What causes lymphedema?

Causes of Lymphedema

Lymphedema is primarily caused by abnormalities or damage to the lymphatic system, resulting in the accumulation of interstitial fluid and fibroadipose tissue in affected body parts. 1

Primary Lymphedema

Primary lymphedema results from congenital or developmental abnormalities of the lymphatic system:

• Congenital malformations that develop during the later stages of lymphangiogenesis 2
• Genetic mutations affecting the formation of lymphatic vessels and valves (identified in approximately one-third of cases) 3
• Structural defects including:
  • Congenital aplasia of the thoracic duct or cisterna chyli 4
  • Congenital lymphatic valvular incompetence 4
  • Reduced number of lymphatics (hypoplasia) 4

Secondary Lymphedema

Secondary lymphedema is more common and results from damage or obstruction to a previously normal lymphatic system:

• Cancer treatment-related causes:

  • Surgical lymph node dissection (especially axillary lymph node dissection for breast cancer) 1
  • Radiation therapy (particularly to the supraclavicular lymph nodes or axilla) 1
  • Risk is lower with sentinel lymph node biopsy compared to full axillary dissection 1

• Other causes:

  • Trauma to lymphatic vessels 5
  • Infections (particularly recurrent cellulitis) 1
  • Inflammatory conditions affecting lymphatic vessels 6
  • Parasitic infections (filariasis - most common cause worldwide) 4
  • Malignant obstruction of lymph nodes or vessels 4

Pathophysiological Mechanisms

The development of lymphedema involves several key processes:

• Lymphatic fluid stasis following vessel damage or obstruction 6
• Inflammatory response involving CD4+ T cells 6
• Abnormal lymphangiogenesis due to disruption of the VEGF-C/VEGFR axis 6
• Progressive fibrosis of affected tissues initiated by Th2 cells and profibrotic cytokines 6
• Adipose tissue deposition and adipocyte hypertrophy 6

Risk Factors

Several factors increase the risk of developing lymphedema:

• Obesity (BMI >30 kg/m²) - significant risk factor that can also complicate diagnosis 1, 5
• Extent of lymph node dissection (five or more lymph nodes removed increases risk) 1
• Combined treatment with surgery and radiation therapy 1
• Recurrent infections in the affected area 1

Clinical Presentation and Diagnosis

Lymphedema presents with distinctive features:

• Swelling that may be unilateral (common in secondary lymphedema) or bilateral 1
• Positive Stemmer sign (inability to lift skin fold at the base of the second toe or finger) 1
• Lack of response to elevation or diuretics, unlike other forms of edema 5
• Progressive worsening if untreated, with increased risk of cellulitis 1

Common Pitfalls in Diagnosis

• Failure to differentiate lymphedema from other causes of edema (cardiac, renal, hepatic) 1
• Obesity can cause false-positive Stemmer sign 1
• Delayed diagnosis leading to progression and complications 5
• Misattribution of symptoms to other conditions 5

Understanding the underlying causes of lymphedema is crucial for proper diagnosis, management, and prevention of complications that can significantly impact quality of life 1, 3.