Unusual case of chylothorax with unilateral limb swelling

Abstract

Here, we present an unusual case of 26-month male toddler who presented with swelling of right lower limb with painless hyperpigmented patch over right groin of 18 months duration associated with recent onset respiratory distress. Evaluation revealed right chylothorax and MRI revealed altered signal intensity in bones and muscles of right lower limb. Lymphoscintigraphy revealed absence of lymphatic channels in right lower limb. Skin biopsy from hyperpigmented patch was suggestive of vasoformative lesion favouring lymphangiomatosis. A diagnosis of Gorham’s syndrome was made, and our patient was managed with drainage of chylothorax followed by pleurodesis, parenteral nutrition and radiotherapy.

Background

Lymphangiomatosis is an intrauterine anomaly that starts at embryogenesis, with unchecked growth of lymphatic vessels.^{1 2} Till now, no genetic, immunological or environmental factors have been linked to the pathogenesis of this disease. The clinical presentation is diverse, and can be isolated disorder, like a cystic hygroma, or present with cardiovascular involvement, chylothoraces and chylous pericardial effusions.³ The diagnosis is established by biopsy of the involved site, and identification of dilated lymphatic channels, which stain positive for D2-40 and CD31 antigens.⁴ It is an atypical condition with single focus and massive type IV osteolysis (a type of idiopathic nonhereditary osteolytic disease) with unhurried progression that is self-limiting over the years. It is distinguished by repetitive vascular tumours with disruption of the anatomical architecture and intraosseous multiplication of vascular channels that causes destruction and resorption of the bone matrix.^{5 6} The clinical course is variable, from spontaneous subsidence to gradual osteolysis with some mild clinical symptoms to a clinical course with a lethal outcome. Average death rate of 13% has been documented.⁷ Histological findings are lymphatic, and vascular tissue in the bone and immunohistochemistry are positive for D2-40, with average sensitivity 92.6% and specificity 98.8%.⁸ The therapeutic approach is subject to discussion. Treatment options include pharmacological treatment with bisphosphonates, vitamin D and biological drugs; surgical treatment; radiotherapy or a combination of these options.^9–13 Despite this, treatment of chylothorax remains without success in several patients. The disease is poorly understood and often gets misdiagnosed as very few clinicians get the opportunity to diagnose and treat this type of disorder. The aim of this case report is to make the medical community acquainted with this unique and interesting disorder of the musculoskeletal system.

Case presentation

A 26-month-old male toddler, first product of a non-consanguineous marriage, was brought to our hospital with complains of a hyperpigmented patch over right groin and progressive swelling of right lower limb since the child was 7 months old and worsening breathlessness of 2 months duration. There was no history of fever, weight loss, diarrhoea, vomiting, rash, joint pains or bleeding from any site. The parents denied any history of altered sensorium, seizures, weakness of any limb or regression of milestones. He was a product of full-term normal delivery and peri-natal history was uneventful. The child was adequately immunised and there was no family history of chronic disease or congenital defects. The nutritional history was non- contributory. On examination, the child was looking sick, pulse rate of 140/min, blood pressure of 96/50 mm Hg, respiratory rate 50/min, SpO2 90% while breathing ambient air and 98% with oxygen, intercostal retractions were present. There was no pallor, icterus, cyanosis or generalised lymphadenopathy. His length was 82 cm and weight 14 kg. In head to toe examination, there was no facial dysmorphism, right lower limb was asymmetrically enlarged than left with circumference of right mid-thigh being 32 cm as compared with 23 cm on left and there was pitting oedema over right lower limb and hyperpigmented patch over the right groin (figure 1). There was no scrotal swelling. Respiratory system examination revealed bulging right hemithorax with reduced movements, tracheal deviation towards left, apex beat in left fifth intercostal space and 1 cm lateral to mid-clavicular line. Percussion note was resonant on left thorax and stony dull on right; breath sounds were absent on the right side and there were normal vesicular breath sounds on the left side. Abdominal examination was normal and there was no hepatosplenomegaly or ascites. Rest of the systemic examination was within normal limits.

Figure 1.

Right lower limb appears grossly hypertrophied and oedematous as compared with the left.

Investigations

The haematological and biochemical parameters were all within normal limits. The chest X-ray revealed opaque right hemithorax (figure 2). Ultrasound of thorax revealed massive pleural effusion on the right side. Pleurocentesis was performed and about 1 L serosanguinous fluid was drained (figure 3). Pleural fluid analysis revealed milky appearance, pH 7.6, 750 cells/cumm and lymphocytic predominance with numerous red blood cells. Pleural fluid was exudative as per Light’s criteria, total protein 4.6 g/dL, triglycerides 215 mg/day and cholesterol 160 mg/dL (corresponding serum values of total protein were 7.8 g/dL, triglyceride 100 mg/dL and cholesterol 190 mg/dL) and the pleural fluid adenosine deaminase was 15 U/L. There was no Acid Fast Bacilli on microscopy and Gram stain revealed no cocci or bacilli. Pyogenic culture of pleural fluid was sterile and there were no malignant cells. Contrast enhanced CT thorax revealed gross pleural effusion of the right side with subjacent collapse of lung with contralateral mediastinal shift (figure 4). CT angiography ruled out any arteriovenous malformation or vascular leak (figure 5). MRI of thigh revealed diffuse extensive altered signal intensity in the bones and muscles of right lower limb with hypertrophy (figure 6). Trucut biopsy from right groin lesion revealed closely packed small capillary sized vascular channels lined by flattened endothelial cells exhibiting bland nuclei. These vascular channels were seen splaying the adjacent muscle fibres and involving adjacent fascia and adipose tissue. The lining cells were positive for CD34 and D2-40 (figure 7), which are markers of vascular endothelium suggestive of vasoformative lesion favouring lymphangiomatosis. Lymphoscintigram showed no radio tracer movement in the right lower limb (figure 8).

Figure 2.

Chest X-ray showing opaque right hemithorax. It was confirmed by chest ultrasound to be massive pleural effusion.

Figure 3.

Serosanguinous appearance of pleural fluid.

Figure 4.

CT scan of chest revealing gross pleural effusion on the right side with subjacent collapse of lung and contralateral mediastinal shift.

Figure 5.

CT angiogram showing no AV malformations or vascular leak.

Figure 6.

MRI scan of the thigh revealing altered signal intensity in the bones and muscles of right lower limb with hypertrophic changes.

Figure 7.

Biopsy from hyperpigmented right groin patch and immunohistochemistry revealing CD34 and D2-40 positive cells suggestive of vasoformative lesion favouring lymphangiomatosis.

Figure 8.

Lymphoscintigram showing no radio tracer movement in the right lower limb.

Differential diagnosis

We kept a differential of hypothyroidism, filariasis or a local cause of lymphatic obstruction, including congenital effects. In view of lymphangiomatosis and involvement of subcutaneous tissue and bone, we also considered possibility of a rare but known entity called Gorham-Stout syndrome. Aetiological evaluation for chylothorax, including thyroid profile, peripheral smear for microfilaria and filarial serology, was negative.

Treatment

Our patient was managed with pigtail insertion (figure 9) and multiple sessions of therapeutic pleurocentesis. In view of re-accumulating right pleural effusion, pleurodesis using talc was done successfully. Propranolol treatment was started at a dose of 0.5 mg/kg but was stopped soon after owing to bradycardia. Alongside, the child also received parenteral nutrition (PN) in calculated dose and high protein and high calorie diet with medium chain triglyceride oil. Injection octreotide at a dose of 50 mcg subcutaneously was given every 8 hours. The child was also subjected to radiotherapy (external beam radiation therapy) to right hemithorax and groin at a dose of 18 Gy over 12 sessions spread over 2 weeks. In view of significant response to above treatment and given the systemic toxicity and cost of immunomodulator therapy like sirolimus, a joint decision was made to continue the treatment and a long follow-up was planned.

Figure 9.

Chest X-ray showing pigtail in situ.

Outcome and follow-up

Our patient showed dramatic response (figure 10). He remained admitted for PN and close follow-up for 4 weeks. Within this period, his respiratory distress settled first followed by general wellbeing. The swelling of right thigh reduced from 32 cm to 26 cm after 3 months of starting treatment. The child remained ambulant during this period and his haematological and biochemical parameters remained stable. At the time of submission of this manuscript, the child had been followed-up for over 6 months, propranolol therapy was re-started at a lower dose of 2.5 mg once daily. The child is tolerating therapy and diet well and is growing satisfactorily. Review MRI is planned for bony lesion and consideration of calcium supplementation, and bisphosphonates will be made thereafter.

Figure 10.

Chest X-ray after multiple sessions of pleurocentesis and after pleurodesis.

Discussion

Lymphangioma is an uncommon benign vascular tumour, 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.¹⁴ 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 developmental anomaly can occur in utero as a part of another syndrome. Syndromes that are associated with lymphatic malformations are Noonan syndrome, Turner syndrome and Down syndrome.² The disorder is marked by masses of fluid-filled channels that are found anywhere in the body, and can be focal or diffuse.¹⁵ Disease manifestation in bone and surrounding soft tissue is called Gorham’s disease or vanishing bone disease.⁵ In 1955, Gorham and Stout reported the histologic features of osteolytic angiomas and reviewed eight published cases.¹⁶ The following criteria are required for diagnosis of this disease: (1) radiographic detection of osteolysis; (2) exclusion of cellular atypia; (3) absence of osteoblastic reaction; (4) detection of progressive local injury; (5) exclusion of ulcerative lesions; (6) exclusion of concomitant visceral disease; (7) positive histological tests for proliferation and angiomatous dysplasia and (8) exclusion of infectious, hereditary, metabolic, neoplastic and immunological aetiology.^10–13 Our patient had radiological evidence of altered MRI signal intensity in the bones and muscles of right lower limb, showing bone erosion and hypertrophy of muscle and right-sided chylothorax. Tissue biopsy from hyperpigmented patch over right groin revealed vasoformative lesion favouring lymphangiomatosis. Lymphangioscintigram confirmed lymphatic obstruction in the right lower limb. These findings in the absence of common causes to explain them led us to a literature search and fitted the broad definition of Gorham-Stout syndrome. Also, the dramatic response to therapy strengthened our diagnosis. The clinical presentation of Gorham-Stout disease of the spine may be local pain, swelling of the affected region, low back pain, pathological fractures, paresthesias, functional alterations and paralysis.^{17 18} The exact aetiology of this entity has not been fully described. Many studies have correlated vascular endothelial growth factor A and interleukin-6 to be increased in the peripheral circulation of affected individuals, and other biomarkers, like erythrocyte sedimentation rate and alkaline phosphatase. Some studies have found an increased concentration of platelet-derived growth factor BB, that plays a significant role in the pathogenesis of lymphedema and lymphangiogenesis in tumours.^19–23 Chylothorax probably occurs secondary to direct extension of lymphatic dysplasia into the pleural cavity or by invasion of the thoracic duct.²⁴ There is no specific treatment for diffuse lymphangiomatosis that is universally accepted. Treatment is aimed at alleviating the patient's symptoms. Recurrent pleural effusions may require pleural fluid drainage or pleurodesis. Palliative options that have been reported to be useful in the literature include radiotherapy, medical therapy with interferon-alpha, corticosteroids and other chemotherapy drugs, which may be associated with systemic toxicity.^{25 26} More recently, propranolol has been used with promising results and without any significant systemic side effects.²⁷ One study reports that radiation therapy may only affect short-term control of osteolytic lesions; nonetheless, it may have a role in patients with fast progressing bone lesions who are at risk of spinal cord transection.²⁸ Somatostatin analogue, particularly octreotide, has been also used in chylothorax.²⁹

Patient’s perspective.

My child was very ill and could not even breathe properly. It was a very hard time for us as a family. Our son being so young, we were feeling hopeless. It is a miracle that he survived through all of this. We are thankful to the entire team for taking such good care of him.

Learning points.

• Gorham-Stout disease is a diagnosis by exclusion; its clinic manifestation is variable from spontaneous remission to lethal outcome.

• Gorham-Stout disease is a very rare, nebulously understood and possibly a lethal skeletal condition.

• All patients with primary idiopathic chylothorax should undergo further investigations to determine whether malformations of the lymphatic system are present.

• Diagnosis behoves a high degree of clinical intuition, sometimes needing multiple images and biopsies.

• Treatment options remain handful, and more research-based evidence is needed to identify high-impact management strategies.

• Radiation therapy should be kept in mind as an additional therapeutic option in diffuse lymphangiomatosis not responding to thoracic duct ligation and/or medical treatment.