Aetiology

Lymphoedema results from the inability of the lymphatic system to transport lymph fluid. Approximately 80% of lymphatic drainage must be non-functional before lymphoedema becomes clinically evident.[18] Secondary lymphoedema is most common, and develops when previously intact lymphatics are obstructed or sustain damage.[1]​ Abnormal lymph flow may result from lymphatic hypoplasia, obstruction, or fibrosis. Infection (filariasis), malignancy, cancer-related treatment, obesity, surgery, or trauma are responsible for the majority of cases of lymphoedema worldwide.[5][10]

Parasitic nematodes, such as Wuchereria bancrofti and Brigia malayi, spread by a mosquito vector cause lymphatic filariasis by obstructing lymphatic channels directly or by regional inflammation.​​ As of 2018, there were approximately 51 million people in mosquito-endemic regions with lymphatic filariasis.[9]​ Lymph node dissection, radiotherapy, or neoplastic infiltration can injure the lymphatic system (e.g., pelvic masses or node dissection can lead to lymphoedema of the lower extremity or genitalia).[19] Significant penetrating trauma, particularly to the axilla or groin, can cause damage to the lymphatic system with consequent lymphoedema. In addition, curvilinear scars may retain lymph fluid, resulting in a raised, swollen area and scar lymphoedema.[20]

Primary lymphoedema is a rare disease due to abnormal development or hypofunctioning of the lymphatic system.[2] Primary lymphoedema is mostly sporadic; however, it can present as familial or syndromic lymphoedema.[2] Approximately 25% of all primary lymphoedemas are caused by known gene mutations.[21] More than 20 different genes (including: VEGFR-3, CCBE1, FOXC2, GATA2, GJC2, PTPN14, SOX18, CCBE1, FAT4, ADAMTS3, FBXL7, GJC2, KIF11, ITGA9, REEKIN, PIEZO1, EPHB4, CALCRL, and CELSR1) have been associated with anomalies in the lymphatic system.[5] Causative mutations in some lymphoedema-associated syndromes are: Milroy's disease (VEGFR3), lymphoedema-distichiasis syndrome (FOXC2), hypotrichosis-lymphoedema-telangiectasia (SOX18), and Hennekam syndrome (CCBE1).[2][22][23][24][25][26]

Autosomal-dominant inheritance is most common (e.g., Milroy's disease, Meige's disease, lymphoedema-distichiasis syndrome), but autosomal-recessive inheritance can also occur (e.g., hypotrichosis-lymphoedema-telangiectasia, Hennekam syndrome).[2] Several other conditions (e.g., Noonan syndrome, Turner syndrome) also have an increased risk of primary lymphoedema.[2]

Pathophysiology

Lymphatic channels are endothelium-lined vessels derived from outpouching of veins with distal to proximal flow. Superficial and deep lymphatic channels drain proteinaceous fluid (lymph) into regional lymph nodes. The lymphatic system returns interstitial fluid and proteins to the circulatory system.[27] Particulate matter and microorganisms are filtered at lymph nodes for immunological presentation.[28]

Pathophysiology of lymphoedema is complex, and incompletely understood.[1]​ Dysfunction of channels or nodes leads to lymph accumulation in the superficial interstitial space. Mechanical insufficiency of the lymphatic system may occur secondary to a number of mechanisms including hypogenesis or agenesis of lymphatic vessels, impaired lymphatic pump activity, inflammatory response, lymphatic obstruction, or surgical removal of lymph nodes.[10]​ Additionally, in lymphoedema associated with cancer, there is an increasing body of evidence to suggest that the cancer itself may have a direct effect on lymphatic pumping mechanisms.[29][30]

Lymphatic stasis leads to fat hypertrophy, with associated thickening of subcutaneous tissue, as well as immunological dysfunction.[31] Elevated concentrations of interstitial protein cause inflammation and fibrosis, leading to a cycle of further damage.[32]

Classification

Types of lymphoedema

Primary lymphoedema is an intrinsic defect in the lymphatic system that can present in isolation or as part of a syndrome.[2] The lower extremities are most commonly involved. It is classified based on the age of onset.[3][4]

  • Infancy: most common in males, usually bilateral, Milroy's disease is a known subset with a familial pattern of inheritance.

  • Childhood: least common time of onset.

  • Adolescence: most common in females, usually unilateral, Meige's disease is a known subset with a familial pattern of inheritance.

  • Adulthood: rare form of primary lymphoedema.

Secondary lymphoedema occurs after injury to the lymphatic system, usually due to infection (filariasis), malignancy, cancer-related treatment, obesity, surgery, or trauma.[5]

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