Lymphatic malformations

Isolated Lymphatic Malformations

• Macrocystic: Contain cysts greater than 2 cm³ in volume
• Microcystic: Contain cysts smaller than 2 cm³ in volume
• Mixed Macro-microcystic: Contain both macrocystic and microcystic components
• Angiokeratoma: Small superficial lesions with lymphatic and vascular components

Complex Lymphatic Malformations

• Generalized Lymphatic Anomaly (GLA): Widespread lymphatic involvement
• Kaposiform Lymphangiomatosis (KLA): Characterized by spindle-shaped lymphatic endothelial cells
• Gorham-Stout Disease (GSD): Progressive bone resorption with lymphatic proliferation
• Central Conducting Lymphatic Anomaly (CCLA): Abnormalities of the central lymphatic system

Lymphedemas

Primary lymphedema:

• Isolated
• Syndromic (including RASopathy-associated)

Secondary lymphedema:

• Acquired due to damage, obstruction, or removal of lymphatic vessels

PIK3CA Mutations

Somatic activating mutations in the PIK3CA gene are found in approximately 75-80% of lymphatic malformations. These are non-inherited mutations that occur specifically in lymphatic endothelial cells during embryonic development.

The PIK3CA gene encodes a subunit of phosphatidylinositol 3-kinase (PI3K), which regulates cell growth through the PI3K/mTOR pathway. Activating mutations lead to abnormal cell proliferation and lymphatic vessel development. The mutations are specifically localized to the lymphatic endothelial cells lining the malformed vessels, not to surrounding tissues.

Syndromic Associations

Lymphatic malformations may also occur as part of genetic syndromes, including:

• Noonan syndrome
• Turner syndrome
• Down syndrome (trisomy 21)
• Trisomies 13 and 18

Complications

While lymphatic malformations are benign (non-cancerous), they can cause significant symptoms and complications that substantially impact quality of life:

• Recurrent infections: Cellulitis and lymphangitis can cause severe pain, swelling, and systemic illness. These infections may be recurrent and difficult to treat, requiring frequent hospitalizations and long-term antibiotic therapy.
• Chronic pain and discomfort: Ongoing pain from tissue distension, pressure effects, and recurrent infections.
• Functional impairment: Depending on location and size, malformations can interfere with movement, eating, speaking, or other essential functions.
• Psychological and social impact: Visible malformations can affect self-esteem, social interactions, and mental health.
• Bleeding: Trauma to superficial vessels can cause bleeding.
• Compression effects: Large malformations can compress vital structures, causing respiratory distress, swallowing difficulties, or neurological symptoms.
• Lymph leakage: Chronic drainage can lead to skin breakdown, secondary infections, and social difficulties.
• Overgrowth: Progressive enlargement of affected tissues and bones can cause asymmetry and functional problems.

Surgical Management

Complete surgical excision remains the treatment of choice when feasible, offering the best chance for a cure. However, complete removal may not be possible without sacrificing important structures, particularly for extensive microcystic malformations.

Sclerotherapy

Sclerotherapy has become a primary treatment modality, particularly for macrocystic malformations. Sclerosing agents work by damaging the endothelial lining of the abnormal lymphatic vessels - various agents can be used:

• Doxycycline
• Bleomycin
• Sodium tetradecyl sulfate
• Ethanol

Pharmacological treatment

Drug therapies for lymphatic malformations aim to reduce abnormal tissue growth by targeting molecular signalling pathways involved in the development and proliferation of lymphatic vessels. Some medications used to treat lymphatic malformations were originally developed for other conditions including cancer before being investigated for vascular anomalies because of their effects on these same signalling pathways. Others, such as sirolimus, were developed for different medical purposes and subsequently found to have potential applications in treating vascular anomalies.

Sirolimus (rapamycin): An inhibitor of the mechanistic target of rapamycin (mTOR), a protein involved in regulating cell growth, proliferation and metabolism. Sirolimus inhibits signalling downstream of the PI3K/AKT/mTOR pathway, reducing cellular proliferation. It has been used to treat complex lymphatic malformations, particularly microcystic lesions, and may help reduce lesion size, lymphatic leakage, bleeding and pain. However, its use requires monitoring because of potential adverse effects, including immunosuppression, mouth ulcers, elevated blood lipids and changes in blood cell counts.

Alpelisib (Piqray or Vijoice): A selective inhibitor of phosphatidylinositol 3-kinase alpha (PI3Kα), the enzyme encoded by the PIK3CA gene. Activating mutations in PIK3CA can cause persistent activation of the PI3K/AKT signalling pathway, resulting in abnormal cell growth and tissue overgrowth. Alpelisib inhibits this overactive signalling, potentially reducing the growth of affected tissues, and has less side effects than sirolimus due to more precise targeting of the overactive gene.

Zovegalisib: An investigational oral inhibitor of PI3Kα designed to selectively target mutant forms of the enzyme while having less activity against its normal, non-mutated form in the rest of the body., therefore causing the least side effects of the three medications listed here. Zovegalisib is currently being evaluated in clinical trials for PIK3CA-related overgrowth spectrum and PIK3CA-driven vascular and lymphatic malformations.

Other Treatments

• Laser therapy: Pulsed dye laser may be effective for superficial microcystic lesions
• Supportive care: Compression garments, wound care for leaking lesions