Lymphangiomatosis: Symptoms, Types, Causes and Treatment

Lymphangiomatosis is a rare and complex disorder, often misunderstood and misdiagnosed due to its diverse presentations and involvement of multiple organ systems. This article provides a comprehensive overview of lymphangiomatosis, focusing on its symptoms, types, causes, and current treatment options. Drawing from the latest research and clinical experience, we aim to empower patients, families, and healthcare professionals with up-to-date, evidence-based information about this challenging disease.

Symptoms of Lymphangiomatosis

Lymphangiomatosis can manifest in a variety of ways depending on which tissues and organs are affected. Because it often involves the abnormal proliferation of lymphatic vessels, symptoms may be subtle and progress slowly, or they can be severe and life-threatening, especially when vital organs are involved.

Symptom	Description	Frequency/Severity	Source(s)
Limb Swelling	Slow, progressive enlargement of limbs	Common in limb-involved	1 12
Respiratory Distress	Shortness of breath, chylothorax (fluid in chest)	Severe in thoracic cases	4 5 12
Bone Pain	Pain or tenderness in affected bones	Variable	1 3 5
Skin Lesions	Visible skin changes, nodules, or vesicles	More common in children	2
Fatigue	Generalized tiredness	Non-specific, variable	9
Organomegaly	Enlargement of internal organs (e.g., spleen)	In generalized cases	3 9

Table 1: Key Symptoms

Overview of Symptom Presentation

Lymphangiomatosis symptoms are driven by the location and extent of lymphatic proliferation:

• Limb Involvement: Patients often experience chronic, painless swelling of one or more limbs. The swelling can begin at birth or develop during childhood or adolescence. Sometimes, affected limbs also show bone involvement, but bone lesions may remain asymptomatic 1.

• Thoracic and Pulmonary Involvement: When the disease affects the chest, symptoms can become severe. These include persistent cough, difficulty breathing, chest pain, and sometimes chylothorax—an accumulation of lymphatic fluid in the pleural space, causing respiratory distress. Chylothorax can be especially dangerous in children, sometimes leading to respiratory failure 4 12.

• Bone and Visceral Symptoms: Involvement of bones may cause pain, especially if the lesions are extensive. Internal organs such as the spleen, lungs, or mediastinum may enlarge, sometimes causing discomfort or systemic symptoms like fatigue 3 9.

Symptom Progression and Variability

Not all patients experience the same symptoms, and the disease can be localized or widespread. Some individuals show only mild swelling, while others have significant multi-organ involvement. In rare forms, the disease remains confined to the limbs and bones and tends to have a benign course 1. However, generalized or thoracic forms can be life-threatening, particularly in children.

Recognizing Lymphangiomatosis

Because lymphangiomatosis is rare and can mimic other conditions, delays in diagnosis are common. Persistent, unexplained swelling of a limb, unexplained respiratory symptoms, or recurrent chylothorax in a child should prompt clinicians to consider lymphangiomatosis as a potential diagnosis 5 12.

Types of Lymphangiomatosis

Lymphangiomatosis encompasses a spectrum of disorders, classified based on the size and distribution of the abnormal lymphatic channels as well as the organs involved. Understanding the different types is crucial for prognosis and management.

Type	Description	Typical Location	Source(s)
Simplex (Capillary)	Small, thin-walled lymphatic channels	Skin (circumscriptum)	2
Cystic (Hygroma)	Large, cyst-like structures	Neck, axilla, soft tissue	2
Cavernous	Dilated lymphatic channels with fibrous walls	Thorax, abdomen, bones	2 5
Generalized	Diffuse, multi-organ involvement	Mediastinum, bones, spleen	3 5
Limb-Limited	Confined to limb soft tissues and/or bone	Limbs, limb girdle	1
Kaposiform	Aggressive, systemic, often with coagulopathy	Children, multiple organs	6

Table 2: Types of Lymphangiomatosis

Traditional Classification

Lymphangiomas—the building blocks of lymphangiomatosis—are traditionally classified into three types:

• Simplex (Capillary) Type: Characterized by small, capillary-sized lymphatic channels. This type commonly affects the skin, presenting as lymphangioma circumscriptum 2.

• Cystic (Cystic Hygroma) Type: Composed of large, fluid-filled cysts, this form is most commonly seen in the neck or axilla of young children. Lesions can grow quite large and cause disfigurement or compress nearby structures 2.

• Cavernous Type: Involves larger, dilated lymphatic spaces with thicker walls. This type often affects deeper tissues and internal organs, such as the thorax, abdomen, and bones 2.

Generalized and Systemic Forms

• Generalized Lymphangiomatosis (GLA): Involves multiple organ systems, including the mediastinum, lungs, spleen, and bones. It often presents in childhood and can be severe, especially when the thorax is involved 3 5. Generalized forms may also be called generalized lymphatic anomaly (GLA).

• Limb-Limited (Localized) Lymphangiomatosis: A rarer, more benign variant, predominantly or exclusively involving the soft tissues and bones of the limbs. Prognosis is generally favorable, with little risk of progression to systemic disease 1.

• Kaposiform Lymphangiomatosis (KLA): A particularly aggressive subtype, marked by coagulopathy and multi-organ involvement, typically affecting children. KLA carries a poorer prognosis and requires intensive management 6.

Overlap and Coexistence

It's important to note that different types of lymphangiomas can coexist in the same patient, and the disease may evolve over time. For example, a child with a cystic hygroma may later develop more generalized involvement 2.

Organ Involvement

Nearly all organs can be affected except the central nervous system, which is devoid of lymphatic vessels. The head and neck are the most common sites in children, while visceral (internal organ) disease accounts for about 10% of cases 2 5.

Causes of Lymphangiomatosis

The precise cause of lymphangiomatosis remains incompletely understood, but recent discoveries have shed light on its origins. Genetic and developmental factors are believed to play a central role.

Cause	Mechanism/Description	Evidence/Notes	Source(s)
Congenital Malformation	Abnormal development of lymphatic vessels	Most common, occurs in children	2 5 4
Somatic NRAS Mutation	Activating mutation in NRAS gene	Identified in GLA and KLA	6 7
Radiation-Induced	Secondary to radiotherapy	Rare, documented case	2
Unknown/Idiopathic	No identifiable cause	Especially in some adults	4 5

Table 3: Causes of Lymphangiomatosis

Developmental Origins

Most cases of lymphangiomatosis are thought to result from congenital malformations of the lymphatic system. During embryonic development, failures in the formation, migration, or connection of lymphatic vessels can lead to the creation of abnormal channels and clusters of lymphatic tissue 2 5.

Genetic Mutations

Recent research has uncovered a significant role for somatic (non-inherited) genetic mutations in the pathogenesis of certain forms of lymphangiomatosis:

• NRAS Gene Mutations: Somatic activating mutations in the NRAS gene have been identified in tissues from patients with generalized lymphatic anomaly (GLA) and kaposiform lymphangiomatosis (KLA). These mutations drive abnormal cell proliferation and survival, contributing to the formation and persistence of lymphatic malformations 6 7.
• PI3K/mTOR Pathway: The NRAS mutation is part of a broader group of vascular anomalies now known to be driven by mutations affecting the RAS/PI3K/mTOR signaling pathways. This knowledge has opened the door to targeted therapies 6 7.

Other Contributing Factors

• Radiation Exposure: Though exceedingly rare, there are reports of cutaneous lymphangioma developing after radiotherapy for cancer, suggesting that damage to lymphatic vessels can occasionally trigger the disease 2.

• Unknown/Idiopathic: In some adults, especially those with limited or atypical disease, no clear cause can be identified 4 5.

Inheritance and Risk

Lymphangiomatosis is generally not inherited, and most cases occur sporadically, with no family history. Its incidence is similar in males and females, though some variants may show a male predominance 1.

Treatment of Lymphangiomatosis

Managing lymphangiomatosis is challenging due to the disease's rarity, variability, and multi-system involvement. There is no universally curative treatment, but advances in surgical, pharmacological, and supportive therapies have improved outcomes for many patients.

Treatment	Approach/Mechanism	Indication/Effectiveness	Source(s)
Surgery	Resection or reduction of lesions	Localized disease, limb type	1 2
Sirolimus	mTOR inhibitor (targeted therapy)	Diffuse, systemic disease	8
Bevacizumab	VEGF inhibitor (anti-angiogenic)	Pulmonary/visceral involvement	9
Propranolol	Beta-blocker, anti-lymphangiogenic	Chylothorax, infants	12
Lung Transplantation	Replacement for end-stage pulmonary disease	Rare, highly selected cases	10
Supportive Care	Symptom management, fluid drainage	All types	4 5 12

Table 4: Treatment Options

Surgical Approaches

• Excision or Debulking: Surgical removal or reduction of lymphangiomatous masses can be effective for localized disease, especially those confined to the limbs. Surgery can provide significant symptom relief and improve function, with low risk of progression in limb-limited types 1 2.
• Limitations: Surgery is usually not feasible for diffuse or internal organ involvement and carries risks of recurrence or complications.

Pharmacological Therapies

• Sirolimus (Rapamycin): An mTOR inhibitor, sirolimus has shown promise in shrinking lymphangiomatous lesions and controlling symptoms in diffuse or systemic disease. It is especially useful when surgery is not possible, or disease is multi-organ. Early case series and reports suggest good tolerability and effectiveness, but formal clinical trials are still needed 8.
• Bevacizumab: This monoclonal antibody blocks vascular endothelial growth factor (VEGF), thereby inhibiting the growth of abnormal lymphatic vessels. Successful use has been reported in patients with diffuse pulmonary lymphangiomatosis 9.
• Propranolol: Best known for treating infantile hemangiomas, propranolol has successfully reduced chylothorax and improved respiratory symptoms in children with diffuse lymphangiomatosis 12.

Transplantation and Advanced Therapies

• Lung Transplantation: In very advanced cases of pulmonary lymphangiomatosis, bilateral lung transplantation has been performed with survival beyond 4 years. However, extra-pulmonary disease (e.g., chest wall, abdominal involvement) can limit recovery, so careful patient selection is essential 10.

Supportive and Symptom-Based Care

• Pleural Drainage: For patients with chylothorax or pleural effusion, repeated drainage and supportive respiratory care can be life-saving 4 12.
• Physical Therapy and Rehabilitation: Especially important for those with limb swelling to maintain mobility and prevent complications.
• Monitoring and Multidisciplinary Care: Regular imaging and follow-up are crucial due to the risk of progression or recurrence, particularly in generalized forms 3 5.

Emerging and Experimental Treatments

• Targeted Molecular Therapies: Given the role of NRAS and related pathways, inhibitors targeting the RAS/PI3K/mTOR signaling axis are under investigation and may offer new hope for refractory or aggressive cases 6 7.
• Other Agents: There are isolated reports of other medications (e.g., propranolol, sildenafil) being used with some benefit, but large studies are lacking 12.

Challenges in Treatment

Due to the disease's rarity, most evidence for these therapies comes from case reports and small series. There are currently no standardized treatment protocols or large clinical trials 5. Therapy must be individualized based on disease type, extent, symptoms, and patient preferences.

Conclusion

Lymphangiomatosis is a rare and heterogeneous disease, presenting unique challenges in diagnosis and management. Its symptoms, types, causes, and treatments are diverse and require a nuanced, multidisciplinary approach.

Key Points:

• Lymphangiomatosis can affect any age group and present with a wide range of symptoms, from isolated limb swelling to life-threatening respiratory distress.
• The disease is classified into several types, including localized (limb-limited), generalized, and aggressive forms like KLA.
• Congenital malformation and somatic NRAS mutations are the primary causes, with most cases occurring sporadically.
• Treatment is tailored to disease extent and includes surgery, targeted pharmacological agents (sirolimus, bevacizumab, propranolol), supportive care, and in rare cases, lung transplantation.
• Advances in genetics and molecular biology are paving the way for new, targeted therapies, offering hope for improved outcomes.

Early recognition and a personalized, multidisciplinary approach remain critical for optimizing the quality of life and prognosis for individuals living with lymphangiomatosis.