Lymphatic malformations (LMs) are congenital, benign slow-flow vascular malformations of the lymphatic system characterized by abnormally dilated lymphatic vessels that do not connect properly to the normal lymphatic circulation. These malformations represent developmental anomalies that occur during embryonic lymphatic system formation and are primarily caused by somatic activating mutations in the PIK3CA gene, found in approximately 75-80% of cases.[1]
The term "lymphatic malformation" has replaced older terminology including "lymphangioma," "cystic hygroma," and "lymphangioma circumscriptum."[2]
Classification
According to the International Society for the Study of Vascular Anomalies (ISSVA), lymphatic malformations are classified as slow-flow vascular malformations (distinguished from vascular tumors which have proliferative endothelial cells) and are divided into three main categories:[3]
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
Acquired due to damage, obstruction, or removal of lymphatic vessels
Epidemiology
The overall incidence of lymphatic malformations ranges from 1 in 6000 to 1 in 16,000, with no predilection for sex or race.[4] However, precise epidemiological data is difficult to establish due to variations in diagnosis, classification systems, and reporting practices across different healthcare systems. Based on these incidence rates, lymphatic malformations are classified as rare diseases.
While lymphatic malformations can become evident at any age, most are identified at birth or in early childhood, though some may not be noticed until the teenage years or early adulthood if small or located inside the body. Approximately 75% occur in the lymphatic-rich head and neck region, though they can affect any part of the body including the axilla, mediastinum, buttock, pelvis, and other locations.[5]
Causes
PIK3CA Mutations
The primary cause of lymphatic malformations is now well understood. Somatic activating mutations in the PIK3CA gene are found in approximately 75-80% of lymphatic malformations.[6] These are non-inherited mutations that occur specifically in lymphatic endothelial cells during embryonic development.[7]
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.[8] 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:
Lymphatic malformations typically present as soft, compressible masses that can vary significantly in size and location. The clinical presentation depends on the type and location:
Present as larger, deeper masses with a soft, doughy consistency
Commonly occur in the neck (75%), axilla, or groin
Can cause compression symptoms if large
May fluctuate in size
Mixed malformations:
Display characteristics of both microcystic and macrocystic types
Can be more complex and challenging to treat
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.
Treatment
Treatment approach depends on the size, location, severity of symptoms, and impact on quality of life and function. The goal is not merely cosmetic improvement, but comprehensive management of symptoms, prevention of complications, and optimization of quality of life. Treatment decisions should involve multidisciplinary teams familiar with vascular anomalies, as these conditions are often poorly understood by general medical practitioners.
Surgical Management
Complete surgical excision remains the treatment of choice when feasible, offering the best chance for 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. Various sclerosing agents are used:
Sclerosing agents work by damaging the endothelial lining of the abnormal lymphatic vessels.
Medical Therapy
Sirolimus (rapamycin): An mTOR inhibitor that has emerged as an important medical treatment option. It can decrease the size of lymphatic malformations, reduce symptoms, and improve quality of life, particularly in patients with PIK3CA mutations affecting the PI3K/mTOR pathway.[9] Sirolimus is a macrolide compound which has immunosuppressant and antiproliferative functions in humans. It inhibits activation of T cells and B cells by reducing their sensitivity to interleukin-2 (IL-2) through mTOR inhibition.[10]
Targeted therapies: Research is ongoing into therapies specifically targeting PIK3CA-mutated cells.
Other Treatments
Laser therapy: Pulsed dye laser may be effective for superficial microcystic lesions
The prognosis for lymphatic malformations is generally good, as they are benign lesions with no malignant potential under normal circumstances. Factors affecting prognosis include:
Location: Head and neck lesions may cause more functional problems
Size and extent: Larger, more extensive lesions are more challenging to treat
Type: Macrocystic lesions generally respond better to sclerotherapy
Associated syndromes: May complicate management and prognosis
Complete cure is possible with total surgical excision, but recurrence can occur if residual tissue remains. Medical therapies like sirolimus can provide significant symptom improvement and size reduction but typically require ongoing treatment.
History
The understanding and classification of lymphatic malformations has evolved significantly:
1828: Redenbacher first described lymphangioma lesions.[11]
1843: Wernher described the condition in his 1843 publication, Die angeborenen Kysten-hygrome und die ihnen verwandten Geschwülste (Congenital cystic hygromas and related tumors).[12]
1965: Bill and Summer proposed that cystic hygromas and lymphangiomas represent variations of a single entity.
1976: Whimster studied the pathogenesis of lymphangioma circumscriptum, providing insights into the developmental basis.[13]
2014-2015: Discovery of PIK3CA mutations as the primary cause of lymphatic malformations, revolutionizing understanding of pathogenesis.
2018: ISSVA classification update standardizing terminology to "lymphatic malformation".[14]
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