What is the cause of lymphedema?

Causes of Lymphedema

Lymphedema results from abnormalities or damage to the lymphatic system, leading to accumulation of interstitial fluid and fibroadipose tissue in affected body parts. 1, 2

Primary Lymphedema

• Primary lymphedema stems from congenital lymphatic system abnormalities that disrupt the development or functioning of the lymphatic vessels and nodes. 1
• This form is thought to have a genetic origin in most cases, with mutations identified in genes involved in lymphatic vessel formation, valve development, and lymphatic system growth and expansion. 3
• Primary lymphedema can present at birth or develop later in life, and may occur in isolation or as part of a syndrome (such as Turner syndrome or Noonan syndrome). 4, 3
• A causative genetic mutation is identified in only about one-third of affected individuals despite the presumed genetic etiology. 3

Secondary Lymphedema

Secondary lymphedema develops from acquired damage to the lymphatic system through several mechanisms:

Cancer Treatment-Related Causes

• Surgical lymph node dissection is a major cause, particularly axillary lymph node dissection for breast cancer, with lymphedema incidence ranging up to 25-40% depending on additional risk factors. 5, 2
• The extent of lymph node removal is critical—five or more nodes removed substantially increases the risk. 1, 2
• Sentinel lymph node biopsy carries significantly lower risk compared to full axillary dissection. 1, 2
• Radiation therapy, especially to supraclavicular lymph nodes or axilla, causes or exacerbates lymphedema by damaging lymphatic vessels. 1, 5, 2
• Combined treatment with both surgery and radiation therapy further increases risk. 2

Other Acquired Causes

• Recurrent infections in the affected area damage lymphatic structures and increase lymphedema risk. 1, 2
• Trauma to lymphatic vessels can result in secondary lymphedema. 4
• Roundworm infections, particularly filariasis, represent a deteriorating consequence leading to acquired lymphedema in endemic regions. 6

Pathophysiologic Mechanisms

Once lymphatic vessel damage or obstruction occurs, three key mechanisms drive lymphedema development:

• Inflammation involving CD4+ T cells as the principal contributing factor, with immune cell effects on the VEGF-C/VEGFR axis resulting in abnormal lymphangiogenesis. 7
• Adipocyte hypertrophy and adipose tissue deposition regulated by the interaction of CCAAT/enhancer-binding protein α and peroxisome proliferator-activated receptor-γ. 7
• Tissue fibrosis initiated by overactivity of Th2 cells, leading to secretion of profibrotic cytokines (IL-4, IL-13) and transforming growth factor TGF-β1. 7

Key Risk Factors

• Obesity (BMI >30 kg/m²) is a significant risk factor that also complicates diagnosis. 5, 2
• Lymphedema may occur immediately after treatment or develop years later. 1
• Progressive worsening occurs if left untreated, with increased risk of cellulitis that can further exacerbate the condition. 1, 2

Critical Clinical Pitfall

• Failing to differentiate between lymphedema and other causes of edema (such as lipedema or venous insufficiency) leads to delayed diagnosis and inappropriate treatment. 1, 2
• Lymphedema presents with a positive Stemmer sign and does not respond to elevation or diuretics, distinguishing it from other forms of edema. 1, 2