Retrospective evaluation of sirolimus (mTOR blocker) for lymphatic malformations presenting in the neonatal period: a single-center experience

Introduction

In accordance with the international classification of ISSVA (International Society for the Study of Vascular Anomalies), lymphangiomas are lymphatic vascular malformations (LM) presented as cystic vascular abnormalities without tumor proliferation of endothelial cells (1).

LMs are the second most prevalent type of vascular malformations, following venous malformations (2). The incidence of lymphatic malformations is about 1.2–2.8 per 1,000 live births. Approximately 50%–60% of cases are detected antenatally or immediately after birth. Around 48% of lesions occur in the head and neck, followed by trunk and extremities (42%), abdomen and thorax (10%) (3, 4).

Lymphatic malformations can manifest in a multitude of ways, leading to a diverse range of clinical presentations. Particular mass in the head and neck may cause major cosmetic and functional problems or even compression of the main airway (5–10).

The most likely pathogenetic mechanism of lymphatic vascular abnormalities is mutations in the PIK3CA gene, which leads to abnormal functioning of endothelial cells and disruption of the structure of lymphatic channels. Mutations in this gene have been identified in the majority (about 80%) of common cystic lymphatic malformations (11).

There are no standardized treatment protocols for patients with lymphatic malformations. The frequent proximity of lymphatic malformations in the head and neck to vital structures poses significant challenges in the treatment. Historically, surgical excision has been the standard of care. Radical surgical correction of lymphatic malformations can lead to technical difficulties associated with extensive damage to tissues and organs. It also causes relapses and life-threatening complications. Complete excision of LM is often difficult to achieve and is accompanied by high level of recurrence. According to Huerta CT et al., rate of complications of surgical treatment for LM account for 26.6% (range 0%–100%) and recurrence is 13.2%. Other methods of treatment of lymphatic malformations include sclerotherapy, radiofrequency ablation and laser treatment with varying rates of treatment success. The effectiveness of LM sclerotherapy is up to 84.2% when using doxycycline and up to 40% when treating with bleomycin (7, 12–14).

The first reports of conservative treatment of vascular malformations with rapamycin (sirolimus) in children appeared in 2008–2011 (5, 15, 16).

Rapamycin (sirolimus) is a natural antibiotic produced by the bacterium Streptomyces hygroscopicus, which was first introduced in the literature in 1975 as a fungicidal agent (17). Rapamycin in the cell combines with the protein FKBP-12 (immunophilin) and inhibits the main enzyme of cell cycle regulation protein kinase mTOR (mechanical/mammalian target of rapamycin). Kinase mTOR inhibits the cell cycle between periods of resting and synthesis phase. Activation of the PI3 K/AKT pathway leads to activation of mTORC1. Diseases associated with disorders in the PI3K->AKT->mTOR signaling pathway, including various vascular malformations, are successfully treated with sirolimus (18–21).

Sirolimus is usually prescribed in a starting dose of 1–1.6 mg/m²/day orally for 2 times (every 12 h). The therapeutic range of the drug concentration in the blood, minimizing toxic and undesirable effects, is 5–15 ng/mL. Side effects include: transient recurrent neuropathy, hypercholesterolemia, hypertriglyceridemia, aphthous stomatitis, mucositis, mild hypertension, increased liver enzymes, functional dyspepsia, nausea/vomiting, diarrhea, neutropenia, lymphopenia, thrombocytopenia, hypophosphatemia, eczema (10, 12).

Sirolimus accumulates in the blood cells, reaches its maximum concentration after a single dose in 60 min and has a half-life of 62 +/−16 h. The coefficient reflecting the ratio of concentration in blood to concentration in plasma is 36 (36:1, blood: plasma). The drug is mainly excreted through the gastrointestinal tract with bile (91%) and, to a lesser extent, by the kidneys (2.2%).

Rapamycin undergoes intensive metabolism under the influence of the CYP3A4 isoenzyme in the intestinal wall and liver. It is also a substrate for P-glycoprotein of the small intestine, the system of excretion of many drugs. This should be considered when administering medications that are strong inducers of CYP3A4 (rifampicin, rifabutin, phenobarbital) or strong inhibitors of CYP3A4 and P-glycoprotein (HIV and hepatitis C protease inhibitors, antifungal drugs from the azole group) simultaneously with rapamycin preparations (18–21).

Several case series have reported the use of sirolimus in neonates with lymphatic malformations, but data on dosing strategies, safety monitoring, and long-term outcomes in this specific population remain limited (12, 22–26). To address this gap, we present a relatively large single-center case series of 16 patients characterized by neonatal initiation of oral sirolimus and a broad anatomical distribution of lesions, aiming to evaluate the drug's efficacy and safety in our hospital.

Methods

Study design and source population

This study is an uncontrolled retrospective case series based on the review of electronic patient records at the St. Petersburg State Pediatric Medical University. Due to the retrospective and observational nature of the study, treatment allocation was non-randomized and strictly determined by clinical indications and multidisciplinary consensus at the time of the patients’ admission. Electronic databases were searched to consecutively identify patients managed for lymphatic malformations (LMs) in the neonatal period or early infancy between January 1, 2021, and December 31, 2025.

Inclusion and exclusion criteria

Patients were included in the final analysis if they met the following criteria: During the chart review, patients were excluded from the final analyzed cohort if they: underwent primary radical surgical treatment as their initial therapy (n = 7) or had an unverified or altered diagnosis upon histological examination.

• age at presentation ≤ 3 months of life;
• clinical and radiological diagnosis of LM verified by ultrasound, CT, or MRI;
• primary conservative therapy with oral sirolimus initiated at our institution.

A total of 24 electronic records with a presumptive diagnosis of neonatal mass or LM were initially screened. One patient presenting with a neck mass was excluded prior to establishing the source population because a formal biopsy and morphological examination established a definitive diagnosis of teratoma. Thus, the baseline source population consisted of 23 consecutively treated infants with verified LMs (Figure 1).

Characterization of treatment allocation

Treatment allocation was determined by a multidisciplinary team based on lesion anatomy and clinical severity. Primary radical surgery was chosen for 7 out of 23 patients (30.4%) who presented with localized, well-demarcated lesions where complete excision carried minimal risk to vital structures. Conversely, primary conservative therapy with oral sirolimus was initiated in 16 patients (69.6%) presenting with extensive, infiltrative, or complex LMs where surgical intervention carried high morbidity or mortality risk. Other modalities, such as primary sclerotherapy or active observation, were not utilized during this study period.

Within the final sirolimus cohort (n = 16), 15 patients initiated therapy during the neonatal period (median age: 15 days). All 16 patients had complete medical records with clinical and laboratory data, and no patients were lost to follow-up or discontinued treatment due to toxicity.

Diagnostic workup and treatment protocol

The complex diagnostic approach included a clinical examination and medical imaging (ultrasound, CT, MRI). In patients with abdominal lymphangioma, diagnostic laparoscopy was performed to confirm the diagnosis. All patients were consulted by a pediatric oncologist, a pediatric surgeon, and an angiosurgeon.

Sirolimus was initiated in infants with lymphatic malformation upon diagnosis confirmation, at a starting dose of 0.5 mg/m²/day orally in two divided doses, with daily clinical and weekly laboratory monitoring. The target concentration of sirolimus in the blood was 5–15 ng/mL. During hospitalization, monitoring was performed weekly.

Since the start and throughout the entire period of therapy, patients were monitored for basic clinical and laboratory parameters on a weekly basis to assess the safety of the drug in this age group. Medical imaging was performed no earlier than 1–2 months after the start of therapy, or in the case of marked local changes in the area of lymphangioma.

The patients were examined once a month after transition to the outpatient stage of treatment. Long-term outpatient follow-up was performed by a pediatric oncologist, pediatrician, pediatric surgeon, or angiosurgeon.

Table 1 summarizes the clinical and anamnestic data of all patients with lymphatic malformations treated during the study period.

Table 1. Clinical and anamnestic data of patients with lymphatic malformations treated for the period 2021-2025.

Antenatal diagnosis was recorded when available from the medical charts, but detailed prenatal imaging data were not consistently documented for all patients due to the retrospective nature of the study.

Response assessment

Given the retrospective nature of this study, response assessment was based strictly on the review of clinical documentation and follow-up imaging studies (ultrasound, CT, or MRI) available in the electronic medical records, closest to the 6-month time point after treatment initiation. Lesion volumes were estimated using the standard ellipsoid formula (length×width×thickness×0.52) based on multi-planar radiologist measurements.

To ensure reproducibility, the original clinical descriptions used in Table 1 were retrospectively harmonized with objective volumetric changes as follows: In strict accordance with the retrospective design, no independent or blinded prospective radiological review was performed, and response categories reflect the validated entries within the institutional database.

• “complete regression” was defined as a near-complete or complete disappearance of the lesion, corresponding to a ≥ 90% reduction in estimated volume;
• “regression” (partial response) corresponded to a 50% to 89% volume reduction; and
• “mild regression/stabilization” (stable disease) was defined as a less than 50% volume reduction without objective disease progression.

Results

In our clinic, 16 patients with lymphatic malformations received primary treatment with sirolimus. At the beginning of treatment, the target concentration of sirolimus in the blood (5–15 ng/mL) was achieved using a minimum dose of 0.5 mg/m²/ day orally in 2 doses. The dose was further increased to 1.0 mg/m²/day as the target concentration decreased. This correlated with the child's weight gain.

Table 2 shows the laboratory data, showing the minimum and maximum levels of each indicator for the entire follow-up period: a biochemical blood test indicating liver and kidney markers of toxicity, a clinical blood test, and data from a basic instrumental cardiological examination and examinations by specialists.

Table 2. Clinical and laboratory parameters of patients receiving sirolimus.

Laboratory parameters showed occasional deviations, which were transient and resolved without specific intervention. No treatment-related serious adverse events requiring permanent discontinuation were observed. Recorded adverse events included transient respiratory infections (n = 2), diarrhea (n = 2), aphthous stomatitis (n = 1), and mild anemia (n = 1), all of which resolved with supportive care or temporary dose adjustment.

Histological examination was performed only in cases where the diagnosis was uncertain. In the study cohort, biopsy was performed in one patient initially suspected of having a cervical lymphangioma, which revealed a teratoma; this patient was excluded from the analysis. In all other cases, the diagnosis was confirmed by imaging studies. Genetic testing for PIK3CA mutations was not routinely performed at our institution during the study period, consistent with the retrospective nature of this analysis.

Discussion

The initial utilization of sirolimus for vascular malformations was documented in early case reports demonstrating significant clinical improvement in pediatric patients (27). Subsequently, accumulating evidence has established the efficacy of this agent in reducing lesion volume and mitigating symptoms in children with complex vascular anomalies (16, 20). More recently, clinical interest has shifted toward evaluating targeted therapy specifically within the neonatal period. Several case series have reported successful first-line sirolimus use in neonates with extensive head and neck lesions requiring respiratory support, with significant clinical improvement in all cases (22). Pharmacokinetic challenges in this population have also been characterized, showing that standard pediatric dosing protocols often result in supratherapeutic drug levels, thereby necessitating modified dosing regimens (23). Clinical observations in infants under one year of age have confirmed that a starting dose of 0.5 mg/m²/day is sufficient to maintain therapeutic trough concentrations (24). More recently, substantial volumetric reductions have been documented in neonates with life-threatening or extensive cervicofacial lesions, with one series reporting a mean volume reduction of 79% in patients treated with sirolimus combined with sclerotherapy (25, 26).

Our study extends these observations to a notably broad anatomical spectrum, including not only head and neck lesions, but also thoracic, abdominal, mesenteric, and extremity involvement—sites where surgical resection often carries significant morbidity and technical challenges. With a median treatment initiation age of 15 days and a starting dose of 0.5 mg/m²/day, titrated to a target trough concentration of 5–15 ng/mL, we observed stable disease stabilization or regression in 100% of our patients. Specifically, complete regression was achieved in 10 out of 16 cases (62.5%), partial regression in 3 cases (18.75%), and disease stabilization in the remaining 3 cases (18.75%) at the 6-month assessment. Importantly, no treatment-related serious adverse events requiring permanent discontinuation were observed. The recorded side effects were mild and manageable, including transient respiratory infections (n = 2), diarrhea (n = 2), aphthous stomatitis (n = 1), and mild anemia (n = 1), all of which resolved with supportive care or temporary dose adjustment.

The role of sirolimus in the management of lymphatic malformations must be considered within the broader context of available treatment options. Surgical excision has historically been the standard of care, but it is associated with significant challenges, particularly in anatomically complex locations. According to a recent systematic review by the APSA Outcomes and Evidence-Based Practice Committee, the complication rate of surgical treatment for LMs is 26.6% (range 0%–100%), with a recurrence rate of 13.2% (12). Sclerotherapy offers an alternative with variable success rates, ranging from 40% with bleomycin to 84.2% with doxycycline (12). In this context, sirolimus provides a valuable conservative option, particularly for neonates with extensive or unresectable lesions where surgical intervention carries high morbidity or mortality risk.

In our cohort, five patients presented with abdominal or mesenteric LMs — sites where surgical resection poses substantial technical challenges and risks of intestinal injury, malabsorption, or short bowel syndrome. Diagnostic laparoscopy was performed to confirm the diagnosis in these patients, but definitive surgical resection was deferred in favor of sirolimus therapy. This approach aligns with the concept of neoadjuvant conservative therapy, which can reduce surgical risks by stabilizing lesion size or achieving sufficient regression to allow for a less extensive procedure (28). In one patient, sirolimus therapy resulted in only mild regression with subsequent stabilization, and secondary surgical intervention was performed at 1.5 years of age. This case illustrates that sirolimus does not always eliminate the need for surgery, but may facilitate a safer, more elective surgical procedure at a more favorable age.

The multidisciplinary management of neonates with vascular malformations is essential, requiring collaboration among neonatologists, pediatricians, pediatric oncologists, vascular surgeons, pediatric surgeons, and radiologists (7, 10). In our institution, a comprehensive imaging protocol was employed, with ultrasound, CT, and MRI used in combination to confirm the diagnosis, define the anatomical extent of the lesion, and assess its relationship to adjacent structures. This multimodal approach was guided by the technical capabilities of our center and the individualized needs of each patient.

Limitations

Several limitations of this study should be acknowledged. First, the retrospective, uncontrolled single-center design introduces potential selection bias, as treatment allocation was influenced by lesion location, resectability, and clinical severity. Second, the small sample size (n = 16) limits the generalizability of our findings and precludes subgroup analysis to identify predictors of response. Third, the absence of a comparator group (e.g., surgery or sclerotherapy) prevents direct comparison of treatment modalities. Fourth, the relatively short follow-up period (median 18 months, range 6–24 months) does not allow for assessment of long-term durability of response or potential recurrence after sirolimus discontinuation. Fifth, while we applied standardized radiological criteria for response assessment, the imaging intervals and modalities were not uniform across all patients due to the retrospective nature of the study. Finally, adverse events may have been underreported due to the retrospective design and reliance on medical record documentation.

Despite these limitations, our study provides valuable data on the feasibility and safety of sirolimus therapy in a relatively large neonatal cohort with diverse anatomical presentations. The detailed clinical and safety data reported here may inform clinical practice and guide future prospective studies.

Conclusion

In this selected single-center cohort of neonates with extensive or unresectable lymphatic malformations, clinical and radiological improvement was observed during sirolimus treatment, with disease stabilization or regression in all patients and a partial or complete radiological response in 81.25% of patients at 6 months. The safety profile was acceptable, with no treatment-related serious adverse events requiring permanent discontinuation. These findings support the feasibility of sirolimus as a conservative first-line strategy, potentially deferring or, in some cases, avoiding high-risk surgical intervention. However, the small sample size, uncontrolled design, heterogeneous outcome assessment, and limitations of retrospective safety reporting preclude definitive conclusions regarding efficacy or safety. Multicenter prospective trials with standardized response criteria and long-term follow-up are needed to establish the optimal role of sirolimus in the management of neonatal lymphatic malformations.

Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Footnotes

Edited by: Jennifer Fang, Tulane University, United States

Reviewed by: Lin Fan, Nanjing Children’s Hospital, China

Melie Sarreau, Université Montesquieu, France