Thoracic involvement of diffuse lymphangiomatosis successfully treated with sildenafil

Abstract

General lymphatic anomaly (GLA) is a very rare disorder, characterised by multifocal lymphatic malformations into various tissues that is due to congenital abnormalities of lymphatic development. No treatment has ever proved its efficiency.

We report a 22-year-old man with recurrent bronchial casts due to thoracic involvement of GLA. After a 6-month treatment with sildenafil (20 mg three times a day), a phosphodiesterase 5 inhibitor, chest CT scan showed a complete regression of ground-glass opacities and lung function test results improved substantially and remained stable for 1 year. The treatment was well tolerated.

This observation suggests that sildenafil may be a therapeutic approach to be tested in thoracic involvement of GLA.

Background

General lymphatic anomaly (GLA) is defined as a multifocal lymphatic malformation (variously dilated lymphatic channels or cysts, lined by endothelial cells with a lymphatic phenotype),¹ that commonly involves bones and lungs, but splenic, cervical and cutaneous involvement has also been described.² The ‘gold-standard’ diagnosis relies on pathological findings, with abnormal proliferation of non-neoplastic lymphatic, but biopsies may lead to persistent lymphatic leak. Non-contrast magnetic resonance lymphography, a non-irradiant technique, may be helpful to detect thoracic abnormalities.³

The prognosis is poor in young patients. The treatment is mostly palliative, aiming to slow the disease progression and decrease chylous accumulation. Systemic chemotherapy, interferon, vascular endothelial growth factor inhibition with bevacizumab or beta blockers,^{4 5} and mammalian target of rapamycin inhibition with sirolimus⁶ have been used only in small series or case reports. In 2012, a reduction in a localised lymphatic malformation of the arm was reported in a child receiving sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, for pulmonary hypertension.⁷ Then, a pilot study of two other children also demonstrated a reduction in lymphatic malformation size.⁷

This is the first observation of GLA treated with sildenafil in adult patient with success.

Case presentation

A 22-year-old Caucasian man was referred for plastic bronchitis as a manifestation of GLA. The first manifestation of the disease occurred when he was 16 years old, with repeated bacterial meningitis due to meningeal lymphangiomas. The treatment was surgery and high dose amoxicillin prophylaxis. A large compressive cervical lymphangioma was resected the same year.

After referral, the patient complained of recurrent chyloptysis with bronchial casts and mild exertional dyspnea after fat-rich meals.

Investigations

Lung function tests showed normal volumes with reduced carbon monoxide diffusion (diffusing capacity of the lung for carbon monoxide (DLCO) 68% predicted). Chest CT scan showed extensive ground-glass opacities in the right upper lobe associated with septal thickening in the right lower lobe (figure 1A, B) and a large mediastinal lymphangioma (figure 1C, E). Non-contrast magnetic resonance lymphography revealed diffuse dilatation of cervical, mediastinal and thoracic lymphatic vessels and multiple well-limited splenic and bone nodules that were hypertense on T2-weighted images, similar to the dilated lymphatic vessels/lymphangiomas (figure 1D, F).

Figure 1.

Chest CT scan before treatment (A, axial plane) showing ground-glass opacities in the right upper lobe and septal lines associated with thickening of bronchovascular bundles in the right lower lobe (B). The latter are nicely depicted on T2-weighted thoracic MRI images (arrowhead) (F). Multiple splenic and a few vertebral nodules were hypertense on T2-weighted images (arrows). A large mediastinal lymphangioma mimicks a pericardial effusion (E). Chest CT scan performed 6 months after treatment with sildenafil was started shows complete regression of ground-glass opacities in the right upper lobe (C), with unchanged septal lines in the lower lobe (D).

Treatment

Chyloptysis incompletely resolved after a medium-chain triglycerides diet. Beta-blockers (propranolol, 160 mg/day for 6 months) failed to improve respiratory symptoms and was poorly tolerated. Sildenafil (20 mg three times a day) was then initiated, with excellent tolerance.

Outcome and follow-up

Cough, chyloptysis and bronchial casts were reduced within few weeks. After 6 months, chest CT-scan showed a complete regression of ground-glass opacities but no changes in septal thickening (figure 1C–F). Lung function test results improved substantially and remained stable for 1 year (table 1).

Table 1.

Evolution of pulmonary function test results after sildenafil treatment

	Before treatment	6 months	12 months
TLC (l)	7.03	7.66	7.51
FVC (l)	5.04	5.62	5.57
FEV1 (l)	4.32	4.72	4.62
DCLO (%)	68	75	75

D LCO, diffusing capacity of the lung for carbon monoxide; FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity; TLC, total lung capacity.

On CT scan, some of the splenic nodules decreased in size. The number and size of lytic bone lesions did not change, nor did the size of the mediastinal lymphangioma. The patient stopped the medium-chain triglycerides diet, without any relapse.

Discussion

GLA is a very rare disease,² although its prevalence is unknown. The rarity of this condition explains the lack of clinical trials and treatments with low evidence, reported only in small series or case reports. Local treatments (surgery or radiotherapy) are proposed for bone and thoracic lesions, but the risk of radiation pneumonitis should be considered for patients with extensive disease.² The role of new procedures such as dynamic contrast magnetic resonance lymphangiography to allow for embolisation of dilated lymphatic vessels remains to be evaluated.⁸ A medium-chain triglycerides diet is often ineffective.² Several medical treatments have been tried in diffuse or localised lymphatic malformations, with various effects. In our patient, we aimed to avoid immunosuppression because of repeated meningeal infections. We considered that a PDE5 inhibitor would have a good long-term safety profile in this young patient.

PDEs constitute a large and complex family of ubiquitously distributed enzymes that catalyse the hydrolytic breakdown of cyclic adenosine monophosphate and cyclic guanosine monophosphate into the biologically inactive derivates 5′-adenosine monophosphate and 5′-guanosine monophosphate. The PDE3 inhibitor cilostazol modulated lymphangiogenesis and lymphatic transport in a murine model of lymphedema.⁹ PDE3 was also involved in lymphatic barrier dysfunction in a type 2 diabetes model.¹⁰ In lymphatic malformation tissues, PDE5 is not expressed in the lymphatic endothelium but it is localised to perivascular smooth muscle adjacent to lymphatic spaces, suggesting that sildenafil may mediate relaxation of perivascular smooth muscle in lymphatic malformation tissue, allowing decompression of dilated lymphatic spaces.¹¹ The role of sildenafil inducing endothelial nitric oxide synthase, known to mediate lymphangiogenesis, is another possible explanation.¹¹

In this first observation of GLA treated with sildenafil, we observed a strong benefit on respiratory symptoms and function and ground-glass opacities but no morphologic changes in thickened bronchovascular bundles in the right lower lobe nor in splenic and bone lesions. Similar evolution was described in a preterm infant with congenital chylothorax successfully treated with oral sildenafil.¹² These data suggest that the effect of sildenafil we observed may be mediated by decompression of lymphatic vessels via indirect effects on adjacent smooth muscle rather than by direct changes on lymphatic vessel remodelling. A prospective study in five children with microcystic lymphatic malformations of the head and neck did not demonstrate any effect of sildenafil.¹³ In a series of 14 children with various vascular malformations, none of them reported any improvement and some side effects including bleeding and infections were observed in 4 of them.¹⁴ The effect of PDE inhibitors may be tissue-specific or depend on the type of vascular anomaly. Further investigations are needed to understand the pathogenesis of GLA, which may differ from localised lymphatic malformations or other complex vascular disorders, to establish a rational therapeutic approach.

Learning points.

• General lymphatic anomaly has poor prognosis in young patients. The treatment is mostly palliative.

• Several molecules have been tested in small series or cases reports with few benefits.

• Sildenafil has been described in paediatric population. This is the first case in adult patient.

• Sildenafil effect may be due to decompression of lymphatic vessels via indirect effects on adjacent smooth muscle rather than by direct changes on lymphatic vessel remodelling.