Sinusoidal Obstruction Syndrome (Veno-occlusive Disease) in Pediatrics

Definition

Sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease (VOD), is characterized by toxic injury to hepatic sinusoidal endothelial cells and terminal venules leading to sinusoidal narrowing, hepatocellular necrosis, and perivenular fibrosis.

Epidemiology

• Incidence varies by risk factors: up to 30% of children after myeloablative hematopoietic stem cell transplantation (HSCT).
• Also occurs with high-dose chemotherapy (busulfan, cyclophosphamide), radiation, liver resection, herbal toxins (pyrrolizidine alkaloids), and congenital immunodeficiencies.

Pathogenesis

• Cytotoxic agents damage sinusoidal endothelial cells → gap formation in sinusoids → extravasation of blood components into space of Disse.
• Subsequent activation of coagulation cascade, thrombosis of central venules, and collagen deposition cause obliteration of the sinusoidal lumen.

Clinical Presentation

• Onset typically within 21–30 days of HSCT conditioning (occasionally after chemotherapy alone).
• Features:
  • Rapid weight gain >5% from baseline (fluid retention)
  • Right upper quadrant pain & tender hepatomegaly
  • Ascites, jaundice (bilirubin >2 mg/dL)
  • Refractory thrombocytopenia despite transfusion
• Severe cases progress to multiorgan dysfunction (renal failure, respiratory distress) with mortality >80% if untreated.

Diagnosis

Clinical Criteria

• Baltimore criteria: bilirubin >2 mg/dL plus two of: hepatomegaly, ascites, weight gain >5%.
• Seattle criteria: two of: bilirubin >2 mg/dL, hepatomegaly, ascites, weight gain >2%.
• EBMT pediatric criteria: include refractory thrombocytopenia and rising bilirubin without strict numeric thresholds.

Imaging and Histology

• Ultrasound with Doppler: hepatomegaly, ascites, reversed or absent flow in hepatic veins, gallbladder wall thickening.
• CT/MRI: patchy periportal heterogeneity, narrowing of hepatic veins, delayed enhancement.
• Liver biopsy: sinusoidal dilation, centrilobular congestion and hemorrhage, loss of terminal hepatic venules, perisinusoidal and perivenular collagen deposition.

Treatment

• Supportive care: fluid balance management, diuretics, paracentesis, correction of coagulopathy.
• Defibrotide: endothelial protectant; 6.25 mg/kg IV every 6 hours for moderate–severe SOS (approved for pediatric use).
• Corticosteroids: low-dose methylprednisolone may benefit selected severe cases.
• Transplant: liver transplantation for fulminant hepatic failure with otherwise favorable prognosis.
• Prevention: ursodeoxycholic acid prophylaxis and defibrotide in high-risk HSCT recipients per EBMT guidelines.

Hepatic Epithelioid Hemangioendothelioma in Pediatrics

Definition

Hepatic epithelioid hemangioendothelioma (HEHE) is a rare vascular neoplasm of endothelial origin with intermediate malignant potential. It often presents as a primary liver tumor but may involve multiple organs.

Epidemiology

• Represents <1% of all vascular tumors; pediatric cases are uncommon.
• Occurs at any age, including infancy, but most often in adults—peak in 30s–40s.
• >85% present with multifocal hepatic nodules; 35% have extrahepatic disease at diagnosis.
• Female:male ratio approximately 3:2.

Pathogenesis

• Clonal endothelial proliferation with characteristic gene fusions: WWTR1–CAMTA1 in most cases; YAP1–TFE3 in a subset.
• Potential roles for environmental exposures and chronic liver injury, though no definitive risk factors identified.

Clinical Presentation

• Up to 25% are asymptomatic—incidental imaging finding.
• Symptoms when present:
  • Vague abdominal discomfort or pain
  • Hepatomegaly, splenomegaly
  • Signs of portal hypertension (ascites, varices)
  • Progressive liver failure in advanced disease
• Laboratory tests often normal; up to 15% show elevated alkaline phosphatase and GGT. AFP, CEA, CA 19-9 remain normal.

Diagnosis

Imaging

• Ultrasound: variable echogenicity; may mimic metastases—non‐specific.
• CT: peripheral hypoattenuating nodules with progressive centripetal “halo” enhancement on portal venous phase.
• MRI: T2‐hyperintense lesions with rim enhancement; capsular retraction overlying nodules is suggestive.

Histology & Immunohistochemistry

• Cords of epithelioid endothelial cells within sinusoids embedded in a myxohyaline stroma.
• Cells stain positive for CD31, CD34, Factor VIII–related antigen, and often podoplanin (D2-40).
• Molecular testing confirms WWTR1–CAMTA1 or YAP1–TFE3 fusions.

Treatment

• Surgical resection: preferred for unifocal disease; 10% of patients are candidates. Recurrence in residual liver can occur post‐resection.
• Liver transplantation: indicated for multifocal or large lesions without extrahepatic spread; 5-year survival 64–83%, with ~30% recurrence.
• Transarterial chemoembolization (TACE): palliative option for symptom control in unresectable disease.
• Systemic therapies: interferon-α, anti-VEGF agents, and tyrosine kinase inhibitors have shown anecdotal efficacy; overall chemotherapy and radiation are largely ineffective.

Prognosis

• Variable clinical course: some lesions remain indolent for years, others progress rapidly.
• Better outcomes with surgical or transplant intervention; close follow-up for recurrence is essential.