Treatment aspects, prognostic factors and outcome measures of lymphatic malformations

Abstract: Lymphatic malformations (LMs) are structural defects in the lymphatic vessels. LMs are histologically benign lesions, however, due to localization, size and unexpected swelling, they may cause serious complications that threaten vital functions such as compression on the airways. A large swelling of the face or neck may also affect the esthetics and thus constitute a psychological strain for the patients and their families. LMs are also highly immunologically reactive and are prone to recurrent infections and inflammation causing pain as well as chronic oozing wounds. There are no available guidelines that describe management and follow up of LMs. Surgery has previously been considered the first treatment option. Surgery, however, has limitations as LMs often infiltrate adjacent structures, such as vessels and nerves making total resection difficult and potentially dangerous. Percutaneous sclerotherapy has replaced surgery as the primary treatment in most cases. Sclerotherapy also has limitations and can potentially cause serious complications such as unpredictable swelling that affects vital functions and cause scarring in the surrounding tissue. Review of the literature raises several questions. It is still unclear, which should be the treatment criteria for LMs and how to follow up the patients. LMs are rare conditions, however, our department has accumulated a large cohort of patients. No other institution has published a larger cohort of patients with LMs. The main objectives of this project was to evaluate the surgical- and interventional outcome of the treatment of LM patients, identify prognostic factors and better understand the inflammatory mechanisms of OK-432 treatment. In this dissertation the following research questions were addressed. 1. Are there immunological pre-requisites that can be analyzed in a blood sample that provide prognostic information on the outcome of sclerotherapy using OK-432? 2. How good is the long-term clinical outcome and the health-related quality of life of patients treated with sclerotherapy using OK-432? 3. Is it possible to establish a treatment algorithm for patients with LMs involving the mediastinum by evaluating the current management with both surgery and sclerotherapy? In Paper I the hypothesis was that Toll-like receptor (TLR) expression in monocytes after treatment with the TLR4-ligand lipopolysaccharide (LPS) could be used to predict successful OK-432 treatment. Blood was analyzed from children with low response (LR, n = 6) and high response (HR, n = 5) to previous OK-432 sclerotherapy. Monocytes were stimulated with LPS. TLR4 expression was analyzed with fluorescence-activated cell sorting (mean fluorescence intensity (MFI)). The mean TLR4 upregulation after LPS stimulation was 3.6 times higher in the HR group than in the LR group and non-stimulated controls (P = 0.037). Dynamic TLR4 expression most probably represents a predictive parameter for the treatment of LMs with OK-432. In Paper II, further analysis showed that the mean expression of TLR 4 after LPS stimulation was comparable in both groups (HR 1142 ± 652 units, LR 839 ± 427 units, P = 0.85). The pre-stimulation values in the LR group compared with the HR group were 950 ± 718 vs. 477 ± 341 with considerable differences of the mean expression changes after LPS stimulation (HR 665±683vs.LR 111±605,P=0.08). The difference in TLR4 upregulation on monocytes after LPS stimulation in the LR group compared with the HR group can be explained by TLR preconditioning. The findings suggest that absolute threshold values of TLR 4 could be a predictive parameter for the treatment of LMs with OK-432. In Paper III demographic data and long-term outcome in patients with LMs treated with OK-432 were analyzed. We enrolled 131 of 138 eligible patients treated with OK-432 for LMs between 1998 and 2013 in a retrospective study. The outcome was assessed with a clinical examination, evaluated with a clinical assessment score (CAS), and a questionnaire. LMs were localized to the head/neck (60%), the trunk (20%) and the extremities (6%) or involved more than one region (14%). Patients with microcystic (10%), macrocystic (21%) and mixed lymphatic malformations (69%) underwent a median number of three, two and two injection treatments, respectively. OK-432 treatment resulted in a successful outcome in 70% of patients with LMs. The long-term outcome was comparable to the short-term outcome. The number of injections, previous treatment and lesion localization predicted the clinical outcome. Four unsatisfactory attempts of sclerotherapy were shown to be a breakpoint for surgery. In Paper IV the management of patients with LMs involving the mediastinum was reviewed and a treatment algorithm was suggested. All patients with LMs involving the mediastinum between 2009-2015 at our institution were reviewed. We collected demographic data, data on investigations, management, and complications of the treatment, as well as outcomes at follow-up. Complications were described according to the Clavien- Dindo classification. The patients treated with sclerotherapy and the operated patients had comparable numbers of Clavien-Dindo grade I-II complications. Clavien-Dindo grade IIIIV complications were five times more frequent after sclerotherapy than after surgery. The clinical outcome was excellent for the operated patients and fair to good for the patients receiving only sclerotherapy. Patients with cervical LM involving the mediastinum represent a high-risk group with respect to the severity of complications following sclerotherapy. Surgical resection of the LM in the mediastinum is recommended, with the possibility of intra-operative sclerotherapy as an adjunctive. In Paper V the health-related quality of life (HRQOL) was assessed in the cohort of Swedish children and adolescents with LMs who underwent injection treatment with OK-432 at our institution between 1998 and 2013. A study-specific questionnaire was sent to all patients with at least five years’ follow up after the first injection treatment asking for persisting symptoms and satisfaction with the treatment and care. KIDSCREEN-52 was used to assess HRQOL. Patients with LMs localized in the head and neck area and repeated sclerotherapy constitute a risk for negatively affected HRQOL.