What causes lymphedema?

Causes of Lymphedema

Lymphedema is primarily caused by dysfunction or damage to the lymphatic system, resulting in impaired lymphatic drainage and subsequent accumulation of lymph fluid in the interstitial tissues. 1, 2

Primary vs. Secondary Lymphedema

Primary Lymphedema

• Results from abnormal development and/or functioning of the lymphatic system 3
• Genetic in origin, with mutations in genes involved in:
  • Initial formation of lymphatic vessels and valves
  • Growth and expansion of the lymphatic system
  • Associated developmental pathways 3
• Can present at birth or develop later in life
• May occur in isolation or as part of a syndrome 3
• Causative mutation is identified in only about one-third of affected individuals 3

Secondary Lymphedema

• Caused by damage to the lymphatic system due to external factors 2
• Major risk factors include:
  • Lymph node removal (5+ nodes), with full axillary lymph node dissection carrying higher risk than sentinel node biopsy 1
  • Radiation therapy, especially to cervical and facial regions, supraclavicular lymph nodes, axilla, and internal mammary lymph nodes 1
  • Obesity, a significant risk factor for both development and worsening of lymphedema 1
  • Infections that damage lymphatic vessels 2
  • Surgery, particularly cancer surgeries involving lymph node removal 2
  • Trauma to lymphatic vessels 2

Pathophysiological Mechanisms

Lymphatic vessel damage or obstruction leads to a cascade of events:

1. Lymphatic fluid stasis - The initial event following lymphatic system impairment 2

2. Inflammatory response:

   • CD4+ T cells are principal contributing factors
   • Disruption of the VEGF-C/VEGFR axis, resulting in abnormal lymphangiogenesis
   • Leukotriene B4 has been identified as a key molecule in lymphedema pathogenesis 4, 2

3. Tissue changes:

   • Adipocyte hypertrophy and adipose tissue deposition regulated by CCAAT/enhancer-binding protein α and peroxisome proliferator-activated receptor-γ 2
   • Tissue fibrosis initiated by overactivity of Th2 cells, leading to secretion of profibrotic cytokines (IL-4, IL-13) and growth factor TGF-β1 2

4. Skin manifestations:

   • Edema, redness, and heat
   • "Peau d'orange" appearance due to superficial cutaneous edema surrounding hair follicles
   • Development of vesicles, bullae, and cutaneous hemorrhage 1

Special Considerations

• In rare cases, lymphedema can be a symptom of other conditions, such as tuberous sclerosis complex (TSC) 5
• Chronic lymphedema increases risk for recurrent infections, which can further damage lymphatic vessels, creating a vicious cycle 1
• Without proper management, lymphedema typically worsens over time and can lead to significant reduction in quality of life 3

Clinical Implications

• Early recognition and intervention are essential to prevent progression
• Weight management is crucial for prevention in at-risk patients
• Meticulous skin care helps prevent complications like infections
• Complete decongestive therapy (CDT) is the most effective treatment approach 1

Lymphedema is a chronic condition that requires ongoing management to prevent complications and maintain quality of life. Understanding the underlying cause is essential for appropriate treatment planning and patient education.