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Lymphangiomatosis is a rare disorder. It is commonly localised in the skeletal system and called Gorham’s disease, and in thoracic or abdominal organs. Involvement of the pericardium is rare and has been described in less than 20 patients worldwide. The case of a 14-year-old boy presenting with asymptomatic chylopericardium and interstitial lung disease is presented. After lung biopsy, performed to confirm the diagnosis of pulmonary lymphangiomatosis, he developed chylothorax and massive loss of chyle via chest drains. Thoracic duct ligation did not result in clinical improvement. Treatment with interferon α2b was given and because of clinical deterioration radiotherapy was added to the treatment. This resulted in a rapid decrease of chyle production in the patient.
This case shows an unusual presentation of a rare disorder. In this case diagnostic investigation caused serious and life-threatening complications, which could probably have been prevented by using less invasive diagnostic procedures. Radiation therapy resulted in rapid clinical improvement after other therapeutic options had failed.
At the age of 11 years the boy presented to the outpatient department of another hospital with a history of stinging retrosternal pain and exercise-induced dyspnoea. He experienced these symptoms sporadically following pneumonia 1 year earlier. A chest x-ray showed signs of interstitial lung disease. An IgM titre for Mycoplasma pneumoniae was positive, suggesting a recent infection. Other infectious causes, systemic or autoimmune diseases and allergic disorders were excluded. Because of his good clinical condition no further investigations were performed and the patient was seen at regular outpatient visits.
At the age of 14 years a follow-up chest x-ray showed cardiomegaly (figure 1). The patient’s condition was stable at that moment, no new symptoms had occurred and there was no history of trauma. Echocardiography demonstrated a significant pericardial effusion with a structurally normal heart. With repetitive pericardial drainage more than 1 litre of milky fluid was obtained, which was confirmed to be chyle because of a high triglyceride level of 22.0 mmol/litre. Cultures were negative for bacteria, no viruses could be detected and auramine staining for tuberculosis (TBC) was negative. No malignant cells were seen. A diet of medium chain triglycerides was given and pericardial drain production diminished. A follow-up CT scan of the chest showed no more pericardial effusion, but hilar and mediastinal lympadenopathy and broadened interlobar septa, consistent with the earlier diagnosis of interstitial lung disease.
Because of the suspicion of an underlying pulmonary disorder and a bronchoalveolar lavage without conclusive results an open lung biopsy was undertaken. Histological examination of the biopsy material showed dilated, irregular and anastomosing vascular structures positive for CD 31 and CD 34, which are markers of the vascular endothelium (figure 2A,B). Expression of vascular endothelial growth factor (VEGF) receptors was positive and the diagnosis of pulmonary lymphangiomatosis was made.
MRI of the skeleton showed no lesions suspect for Gorham’s disease. Ultrasonography of the abdomen revealed no involvement of the intra-abdominal organs.
After the open lung biopsy the patient developed a chylothorax. Chest tubes were placed and up to 6 litres of chyle were produced daily. With no oral intake, total parenteral nutrition and octreotide at a maximum dosage of 5 μg/kg/min the drain production decreased to 3 litres per day over a period of 1 week.
Attempts to tamponade the chylothorax by occluding the chest drains resulted in severe respiratory distress due to rapid accumulation of pleural fluid.
Conventional lymphangiography with radio-opaque contrast (lipiodol) showed a tortuous aspect of the thoracic duct with multiple collaterals and leakage of lymph to the lungs (figure 3). Obliteration of the thoracic duct with histoacrylic glue and coils was performed without clinical improvement.
The persistent leakage of several litres of chyle per day caused a dramatic decline in the patient’s condition. Despite caloric suppletion up to 4300 kcal daily, the patient lost 5 kg of weight. Administration of total parenteral nutrition was complicated by cholestasis and treatment with ursodeoxycholic acid was given.
Massive protein loss caused hypoalbuminaemia, hypo-γ-globulinaemia and hypothyroidism. Hypo-γ-globulinaemia and leucopoenia necessitated the prophylactic use of antibiotics and weekly infusion of immunoglobulins. Broad spectrum antibiotics were given several times because of suspected infections. Daily albumin infusions and diuretic treatment were given to keep the patient in an acceptable fluid balance. Suppletion with levothyroxine was given.
At 1 month after the open lung biopsy interferon α2b was given at a daily dosage of 4 million units/m2, which was reduced to 3 million units/m2 later in the course due to elevated hepatic enzymes and fever. Because of further clinical deterioration the patient also received radiation therapy (16 Gy, divided into 10 fractions) 10 days after initiation of interferon α2b.
Loss of chyle then gradually decreased. At 6 weeks after initiation of interferon α2b and 1.5 weeks after completion of radiotherapy the chest drains could be removed (figure 4). Treatment with octreotide had been discontinued a few days earlier.
Because of the lymphangiomatosis involving parietal pleura, mediastinum and pericardium, lung transplantation was not considered to be a possible treatment option.
Over the next few months the patient recovered slowly. Enteral tube feeding was restarted. Because of a suspected Pneumocystis carinii pulmonary infection trimethoprim-sulfamethoxazole and prednisolone were given. No causative organism could be cultured from the sputum. After discontinuation of the antibiotics the corticosteroids were continued because of possible positive effects on lymphangiomatosis reported in the literature. The patient was discharged from hospital after 5 months. After another 3 months at a rehabilitation centre he was able to return home.
At this time it is 3 years since the diagnosis was made. After the initial treatment the patient, now 17 years old, has been readmitted to our hospital several times because of pulmonary infections and simultaneous increases of chylous pleural effusion requiring antibiotic treatment and drainage. Otherwise he is in a stable condition but has a permanent pleural effusion of approximately 1 litre. He is able to go to school and he is on a diet of medium chain triglycerides. He is still on interferon α2b treatment in a dosage of 3 MIE/m2 and on low dose prednisone treatment. Apart from scars due to the daily subcutaneous injections of interferon α he is not experiencing any side effects.
Lymphangioma are uncommon benign vascular tumours, thought to originate from congenital malformation and aberrant proliferation of lymphatic vessels. They involve the skin and subcutaneous tissues and commonly present in the head and neck region, trunk and extremities in children. Only 10% of lymphangioma involve internal organs such as lungs, liver or spleen.1
Diffuse lymphangiomatosis, a generalised abnormality of the lymphatic system, resembles lymphangioma but is characterised by a more diffuse proliferation of lymphatic vessels at multiple sites. The increased number of complex anastomosing lymph vessels with secondary dilatation helps to differentiate this disorder from primary lymphangiectasia.2,3
Diffuse lymphangiomatosis is particularly difficult to treat and no consensus has been reached on the most appropriate treatment.
In the English literature only around 300 cases of diffuse lymphangiomatosis have been reported worldwide. Disease manifestation in bone and surrounding soft tissue is called Gorham’s disease or vanishing bone disease.4–6 Other localisations are liver, spleen and mediastinum.7–14
Lung or pleura involvement has been described and is associated with a poor prognosis.12
Pericardial involvement is rare. To our knowledge only 16 cases, including the present case, have been reported in the past 35 years and 12 of these are children (table 1). The male/female ratio seems equal. Seven patients died because of complications of lymphangiomatosis or treatment.
Chylopericardium often results from an infectious problem, malignancy or a traumatic lesion. Also disorders of the lymphatic system, such as mechanical obstruction of the thoracic duct, reflux of lymph or lymphangiomatosis, as in our patient, can cause chylopericardium.
To visualise such lymphatic abnormalities lymphangiography in combination with computerised tomography has been used several times and has been proven to be suitable for establishing the diagnosis of diffuse lymphangiomatosis.15–20 Therefore it should be kept in mind as a useful diagnostic option.
In our patient a diagnostic pulmonary biopsy caused serious and life-threatening complications due to massive chyle loss. Since this problem has been reported before13,21,22 non-invasive methods for diagnosis should be considered, especially in asymptomatic patients.
In our patient it would have been appropriate to perform lymphangiography combined with computerised tomography before open lung biopsy, especially since pericardiocentesis had already raised the suspicion of a lymphatic origin of his pulmonary disease. This might have led to the correct diagnosis and would have probably prevented his dramatic clinical course.
Another option would have been the measurement of vascular endothelial growth factor (VEGF) by PCR or ELISA, which has been reported to be abnormally raised in a patient with lymphangiomatosis.7
There are different therapeutic options for the treatment of diffuse lymphangiomatosis. Surgical interventions, such as excision of a localised lesion, pleurodesis, pleurosclerosis, pleuroperitoneal shunting, chest wall resection or thoracic duct ligation in the case of thoracal involvement have been applied with differing results.14,21,23–27 Systemic treatment with corticosteroids, immunomodulating agents and chemotherapy have shown varying results.2,9,12,24,26,27 Interferon α, a cytokine with antiangiogenic activity, appears to be beneficial and has been used for the treatment of lymphangiomatosis for almost 20 years. Clinical improvement has been reported in the majority of cases, although the optimal treatment duration remains unclear and ranges from 3 weeks to several years.7,21,24,26,27
Radiation therapy has mainly been used for patients with cutaneous or abdominal involvement,28 but has also proven successful in patients with thoracic lymphangiomatosis.29–31 Acute adverse effects such as radiation pneumonitis have been described23,32 but seldom occur with fractional doses of 20 Gy or less.33 Chronic complications such as secondary malignancies and restrictive lung disease are rare.34
The exact mechanism of radiation therapy is not known, but is possibly a result of radiation induced lymphatic endothelial oedema and proliferation leading to obstruction of the abnormal lymphatic channels.28,35
In our patient radiotherapy seems to have been an effective intervention for the acute management of chyle loss, although its simultaneous use with interferon α and steroids makes it difficult to determine what its effect would have been had it been used alone.
Still we believe radiotherapy might have had an important additional effect to the use of interferon α and steroids and should be considered as a treatment option in lymphangiomatosis when surgery or systemic treatment alone fail, especially since side effects such as radiation pneumonitis or pulmonary fibrosis are infrequent when correct radiation doses are used.
We would like to thank AR van Erkel, radiologist, VTHBM Smit, pathologist and KF Rabe, pulmonologist for their comments on our document.
Competing interests: None.
Patient consent: Patient/guardian consent was obtained for publication.