Pulmonary lymphangiomatosis is caused by proliferation of lymphatic vessels in soft tissue [2]. Our case series illustrates the variability of clinical presentation and affections of different sites of the thorax in pulmonary lymphangiomatosis. Because of the rarity of lymphangiomatosis, it is difficult to establish an evidence-based treatment strategy. Most treatments are supportive aiming to decompress adjacent structures and chylous fluid accumulation. Here, we give further insights into this ultrarare disease by adding more knowledge on diagnostics and therapeutic possibilities, especially under the treatment with sirolimus. Among our patients, those treated with sirolimus showed significant clinical, pulmonary and CT morphological improvement with a therapeutic level of 5 ng/ml. This is in line with a recent systematic review which reports that treatment with the mTOR inhibitor sirolimus was an effective and safe treatment for patients with complicated vascular anomalies including lymphangiomatosis that was refractory to other therapies [10]. As an underlying effect of sirolimus it is discussed that sirolimus binds to VEGF receptor 3 on the surface of the lymphatic endothelium [11]. Our data are also in line with some limited data from case reports confirming a successful treatment with sirolimus in several cases [12,13,14,15]. Reports on other therapies in PL are sparse. One potential treatment option might be radiation therapy by radiation-induced fibrosis of the lymphatic endothelium leading to destruction of the lymph vessels resulting in a regression of lesions for several months [16]. This therapy option was also chosen in one of the patients, where the combination of radiotherapy and sirolimus finally lead to a significant clinical improvement. Regarding surgical therapy, our data suggest that resection may have an effect for localized lung or mediastinal lesions. Other surgical treatments are pleurodesis, parietal pleurectomy and ligation of the thoracic duct [17]. However, disease manifestations might relapse after surgical procedures since remaining diseased tissue can lead to uncontrolled proliferation of lymphatic vessels. One case report illustrates a successful bilateral lung transplantation which underscores the importance of accurate selection of patients [18].

Other drugs such as bevacizumab or interferon alpha 2b seem to have a positive impact on the clinical course of the disease [19, 20].

In certain clinical cases sclerotherapy e.g. with doxycycline might be a therapeutic option [21].

Conservative treatment strategies such as medium-chain triglycerides and high-protein diets or total parenteral nutrition were not effective [22].

Vascular endothelial growth factor (VEGF)–D is an established growth factor for lymphangiogenesis, e.g. in lymphangioleiomyomatosis (LAM) [23]. Thus, this protein might be important as a therapeutic and/or diagnostic biomarker also in lymphangiomatosis. In 3 of the presented cases, serum levels of VEGF-D were useful for diagnosing pulmonary lymphangiomatosis. However, further investigation is needed to establish a cut-off for serum levels of VEGF-D as useful guidance for diagnostic and therapeutic approaches in this disease. As propranolol, a non-selective β-blocker, reduces the levels of VEGF-D, also this may be an alternative treatment option. In a case report of a child suffering from lymphangiomatosis, reduction of pleural effusion could be shown after the treatment with propranolol [9]. In one of our cases propranolol was used in combination with sirolimus and could stabilize disease progression but for 9 months only.

In the light of these considerations, we assume that sirolimus treatment is effective in pulmonary lymphangiomatosis. However, it is unclear if sirolimus may substitute or complement surgical therapy. Furthermore, also disadvantages of a possible treatment with sirolimus have to be considered including stomatitis and immunosuppression as also experienced in our patients. Furthermore, our clinical follow-up is limited and a longer follow up time is needed to assess long-term outcomes and potential complications. Nevertheless, further investigation is needed to understand the pathogenesis of lymphangiomatosis to establish further therapeutic approaches. In order to obtain further insights into clinical characteristics and to investigate long-term results of therapy in a larger population, a patient registry of lymphangiomatosis should be implemented.

In conclusion, we report here the largest series of an ultrarare disease, pulmonary lymphangiomatosis giving new insights into clinical characteristics and outcome. Furthermore, the reported data support a potential efficacy and effectiveness of sirolimus in the treatment of pulmonary lymphangiomatosis.