Lymphatic malformations (LMs) are congenital low-flow vascular anomalies caused by abnormal development of the lymphatic vascular system. The incidence rate is approximately 1 in 4,000 [1]. Through the lymphatic channels, the body fluid and solutes that leak from the blood capillaries to the tissue interstitium are reabsorbed, and this fluid, called lymph, is transported back to the venous circulation to control the tissue fluid balance. Lymphatic vessels also play a pivotal role in immunity as pathways by which immune cells are transported to lymph nodes, and lymphatic vessels of the intestinal villi absorb dietary lipids from the intestine. When lymphatic function is impaired, fluid accumulates in tissues between the cells, resulting in lymphedema. Furthermore, this can lead to impairment of humoral homeostasis and immune function and can cause malnutrition through the accumulation of chyle or the development of protein-losing enteropathy [2].

The International Society for the Study of Vascular Anomalies classified vascular anomalies in 2014, and LMs are divided into cystic LM, generalized lymphatic anomaly, Gorham-Stout disease, etc. Cystic LMs are the most common LM, manifesting in solitary lesions of various sizes, and are classified as macrocytic, microcytic, or mixed cystic LMs. Macrocystic LMs manifest as large cysts with a diameter of more than 2 cm, whereas microcystic and mixed cystic LMs are made up of smaller cysts and diffuse vessel-like lesions [3]. In addition to the cystic form, LMs may have other manifestations, including generalized lymphatic anomalies, LM in Gorham-Stout disease, channel-type LM, primary lymphedema, and others. LMs may cause various symptoms depending on the size and location of the lesion, which determine the disfigurement and functional damage of the surrounding structures or organs. LMs primarily penetrate soft tissues and can occur anywhere in the body, including in the extremities, trunk, abdomen, retroperitoneum, and thorax. In many cases, the boundaries of the lesion are unclear, and the invasive involvement with infiltration of adjacent tissues can lead to serious complications, including organ dysfunction, airway obstruction, impairment of oral feeding, and speech or communication difficulties [4].

Physicians have to decide whether to treat or not for symptomatic LMs and asymptomatic LMs causing concern for cosmesis. Various treatment options, such as radiofrequency ablation (RFA), laser therapy, sclerotherapy, and surgical resection, can provide local control and symptom relief in patients with LM. However, complicated LMs involve vital organs, major vessels, and nerves that cannot be surgically removed. Non-surgical treatments have been accepted as optional therapy for complicated LMs. However, most of them remained refractory lesions that do not respond well because sclerotherapy or laser, RFA have limited ability to alleviate symptoms and are not effective in deep areas of LM [56]. Furthermore, in complicated LMs, these treatments may lead to substantial morbidity: cosmetic deformity, organ injury, buildup of scar tissue which may be associated with LM recurrence and regrowth, complications from serial anesthesia, and sclerosing agent risks [6]. Through multidisciplinary approach, complicated LMs are regarded as intractable untreatable diseases.

Since 2010, satisfactory outcomes of mammalian target of rapamycin (mTOR) inhibitors administration have been sporadically reported for patients with complicated LM [7]. The mTOR is a serine/threonine kinase regulated by phosphoinositide 3-kinase (PI3K) and is the basis of various cellular processes, such as metabolism, growth, and proliferation. The PI3K/mTOR pathway increases the expression of vascular endothelial growth factor, which is an important regulator of angiogenesis and lymphangiogenesis. Inhibitors of mTOR may have antiangiogenic effects [89] and have been used as immunosuppressants after kidney transplantation. Many reports have shown excellent clinical improvements in complicated vascular anomalies [1011121314]. We also evaluated the safety and therapeutic potential of sirolimus in patients with a small number of vascular anomalies [15]. Based on these data, we conducted the present study in multicenter to evaluate the efficacy and safety of sirolimus in complicated LM using a dedicated protocol.

Fifty-eight patients were treated with sirolimus for LM between July 2018 and January 2023. Twenty-seven boys and 31 girls were enrolled, with a median birth weight of 3.3 kg (range, 2.6–4.1 kg) (Table 2). Most of the patients were diagnosed with LM prenatally through ultrasonography (25 of 58, 43.1%). Among the remaining patients, 11 were diagnosed at birth, and 22 were diagnosed during childhood.

As shown in Table 3, patients with refractory head and neck LM accounted for the majority with 25 cases (43.1%). Multiple sites with 3 or more lesions accounted for 7 patients (12.1%). Five patients underwent tracheostomy due to respiratory difficulties following airway compression, and 2 patients underwent gastrostomy due to difficulties in feeding through the esophagus. Two of the 5 patients who underwent tracheostomy could be weaned off mechanical ventilation with 1 year of sirolimus treatment with an improvement of lung atelectasis following size reduction of the mediastinal LM as shown in Fig. 1.

Among the patients with LMs, the lymphatic-venous type, characterized by a combination of vascular and lymphatic lesions, exhibited the highest prevalence (n = 22, 37.9%). Ten macrocystic LMs, 16 microcystic LMs, and 10 mixed macrocystic-microcystic types were observed. Nineteen patients (32.8%) had a treatment history of the same modality 4 or more times, including sclerotherapy and excision.

The median age at the initiation of sirolimus treatment was 6.0 years (range, 1 month–26.7 years) (Table 4). The median duration of sirolimus use was 2.0 years (range, 6 months–4.4 years), and most patients were administered sirolimus until the end of the study period. Four patients have discontinued sirolimus treatment. Among them, 2 patients ceased the treatment due to complete resolution, while 1 patient discontinued it due to disease progression, prompting consideration of alternative therapeutic approaches. And the other one discontinued treatment due to a preexisting mood disorder deterioration. Thirteen patients (22.4%) temporarily halted sirolimus during treatment (the median sum of the time off sirolimus, 31 days; range, 3–130 days). Ten patients (17.2%) temporarily discontinued the drug due to the occurrence of adverse reactions. Recurrent viral infection of the upper respiratory tract was the cause in 3 patients (5.2%). Four of the 9 patients with gastrointestinal discomfort had time off sirolimus (6.9%). Other causes of temporary drug cessation included headache and hypercholesterolemia, accounting for 1 (1.7%) and 2 (3.5%), respectively.

A significant to moderate reduction in mass volume in the radiologic evaluation was observed in 40 patients, ranging from 20.2% to 94.8%. Eight of the 15 patients who had a volume reduction of less than 20% on MRI showed clinical improvement such as external portion size reduction, relief of pain, and reduced bleeding episode (Fig. 2), and removal of tracheostomy and gastrostomy. As shown in Table 4, 51 patients (87.9%) showed results ranging from complete to partial, according to the evaluation of the disease response.

To compare treatment outcomes, patients were categorized based on their response to the drug (Table 5). Those who demonstrated a significant response, including CR and significant/moderate response (a subgroup of PR), were classified into group A. On the other hand, patients who showed PD despite undergoing treatment and modest response (a subgroup of PR) were categorized into group B, showing an ineffective response to the drug. This classification allowed for a comprehensive evaluation of the drug’s efficacy in the study population. It is evident that group A exhibited a younger age at the time of treatment initiation and a lower number of previous treatments, although statistically insignificant. In group A, a slightly higher incidence of sirolimus-related adverse reactions in patients was observed. However, the median duration of drug discontinuation due to these adverse reactions was 10 days in group A and 26.5 days in group B.

The graph presented in Fig. 3 illustrates the regional effects of sirolimus treatment. It was observed that patients with lesions in the head and neck exhibited relatively better results compared to those with lesions in other locations.

None of the patients developed systemic or opportunistic bacterial infection during the study period. No CTCAE grade ≥3 toxicity was observed during the study or on follow-up. Patients have been monitored on an outpatient basis for persistent long-term side effects; however, none have occurred thus far.

To date, many studies have shown that treatment of vascular anomalies with sirolimus is safe and well-tolerated under a well-planned protocol. These studies included heterogeneous patients with several types of vascular anomalies, including LMs, involving multiple sites [8111319]. They suggest that sirolimus could be a new therapeutic option for refractory lesions in current multimodal treatments or complicated cases. Based on our previous experience, we established a safe protocol through a study of a heterogeneous patient group [15] and conducted a multicenter study including only patients with complicated LMs.

LMs have a diverse natural history depending on their size, location, and complexity. Thus, it is difficult to assess treatment outcomes because patients often do not achieve complete remission even with repeated multimodal treatments. Therefore, treatment could be supportive, rather than curative [20212223]. Considering these points, we evaluated the patients’ or parents’ satisfaction with the improvement in clinical symptoms and quality of life, as well as the imaging results, to evaluate treatment response. In the imaging tests of patients participating in this study, the volume reduction varied from no change to 94.8%. Most patients underwent conventional treatments, such as surgery or sclerotherapy, prior to sirolimus administration. In particular, 32 patients (55.2%) received sclerotherapy the most, and 13 of them received sclerotherapy 4 or more times. Although sclerosing agents, such as OK-432, doxycycline, and bleomycin act via different mechanisms, they eventually deposit collagen and fibrin, resulting in the formation of dense adhesions and fibrosis [2425]. Multiple treatments aggravated the conversion from cyst to scar in our patients, and this may have affected our treatment results. In our study, most patients with impressive disease outcomes as a significant result (CR and significant/moderate [subgroups of PR]) received only 1 other treatment before sirolimus treatment, and patients who experienced less effect (modest, a subgroup of PR) and no effect (PD) of received 3 or more treatments and adhered to conventional treatment up to 9 times. It is plausible that untreated LM responds better to medical treatment, sirolimus, than scarred tissues. It is consistent with the previous literature [19].

Even though it did not show a significant decrease in LM volume on imaging studies, the subjective satisfaction of patients or parents was quite considerable. Especially in case of complications with bleeding, the episode of bleeding and the amount of bleeding were dramatically decreased (Fig. 2). It might be associated with an antiangiogenic property of sirolimus.

Another factor influencing the outcome of sirolimus treatment is the age at initiation [26]. LMs often change from thin-walled macrocysts to fibrotic, thick-walled, or microcystic LMs with repeated infection or bleeding. Furthermore, as hormones that change with age also affect the natural history of LM, medical management becomes less effective over time. The physiological changes in the lymphatic system may explain why younger patients showed a favorable response [111926]. Consistent with this explanation, Table 5 shows that the patients with significant results were younger than those in the other groups at the start of sirolimus administration, although statistically insignificant. However, this might lead to confusion because the older age group did not have an opportunity for sirolimus administration at their young age when we had not had the experience of sirolimus.

Surgery is usually preferred as the initial treatment [427], but it can be limited because of concerns about damage to vital organs, nerves, or large blood vessels. Our results are consistent with previous studies that showed the lesions close to the mucosal area or vital organs respond more effectively to sirolimus treatment because existing treatments are less likely to be aggressive [1128]. In group A, which was effective for sirolimus treatment, patients with complicated LM in the head and neck accounted for the highest proportion. These promising results suggest that sirolimus can be the first treatment option for head and neck LMs which mainly involve critical structures such as the airway, cranial nerves, brachial plexus, and mediastinum, etc.

The majority of patients with multiple lesions had significant effects with sirolimus (5 of 7, 71.4%). Sclerotherapy and surgical resection have limitations in patients with multiple lesions. These treatments may have side effects from repeated general anesthesia and reduced quality of life due to frequent hospital admissions. These findings provide evidence that sirolimus with systemic effects may be a more effective treatment method than local treatment such as excision or sclerotherapy in patients with multiple lesions.

No CTCAE grades 3 or 4 serious adverse reactions were observed in participating patients. Group A, which was effective for sirolimus treatment, experienced a higher rate of adverse reactions compared to group B (37.0% and 25.0%, respectively). The study results suggested that temporary drug discontinuation due to minor side effects does not significantly reduce the efficacy of sirolimus.

Though we observed many LMs and treatment complicated LMs for the last 5 years, we have several limitations in this study. At first, the enrolled patients were selected by individual pediatric surgeons depending on their own decisions. It could make a heterogenous group in that point of previous treatment outcome following different modalities, anatomical sites, and age groups. Second, to many researchers, the cessation of drugs or the tapering protocol of drugs was not clear. It might lead to different treatment periods with cumulative doses during the study period. Third, we did not get surgical biopsy specimens in most patients, we could not analyze histologic findings according to treatment response. In the literature, Pandey suggested one of the predictive factors of sirolimus treatment as the microvessel density within the LMs. Using D2-40 immunohistochemical staining, they found that the more the proliferation of vessels, the better the response to sirolimus [29]. It means lymphangiogenesis could be a valuable predictive biomarker for the therapeutic response to sirolimus in children with LMs. We anticipate our further study protocol, including surgical biopsy, to obtain the microvessel density and somatic mutation.

Notwithstanding, our study holds significant value as it provides reliable results based on a substantial cohort of patients and incorporates a relatively extended treatment duration and follow-up period compared to preceding sirolimus studies. Furthermore, we intend to continue our research efforts aimed at exploring clinical prognostic factors, histologic variables, and genetic markers that hold the potential to predict drug response. By conducting these supplementary investigations, we aim to develop a comprehensive sirolimus treatment protocol for favorable outcomes observed when initiating sirolimus therapy early, without the need for concurrent interventions. These efforts will contribute to an enhanced understanding of sirolimus’s therapeutic effects and pave the way for more effective and tailored treatment strategies in the future.

Our study showed that sirolimus is an effective and well-tolerated therapeutic option in pediatric patients with complicated LMs who do not respond to conventional treatment. In patients treated with complicated LMs, the therapeutic effect was greater when sirolimus was started at a young age or exposure to other treatments was less. The timely administration of sirolimus, guided by careful patient selection, exhibits the potential to effectively manage the condition, thereby presenting a compelling case for its consideration as a first-line therapy in complicated LMs. Moreover, the establishment of a comprehensive treatment protocol in the future would further reinforce the rationale for sirolimus as a primary therapeutic option for managing this condition.