What is the appropriate management for lymphangioendotheliomatosis?

Management of Multifocal Lymphangioendotheliomatosis with Thrombocytopenia (MLT)

Sirolimus (rapamycin) is the first-line treatment for multifocal lymphangioendotheliomatosis with thrombocytopenia, particularly in cases with severe gastrointestinal bleeding or extensive extracutaneous involvement. 1

Disease Characteristics

MLT is a rare vascular disorder characterized by:

• Multiple vascular lesions affecting various tissues including skin, gastrointestinal tract, lungs, bones, and brain
• Distinct endothelial proliferation with lymphatic differentiation (LYVE-1 or D2-40 positive, GLUT-1 negative on histology)
• Often associated with refractory thrombocytopenia and life-threatening bleeding
• Significant clinical variability in presentation

Key Clinical Variants

1. Classic presentation: Multiple cutaneous vascular lesions with gastrointestinal involvement and thrombocytopenia
2. Atypical presentations:
   • Cases without thrombocytopenia 2
   • Cases with minimal cutaneous involvement 2
   • Cases with severe organ involvement (brain, lungs, liver) 3

Diagnostic Approach

1. Histopathological examination:

   • Biopsy of accessible lesions (skin or affected organs)
   • Key markers: LYVE-1 or D2-40 positive (lymphatic markers)
   • Negative for GLUT-1 (differentiating from infantile hemangiomas) 1

2. Imaging studies:

   • Contrast-enhanced CT to evaluate extent of disease
   • MRI for brain involvement assessment
   • Consider PET-CT for comprehensive staging of disease extent

3. Laboratory evaluation:

   • Complete blood count with special attention to platelet count
   • Coagulation profile
   • Consider monitoring angiopoietin-2 levels as a potential biomarker 4

Treatment Algorithm

First-line therapy:

• Sirolimus (rapamycin) at 0.1 mg/kg/day 1
  • Effective for severe cases with gastrointestinal bleeding
  • Shows response typically within the first month of treatment
  • Targets the underlying pathophysiology through anti-lymphangiogenic properties

For gastrointestinal bleeding management:

• Aminocaproic acid daily
• Octreotide drip
• Corticosteroids 5

For cases with thrombocytopenia:

• Combination therapy of sirolimus and prednisolone 4
• Platelet transfusions as needed for acute bleeding episodes

Treatment duration:

• Continue treatment until resolution of symptoms and vascular lesions
• Some patients may require treatment for 12+ months 5
• Monitor for complete resolution, which may occur by 2 years of age in responsive cases

Monitoring and Follow-up

• Regular monitoring of platelet counts
• Surveillance imaging to assess response of vascular lesions
• Monitoring for treatment-related complications
• Long-term follow-up for potential recurrence

Prognosis

Prognosis varies significantly based on:

1. Extent of organ involvement: Brain involvement carries particularly poor prognosis 3
2. Severity of bleeding complications: Refractory GI bleeding is a major cause of morbidity
3. Response to therapy: Early response to sirolimus is associated with better outcomes

Important Considerations

• MLT is often misdiagnosed as multifocal infantile hemangioma, but treatments for infantile hemangioma are typically ineffective for MLT 1
• Early aggressive intervention is justified in cases with widespread or severe extracutaneous involvement 1
• The pathogenesis remains unclear, but lymphatic differentiation is widely acknowledged 1
• Cases with severe brain involvement may have fatal outcomes despite treatment 3

Pitfalls to Avoid

• Delayed diagnosis due to clinical variability and rarity of the condition
• Misdiagnosis as infantile hemangioma leading to inappropriate treatment
• Underestimating the potential for life-threatening complications, particularly in cases with minimal cutaneous manifestations
• Inadequate monitoring of extracutaneous involvement