Lymphedema

Lymphedema is a complex condition with ongoing evolution in medical and surgical management. As our understanding advances, new treatment approaches continue to shape patient care. Here, we present a comprehensive approach to lymphedema management, highlighting the strategies and techniques commonly employed by our institution. Additionally, we integrate insights from current literature to provide a well-rounded perspective on best practices and emerging therapies.

Key points

•
Lymphedema is a chronic condition that causes the accumulation of lymphatic fluid, leading to swelling and discomfort.
•
Advances in imaging techniques like indocyanine green lymphography and magnetic resonance lymphography have improved diagnosis and treatment planning.
•
Complete decongestive therapy remains the standard medical treatment, while research into pharmacologic therapies continues.
•
Surgical options including lymphovenous bypass, vascularized lymph node transplant, debulking procedures, address different aspects of the disease and offer improvement through distinct mechanisms.

Abbreviations

CDT	complete decongestive therapy
ICG-L	indocyanine green lymphography
LVB	lymphovenous bypass
MR-L	magnetic resonance lymphography
UHFUS	ultrahigh-frequency ultrasound
VLNT	vascularized lymph node transplant

Background

Lymphedema is a chronic and progressive condition characterized by the abnormal accumulation of lymphatic fluid, most often in the arms or legs, resulting in swelling, heaviness, and discomfort. In addition to these physical symptoms, lymphedema can lead to a host of secondary complications, including skin infections, reduced mobility, and diminished quality of life. The condition can be broadly categorized into 2 forms: primary lymphedema, which is typically congenital or inherited, and secondary lymphedema, which is more commonly acquired due to trauma, surgery, or radiation therapy—often as a result of cancer treatments.

Historically, the management of lymphedema focused largely on symptom control and patient education, with limited options available for long-term relief. However, advancements in both medical and surgical approaches to lymphedema management over the past few decades have led to significant improvements in patient outcomes. Modern treatment strategies involve a comprehensive, multidisciplinary approach that integrates weight management, physical therapy, compression therapy, and infection prevention. Additionally, the development of advanced surgical options, such as vascularized lymph node transplant (VLNT) and lymphovenous bypass (LVB) procedures together with debulking surgeries, offers promising solutions for patients with more severe cases. In addition, advancements in diagnostic techniques have enhanced early detection and tailored treatment.

This review aims to synthesize current knowledge on the diagnosis and treatment of lymphedema, highlighting recent therapeutic advances and clinical practices.

Diagnosis

Clinical Assessment

Accurate diagnosis is a critical aspect of lymphedema management. A comprehensive patient history is essential to identify potential contributing factors such as previous cancer, trauma, or surgical interventions that could lead to lymphedema. The physical examination should focus on assessing the affected limb, determining whether the swelling is primarily due to fluid or fat accumulation, and evaluating for the presence of pitting edema. The Stemmer sign—difficulty lifting the skin off the base of the second toe or finger—is a key diagnostic indicator of lymphedema.

In cases where the patient’s history is clear, such as a history of breast cancer, axillary lymph node dissection, and radiation therapy followed by upper limb swelling and heaviness, the history and physical examination may be sufficient for diagnosis. However, for patients without such a straightforward history, the differential diagnosis for limb swelling can be broad. In these cases, imaging studies play a crucial role in determining whether the symptoms are lymph-related. Recent advancements in imaging technologies have greatly enhanced the accuracy of lymphedema diagnosis and have enabled more effective surgical treatments.

Lymphoscintigraphy

Radionuclide lymphoscintigraphy has long been considered the gold standard for diagnosing lymphedema. The procedure involves injecting a radiotracer, typically Technetium-99, into the web spaces of the upper or lower extremity. Serial images are then captured to track the tracer’s movement through the lymphatic system, allowing for the visualization of lymphatic drainage patterns using a gamma camera. While this imaging technique is invaluable in diagnosing lymphedema, it is limited by several factors: its time-consuming nature, often poor image resolution, and its inability to provide detailed anatomic information about the lymphatic channels, which hinders surgical planning, especially for procedures like LVBs. Given these limitations, new advances in imaging technologies have emerged to address these shortcomings.

Indocyanine Green Lymphography

The rise of physiologic surgeries for lymphedema has fueled increased interest in developing imaging techniques capable of accurately identifying functional lymphatic channels. Indocyanine green lymphography (ICG-L) has emerged as a highly valuable tool for locating functional lymphatic vessels, which is crucial for determining the optimal sites for LVB procedures. ICG-L utilizes near-infrared light to capture the fluorescence of the injected indocyanine green dye, providing real-time imaging of lymphatic vessels, and has become a widely adopted diagnostic tool, aiding in both staging and treatment planning by revealing lymphatic drainage patterns when the dye is injected into the intradermal web spaces.

Several staging systems have been developed based on ICG-L imaging. Yamamoto and colleagues classified lymphedema severity based on the extent of dermal backflow seen, ranging from a linear pattern with no backflow (stage 0) to diffuse extensive dermal backflow (stage V). Similarly, Chang and colleagues outlined 4 stages based on extent of dermal backflow seen on ICG-L, while additionally incorporating the presence of patent lymphatic channels amenable for bypass.

These classification systems have proved invaluable in helping surgeons determine the most appropriate treatment strategies. Patients with early stage disease may still be candidates for LVB, whereas those without patent channels seen in ICG-L may benefit more from VLNT. Additionally, ICG-L plays a crucial role in preoperative planning by identifying areas for LVB and can be used intraoperatively to guide the surgeon in choosing incision sites.

Despite its many advantages, ICG-L has limitations, including its inability to penetrate enough to visualize the deep lymphatic circulation, and it provides limited information regarding the fluid-to-fat ratio in the limb.

Magnetic Resonance Lymphography

Magnetic resonance lymphography (MR-L) uses a water-soluble gadolinium-based contrast agent injected into the intradermal web spaces of the limb. A combination of 2 imaging sequences are employed, a T2-weighted fat-suppressed sequence highlighting areas of dermal backflow and edema together with a 3 dimensional T1 sequence that captures the lymphatic channels themselves. ^, This combined imaging approach enables the surgeon to assess both the extent and severity of lymphedema, while also identifying the lymphatic channels and nodes and distinguishing between fatty and fluid tissue composition in the affected limb. In addition to revealing changes in the lymphatics, MR-L also provides insight into alterations in the surrounding skeletal muscle and other secondary lymphedema-related changes.

While MR-L is less commonly used than ICG-L, it remains a powerful tool for staging lymphedema and assisting in surgical decision-making. It provides crucial information on fluid-to-fat ratios, which can significantly influence treatment options. For example, a fat-dominant extremity may be better suited for debulking procedures, while a fluid-dominant one might be a candidate for LVB or VLNT. Like ICG-L, MR-L can also help determine when bypass surgery is not appropriate, guiding clinicians toward VLNT instead.

Despite its advantages, MR-L is an expensive and time-consuming technique, which can limit its accessibility in certain settings.

Ultrasound

In recent years, ultrahigh-frequency ultrasound (UHFUS) has gained increasing attention as a promising tool for improving the selection of lymphatic vessels in lymphedema surgery. This advancement follows the study of Hayashi and colleagues in 2015, who pioneered the use of high-frequency ultrasound probes operating around 19 MHz to map lymphatic vessels. Since then, ultrahigh frequency probes have been developed with frequencies up to 70 MHz, allowing for a more detailed and precise assessment of lymphatic vessels compared to earlier methods.

UHFUS is particularly useful in guiding surgical decisions, as it provides critical information about the quality of lymphatic vessels. One of the key factors in the success of LVB is the condition of the lymphatic vessel itself. In the early stages of lymphedema, vessels dilate due to increased pressure, but as the condition progresses, they may become sclerotic, with thickened walls and occluded lumens. UHFUS has shown promise in visualizing the degree of vessel dilation and wall thickening, offering a noninvasive method to assess the lymphatic structure before surgery. This feature enables the identification of optimal surgical sites, ultimately improving the accuracy and success of LVB. However, the widespread use of this modality has been hindered by its steep learning curve and significant reliance on operator skill.

Medical management

Complete Decongestive Therapy

Once a definitive diagnosis of lymphedema has been made, all patients should be promptly referred to a licensed lymphedema therapist to initiate complete decongestive therapy (CDT). Recognized as the gold standard for first-line medical treatment of lymphedema, CDT consists of 2 distinct phases. In the initial phase, patients follow an intensive treatment regimen, involving regular sessions with the therapist for manual lymphatic drainage and bandage wrappings. This phase typically lasts around 6 weeks, during which the primary objective is to manually reduce excess fluid from the lymphatic system and decrease the size of the affected extremity. Upon completion of this phase, patients transition to the maintenance phase. The focus of this phase is to sustain the limb’s size posttreatment through consistent use of custom-fitted compression garments, diligent skin care, weight management, and prevention of infection. Numerous studies have shown that CDT not only improves the symptoms of lymphedema but also enhances overall quality of life for patients. ^,^,

Pharmacotherapy

Given the debilitating nature of lymphedema, there has been significant interest in developing pharmacologic treatments for the disease. Despite extensive research, no therapies have yet been approved to specifically target nonfilarial lymphedema. Several potential agents, including anti-inflammatory, antifibrotic, and lymphangiogenic therapies, have been proposed, each targeting different aspects of the condition.

Research into lymphangiogenic therapies has primarily focused on the expression of growth factors, particularly vascular endothelial growth factor C (VEGF-C), which plays a crucial role in both angiogenesis and lymphangiogenesis. The potential of VEGF-C for treating lymphedema has been investigated through various delivery methods, including topical formulations, hydrogels, and gene therapy, with studies demonstrating improved lymphatic vessel regeneration in both primary and secondary lymphedema models. Despite these promising results, challenges persist, such as the high cost of recombinant VEGF-C and the need for more efficient delivery systems. Additionally, concerns have been raised about VEGF-C’s potential to worsen interstitial fluid accumulation in already lymphedematous tissues, as well as its role in tumor progression, given its involvement in promoting metastasis in cancers like breast cancer.

Ketoprofen, a nonsteroidal anti-inflammatory drug, has been explored as a potential treatment of lymphedema. In mouse models, ketoprofen injections effectively reduced tail volume, epidermal thickening, and neutrophil infiltration. This promising preclinical data led to a clinical trial in humans, where oral ketoprofen improved histopathological markers in patients with lymphedema, though it did not impact limb volume or extracellular fluid. However, concerns have been raised regarding the long-term use of ketoprofen due to potential side effects, including stomach ulcers and kidney injury.

Other agents explored for lymphedema treatment include selenium, platelet-rich plasma, pentoxifylline, Vitamin E, and stem cell therapy. ^,^,^, However, evidence supporting their efficacy is limited, and additional research is needed to assess their reliability and long-term effectiveness in treating lymphedema. Doxycycline, primarily used to treat filarial infections worldwide, has also shown promise in alleviating lymphedema symptoms, even in the absence of a filarial infection. Its mechanism of action is thought to be more related to its anti-inflammatory properties than its antimicrobial effects, with studies suggesting it could be a valuable adjunct in the management of lymphedema. ^,

Surgical management

Once medically optimized, select patients may be considered for surgical management of lymphedema. Surgical options generally fall into 2 categories: (1) physiologic procedures and (2) debulking procedures. Physiologic surgeries focus on the lymphatic system itself, aiming to reroute or regenerate the lymphatic network, while debulking procedures are ablative, seeking to reduce the size of the affected extremity directly. Limb swelling in lymphedema can be driven primarily by fluid retention or by fatty deposition. Patients with swelling mainly caused by fluid accumulation tend to benefit more from physiologic procedures, whereas those with advanced lymphedema and significant fatty deposition are often better served by debulking surgery. As our understanding of lymphedema progresses, we recognize that a patient’s condition may involve varying degrees of fluid accumulation and fatty deposition, and in some cases, a combination of both surgical approaches may offer the most benefit.

Physiologic procedures

Lymphovenous Bypass

LVB is a surgical technique designed to restore lymphatic flow by creating direct connections between lymphatic vessels and nearby veins. The goal of LVB is to bypass damaged or obstructed lymphatic pathways, allowing lymph fluid to drain into the venous system. Candidacy for LVB is typically evaluated using advanced imaging techniques such as ICG lymphography or UHFUS, which allow for direct assessment of the lymphatic channels to determine their presence and patency. ^, Patients with early stage lymphedema, who still retain some integrity in their lymphatic network, are usually the best candidates for LVB ( Fig. 1 ). However, as the disease progresses and the lymphatic system degenerates, channels amenable to bypass may no longer be available, and in such cases, alternative treatments, such as VLNT, may be more appropriate.

A series of four lymphangiographic photos shows the progressive stages of lymphatic vessel dysfunction and increasing dermal backflow in the arm. — Fig. 1

Techniques on LVB have been previously published ( Fig. 2 ). Studies have demonstrated significant reduction in limb volume following the procedure as well as improvement in quality of life. Winters and colleagues demonstrated a 29% reduction in limb volume at 6 months and 3% reduction at 12 months, accompanied by an increase in quality-of-life scores. Chang and colleagues demonstrated subjective symptomatic improvement by 96% of patients, and a 42% volume reduction at 12 months. Additionally, Mihara and colleagues studied 95 patients and found a significant reduction in cellulitis episodes in patients who underwent LVB.

A surgical photo shows a small vein graft with sutures placed over a supporting grid during microsurgical reconstruction. — Fig. 2

The indications for LVB have expanded in recent years. Patients with head and neck lymphedema have been proposed as potential candidates for the procedure, with several case reports published of the efficacy of LVB in treating these conditions. However, no high-quality evidence exists to date. ^,^, Additionally, evidence for prophylactic LVB is mounting, with numerous studies demonstrating its efficacy in reducing the risk of breast cancer-related lymphedema by rates as high as 20% to 30%. ^, Recent studies have also proposed its potential benefits in other solid tumors, such as melanoma and sarcoma, though further studies are needed to fully assess its oncologic safety in these contexts. ^, Looking ahead, emerging data suggest that LVB may even have potential in treating Alzheimer’s disease, although this field of study is still in its early stages and more research is necessary to confirm its efficacy in these areas. ^,

Vascularized Lymph Node Transplant

In patients with advanced lymphedema for whom LVB is no longer an option, VLNT provides an alternative physiologic treatment. While the exact mechanism by which VLNT improves lymphedema is not fully understood, 2 primary pathways have been identified. The first is lymphangiogenesis, where the transplanted lymph nodes release growth factors, particularly VEGF-C, which stimulates the formation of new lymphatic vessels. The second pathway involves a “pumping” mechanism whereby the transplanted tissue absorbs the interstitial fluid that has accumulated in the limb, and redirects it into the systemic circulation through the inherent lymphovenous shunt within the nodes. ^,^,^,^,^,

Various donor sites for vascularized lymph node transplant (VLNT) have been described in the literature. The selection of the donor site depends on the specific case and the surgeon’s preference. The groin flap is particularly popular due to its consistent anatomy, favorable scar appearance, and its ability to be combined with abdominal flaps for breast reconstruction. However, concerns have been raised regarding the potential development of donor site lymphedema after harvesting this tissue. To minimize this risk, surgeons should be cautious to limit their dissection superficial to the deep fascia and avoid dissection medial to the femoral artery or inferior to the groin crease. Additionally, studies have recommended using reverse lymphatic mapping to prevent the removal of lymph nodes that drain the lower limb. ^,

Other potential donor sites for VLNT include the supraclavicular basin, groin, omentum, lateral thoracic, and mesenteric nodes. In the senior author’s practice, the supraclavicular lymph nodes are most commonly used for treating lower extremity lymphedema, while lateral thoracic nodes are preferred for upper extremity lymphedema. Groin lymph nodes are typically reserved for cases where breast reconstruction is combined with lymphedema treatment, or when the preferred aforementioned donor sites are unavailable for harvest ( Fig. 3 ). Regardless of the selected donor site, a critical factor for the success of VLNT is performing a thorough scar release at the recipient site in patients with secondary lymphedema who have a history of prior surgery or radiation. This step is vital to create a healthy wound bed, promote lymphangiogenesis, and facilitate venous decompression.