Oral sildenafil as a treatment option for lymphatic malformations in PIK3CA-related tissue overgrowth syndromes

Abstract

Patients with extensive lymphatic malformations associated with tissue overgrowth syndromes (such as Klippel-Trenaunay syndrome and CLOVES) often pose a therapeutic challenge for physicians. In recent years, it has been suggested that oral sildenafil therapy might be used to treat congenital lymphatic malformations. However, this possible new therapy has not yet been used in patients with lymphatic malformations associated with tissue overgrowth syndromes. A 30-year-old man with extensive capillary-lymphatic malformations of the right leg and thorax, and a tissue overgrowth syndrome caused by a somatic mutation in the PIK3CA gene, was treated with oral sildenafil due to symptoms of pain, dyspnea, and functional impairment. Several weeks after the start of the treatment, the patient reported softening of the lymphatic malformation and a significant improvement of his symptoms and physical condition. So far, sildenafil is still considered a last resort in the treatment of complex treatment-resistant lymphatic malformations. With this case report, we demonstrate that sildenafil could also be an alternative treatment option for lymphatic malformations in patients with syndromes belonging to the PIK3CA-related overgrowth spectrum.

Long‐Term Follow‐Up of Lymphatic Malformations in Children Treated with Sildenafil

“…With the identification of PIK3CA mutations in LMs (14), there has been increased use of sirolimus therapy (15)(16)(17)(18), because mTOR inhibition reduces downstream signaling of PI3 kinase, inhibiting cell proliferation. A case report has also documented improvement of LM symptoms with sildenafil treatment in an individual with PIK3CA-related overgrowth syndrome (19).…”

“…Sildenafil's hypothesized effects on LMs are that the resulting smooth muscle relaxation perpetuates cystic decompression and allows secondary lymphatic spaces to open or that sildenafil mobilizes normal lymphatic progenitor cells to reduce lymphatic endothelial dysfunction at disease sites . These mechanisms may collectively account for the reported softening and improvement in LM symptoms . Mouse models and human studies have identified increased circulating endothelial and hematopoietic progenitor cells with PDE‐5 inhibition , suggesting an alternative mechanism of action for sildenafil.…”

Vascular anomalies: special considerations in children

“…Sirolimus has a role in the treatment of both PIK3CArelated overgrowth and non-PROS growth disorders but it is clear that such medical therapies are still in their infancy (Adams et al 2016;Horbach et al 2016). More specific gene mutations need to be identified so that the vast range of differing phenotypes can be targeted more effectively.…”

Application of the adenosine triphosphate sensitivity assay in infantile vascular anomalies

“…In addition, some other beta-blockers (atenolol [11], timolol [12], etc. ), itraconazole [13], rapamycin (sirolimus) [14] and sildenafil [15,16] have been reported to be effective in treating certain vascular anomalies.…”