Emerging Role of Sirolimus in the Treatment of Diffuse Venous Malformation in a Woman with Klippel-Trenaunay Syndrome

Abstract

Klippel-Trenaunay syndrome (KTS) is a congenital disorder that presents as a triad of capillary malformations, venous malformations (VMs), and limb overgrowth. Lymphatic malformations are commonly reported but not considered a defining feature of KTS [1]. Historically, treatment options have been limited, with embolotherapy and surgical resection serving only as means of symptom palliation. Sirolimus, an mTOR inhibitor, modulates the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway and coordinates normal vascular proliferation and growth by regulating ribosomal activities and protein synthesis [2]. We present the case of a woman with KTS who had a treatment-refractory abdominopelvic venous malformation (VM) that caused chronic, debilitating pain and was treated successfully with sirolimus. At 38 years old, the patient presented to our vascular anomaly clinic for management of multiple symptomatic VMs, involving the vulvovaginal, abdominopelvic, and right lower extremity. Secondary to her extensive malformation, she had chronic intravascular coagulopathy with elevated levels of D-dimer and low fibrinogen treated with enoxaparin. Her extensive abdominopelvic VM caused debilitating symptoms, including abdominal pain (3–5 on a 10-point scale, daily) and bloating, and exercise intolerance, which diminished her quality of life. She underwent surgical resections and 9 sessions of image-guided percutaneous sclerotherapy of the abdominopelvic VM (Fig. 1) using ethanol and/or sodium tetradecyl sulfate (Sotradecol, Upjohn, Kalamazoo, MI) for symptom control. Despite technically successful interventions, she had minimal pain relief. Given her refractory symptoms, after consultation with hematology, we decided to initiate sirolimus therapy based on early reports of its effectiveness in treating pediatric patients with similarly treatment-resistant VMs. At age 43, she received her first dose of sirolimus (2.2 mL daily in 1 mg/mL suspension, orally), after which the dosage was titrated according to weekly drug trough levels using a target plasma range of 3–20 ng/mL. Six months after beginning sirolimus therapy, she was tolerating the medication with mild adverse effects, which included 9.1–14 kg of weight gain and nocturnal headache that improved with oral acetaminophen. Serum lipid markers were mildly elevated. She reported symptom improvement (0–1 on a 10-point scale, daily). On contrast-enhanced abdominal (Fig. 2) and pelvic (Fig. 3) magnetic resonance imaging, her diffuse abdominopelvic VM decreased in size. This size reduction remained at 1-year follow-up, suggesting treatment response to continuous sirolimus therapy (Figs. 2 and 3). Surveillance scans taken in 2017 (most recent imaging) showed that vascular lesion size was stable, representing a sustained response to the medication. As of 2020, the patient continued on her oral sirolimus regimen without complications and returns to our institution for annual follow-up. In 2011, 6 children with treatment-resistant venous and/ or lymphatic malformations were treated with sirolimus [3] in what appears to be the first report showing the effectiveness of sirolimus as salvage therapy. These children SIR Annual Scientific Meeting: This has been accepted by SIR as an educational abstract for the 2021 SIR Annual Scientific Meeting.