Lymphedema is a chronic progressive condition resulting from the persistent accumulation of protein-rich interstitial fluid. It occurs when the lymphatic load in a specific region exceeds the lymphatic transport capacity over time. It commonly affects the extremities, with the lower limbs being more frequently involved.
Anatomy and Pathophysiology
The lymphatic system consists of lymphatic vessels and lymph nodes. Capillary lymphatic vessels are present in most tissues and organs, except for structures such as the epidermis, central nervous system, cornea, skeletal muscle, cartilage, and ligaments. These vessels are particularly abundant within the dermis. In the extremities, lymphatic vessels are divided into a superficial and a deep system. The deep lymphatic vessels accompany neurovascular bundles and drain toward the axillary or inguinal regions. Multiple afferent lymphatic vessels enter lymph nodes, and efferent lymphatic vessels, typically singular, exit the nodes. Lymphatic vessels have well-formed outer membranes, a middle layer containing smooth muscle cells, and a thin intima without a basal membrane. The endothelial cells of lymphatic vessels have relatively large gaps, permitting the passage of bacteria, red blood cells, and even lymphocytes. These vessels have autonomous contractile functions, and valves within the vessels direct lymph flow.
Lymphatic vessels serve as a pathway for the return of interstitial fluid, while lymph nodes perform filtering and immunoprotective functions. In normal conditions, the volume of fluid that extravasates from blood vessels exceeds the amount reabsorbed by venules. Approximately 2–4 liters of fluid are returned daily via the lymphatic system to maintain balance. Large molecules in the interstitial fluid, such as proteins, cannot cross the endothelial gaps of capillaries and primarily rely on lymphatic resorption. In pathological conditions, such as increased venous pressure or hypoproteinemia, there is an increase in fluid extravasation and reduced reabsorption. Diseases affecting the lymphatic system itself can directly impair lymphatic absorption and circulation. Both of these scenarios can lead to the accumulation of interstitial fluid and result in edema.
Etiology and Classification
Lymphedema can be classified based on etiology (primary or secondary), pathophysiology (low-output or high-output), genetics (familial or sporadic), or onset timing (congenital or delayed-onset). The most commonly used classification divides lymphedema into two primary categories based on etiology.
Primary Lymphedema
Primary lymphedema can be classified as:
- Congenital: Onset occurs before the age of 1. Cases with a family history are referred to as Milroy disease.
- Early-Onset: The most common presentation, with onset between the ages of 1 and 35. Cases with a family history are termed Meige disease.
- Late-Onset: Onset occurs after the age of 35. The exact cause remains unclear but may be related to fibrotic obstruction or lymphatic dysfunction, including impaired contraction and emptying.
Secondary Lymphedema
Common causes include lymphatic system disruption due to surgery or trauma, fibrosis following radiation therapy, lymphatic infiltration or obstruction caused by tumors, chronic bacterial infections, and parasitic infections. Axillary lymph node dissection and postoperative radiotherapy for breast cancer are frequent causes of upper limb lymphedema. Pelvic tumors can lead to lymphatic infiltration or obstruction in the pelvic region, resulting in lower limb lymphedema. Repeated infections (e.g., Group B hemolytic streptococcus, or in rare cases, staphylococcus) can cause fibrotic obstruction of lymphatic vessels, eventually leading to lymphedema in the affected limb. In areas endemic for filariasis or with high rates of tuberculosis, these diseases remain significant causes of lymphedema.
Clinical Manifestations
Congenital lymphedema is more common in males and often involves both lower limbs simultaneously. Early-onset lymphedema is more prevalent in females, typically presenting unilaterally in a lower limb and usually not extending beyond the knee. In late-onset cases, approximately half of the patients have a history of infection or trauma preceding the onset.
Key clinical features are as follows:
- Edema: Chronic, progressive, painless edema that extends from the distal to the proximal extremity and can involve the genitals or internal organs.
- Skin Changes: Mild redness and slightly elevated skin temperatures are observed. Over time, the skin becomes progressively thicker, develops a lichenified or peau d’orange (orange peel-like) texture, and may exhibit warty hyperplasia. In later stages, the limb presents a characteristic "elephantiasis" appearance.
- Secondary Infections: Most cases are caused by Group B hemolytic streptococcal infections, leading to cellulitis or lymphangitis, presenting with localized redness, swelling, heat, pain, and systemic infection symptoms.
- Ulceration: Chronic ulcers that fail to heal may develop after minor skin trauma.
- Malignancy: Rarely, patients may develop lymphangiosarcoma.
The disease progression is typically staged as follows:
- Latent Stage: Early accumulation of interstitial fluid and perilymphatic fibrosis occur without noticeable limb swelling.
- Stage I: Pitting edema is present, which partially or completely resolves with limb elevation. No significant skin changes are observed.
- Stage II: Non-pitting edema develops, and edema does not resolve with elevation. Skin begins to show signs of fibrosis.
- Stage III: Irreversible edema occurs, accompanied by recurrent infections and fibrosis or sclerosis of the skin and subcutaneous tissues. The affected limb adopts the characteristic "elephantiasis" appearance.
Examinations and Diagnosis
Clinical diagnosis is not difficult with the help of medical history and physical examination. Primary lymphedema is characterized by chronic progressive painless limb edema, and classification can be based on the age of onset and family history. Secondary lymphedema is typically linked to an identifiable cause. Advanced cases often present with "elephantiasis." Further examination aims to assess the type, location, cause, and severity of the lymphatic obstruction. The main diagnostic methods are as follows:
Lymphoscintigraphy
Using radiolabeled colloids (e.g., 99mTc, 198Au, or 131I-labeled human serum albumin) injected subcutaneously, lymphatic absorption and proximal lymphatic flow can be tracked with a gamma camera. A diagnosis can be based on findings such as accumulation of tracer at the injection site, delayed or absent visualization of lymphatic vessels and nodes, lymphatic vessel dilation, or retrograde flow from lymphatic vessels into the skin.
Fluorescence Microlymphography
Using subcutaneous injection of indocyanine green, the lymphatic drainage pathway can be traced in real-time under fluorescent light illumination. This method provides insights into the direction and pathway of lymphatic drainage, the site of blockage, and retrograde skin flow.
Lymphangiography
This invasive procedure, less commonly used due to potential adverse reactions, involves direct imaging of lymphatic vessels.
CT and MRI
These imaging techniques are often used to diagnose or exclude local pathological changes that may cause secondary lymphedema or high-output lymphedema. They can also help evaluate the characteristics of local tissue.
Prevention and Treatment
The early diagnosis, intervention, and treatment of lymphedema play a critical role. The primary goals of treatment are to preserve function, reduce physical and psychological distress, and prevent skin damage and infections. While there is no known preventive method for primary lymphedema, secondary lymphedema incidence can be reduced through measures such as the prevention and prompt treatment of cellulitis or erysipelas in the affected limbs, minimizing the extent of lymphatic tissue removal for diagnostic or therapeutic purposes, and controlling infectious diseases such as filariasis or tuberculosis.
Non-Surgical Treatments
Elevation of the affected limb, local skin care, avoidance of trauma, appropriate use of venotonic medications, and wearing gradient compression elastic stockings are critical.
Pneumatic compression devices sequentially compress the limb starting from the distal end toward the proximal end to promote lymphatic drainage.
Manual lymphatic drainage therapy involves gentle massage starting proximally at the edematous area to reduce fluid accumulation before gradually expanding to the distal regions.
Heat compression therapy involves the use of thermal effects (60–80°C) from devices such as radiation heat therapy machines to promote lymphatic drainage, lymphatic vessel regeneration, and patency. Elastic bandages are used for compression wrapping after the therapy.
Surgical Treatments
Surgical treatment for lymphedema is typically palliative rather than curative. Long-term postoperative compression therapy remains essential for achieving favorable outcomes.