Neonatal Head and Neck Lymphatic Malformations Show Marked Regression Under Sirolimus Therapy

A clinical case series evaluating three neonates with extensive congenital lymphatic malformations of the head and neck demonstrated that early systemic therapy with sirolimus induced substantial lesion volume regression across all treated infants while presenting manageable yet serious complications. Congenital lymphatic malformations are slow-flow vascular anomalies stemming from abnormal venous endothelial development during embryogenesis, often linked to somatic activating mutations in the PIK3CA gene that drive excessive PI3K/AKT/mTOR pathway signaling and lymphatic hyperplasia. Because conventional interventions including radical surgical resection, sclerotherapy using agents such as doxycycline, bleomycin, or alcohol, and radiofrequency ablation frequently carry high failure rates, nerve damage risks, and recurrence rates reaching 53 percent in tissue-infiltrating cervicofacial lesions, oral sirolimus was administered as a targeted direct mechanistic target of rapamycin inhibitor to block protein synthesis and cellular proliferation.

The first patient described in the investigation was a full-term male delivered via cesarean section at an Apgar score of 10 and a birth weight of 3180 grams following a pregnancy complicated by maternal hypothyroidism. Prenatal ultrasound performed at 29 weeks of gestation had initially identified a septated cystic mass measuring 104 by 53 by 60 millimeters on the left side of the fetal neck with evident compression of the thyroid gland, which subsequently expanded to 140 by 71 by 75 millimeters before delivery without any invasive prenatal diagnostics. Baseline magnetic resonance imaging confirmed an extensive multiloculated fluid-filled lesion measuring 94 by 87 by 80 millimeters across transverse, sagittal, and anteroposterior planes, originating at the level of the auricle, extending into paraspinal and retropharyngeal spaces, descending to the thoracic inlet, and visibly displacing the trachea, midline cervical structures, and the patent left common carotid artery toward the right side.

Systemic sirolimus therapy for this first neonate commenced on day 16 of life at an initial oral dosage of 0.4 milligrams per square meter administered twice daily, with ongoing therapeutic drug monitoring and regular biochemical evaluations. Although serum sirolimus concentrations were maintained within the designated target window of 5 to 10 nanograms per milliliter, the therapeutic course was interrupted on the seventh day of administration by an acute infection of a cystic compartment and overlying subcutaneous tissue. The infant manifested high fever, localized erythema, tenderness, and sudden mass enlargement, with systemic blood, cerebrospinal fluid, and direct cyst aspirate cultures yielding sterile results while urine cultures grew Klebsiella pneumoniae and Klebsiella variicola. Sirolimus was temporarily halted while intravenous antimicrobial therapy comprising piperacillin/tazobactam and vancomycin supplemented with clarithromycin was administered over 11 and 7 days, achieving clinical resolution and permitting hospital discharge on day 56 under outpatient oncological supervision.

Two days following discharge, on day 58 of life, the infant required emergency rehospitalization due to recurrent high fever, acute cervical swelling, localized erythema, and concurrent oral candidiasis. Following empiric broad-spectrum antimicrobial administration without immediate response, needle aspiration of an inflamed cystic chamber yielded blood-tinged chylous fluid containing massive growth of methicillin-sensitive Staphylococcus aureus. Despite tailored treatment with cloxacillin, local progression and elevating inflammatory markers necessitated switching to meropenem and vancomycin alongside surgical placement of drains into two distinct compartments. Complications escalated during this hospitalization when an occluded central venous catheter triggered internal jugular vein thrombosis, with Doppler ultrasound identifying a thrombus measuring 3 millimeters in diameter and 10 millimeters in length that significantly impaired venous return. Anticoagulation with enoxaparin successfully resolved the vascular thrombus, surgical drains were removed after stabilization, and targeted antibiotics were completed over 22 days, leading clinicians to introduce long-term amoxicillin prophylaxis to mitigate ongoing infection risks associated with retropharyngeal pharyngeal-wall mucosal bulging.

Serial magnetic resonance imaging performed at 2.5, 6, and 11 months of age in this first patient objectively tracked progressive structural shrinkage of the multiloculated malformation. At 2.5 months of age, follow-up imaging recorded overall lesion dimensions of 45 by 42 by 40 millimeters, confirming more than a twofold reduction from baseline, although a deep residual pocket continued to deform the posterior pharyngeal wall. By 6 months of age, the lesion had contracted further to 28 by 26 by 29 millimeters, and by 11 months, dimensions measured just 13 by 20 by 17 millimeters, leaving only a small residual palpable mass within redundant cervical skin. Physical examination at 3 months had already confirmed marked regression without active inflammatory signs, while secondary cranial deformation resulting from persistent head positioning was managed conservatively alongside continuing outpatient oncological care, illustrating profound morphological response achieved despite severe early infectious interruptions.

The second evaluated patient was a female neonate transferred on her fifth day of life from a primary care facility following an uneventful 39-week gestation and spontaneous vaginal delivery with a birth weight of 3520 grams and an Apgar score of 10. Initial hospital ultrasound had suggested a primary salivary gland neoplasm, but repeat specialized ultrasound demonstrated three to four discrete, non-vascular cystic cavities with hyperechoic strands, hemolyzed blood, and fluid-fluid levels, the largest cavity measuring 32 by 14 millimeters. Subsequent magnetic resonance imaging verified a mixed-type lymphatic malformation spreading throughout the subcutaneous anterior cervical region, bilateral cheeks, and superficial parotid parenchyma, forming a narrow band extending toward the suprasternal notch and left clavicle without vascular invasion or compressive luminal compromise.

Sirolimus was initiated in this second patient on day 11 of life at 0.4 milligrams per square meter twice daily, but serial serum concentration assays revealed elevated drug levels that prompted an immediate 50 percent dosage reduction to 0.2 milligrams per square meter twice daily. This reduced dosage maintained therapeutic stability without inducing hepatic, renal, or hematological toxicity, and percutaneous sclerotherapy was withheld due to widespread anatomical dissemination across adjacent fascial planes. The exclusively breastfed infant exhibited normal abdominal and neurosonographic findings throughout inpatient admission and was discharged home on day 24 of life.

The third patient in the series, a female infant delivered at 39 weeks and 1 day of gestation via planned cesarean section, presented with extensive craniofacial and cervical involvement initially detected on routine prenatal ultrasound at 29 weeks. Fetal magnetic resonance imaging at 31 weeks characterized a heterogeneous, multicystic craniofacial mass concentrated on the right side and crossing the midline floor of the mouth, while postnatal assessment revealed a birth weight of 3670 grams, body length of 60 centimeters, and head circumference of 34 centimeters alongside asymmetrical cervical enlargement. Postnatal magnetic resonance imaging delineated an 80 by 48 by 45 millimeter mixed-type cystic mass traversing cervical compartments bilaterally from the skull base to the lower neck, deforming the larynx and trachea, displacing the right perivascular sheath, and abutting the thyroid cartilage while sparing prevertebral and retropharyngeal spaces.

Medical therapy with sirolimus commenced on day 12 of life at the standard starting dose of 0.4 milligrams per square meter twice daily, but early blood level monitoring revealed excessive drug accumulation, requiring a 50 percent reduction to 0.2 milligrams per square meter twice daily. Clinical immunology consultation advised deferral of live vaccines and structured surveillance of immunoglobulin concentrations and lymphocyte subpopulations, while neurological assessment noted asymmetric cervical posturing and variable axial muscle tone attributable to mass volume without cranial nerve palsy or ocular abnormalities. Following transfer on day 28 to the Department of Oncology and Hematology at the Medical University of Warsaw, stable target concentrations between 5 and 25 nanograms per milliliter were attained with difficulty, yet the infant tolerated oral enteral nutrition without systemic toxicity, negative inflammatory markers, or infectious episodes. Elective outpatient reassessment at 7 weeks documented sustained mass reduction, and consecutive magnetic resonance imaging scans at 3, 7, and 12 months verified striking structural involution from 55 by 44 by 35 millimeters to 38 by 36 by 30 millimeters, and finally to 28 by 25 by 20 millimeters.

In their comparative discussion of neonatal vascular anomalies, the authors highlighted that while historical literature quotes sirolimus efficacy rates as high as 91.4 percent in pediatric cohorts spanning birth to 17 years, treating neonates demands heightened vigilance regarding pharmacokinetics, immature hepatic metabolism, and immunosuppressive vulnerability. Across all three cases, initial dosing of 0.4 milligrams per square meter twice daily produced serum concentrations reaching 11.1 to 26.7 nanograms per milliliter, demonstrating that newborns frequently require 50 percent dosage reductions to avoid supra-therapeutic exposure, whereas concentrations even below 5 nanograms per milliliter proved clinically sufficient to halt lymphatic growth. The authors outlined a pragmatic local protocol recommending abrupt discontinuation only after two consecutive imaging examinations confirm complete morphological stabilization, recognizing that consensus is currently lacking regarding duration and tapering. The clinical team underscored that while sirolimus offers an indispensable non-surgical alternative for unresectable cervicofacial lesions, multicenter randomized trials remain essential to define neonatal therapeutic targets, establish standardized duration protocols, and optimize candidate selection.

Subject of Research: Systemic sirolimus therapy and clinical outcomes in neonates with congenital head and neck lymphatic malformations

Article Title: Congenital lymphatic malformations of the head and neck: clinical course and sirolimus therapy in infancy – case series

Article References: Schreiber-Zamora, J., Kamińska, M., Pęgierska, H., Czaplińska, N., Hutnik, Ł., & Kociszewska-Najman, B. (2026). Congenital lymphatic malformations of the head and neck: clinical course and sirolimus therapy in infancy – case series. Egyptian Pediatric Association Gazette, 74(1), Article 137. https://doi.org/10.1186/s43054-026-00637-x

Image Credits: AI Generated

DOI: 10.1186/s43054-026-00637-x

Keywords: lymphatic malformations, sirolimus, mTOR inhibitors, neonatology, pediatric vascular anomalies, cervicofacial masses, magnetic resonance imaging, pharmacokinetics, Congenital, lymphatic, malformations, head