Case Study Cardiopulmonary Imaging Pediatric Imaging

Generalized Lymphatic Anomaly

By Zari O’Connor, BS, Morgan P. McBee, MD

Case Summary

An adolescent was referred to pediatric pulmonology for difficulty recovering from pneumonia the preceding year, with multiple prior episodes of pneumonia. The patient presented with cough, dyspnea, chest pain, abdominal pain, and extremity bruising. Pulmonary physical examination findings included asymmetric breath sounds predominantly in the left lung; crackles in the left base; and suprasternal, intercostal, and subcostal retractions. Imaging revealed mediastinal and interstitial thoracic abnormalities in addition to pericardial and pleural effusions. The patient underwent a pericardiocentesis with drain placement, pleural effusion drainage, and biopsy of the mediastinal soft tissue. The biopsy demonstrated irregular, dilated lymphatic channels with positivity for CD31 and D2-40, which are diagnostic of a lymphatic malformation. Further imaging revealed additional areas of involvement.

Imaging Findings

Chest radiograph showed an enlarged cardiothymic silhouette with interstitial opacities and small bilateral pleural effusions ( Figure 1 ). An echocardiogram showed a large pericardial effusion. Following pericardiocentesis and bilateral chest tube placement, chest CT ( Figure 2 ) showed infiltrative low-density mediastinal soft tissue extending along the bronchovascular bundles into the lungs where there was diffuse thickening of the interlobular septa. Whole-body MRI ( Figure 3 ) also showed diffuse thoracic vertebral T2 hyperintense lesions, abnormal T2 hyperintensity throughout the mediastinum and lungs, as well as small pleural effusions. The appendicular and axial skeleton were involved with the majority of the spine and long bones having patchy confluent marrow signal abnormality with metaphyseal predilection. There were scattered lobulated T2 hyperintense soft-tissue lesions. The spleen had serpiginous T2 hyperintense signal as well. The findings overall were compatible with multifocal, multicompartmental lymphatic malformations.

Diagnosis

Generalized lymphatic anomaly (GLA).

The primary differential diagnoses for multifocal lymphatic malformations and bone lesions are Gorham-Stout disease and Kaposiform lymphangiomatosis (KLA). KLA is more aggressive than GLA and is even more rare. The two must be differentiated from each other histologically.¹GLA and Gorham-Stout disease share many features. However, Gorham-Stout will have associated osteolysis, hence its other name vanishing bone disease .²The differential diagnosis of pulmonary lymphangiomatosis also includes congenital pulmonary lymphangiectasia and primary and secondary lymphedema. If the bone lesions were the presenting abnormality, differential considerations would include Langerhans cell histiocytosis, metastatic disease, and polyostotic fibrous dysplasia.

Discussion

GLA is a rare congenital condition characterized by multiple lymphatic malformations (abnormal proliferation, dilation, and anastomosis of lymphatic channels) throughout the body. It may involve the bones, thoracic and abdominal viscera, and soft tissues.³The former term diffuse systemic lymphangiomatosis was renamed GLA. The disease often presents in childhood, but may also be diagnosed in adults and seems to have no preference for sex.⁴Due to the rarity of GLA and its indolent course, delayed diagnosis is common.

However, patients with pulmonary involvement can experience symptoms long before their diagnosis. Common symptoms include cough, wheezing, milky sputum, and shortness of breath, potentially leading to misdiagnosis with asthma.⁵Pleural effusions, pericardial effusions, and respiratory infections often occur. The pleural effusions are attributed to the compression of lymphatic channels by mediastinal masses. Chylothorax, chyle accumulation in the pleura, is common among these patients. Chyloptsis, hemoptysis, chylopericardium, protein-wasting enteropathy, peripheral lymphedema, and disseminated interstitial coagulopathy may also occur. Bone involvement of the axial or appendicular skeleton occurs in up to 75% of patients with GLA.⁶

Chest radiographs typically show pulmonary bilateral interstitial thickening associated with pericardial and/or pleural effusions.⁶Mediastinal widening or soft-tissue masses may also be observed. Whole-body MRI can determine the extent of organ involvement.³Potential thoracic findings include interlobular septal thickening tracking along the bronchovascular bundles, ground-glass opacities, perihilar infiltration, pleural effusions, and infiltration and thickening of the mediastinal soft tissues. MRI may also show pleural effusions and multifocal lymphatic malformations of the spleen, bones, and soft tissues.⁷

Radiographs of GLA may identify lucent bone lesions. Osteolytic lesions due to a general lymphatic anomaly are best appreciated via CT, but MRI is often necessary for accurate assessment of bone marrow changes and soft-tissue involvement.⁸Lymphangiography reveals lesions of the thoracic duct, dilated lymphatic channels, and lymphangiomas within the bones and lungs. It also helps differentiate malformations from malignant tumors and evaluate the extent of the disease.⁶However, the technique used can cause pulmonary complications such as pulmonary oil embolism from blockage of the thoracic duct and inflammatory responses to ethiodized oil.

A biopsy of lymphatic areas or soft-tissue masses aids in definitive diagnosis. Histopathology of the lymphatic channels demonstrates anastomosing endothelial cells along pulmonary lymphatic routes.⁶These endothelial cells within lymphatic channels will stain positive for CD31 and D2-40 in patients with GLA. CD31 is a vascular marker for blood vessel endothelium and positivity indicates angiogenesis. D2-40 is a marker specific to lymphatic endothelium; a positive stain signifies lymphatic proliferation and differentiation.⁹

GLA has no established cure. Current treatment regimens focus on supportive care and symptomatic relief from the compressive effects of mediastinal masses and chylous fluid accumulations. Surgical resection of lymphatic malformations is rare as it is difficult to separate lymphatic channels from surrounding structures.⁶Treatment options include low-fat, medium-chain triglyceride diets, corticosteroids, interferon-α, sirolimus, propranolol, somatostatin, and bevacizumab.¹⁰Propranolol, sirolimus, and bevacizumab work to repress lymphangiogenesis by binding vascular endothelial growth factor or its receptor. Sirolimus, in particular, has been beneficial in reducing lymphatic proliferation.⁴

Conclusion

GLA is a rare condition of multisystemic lymphatic proliferation and dilation often involving the bones, viscera, and mediastinum. Due to the generalized initial symptoms of this disease and its slow course, diagnosis is often delayed. Milky sputum, recurrent respiratory infections, chylothorax, and bony involvement are strong indicators of GLA. The primary goal of imaging is to determine the extent of lymphatic malformations throughout the body and which organ symptoms are involved. While there is no definitive cure, sirolimus treatment has shown promise in symptom management.

References

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Citation

Zari O’Connor, BS, Morgan P. McBee, MD. Generalized Lymphatic Anomaly. Appl Radiat Oncol. 2024;(5):29 - 32.
doi:10.37549/AR-D-24-0034

October 1, 2024