Topical Sirolimus Gel for the Treatment of Superficial Microcystic Lymphatic Malformations in Pediatric Patients: A Case Series

Abstract

Background

Superficial microcystic lymphatic malformations (MLMs) can cause persistent lymphatic leakage, bleeding, recurrent infection, and disfigurement. Conventional treatments, including surgical excision and sclerotherapy, are invasive and may result in scarring or incomplete resolution. Topical sirolimus may offer a localized, mechanism-based alternative with potentially limited systemic exposure.

Objective

To describe the clinical response and safety of 0.2% topical sirolimus gel in pediatric patients with superficial MLMs.

Methods

This retrospective case series included three pediatric patients with clinically and radiologically confirmed superficial MLMs. Patients received 0.2% topical sirolimus gel twice daily for 6 months. Treatment response was assessed by two independent dermatologists based on clinical examinations and serial clinical photographs, including changes in lesion size, color, thickness, bleeding, exudation, pain, pigmentation, and surface texture. Improvement was categorized as none (0%), minimal (1–25%), moderate (26–50%), or marked (>50%). Safety assessments included local and systemic adverse events and serum sirolimus concentrations.

Results

All three patients were classified as having marked improvement (>50%), with reductions in lesion size and thickness, fading of pigmentation, decreased lymphatic leakage, and improvement in surface texture. One patient showed near-complete regression after 6months of treatment. The earliest clinical response was documented 10 days after treatment initiation in one patient. Local adverse events included transient stinging, erythema, pruritus, xerosis, and desquamation and were managed with supportive care or resolved spontaneously. Serum sirolimus concentrations measured at the assessed time points were consistently< 3.5 ng/mL in all three patients, well below the lower limit of quantification (LLOQ) and far lower than the therapeutic trough concentrations (4–12 ng/mL) associated with oral sirolimus therapy.

Conclusion

In this three-patient case series, 0.2% topical sirolimus gel was associated with greater than 50% clinical improvement and predominantly mild local adverse events. Larger controlled studies using standardized and independently assessed outcomes are needed to establish efficacy and long-term safety.

Background

Superficial microcystic lymphatic malformations (MLMs) are congenital vascular anomalies involving the superficial dermis, often presenting with chronic lymphatic leakage, recurrent infections, and significant psychosocial burden. In contrast to macrocystic lymphatic malformations, MLMs form vesicles, papules, or plaques that can leak lymph (lymphorrhea), often leading to hyperkeratosis and spontaneous bleeding. Driven by activating growth-related mutations, these lesions enlarge over time, recur frequently after treatment, and commonly cause hemorrhage and infection, making management particularly challenging.¹ Unlike macrocystic malformations, which consist of larger and generally deeper cystic spaces, superficial microcystic lesions are distributed within or close to the skin and may therefore be more accessible to topical therapy. Conventional treatments, including surgical excision and sclerotherapy, can be invasive and may result in scarring, incomplete resolution, or recurrence.

Somatic mutations involving the PI3K/Akt/mTOR pathway contribute to the development of lymphatic malformations, providing a mechanistic rationale for treatment with the mTOR inhibitor sirolimus. The 0.2% concentration was selected because it was the commercially available sirolimus gel formulation accessible to the treating institution. This choice was also supported by previous evidence from patients with tuberous sclerosis complex (TSC), in whom 0.2% topical rapamycin gel improved facial angiofibromas and demonstrated greater in vitro percutaneous absorption than the corresponding ointment formulation, without detectable blood concentrations or reported adverse effects.² However, although topical sirolimus gel has been studied primarily for TSC-associated facial angiofibromas, its use in superficial microcystic lymphatic malformations remains rarely reported. This retrospective case series therefore describes the clinical response and safety of commercially available 0.2% sirolimus gel in three pediatric patients with superficial MLMs.

Methods

In this series, all three cases were confirmed by dermoscopy, while Cases 1 and 2 were further evaluated with MRI, which is consistent with our prior experience in diagnosing similar lesion. Histopathological examination was not performed because these non-invasive findings were considered sufficiently characteristic to support the diagnosis and biopsy was not clinically necessary. In addition, the potential risks of bleeding, scarring, and secondary infection associated with biopsy were considered, particularly in pediatric patients.

All three patients received commercially obtained Xianluoli™ (sirolimus topical gel) 0.2%. Each gram contains 2 mg of sirolimus solubilized in a colorless, transparent gel consisting of 51% alcohol, Carbomer 940, purified water, and trolamine. The product is supplied in 10-g aluminum tubes and was stored refrigerated at 2–8°C and protected from light, in accordance with the prescribing information. The vehicle pH was not reported in the prescribing information and was not independently measured. The medication was obtained commercially and was not donated or otherwise provided for this study by Nobelpharma.

The specific regimen was: one application every 12 hours for a treatment course of 6 months one fingertip unit (FTU) per application, evenly applied as a thin film on the lesion surface, avoiding use on areas with ulceration, erosion, or exudation. For areas with ulceration, erosion or exudation, mupirocin ointment was topically applied until crust formation; twice daily sirolimus gel administration was then resumed. Efficacy and safety assessments were conducted at baseline and after treatment. Two senior attending dermatologists independently delineated lesion boundaries and quantified lesional pixel area using ImageJ software on paired clinical photographs captured under consistent shooting parameters. Owing to the presence of physical scale bars in the original clinical images, pixel values were converted into actual physical dimensions via ImageJ to obtain the absolute lesional area (cm²) for inter‑group comparison and the percentage of lesion area reduction was calculated to evaluate therapeutic response. The inter-observer agreement was assessed, and when the difference between the two measurements was within a predefined acceptable range (ie, <10% for area measurements), the average value was adopted. In cases where the discrepancy exceeded this threshold, a third, more experienced dermatologist was invited to review the images and arbitrate the final measurement. The primary efficacy endpoint was defined as the percentage change in lesional area from baseline, computed using the following formula: [(Area_baseline − Area_post-treatment)/Area_baseline] × 100%. Therapeutic benefit was provider reported as 0% (none), 1–25% (minimal), 26–50% (moderate), or >50% (marked) improvement. At each monthly follow-up, peripheral venous blood samples were collected on the morning of the visit prior to gel application (12 hours after the previous topical administration), and serum trough sirolimus levels were quantified via chemiluminescence immunoassay. The generally accepted target trough concentration for oral sirolimus when used for vascular anomalies ranges from 4 to 12 ng/mL, based on the 2019 Chinese Technical Specification for Clinical Application of Immunosuppressants in Organ Transplantation.

Case Presentation

Case 1

The patient is a 12-year-old girl born to non-consanguineous parents, with a medical history notable for surgical excision of a right axillary hemangioma at 11 months of age. Four years prior to presentation, multiple papular lesions developed insidiously over the right chest and chest wall. The initial lesions were pink, vesicular papules ranging from 2 mm to 10 mm in diameter and were tender on palpation. Over time, the number of lesions progressively increased, with color evolution from pink to purplish-red and eventually deep black. Dermatological examination revealed well-demarcated, vesicular papules measuring between 2 mm and 10 mm in diameter, exhibiting pink, purplish-red, and black hues. The lesions were distributed in isolated, scattered, and clustered configurations. The overall clinical presentation is consistent with a diagnosis of MLMs (Figure 1A).

Figure 1.

(A) Prior to treatment, Well-demarcated vesicular papules on the right chest and chest wall, with pink, purplish-red, and black hues, in isolated, scattered, and clustered arrangement. (B) Following six months of twice daily topical treatment with 0.2% sirolimus gel, examination of the lesions on right chest and right chest wall demonstrated a decrease in the erythema of papules and vesicles, as well as a reduction in their diameter and volume.

Dermoscopy revealed yellowish, purplish-red, and black multiloculated lacunae, with white lines visible between the lacunae, and dotted and linear vessels visible within the lacunae. Unenhanced MRI demonstrated a patchy focus of abnormal signal within the cutaneous and subcutaneous fat layer extending from the right chest wall to the axilla. The lesion appeared hypointense on T1-weighted imaging and markedly hyperintense on fat-suppressed T2-weighted imaging, exhibiting ill-defined margins and an infiltrative growth pattern. It was poorly delineated from the neighboring breast parenchyma and showed no involvement of the underlying pectoral muscle fascia. No flow-void signals or phleboliths were identified. These imaging features are characteristic of a MLMs. Key differential considerations include venous malformation (often associated with phleboliths or significant enhancement) and capillary malformation (typically superficial and lacking cystic T2-hyperintensity).

The patient underwent topical treatment with 0.2% sirolimus gel applied twice daily, with onset of action at 2 weeks. After six months of therapy, the cutaneous lesions exhibited marked fading in pigmentation along with a significant reduction in both diameter and volume (Figure 1B). During treatment, the patient reported transient local adverse effects including intermittent stinging, erythema, pruritus, xerosis, and desquamation, all of which were effectively managed with concomitant use of urea cream. No serious systemic or cutaneous adverse events were observed throughout the treatment course. Serum sirolimus levels measured at the six-month follow-up remained consistently within the therapeutic window, supporting the favorable tolerability and safety profile of this topical regimen (Table 1).

Table 1.

Baseline Demographics and Treatment Efficacy Outcomes

Patient Number	1	2	3
Sex	Female	Female	Female
Age/years	12	9	7
Duration of treatments, months	6	6	6
Lesion site	Right chest and chest wall	Right scapular region	Right lower leg
Baseline lesional area, cm2	42.1	57.15	1.29
Post-treatment area, cm2	18.82	3.5	0.61
Area improvement (%)	55.3	93.9	52.7
Onset time	2 week	2 weeks	10 days
Adverse reactions	Stinging, erythema, pruritus, xerosis, and desquamation	Erythema, pruritus, xerosis, and desquamation	Pruritus
Sirolimus blood concentration/(ng/mL)	<3.5	<3.5	<3.5
Efficacy grading	Marked	Marked	Marked

Case 2

We report a case of a 9-year-old girl, born to non-consanguineous parents, with no significant past medical history. At approximately 3 years of age, she developed multiple asymptomatic papular lesions on the right shoulder, back, and posterior aspect of the right upper arm. The lesions initially appeared as light-yellow, translucent, vesicular papules ranging from 1 mm to 8 mm in diameter and were non-tender on palpation. Over the ensuing 6 years, the lesions progressively increased in number and evolved to include yellowish-white transparent, pink, purplish-red, and black papules. Dermatologic examination revealed well-demarcated pink, purplish-red, skin-colored, and light-yellow vesicular papules measuring 1 mm to 8 mm in diameter. The lesions were distributed either isolated or in clusters, with some coalescing into smooth-surfaced, linear, irregular plaques, consistent with a clinical diagnosis of MLMs (Figure 2A).

Figure 2.

(A) Prior to treatment, Well-demarcated vesicular papules on the right scapular region, varying in color (pink, purplish-red, skin-colored, light-yellow) and distributed in isolated and clustered patterns. (B) Following 6 monthsof twice daily topical treatment with 0.2% sirolimus gel, the lesions showed substantial resolution. Only a few residual papules, approximately pinpoint to millet-seed in size, remained.

Dermoscopy revealed purple, yellow, and black multiloculated lacunae, with hanging drop sign visible in some lacunae. Enhanced MRI demonstrated an irregular, patchy area of abnormal signal intensity within the subcutaneous fat layer of the right shoulder and back, which appeared hypointense on T1-weighted imaging and markedly hyperintense on T2-weighted SPAIR sequences. The lesion was predominantly located in the subcutaneous tissue and exhibited infiltrative growth with ill-defined borders relative to the underlying muscular fascia. No definitive involvement of the adjacent intermuscular septa was observed. A small amount of fluid signal was also noted within the right shoulder joint cavity.

Topical 0.2% sirolimus gel was applied twice daily, with onset of action at 2 weeks. Following 6 months of treatment, the lesion area demonstrated marked regression, with only a few residual papules-approximately pinpoint to millet-seed in size-remaining (Figure 2B). Throughout the treatment period, the patient reported intermittent stinging, along with episodes of cutaneous erythema, pruritus, xerosis, and desquamation. These local adverse effects were alleviated with the use of urea cream. No serious systemic or cutaneous adverse reactions were observed. Throughout the treatment course, serum sirolimus concentrations were consistently <3.5 ng/mL at all measured time points (Table 1).

Case 3

The patient is a 7-year-old girl who presented with a 3-year history of multiple papules on the right lower extremity that had gradually increased in number. Three years prior to presentation, without obvious triggers, the patient developed scattered, light pink and translucent vesicular papules on the right lower extremity, ranging from 2 mm to 9 mm in diameter, with no subjective symptoms or tenderness on palpation. Subsequently, the papules gradually increased in number, and some coalesced to form an elliptical plaque and a linear plaque, respectively. Dermatological examination revealed two adjacent but non-confluent plaques on the right lower extremity — one translucent, irregularly linear in shape, and the other light pink, elliptical in shape; punctate hemorrhage was visible within the light pink plaque, and the surface of the plaques was smooth (Figure 3A).

Figure 3.

(A) Prior to treatment, two adjacent non-confluent plaques (translucent linear and light pink elliptical) on the right lower leg; punctate hemorrhage in the latter. (B) After six months of twice daily topical treatment with 0.2% sirolimus gel, the lesion volume significantly decreased or resolved.

Ultrasound of the right lower leg extremity revealed several hypoechoic lesions within the superficial dermis, with a maximum depth of 1.2 mm, ill-defined borders, heterogeneous internal echotexture, and no blood flow signal. Dermoscopic examination before treatment demonstrated transparent and light-yellow lacunae of varying sizes, within which punctate and linear blood vessels were visible.

Topical 0.2% sirolimus gel was applied twice daily, with onset of action at 10 days. After six months of treatment, the lesion volume was significantly reduced compared to baseline (Figure 3B). During the treatment period, occasional pruritus occurred, which resolved spontaneously. The patient’s complete blood count, liver and kidney function remained normal, and no detectable systemic sirolimus exposure was observed, with all serum levels below 3.5 ng/mL (Table 1).

Discussion

Previous studies have reported the use of topical sirolimus for MLMs and other superficial vascular anomalies, predominantly using compounded ointments, creams, or solutions. However, limited formulation-specific evidence is available for commercially manufactured 0.2% sirolimus gel in Chinese pediatric patients with superficial MLMs. These observations add preliminary evidence from a previously underrepresented geographic population but do not establish efficacy, safety, or superiority over other topical formulations.

Our findings demonstrate marked clinical improvement with minimal systemic exposure: during monthly follow-up, serum sirolimus levels were consistently below 3.5 ng/mL, which is lower than the 4 ng/mL threshold typically associated with immunosuppression. This provides real-world evidence that this approach may serve as a safe, non-invasive alternative to conventional therapies.

The pathogenesis of MLMs is primarily driven by somatic mutations such as PIK3CA that constitutively activate the PI3K/Akt/mTOR pathway. This aberrant signaling triggers excessive proliferation and migration of lymphatic endothelial cells, supporting targeted inhibition with the mTOR inhibitor sirolimus.^3,4 Topical sirolimus locally suppresses mTOR activity, exerting both anti-proliferative and anti-inflammatory effects that explain the reduced lesion thickness, erythema and irritation observed in our cohort, consistent with prior dermatologic and immunologic research.

Three topical formulations of sirolimus are currently available, including gel, ointment, and solution. Among these, the solution has been associated with a higher risk of cutaneous irritation, whereas the ointment is often limited by its greasy consistency and suboptimal cosmetic acceptability, which may reduce patient adherence.^5,6 Gel formulations enhance passive diffusion by increasing stratum corneum hydration, which can raise permeability by two- to threefold—an effect particularly relevant for compounds near 1000 Da. In this context, sirolimus gel promotes hydration, expands intercellular spaces, and facilitates the passive diffusion of rapamycin (molecular weight: 914 Da). Consistently, it has demonstrated significantly greater in vitro transdermal absorption than ointment (1358.5 ± 226.4 vs 679.3 ± 71.6 pg/mg; P < 0.01), supporting the utility of the 0.2% gel due to its superior penetration and low irritancy.^7,8

Topical sirolimus has been shown to reduce lymphatic leakage, bleeding, and pain associated with MLMs, while also improving lesion discoloration, thereby enhancing both cosmetic outcomes and quality of life in affected children.⁹ Current clinical evidence suggests that topical sirolimus is generally well tolerated, with a safety profile distinct from that of oral administration. Oral sirolimus, as a systemic therapy, can effectively target deep or extensive lesions through sustained serum concentrations; however, it requires routine therapeutic drug monitoring and carries a risk of systemic adverse effects, including myelosuppression, oral mucositis, metabolic disturbances, and interstitial pneumonitis. In contrast, topical application primarily confines drug activity to the lesion site, thereby minimizing systemic exposure and associated risks.¹⁰ This localized approach makes it particularly suitable for pediatric patients requiring long-term management, especially in anatomically sensitive or functionally critical areas. For example, a case of recurrent mucocutaneous lymphatic malformation at the external urethral meatus showed rapid regression within two weeks of initiating topical sirolimus gel, followed by relapse upon discontinuation and subsequent improvement after re-treatment.¹¹ Another report described microcystic lymphatic malformations of the scrotum and penile root refractory to surgery, cryotherapy, and intralesional sclerotherapy, which responded with marked reductions in lymphorrhea and lesion size after daily topical sirolimus application.¹²

Topical sirolimus has demonstrated efficacy in the treatment of a range of vascular anomalies, including venous malformations, venolymphatic malformations, lymphatic malformations, tufted angiomas, and kaposiform hemangioendotheliomas. Increased systemic exposure to sirolimus may be associated with enhanced therapeutic efficacy.^13,14 Although topical sirolimus gel achieved near-complete resolution in Case 2, new lesions developed following a 3-week treatment interruption, consistent with previous reports of post-therapy recurrence.¹¹

In contrast to systemic sirolimus therapy, serum sirolimus concentrations in all three patients were below the lower limit of quantification of the assay used at our institution (<3.5 ng/mL) at the assessed time points. However, these findings should not be interpreted as demonstrating the complete absence of systemic absorption, because concentrations below 3.5 ng/mL could not be quantified. Systemic exposure may also vary according to the treated surface area, integrity of the skin barrier, lesion depth, treatment duration, and patient age. Although no serious systemic adverse events or clinically relevant abnormalities in the monitored laboratory parameters were observed, the small sample size and limited monitoring preclude definitive conclusions regarding systemic safety. Clinical and laboratory monitoring should therefore be considered during prolonged treatment, particularly when the medication is applied to extensive or compromised skin.

Several limitations of this case series should be acknowledged. First, all efficacy assessments were performed while patients remained on active treatment, with no standardized off-treatment follow-up. Temporary lesion regrowth observed in Case 2 after a brief treatment interruption suggests clinical improvement depends on sustained drug-induced suppression rather than permanent remission; this retrospective cohort lacked a 6 month post-treatment observation window to evaluate relapse risk, and all efficacy statements in the manuscript have been revised to clarify that benefits only reflect on-treatment response instead of durable remission. Second, the 6 month treatment window is inadequate to rule out delayed cumulative adverse effects in children, including skin atrophy and telangiectasia, as well as subtle systemic impacts on growth, pubertal development, lipid metabolism and immune function. Notably, standardized serial assessments of growth and puberty were not prospectively scheduled in this retrospective study and cannot be retroactively supplemented from archived medical records, which limits our ability to fully characterize long-term pediatric safety.

On the other hand, a previous study in patients with TSC-associated facial angiofibromas reported greater in vitro percutaneous absorption of 0.2% rapamycin gel than the corresponding ointment formulation. This prior evidence, together with the commercial availability of the 0.2% gel, supported the selection of the formulation used in the present cases. However, our study did not directly compare formulations and therefore cannot establish that gel provides superior penetration, efficacy, tolerability, cosmetic acceptability, or adherence. Head-to-head clinical and pharmacokinetic studies would be required to evaluate these differences. These findings should therefore be interpreted as preliminary, formulation-specific clinical observations rather than definitive evidence of efficacy, comparative advantage, or long-term safety.

Additionally, outcome evaluation relied on unblinded clinical assessment combined with photographic pixel measurement via ImageJ, whereas objective baseline examinations including MRI and ultrasound were not repeated for post-treatment follow-up, which may introduce subjective bias. Finally, generalizability of our findings is limited: all enrolled patients are girls with non-infected superficial lesions confined to the chest, shoulder and lower limbs, and our data cannot be extrapolated to male patients, lesions at other anatomical sites, or lesions complicated by active infection.

In conclusion, topical sirolimus gel represents a promising targeted intervention for superficial microcystic lymphatic malformations in female pediatric patients with non-infected superficial lesions. Apart from its anti-proliferative effects, the gel modulates the local immune microenvironment to reduce lesion burden. Rigorous controlled trials with larger patient cohorts, standardized unified treatment schedules, standardized objective imaging at baseline and follow-up, blinded assessment, long-term post-discontinuation relapse surveillance, and multi-year pediatric safety monitoring incorporating serial growth and pubertal assessments (paired with biomarker analysis) are required to validate its efficacy and safety across diverse populations including male patients and those with active infectious lesions prior to broad clinical use. Future research will further define its place among anti-inflammatory targeted therapies for pediatric cutaneous vascular anomalies.

Conclusion

In this three-patient case series, 0.2% topical sirolimus gel was associated with >50% physician-assessed improvement in superficial MLMs and predominantly mild local adverse events. No serious systemic adverse events were observed, and serum sirolimus concentrations were below the assay’s lower limit of quantification (<3.5 ng/mL) at the assessed time points and were far lower than the systematic therapeutic concentrations (4–12 ng/mL) associated with oral sirolimus therapy. However, low-level systemic absorption cannot be excluded, and the small sample size, uncontrolled design, subjective outcome assessment, and limited follow-up preclude definitive conclusions regarding efficacy or long-term safety. Larger prospective controlled studies with standardized outcome and pharmacokinetic assessments are warranted.

Funding Statement

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Ethical Approval and Consent to Participate

This study was approved by the Medical Ethics Committee of Shanghai Children’s Hospital (Approval No.2024R116-E03), and written informed consent was obtained from all patients’ parents or legal guardians prior to participation in the study.

Consent to Publish

Written informed consent for publication of the clinical data and images was obtained from all patients’ parents or legal guardians.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

Ke Ma is an employee of Nobelpharma Co., Ltd., a company with a commercial interest in topical sirolimus products. Nobelpharma did not fund this study, provide the topical sirolimus gel, or participate in the conception or design of the study, patient selection, clinical treatment, data collection, data analysis, validation, outcome assessment, interpretation of the findings, manuscript preparation, or the decision to submit the manuscript for publication. The gel used in all three cases was commercially available in China and was obtained independently of Nobelpharma through routine clinical channels. Ke Ma’s involvement was undertaken in his individual capacity as a researcher, and his authorship was based on his scholarly contributions to the study and manuscript. The authors report no other conflicts of interest in this work.