The efficacy of bleomycin sclerotherapy in the treatment of lymphatic malformations: a review and meta-analysis.

OBJECTIVE: At present, bleomycin has been widely used in the treatment of Lymphatic Malformations (LMs). This study aims to perform a meta-analysis to investigate the effectiveness and influencing factors of bleomycin in the treatment of LMs. METHODS: We conducted a systematic review and meta-analysis to clarify the relationship between bleomycin and LMs. PubMed, ISI Web of Science and MEDLINE were searched. RESULTS: A total of 21 studies (including 428 cases) about bleomycin sclerotherapy for LMs were included in the current meta-analyses. We calculated pooled effective rate and 95% Confidence Interval (95% CI) using random effects model to evaluate the relations between bleomycin and LMs. The results suggested that the effective rate of bleomycin was the combined effective rate was 84.0% (95% CI 0.81‒0.87) and ranged from 39% (95% CI 0.22‒0.56) to 94% (95% CI 0.87-1.02). The heterogeneity among the studies was substantial (I2=61.7%, p= 0.000). In subgroup analyses, it was observed that among retrospective study and prospective study, the estimated effective rate was 80.0% (95% CI 0.76‒0.84) and 91.0% (95% CI 0.85‒0.97), respectively. In terms of the dosage, the combined effective rates of weight-based group and fixed-dose group were 86% (95% CI 0.83‒0.90) and 74.0% (95% CI 0.66‒0.82), respectively. There was no significant publication bias in Egger's test (p=0.059, 95% CI -3.81 to 0.082), but Begg's test did (p=0.023), and the funnel plot is asymmetric. CONCLUSION: Our study suggested that bleomycin was safe and effective in the treatment of LMs and was primarily dose dependent.

Sirolimus treatment for paediatric head and neck lymphatic malformations: a systematic review.

PURPOSE: This PRISMA-compliant systematic review aimed to assess risks and benefits of sirolimus treatment for paediatric lymphatic malformations by focusing not only on treatment efficacy but also on possible treatment-related adverse events, and treatment combinations with other techniques. METHODS: Search criteria were applied to MEDLINE, Embase, Web of Science, Scopus, Cochrane Library, and ClinicalTrials.gov databases and included all studies published up to March 2022 reporting paediatric lymphatic malformations treated with sirolimus. We selected all original studies that included treatment outcomes. After the removal of duplicates, selection of abstracts and full-text articles, and quality assessment, we reviewed eligible articles for patient demographics, lymphatic malformation type, size or stage, site, clinical response rates, sirolimus administration route and dose, related adverse events, follow-up time, and concurrent treatments. RESULTS: Among 153 unique citations, 19 studies were considered eligible, with reported treatment data for 97 paediatric patients. Most studies (n = 9) were case reports. Clinical response was described for 89 patients, in whom 94 mild-to-moderate adverse events were reported. The most frequently administered treatment regimen was oral sirolimus 0.8 mg/m2 twice a day, with the aim of achieving a blood concentration of 10-15 ng/mL. CONCLUSION: Despite promising results for sirolimus treatment in lymphatic malformation, the efficacy and safety profile of remains unclear due to the lack of high-quality studies. Systematic reporting of known side effects, especially in younger children, should assist clinicians in minimising treatment-associated risks. At the same time, we advocate for prospective multicentre studies with minimum reporting standards to facilitate improved candidate selection.

Differences in Efficacy and Safety of Sirolimus and Sildenafil in Pediatric Lymphatic Malformations.

OBJECTIVES: To explore the differences in the efficacy and safety of oral sirolimus and sildenafil in the treatment of pediatric intractable lymphatic malformations (LMs). METHODS: From January 2014 to May 2022, we retrospectively enrolled children with intractable LMs treated with oral drugs (sirolimus or sildenafil) and divided the patients into sirolimus and sildenafil groups from Beijing Children's Hospital (BCH). Clinical features, treatment, and follow-up data were collected and analyzed. The indicators were the ratio of reduction in lesion volume pre and posttreatment, the number of patients with improved clinical symptoms, and adverse reactions to the two drugs. RESULTS: Twenty-four children in the sildenafil group and 31 children in the sirolimus group were included in the present study. The effective rate in the sildenafil group was 54.2% (13/24), with a median lesion volume reduction ratio of 0.32 (-0.23, 0.89) and clinical symptoms improved in 19 patients (79.2%). On the contrary, the effective rate in the sirolimus group was 93.5% (29/31), with a median lesion volume reduction ratio of 0.68 (0.34, 0.96), and clinical symptoms improved in 30 patients (96.8%). There were significant differences (p < 0.05) between the two groups. Regarding safety, four patients in the sildenafil group and 23 patients in the sirolimus group with mild adverse reactions were reported. CONCLUSION: Both sildenafil and sirolimus can reduce the volume of LMs and improve clinical symptoms in partial patients with intractable LMs. Sirolimus is more effective than sildenafil and the adverse reactions associated with both drugs are mild and controllable. LEVEL OF EVIDENCE: III Laryngoscope, 133:3192-3199, 2023.

Two-Year Outcomes of Transcutaneous Non-Image Guided Bleomycin Sclerotherapy in Conjunctival Lymphatic Malformations: A Protocol-Based Management in 16 Eyes.

OBJECTIVES: To study the efficacy and the 2-year outcomes of treating conjunctival lymphatic malformations (LM) with protocol-based bleomycin sclerotherapy. METHODS: A retrospective interventional study of 16 eyes with conjunctival LM treated with bleomycin sclerotherapy between December 2016 and 2019. A clinical resolution was assessed as poor (less than 25% decrease in size), fair (25%-50% decrease in size), good (50%-75% decrease in size), excellent (more than 75% decrease in size), and complete resolution. RESULTS: Mean age at presentation was 18 ± 13.09 (15 years, 3 to 59 years) years. The conjunctival component was classified based on clinical appearance as conjunctival mass (12) and microcystic LM (4). Mean clock hours of involvement were 3.32 ± 5.29 clock hours (4, 2-9 clock hours). An average per session dose of 1.8 ± 0.3 IU (median 2 IU, range 1-2 IU) and a cumulative dose of 3 ± 1.5 IU (3, 1-6 IU) of bleomycin were injected over an average of 1.6 ± 0.7 (median 2, range 1-3) treatment sessions per patient. Excellent response was observed in 11 (69%) cases. A residual lesion requiring surgical debulking was noted in 1 case. Recurrence was noted in 2 (13%) cases one of which was treated with repeat sclerotherapy resulting in complete resolution. Adverse reactions included restricted extraocular motility in extreme gaze in 2 eyes (13%). Sustained tumor resolution was observed over a mean follow-up of 29.24 + 9.45 months (24, 24-38 months). CONCLUSIONS: Bleomycin sclerotherapy gives excellent response in conjunctival LMs and is an effective first-line therapy in these cases.

A nomogram for predicting sclerotherapy response for treatment of lymphatic malformations in children.

PURPOSE: In this manuscript, we purposed to identify the prognostic factors for treatment of lymphatic malformations in children using polidocanol foam combined with pingyangmycin and to construct nomogram for predicting sclerotherapy response. METHODS: A retrospective analysis of 77 children having LMs who underwent sclerotherapy using polidocanol foam combined with pingyangmycin under ultrasound display from January 2017 to April 2020 was done. The clinical response was graded as excellent (≥ 90%), good (≥ 50%, < 90%), and poor (< 50%). More than 50% was considered as acceptable response. Prognostic factors were identified by Pearson's Chi-square or Fisher's exact test and multivariable logistic regression model was used to construct a nomogram to predict sclerotherapy response. The discrimination and calibration of nomogram were verified through the receiver operating characteristic cure and calibration plots. RESULTS: The mean number of treatment sessions was 3.1 (range, 1-6). Among 77 patients, 58 patients (75.3%) had excellent response to treatment (≥ 90%) and 68 patients (88.3%) had an acceptable response (≥ 50%, < 90%). Clinical disfigurement (P = 0.014), skin discoloration (P = 0.040), morphological subtype (P < 0.001) and extent of the lesion (P < 0.001) correlated with clinical response to sclerotherapy in LMs. Sclerotherapy response was predicted through nomogram constructed in this study, which shows good calibration and discrimination. Also, focal lesion and macrocystic or mixed morphological subtype lesion were seen more often in lower number of treatment sessions among the patients with excellent response. CONCLUSIONS: An acceptable response to sclerotherapy using polidocanol foam combined with pingyangmycin was achieved in majority of LMs in children with extremely low complication rates. Nomogram based on the prognostic factors of sclerotherapy response for LMs in children was shown to possess an excellent performance to predict the probability of LMs sclerotherapy response.

Treatment With Topical Sirolimus for Recurrent Lymphatic Malformation of the External Urethral Meatus.

This case report describes a 17-year-old male patient with frog spawn­like vesicles around the urethra.

Genomic landscape of lymphatic malformations: a case series and response to the PI3Kα inhibitor alpelisib in an N-of-1 clinical trial.

Background: Lymphatic malformations (LMs) often pose treatment challenges due to a large size or a critical location that could lead to disfigurement, and there are no standardized treatment approaches for either refractory or unresectable cases. Methods: We examined the genomic landscape of a patient cohort of LMs (n = 30 cases) that underwent comprehensive genomic profiling using a large-panel next-generation sequencing assay. Immunohistochemical analyses were completed in parallel. Results: These LMs had low mutational burden with hotspot PIK3CA mutations (n = 20) and NRAS (n = 5) mutations being most frequent, and mutually exclusive. All LM cases with Kaposi sarcoma-like (kaposiform) histology had NRAS mutations. One index patient presented with subacute abdominal pain and was diagnosed with a large retroperitoneal LM harboring a somatic PIK3CA gain-of-function mutation (H1047R). The patient achieved a rapid and durable radiologic complete response, as defined in RECIST1.1, to the PI3Kα inhibitor alpelisib within the context of a personalized N-of-1 clinical trial (NCT03941782). In translational correlative studies, canonical PI3Kα pathway activation was confirmed by immunohistochemistry and human LM-derived lymphatic endothelial cells carrying an allele with an activating mutation at the same locus were sensitive to alpelisib treatment in vitro, which was demonstrated by a concentration-dependent drop in measurable impedance, an assessment of cell status. Conclusions: Our findings establish that LM patients with conventional or kaposiform histology have distinct, yet targetable, driver mutations. Funding: R.P. and W.A. are supported by awards from the Levy-Longenbaugh Fund. S.G. is supported by awards from the Hugs for Brady Foundation. This work has been funded in part by the NCI Cancer Center Support Grants (CCSG; P30) to the University of Arizona Cancer Center (CA023074), the University of New Mexico Comprehensive Cancer Center (CA118100), and the Rutgers Cancer Institute of New Jersey (CA072720). B.K.M. was supported by National Science Foundation via Graduate Research Fellowship DGE-1143953. Clinical trial number: NCT03941782.

Topical sirolimus solution for lingual microcystic lymphatic malformations in children and adults (TOPGUN): study protocol for a multicenter, randomized, assessor-blinded, controlled, stepped-wedge clinical trial.

BACKGROUND: Lingual microcystic lymphatic malformations (LMLMs) are rare congenital vascular malformations presenting as clusters of cysts filled with lymph fluid or blood. Even small well-limited lesions can be responsible for a heavy burden, inducing pain, aesthetic prejudice, or oozing, bleeding, infections. The natural history of LMLMs is progressive worsening punctuated by acute flares. Therapeutic options include surgery, laser excision, and radiofrequency ablation but all are potentially detrimental and expose to local relapse. Therefore, the management frequently relies on a "watchful waiting" approach. In complicated LMLMs, treatment with oral sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is often used. Topical applications of sirolimus on the buccal mucosae have been reported in other oral diseases with good tolerance and none to slight detectable blood sirolimus concentrations. We aim to evaluate the efficacy and safety of a 1 mg/mL sirolimus solution applied once daily on LMLM of any stage in children and adults after 4, 8, 12, 16, 20, and 24 weeks of treatment compared to usual care (no treatment). METHODS: This is a randomized, multicentric study using an individually randomized stepped-wedge design over 24 weeks to evaluate topical application of a 1 mg/mL sirolimus solution once daily, on LMLM, versus usual care (no treatment), the control condition. Participants begin with an observational period and later switch to the intervention at a randomized time (week 0, 4, 8, or 12). Visits occur every 4 weeks, either in the study center or by teleconsulting. The primary outcome will be the evaluation of global severity of the LMLM on monthly standardized photographs by 3 independent blinded experts using the physical global assessment (PGA) 0 to 5 scale. Secondary outcomes will include lesion size measurement and quality of life assessment, investigator, and patient-assessed global disease and specific symptoms (oozing, bleeding, sialorrhea, eating impairment, taste modification, aesthetic impairment, pain, and global discomfort) assessment. A biological monitoring will be performed including residual blood sirolimus concentration and usual laboratory parameters. DISCUSSION: Given the disappointing state of current treatment options in LMLMs, topical sirolimus could become firstline therapy in treating LMLMs if its efficacy and safety were to be demonstrated. TRIAL REGISTRATION: ClinicalTrials.gov NCT04128722 . Registered on 24 September 2019. EudraCT: EUCTR2019-001530-33-FR Sponsor (University Hospital Center of Tours - CHRU Tours): DR190041-TOPGUN French regulatory authorities: ID RCB: 2019-001530-33.

Annual prevalence estimation of lymphatic malformation with a cutaneous component: observational study of a national representative sample of physicians.

BACKGROUND: Lymphatic malformations (LMs) represent a potentially life-threatening, rare disease of the lymphatic system characterized by development of abnormal vessels, outpouchings, or cysts filled with lymphatic fluid. There are three morphologic types of LMs based on the size of the individual cysts: macrocystic (typically > 2 cm), microcystic (generally < 2 cm), and mixed (includes aspects of both). Macrocystic LMs typically exist beneath the skin and often can involve vascular components and/or organs. Microcystic LMs often have a cutaneous component and clinically present with lymphorrhea, bleeding, pain, itching, malodor, and functional deficits. There are no treatments approved by the US Food and Drug Administration (FDA) for either macrocystic or microcystic lymphatic malformations. The totality of the epidemiologic literature for LM is limited to the incidence of the disease among various birth cohorts. This is the first nationally representative study to estimate the national managed prevalence for patients with microcystic LM or combined LM with a cutaneous component annually across physician specialties likely to manage this condition. We conducted a retrospective observational survey of a nationally representative sample of patient-care physicians in the United States most likely to manage lymphatic malformations with a cutaneous component (LMC). Once recruited, target physicians participated via an electronic questionnaire. We weighted study physician self-estimates of the number of LMC patients treated in the past 12 months to reflect the specialists' corresponding proportion in the national universe. All patient information was anonymous; no personally identifiable information was collected. RESULTS: Of the 420 physicians who visited the study website, 316 agreed to be screened and to participate (75.2% participation rate). Our survey results indicated the estimated number of unique annually managed LMC patients by target specialists is 79,920 (CI 66,600-93,250). This number corresponds to managed prevalence of 24.1 LMC patients per 100,000 population (CI 19.6/100,000-28.4/100,000). CONCLUSIONS: The study indicates that while rare, LMC affects a substantial number of people in the US (79,920) who are being managed by one or more specialists. By better understanding the prevalence of people living with LMC who require treatment, efforts to both increase disease awareness and to identify underserved populations in need of potential new treatments can be better focused.

Efficacy of sirolimus in children with lymphatic malformations of the head and neck.

PURPOSE: Children with extensive lymphatic malformations of the head and neck often suffer from functional impairment and aesthetic deformity which significantly affect the quality of life and may be life-threatening. Treatment with sirolimus has the potential to improve symptoms and downsize lymphatic malformations. This systematic review summarizes the current information about sirolimus treatment of lymphatic malformations of the head and neck in children, its efficacy and side effects. METHODS: A systematic search of the literature regarding studies on sirolimus treatment of children with lymphatic malformations of the head and neck was performed in PubMed, Embase, and Google Scholar up to July 2021 with the search terms "lymphatic malformation", "lymphangioma", "cystic hygroma", "low-flow malformation", "sirolimus", "rapamycin", "mTOR inhibitor" and "children". RESULTS: In all, 28 studies including 105 children from newborn to 17 years treated with sirolimus for lymphatic malformations of the head and neck were analyzed. The most frequent initial dose was 0.8 mg/m2 per dose, twice daily at 12-h interval. The target blood level differed between studies, 10-15 ng/mL and 5-15 ng/mL were most often used. More than 91% of the children responded to sirolimus treatment which lasts from 6 months to 4 years. Typical side effects were hyperlipidemia, neutropenia and infections. METHODS: Sirolimus could be an effective treatment for children with large complicated lymphatic malformations of the head and neck. As not all patients will benefit from treatment, the decision to treat sirolimus should be made by a multidisciplinary team.

Complex lymphatic malformations in pediatrics: a review of treatment options.

INTRODUCTION: Lymphatic malformations (LMs) are low-flow lesions resulting from abnormalities in the development of lymphatics. The management of these lesions is complex and involve the collaboration of many specialties. The purpose of this review is to summarize current knowledge regarding the different therapeutic options used in complex lymphatic malformations, analyzing their indications, efficacy and complications. EVIDENCE ACQUISITION: A search was made using the algorithm: "(lymphatic abnormality OR lymphatic malformation OR lymphangioma OR cystic hygroma) AND (extensive OR giant OR complex) AND (therapeutics OR treatment) AND (child OR children)". Of the 120 articles found, 53 were included. EVIDENCE SYNTHESIS: Historically, surgery was the treatment of choice for this type of lesions. However, excision was often incomplete, associated with high rates of recurrence and severe complications. The use of sclerotherapy emerged as a minimal invasive option appropriate in selected cases as a single or adjuvant therapy. Inhibitors of the mammalian target of rapamycin, such as sirolimus, now play a central role in the treatment of complex malformations resistant to sclerotherapy, recurrent after surgery or more extensive malformations that affect vital structures. Other therapeutic options as sildenafil and laser ablation are also recognized as effective in selected cases. CONCLUSIONS: Looking through the literature over the last decade authors realize that surgery had gradually been replaced by less invasive options such as sirolimus with or without adjuvant sclerotherapy. In conclusion, each treatment option seems to have its own indications and characteristics, which must be considered in therapeutic decision and individualized for each patient.

Sclerosing agents in the management of lymphatic malformations in children: A systematic review.

PURPOSE: Sclerotherapy is frequently employed in treating lymphatic malformations (LMs), and multiple agents, practitioners and strategies exist. This review investigates the reported efficacy and safety of sclerosants in the pediatric population. METHODS: Adhering to PRISMA guidelines, multiple databases were queried without linguistic or temporal restriction. Inclusion criteria were patients aged 0-18 exclusively receiving injection sclerotherapy for the treatment of LMs with follow-up data. Data abstracted included agent, dose, anatomic site and key outcome measures including complications (major/minor) and resolution rates (>95% reduction in volume). Critical appraisal was undertaken using the MINORS tool. RESULTS: Forty-eight studies met the inclusion criteria with a mean MINORS score of 0.65 ±â€¯0.08. Included studies yielded 886 patients, across nearly 30 years. The overall observed rate of success was 89%, with variable follow-up across publications (6 weeks - 10 years). Most reported LMs were macrocystic (82%) and had a higher resolution rate than mixed/microcytic variants (89%, 71%, 34%, p<0.01) For head/neck LMs, rates of complete regression for OK-432, bleomycin, and doxycycline were 67% ± 27% (n = 26), 91% ± 53% (n = 34) and 85% ± 16% (n = 52) respectively. Major complications were most commonly reported with OK-432, including airway compromise or subsequent operation. CONCLUSIONS: In pediatric patients treated for LM by sclerotherapy, complication rates were low. Macrocystic lesions respond well but success rates were modest at best for microcystic disease. Differences in agent utilization were noted between high and low resourced contexts; despite its lack of federal approval, OK-432 was the most reported agent. Further prospective research is warranted. LOE: 3a.

How we approach the diagnosis and management of complex lymphatic anomalies.

Complex lymphatic anomalies (CLA) are congenital diseases of the lymphatic circulation system that are associated with significant morbidity and early mortality. While guidelines for the comprehensive evaluation of the CLA were recently published, the diagnostic approach and medical management are not standardized. This article presents the clinical features of four CLA: Gorham-Stout disease, generalized lymphatic anomaly, kaposiform lymphangiomatosis, and central collecting lymphatic anomaly. We also offer three cases from the authors' practice and our views on diagnostic testing and disease management including supportive care, medical therapies, and other interventions.

Sclerotherapy with polidocanol microfoam in head and neck venous and lymphatic malformations.

Objective: Polidocanol sclerotherapy of head and neck venous malformations (VMs) and lymphatic malformations (LMs) has been reported only in limited series. In this manuscript we evaluated the efficacy and safety of polidocanol sclerotherapy in a series of head and neck venous and lymphatic malformations. Methods: This retrospective observational study analysed data on 20 head and neck VMs and LMs that underwent to percutaneous or endoscopic intra-lesional 3% polidocanol microfoam sclerotherapy at our institution. Clinical response was ranked as excellent, moderate and poor based on volume reduction by MRI and resolution of symptoms. Results: The median volume decreased from 19.3 mL to 5.8 mL after sclerotherapy (mean volume reduction: 72.98 ± 16.1%). An excellent-moderate response was observed in 94.4% of cases. We observed a mean volume reduction of 79.5 ± 16.1 in macrocystic LMs, of 76.1 ± 13.0% in VMs, of 60.5 ± 10.9% in mixed lymphatic ones and 42.5% in microcystic lymphatic ones. Conclusions: Polidocanol sclerotherapy appears to be an effective and safe treatment for venous and lymphatic head and neck malformations. We observed the best responses in macrocystic LMs and VMs, whereas mixed lymphatic ones showed a moderate response and microcystic lymphatic ones a poor response.

Multidisciplinary Multiagent Treatment of Complex Lymphatic Anomalies with Severe Bone Disease: A Single-Site Experience.

Background: Complex lymphatic anomalies (CLA) are a group of conditions that pose diagnostic and therapeutic challenges due to their rarity and overlapping clinical findings. This case series describes the complex pathology and novel combination therapies of three patients diagnosed with various types of CLA. Methods and Results: A retrospective review of medical records was performed for three patients treated for CLA between 2011 and 2019. Diagnostics, imaging, treatment, and follow-up were reviewed in the electronic medical record and combined with the literature review within the analysis. One patient had involvement of her skull base and ear canals, diagnosed after ear canal abnormalities were detected on computed tomography following meningitis. The second patient had involvement of her posterior ribs and T7-T12 vertebral bodies, with thoracic instability requiring a back brace. The third patient had involvement of his left lower extremity and hemipelvis, necessitating a left above the knee amputation. Case 1 progressed on sirolimus and pamidronate but responded to zoledronic acid (ZA). She developed flares of coagulopathy and cellulitis that required reinforcement with vincristine and steroid pulses. Similarly, case 2 progressed on sirolimus and ZA alone, but achieved stable disease with added vincristine. Upon further disease progression, stabilization was obtained by the reinforcement of ZA. Case 3 required a combination of surgery as well as medical management with sirolimus and pamidronate. All three patients now have stable disease. Conclusion: This case series depicts a multidisciplinary and multiagent approach to the management of CLA with severe bony involvement using sirolimus, bisphosphonates, vincristine, and steroids.