment lymphatic collateralization. Supplemental VEGF-C (vascular endothelial growth factor-C) could aid in the local integration of the transplanted vascularized lymph node transfer tissue.181 182 Supermicrosurgical lymphaticovenular anastomosis is another new promising technique. Vascularized lymph node transfer can be considered in select cases. A systematic review identified one randomized controlled trial on vascularized lymph node transfer.127 The trial included 36 patients with stage II lymphedema who completed vascularized lymph node transfer or standard of care (conservative management). It found that vascularized lymph node transfer resulted in greater reductions in limb volume (mean pre-post procedure difference −39.00%, 95% confidence interval −47.37% to −30.63%), pain scores (−4.16%, −5.17% to −3.15%), heaviness sensation (−4.27%, −5.74% to −2.80%), mean number of infections per year (−1.22%, −2.00% to −0.44%), and an improvement in overall function scores (−3.77%, −4.89% to −2.65%) though most findings were considered to have very low-certainty evidence.183 The literature is heterogeneous with respect to the indications, timing, and preoperative preparation for these procedures. Further, follow-up and post-surgery care (eg, the need for compression garments or arm mobility/restrictions) are not uniformly standardized, which can make comparison of results and long term durability difficult across studies.

Emerging treatments

Several therapeutic studies are active, including: an open label prophylactic study comparing pravastatin with pentoxifylline/tocopherol in the prevention of fibrosis associated with lymphedema (NCT06494111); a phase II/III double blind, controlled trial testing tacrolimus ointment for lymphedema volume and bioimpedance index (NCT06306274); and a phase II placebo-controlled trial of acebilustat, a leukotriene A4 hydrolase inhibitor, for upper limb lymphedema (NCT05203835). The latter two trials are anticipated to be complete in March 2026 and August 2025, respectively. Design of an implantable pump to bypass injured lymphatics and transport accumulated interstitial fluid to an area with intact lymphatic drainage is ongoing. The first in human study of the pump showed no safety concerns and reductions in limb volume.184

Guidelines

In 2020, the Oncology Nursing Society and the American Physical Therapy Association issued guidelines for managing lymphedema related to cancer treatment and breast cancer, respectively.135 185 The guidelines were based on rigorous systematic reviews and included recommended tools and methods to grade the available evidence. The guideline panels were discipline specific (ie, nurses predominantly developed the Oncology Nursing Society guideline, and physical therapists predominantly developed the American Physical Therapy Association guideline). The guidelines are remarkably consistent about key treatment recommendations. Both endorse monitoring and educating patients that undergo surgery for cancer and initiating tailored exercise programs that include resistance training. Neither guideline endorses the use of prophylactic compression sleeves in the absence of symptoms or swelling. However, the Oncology Nursing Society guideline recommends phase 1 CDT as first line treatment after diagnosis of breast CRL, although the American Physical Therapy Association supports the use of sleeves as first line therapy for stage I and phase 1 CDT for stages II-III breast CRL. Both guidelines endorse integration of compression pumps, and other adjunctive approaches (eg, myofascial therapy, stretching, exercise, and scar massage), but differ between the guidelines.

The International Society of Lymphology renewed its consensus document on The Diagnosis and Treatment of Peripheral Lymphedema in 2020.98 The document provides recommendations for primary and secondary lymphedema and a thorough overview of treatment approaches. However, it is unclear how the evidence was identified, reviewed, and synthesized. Moreover, the absence of an author list and citations for specific recommendations limit the assessment of potential disciplinary bias and inference about the strength of the supporting evidence. The American Venous Forum, American Vein and Lymphatic Society, and the Society for Vascular Medicine consensus on lymphedema from 2022 similarly does not describe the evidence base for its recommendations, which were developed by a well delineated Delphi process among vascular medical and surgical specialists.186

National Institute for Health and Care Excellence (NICE) offers guidance only with regard to interventional procedures for lymphedema. Specifically, NICE endorses liposuction for chronic lymphedema irrespective of etiology.187 For lymphovenous anastomosis to prevent secondary CRL, NICE maintains that the approach can be used in association with axillary node dissection while evidence is being generated, but cautions against considering the procedure with inguinal node dissection outside of a formal research study.188

Most lymphedema treatment guidelines are over five years old and vulnerable to disciplinary bias, with varying degrees of explicit supporting evidence. Guidelines consistently emphasize the importance of interdisciplinary lymphedema management, yet virtually all guidelines reflect the perspectives of individual disciplines. In 2023, the American Cancer Society and Lymphology Association of North America coordinated the development of a manuscript series that advance interdisciplinary recommendations spanning the full gamut of CRL evaluation, diagnosis, monitoring, and treatment.159 189 190 191 192

Conclusion

CRL is a prevalent, chronic condition that can lessen quality of life among people living with and beyond cancer. Early detection and a growing collection of evidence based treatments, particularly resistive exercise, prevent and temporize CRL. Surgical approaches that spare lymphatics for CRL prevention have become standard care, although approaches used to restore lymphatic function are a focus of intense investigative and clinical interest. Manual and behavioral therapies, delivered by an interdisciplinary team, remain the cornerstone of reductive CRL treatment.

Footnotes

Series explanation: State of the Art Reviews are commissioned on the basis of their relevance to academics and specialists in the US and internationally. For this reason they are written predominantly by US authors
Competing interests: none.
Provenance and peer review: Commissioned; externally peer reviewed.
Patient involvement statement: A patient and family advisory committee comprised exclusively of patients living with and beyond cancer, and including patients with lymphedema, provided guidance before preparation of the manuscript regarding aspects of CRL prevention, education, and management that should be included. In addition, they offered patient perspectives about these topics, particularly the burden of current CRL treatments.

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