Recent Advances in Interventional Management of Extracranial Vascular Malformations in Children

Abstract

Vascular malformations are congenital abnormalities arising from dysregulated angiogenesis, often due to gain-of-function somatic mutations. Extracranial disease involvement can cause significant pain, disfigurement, and functional limitations. Conventional sclerosing agents such as ethanol, sodium tetradecyl sulfate, and doxycycline are effective in treating the majority of slow-flow vascular malformations. However, these sclerosants have limited efficacy in lesions with significant lipomatous or stromal components and can be associated with significant local toxicity, especially if extravasated. The wider adoption of bleomycin and new interventional techniques such as bleomycin electrosclerotherapy using reversible electroporation and percutaneous thermal ablative modalities has shifted treatment paradigms for challenging cases which are refractory to conventional sclerosants. This article aims to provide an overview of these recent advances in interventional techniques and to highlight the importance of the integration of personalized precision medicine in the multidisciplinary care of children with extracranial vascular malformations.

Keywords

vascular malformation - sclerotherapy - bleomycin - electrosclerotherapy - interventional radiology

Compliance with Ethical Standards

- This article does not contain any studies with human participants or animals performed by any of the authors. Formal institutional board approval is waived for this type of study.

- For this type of study, formal consent is not required.

- For this type of study, consent for publication is not required.

Publikationsverlauf

Artikel online veröffentlicht:
17. Juni 2025

• References

• 1 Blei F. Nomenclature of vascular anomalies: evolution to the ISSVA 2018 classification system. In: Trenor III CC, Adams DM. eds. Vascular Anomalies: A Guide for the Hematologist/Oncologist. Springer International Publishing; 2020: 1-8
• 2 Classification | International Society for the Study of Vascular Anomalies. Accessed April 27, 2025 at: https://www.issva.org/classification
• 3 Seront E, Hermans C, Boon LM, Vikkula M. Targeted treatments for vascular malformations: current state of the art. J Thromb Haemost 2024; 22 (11) 2961-2975
• 4 Van Damme A, Seront E, Dekeuleneer V, Boon LM, Vikkula M. New and emerging targeted therapies for vascular malformations. Am J Clin Dermatol 2020; 21 (05) 657-668
• 5 Scollan ME, Azimov N, Garzon MC, Tulin-Silver S. An overview of interventional radiology techniques for the diagnosis and management of vascular anomalies: Part 1. Pediatr Dermatol 2023; 40 (02) 242-249
• 6 Scollan ME, Azimov N, Garzon MC, Tulin-Silver S. An overview of interventional radiology techniques for the diagnosis and management of vascular anomalies: Part 2. Pediatr Dermatol 2023; 40 (05) 767-774
• 7 Vogelzang RL, Atassi R, Vouche M, Resnick S, Salem R. Ethanol embolotherapy of vascular malformations: clinical outcomes at a single center. J Vasc Interv Radiol 2014; 25 (02) 206-213 , quiz 214
• 8 Gorman J, Zbarsky SJ, Courtemanche RJM, Arneja JS, Heran MKS, Courtemanche DJ. Image guided sclerotherapy for the treatment of venous malformations. CVIR Endovasc 2018; 1 (01) 2
• 9 Hawkins CM, Chewning RH. Diagnosis and management of extracranial vascular malformations in children: arteriovenous malformations, venous malformations, and lymphatic malformations. Semin Roentgenol 2019; 54 (04) 337-348
• 10 Bertino FJ, Hawkins CM. Contemporary management of extracranial vascular malformations. Pediatr Radiol 2023; 53 (08) 1600-1617
• 11 Gibson CR, Barnacle AM. Vascular anomalies: special considerations in children. CVIR Endovasc 2020; 3 (01) 60
• 12 Stuart S, Barnacle AM, Smith G, Pitt M, Roebuck DJ. Neuropathy after sodium tetradecyl sulfate sclerotherapy of venous malformations in children. Radiology 2015; 274 (03) 897-905
• 13 Berenguer B, Burrows PE, Zurakowski D, Mulliken JB. Sclerotherapy of craniofacial venous malformations: complications and results. Plast Reconstr Surg 1999; 104 (01) 1-11 , discussion 12–15
• 14 Hafner F, Froehlich H, Gary T, Brodmann M. Intra-arterial injection, a rare but serious complication of sclerotherapy. Phlebology 2013; 28 (02) 64-73
• 15 Apostle KL, Heran MKS, Tredwell SJ. Acute compartment syndrome after sclerotherapy for a low-flow vascular malformation. Can J Surg 2008; 51 (03) E50-E51
• 16 Bennett JM, Reich SD. Bleomycin. Ann Intern Med 1979; 90 (06) 945-948
• 17 Dorr RT. Bleomycin pharmacology: mechanism of action and resistance, and clinical pharmacokinetics. Semin Oncol 1992; 19 (2, Suppl 5): 3-8
• 18 Yamamoto T, Katayama I. Vascular changes in bleomycin-induced scleroderma. Int J Rheumatol 2011; 2011: 270938
• 19 Zhang W, Chen G, Ren JG, Zhao YF. Bleomycin induces endothelial mesenchymal transition through activation of mTOR pathway: a possible mechanism contributing to the sclerotherapy of venous malformations. Br J Pharmacol 2013; 170 (06) 1210-1220
• 20 Hashimoto N, Phan SH, Imaizumi K. et al. Endothelial-mesenchymal transition in bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 2010; 43 (02) 161-172
• 21 Chaudry G, Guevara CJ, Rialon KL. et al. Safety and efficacy of bleomycin sclerotherapy for microcystic lymphatic malformation. Cardiovasc Intervent Radiol 2014; 37 (06) 1476-1481
• 22 Jin Y, Zou Y, Hua C. et al. Treatment of early-stage extracranial arteriovenous malformations with intralesional interstitial bleomycin injection: a pilot study. Radiology 2018; 287 (01) 194-204
• 23 Zou Y, Qiao C, Hua C. et al. Intralesional interstitial injection of bleomycin for management of extracranial arteriovenous malformations in children. Chinese Journal of Plastic and Reconstructive Surgery 2021; 3 (02) 68-75
• 24 Ul Haq F, Mitchell SE, Tekes A, Weiss CR. Bleomycin foam treatment of venous malformations: a promising agent for effective treatment with minimal swelling. J Vasc Interv Radiol 2015; 26 (10) 1484-1493
• 25 Cherny NI, Sullivan R, Torode J, Saar M, Eniu A. ESMO International Consortium Study on the availability, out-of-pocket costs and accessibility of antineoplastic medicines in countries outside of Europe. Ann Oncol 2017; 28 (11) 2633-2647
• 26 Poole S. Bleomycin sulphate dosing nomenclature. Aust J Hosp Pharm 1998; 28 (03) 211-211
• 27 Stefanou A. Errors due to Bleomycin Nomenclature. Published online January 10, 2025. Accessed January 12, 2025 at: https://www.bmj.com/rapid-response/2011/10/28/errors-due-bleomycin-nomenclature
• 28 Tanigawa N, Shimomatsuya T, Takahashi K. et al. Treatment of cystic hygroma and lymphangioma with the use of bleomycin fat emulsion. Cancer 1987; 60 (04) 741-749
• 29 Zhang H, Zhang HS, Chen AW, Zhang F, Liu SH. Modified method to increase the volume and stability of bleomycin foam: an experimental study. Dermatol Surg 2020; 46 (08) 1030-1034
• 30 Zorzi AP, Yang CL, Dell S, Nathan PC. Bleomycin-associated lung toxicity in childhood cancer survivors. J Pediatr Hematol Oncol 2015; 37 (08) e447-e452
• 31 Azambuja E, Fleck JF, Batista RG, Menna Barreto SS. Bleomycin lung toxicity: who are the patients with increased risk?. Pulm Pharmacol Ther 2005; 18 (05) 363-366
• 32 Méndez-Echevarría A, Fernandez-Prieto A, de la Serna O. et al. Acute lung toxicity after intralesional bleomycin sclerotherapy. Pediatrics 2018; 141 (01) e20161787
• 33 Atwa K, Abuhasna S, Shihab Z, Hashaykeh N, Hasan R. Acute pulmonary toxicity following intralesional administration of bleomycin for a lymphovenous malformation. Pediatr Pulmonol 2010; 45 (02) 192-196
• 34 Cho AL, Kiang SC, Lodenkamp J, Tritch WTH, Tomihama RT. Fatal lung toxicity after intralesional bleomycin sclerotherapy of a vascular malformation. Cardiovasc Intervent Radiol 2020; 43 (04) 648-651
• 35 Verma R. Supplemental oxygen therapy in bleomycin-induced pulmonary toxicity. Med J Armed Forces India 2011; 67 (02) 194
• 36 Kessell G, Panchatsharam S, Kothmann E. et al. General anaesthesia for intralesional bleomycin therapy of vascular malformations: initial 3 yr experience. Br J Anaesth 2009; 102 (03) 431-432
• 37 Milbar HC, Jeon H, Ward MA, Mitchell SE, Weiss CR, Cohen BA. Hyperpigmentation after foamed bleomycin sclerotherapy for vascular malformations. J Vasc Interv Radiol 2019; 30 (09) 1438-1442
• 38 Davis KP, Gaffey MM, Kompelli AR, Richter GT. Cutaneous hyperpigmentation following bleomycin sclerotherapy for vascular malformations. Pediatr Dermatol 2022; 39 (01) 103-106
• 39 Horbach SER, Rigter IM, Smitt JHS, Reekers JA, Spuls PI, van der Horst CMAM. Intralesional bleomycin injections for vascular malformations: a systematic review and meta-analysis. Plast Reconstr Surg 2016; 137 (01) 244-256
• 40 Gothelf A, Mir LM, Gehl J. Electrochemotherapy: results of cancer treatment using enhanced delivery of bleomycin by electroporation. Cancer Treat Rev 2003; 29 (05) 371-387
• 41 Campanacci L, Cevolani L, De Terlizzi F. et al. Electrochemotherapy is effective in the treatment of bone metastases. Curr Oncol 2022; 29 (03) 1672-1682
• 42 Mir LM, Orlowski S, Belehradek Jr J, Paoletti C. Electrochemotherapy potentiation of antitumour effect of bleomycin by local electric pulses. Eur J Cancer 1991; 27 (01) 68-72
• 43 Campana LG, Kis E, Bottyán K. et al. Electrochemotherapy for advanced cutaneous angiosarcoma: a European register-based cohort study from the International Network for Sharing Practices of electrochemotherapy (InspECT). Int J Surg 2019; 72: 34-42
• 44 Guida M, Campana LG, Curatolo P. et al. Local treatment with electrochemotherapy of superficial angiosarcomas: efficacy and safety results from a multi-institutional retrospective study. J Surg Oncol 2016; 114 (02) 246-253
• 45 Sersa G, Cemazar M, Parkins CS, Chaplin DJ. Tumour blood flow changes induced by application of electric pulses. Eur J Cancer 1999; 35 (04) 672-677
• 46 Sersa G, Jarm T, Kotnik T. et al. Vascular disrupting action of electroporation and electrochemotherapy with bleomycin in murine sarcoma. Br J Cancer 2008; 98 (02) 388-398
• 47 Jarm T, Cemazar M, Miklavcic D, Sersa G. Antivascular effects of electrochemotherapy: implications in treatment of bleeding metastases. Expert Rev Anticancer Ther 2010; 10 (05) 729-746
• 48 Markelc B, Bellard E, Sersa G. et al. Increased permeability of blood vessels after reversible electroporation is facilitated by alterations in endothelial cell-to-cell junctions. J Control Release 2018; 276: 30-41
• 49 Markelc B, Sersa G, Cemazar M. Differential mechanisms associated with vascular disrupting action of electrochemotherapy: intravital microscopy on the level of single normal and tumor blood vessels. PLoS One 2013; 8 (03) e59557
• 50 McMorrow L, Shaikh M, Kessell G, Muir T. Bleomycin electrosclerotherapy: new treatment to manage vascular malformations. Br J Oral Maxillofac Surg 2017; 55 (09) 977-979
• 51 Wohlgemuth WA, Müller-Wille R, Meyer L. et al. Bleomycin electrosclerotherapy in therapy-resistant venous malformations of the body. J Vasc Surg Venous Lymphat Disord 2021; 9 (03) 731-739
• 52 Kostusiak M, Murugan S, Muir T. Bleomycin electrosclerotherapy treatment in the management of vascular malformations. Dermatol Surg 2022; 48 (01) 67-71
• 53 Guntau M, Cucuruz B, Brill R. et al. Individualized treatment of congenital vascular malformations of the tongue. Clin Hemorheol Microcirc 2023; 83 (04) 421-429
• 54 Loeser JH, Kisser U, Dießel L. et al. Interdisciplinary treatment of macroglossia due to a microcystic lymphatic malformation with bleomycin electrosclerotherapy followed by partial resection. Cardiovasc Intervent Radiol 2024; 47 (06) 852-854
• 55 Schmidt VF, Cangir Ö, Meyer L. et al. Outcome of bleomycin electrosclerotherapy of slow-flow malformations in adults and children. Eur Radiol 2024; 34 (10) 6425-6434
• 56 Muir T, Wohlgemuth WA, Cemazar M. et al. Current operating procedure (COP) for bleomycin electrosclerotherapy (BEST) of low-flow vascular malformations. Radiol Oncol 2024; 58 (04) 469-479
• 57 Horbach SER, Wolkerstorfer A, Jolink F, Bloemen PR, van der Horst CMAM. Electrosclerotherapy as a novel treatment option for hypertrophic capillary malformations: a randomized controlled pilot trial. Dermatol Surg 2020; 46 (04) 491-498
• 58 Cossio ML, Dubois J, McCuaig CC. et al. Non-involuting congenital hemangiomas (NICH) with postnatal atypical growth: a case series. Pediatr Dermatol 2019; 36 (04) 466-470
• 59 Wang KK, Glenn RL, Adams DM. et al. Surgical management of fibroadipose vascular anomaly of the lower extremities. J Pediatr Orthop 2020; 40 (03) e227-e236
• 60 Greene AK, Perlyn CA, Alomari AI. Management of lymphatic malformations. Clin Plast Surg 2011; 38 (01) 75-82
• 61 Keane OA, O'Guinn ML, Adams S. et al. Short-term postoperative complications of lymphatic malformation surgical excision: a 20-year institutional review. J Pediatr Surg 2025; 60 (03) 162146
• 62 Shaikh R. Percutaneous image-guided cryoablation in vascular anomalies. Semin Intervent Radiol 2017; 34 (03) 280-287
• 63 Gao Y, Wang X, Suo W. Management of venous malformations with percutaneous radiofrequency thermal ablation. Br J Dermatol 2012; 167 (03) 637-642
• 64 van der Linden E, Overbosch J, Kroft LJM. Radiofrequency ablation for treatment of symptomatic low-flow vascular malformations after previous unsuccessful therapy. J Vasc Interv Radiol 2005; 16 (05) 747-750
• 65 Wang L, Lu M, Zhuang M, Liang Y, Wang SS, Li JM. Microwave ablation with hydrodissection used for the treatment of vascular malformations: effectiveness and safety study. Front Oncol 2024; 14: 1146972
• 66 Sporns PB, Psychogios M, Blackham K, Zech C, Wildgruber M, Takes M. Ultrasonography-guided radiofrequency ablation of vascular malformations - the moving shot technique. Front Med (Lausanne) 2024; 10: 1345904
• 67 Yin HH, Wen R, Lin P, Yang H, Hu M, Yang H. Ultrasound-guided microwave ablation of soft tissue venous malformations. J Vasc Surg Venous Lymphat Disord 2023; 11 (03) 605-609
• 68 Ko HK, Kim AH, Kim HB. et al. Experience at 1 year with the moving tip technique of radiofrequency ablation for the treatment of symptomatic venous malformations in the head and neck. J Vasc Surg Venous Lymphat Disord 2013; 1 (03) 263-269
• 69 Fish A, Moushey A, Chan SM, Staib L, Marino A, Schlachter T. Cryoablation of venous malformations: a systematic review. J Vasc Interv Radiol 2022; 33 (08) 993-1000
• 70 Woolen S, Gemmete JJ. Treatment of residual facial arteriovenous malformations after embolization with percutaneous cryotherapy. J Vasc Interv Radiol 2016; 27 (10) 1570-1575
• 71 Salehian S, Gemmete JJ, Kasten S, Edwards SP. Novel application of percutaneous cryotherapy for the treatment of recurrent oral bleeding from a noninvoluting congenital hemangioma involving the right buccal space and maxillary tuberosity. Cardiovasc Intervent Radiol 2011; 34 (Suppl. 02) S277-S281
• 72 Sebastian AS, Adair MJ, Morris JM, Khan MH, Arndt CAS, Nassr A. Minimally invasive treatment of a painful osteolytic lumbar lesion secondary to epithelioid hemangioendothelioma. Global Spine J 2015; 5 (02) 135-139
• 73 Shashi KK, Shahin MM, Johnston P, Shaikh R. Cryoablation for bone and soft tissue lesions in pediatric patients: complications and preventive measures. Cardiovasc Intervent Radiol 2023; 46 (09) 1249-1256
• 74 Cohen-Cutler S, Blatt J, Bayliff S, Iacobas I, Hammill A, Sisk BA. Vascular anomalies care in the United States: a cross-sectional national survey. J Pediatr 2023; 261: 113579
• 75 Borst AJ, Swerdlin RF, Phillips JD, Hawkins CM, Briones MA. How we established a multidisciplinary program for vascular anomalies. Pediatr Blood Cancer 2022; 69 (Suppl. 03) e28863
• 76 Cell-free DNA next-generation sequencing liquid biopsy as a new revolutionary approach for arteriovenous malformation - PMC. Accessed January 12, 2025 at: https://pmc.ncbi.nlm.nih.gov/articles/PMC8489236/
• 77 Serio VB, Palmieri M, Loberti L. et al. Nosological and theragnostic approach to vascular malformation through cfDNA NGS liquid biopsy. J Clin Med 2022; 11 (13) 3740
• 78 Zenner K, Jensen DM, Cook TT. et al. Cell-free DNA as a diagnostic analyte for molecular diagnosis of vascular malformations. Genet Med 2021; 23 (01) 123-130
• 79 Winkler E, Wu D, Gil E. et al. Endoluminal biopsy for molecular profiling of human brain vascular malformations. Neurology 2022; 98 (16) e1637-e1647
• 80 NAMAS. Keys to Correct Embolization Coding: CPT® Codes 37241–37244. NAMAS. May 2, 2023. Accessed April 27, 2025 at: https://namas.co/keys-to-correct-embolization-coding-cpt-codes-37241-37244/
• 81 https://fyra.io Coding for Endovascular Therapies for Incompetent Extremity Veins. Endovascular Today. Accessed April 27, 2025 at: https://evtoday.com/articles/2014-july/coding-for-endovascular-therapies-for-incompetent-extremity-veins
• 82 Freixo C, Ferreira V, Martins J. et al. Efficacy and safety of sirolimus in the treatment of vascular anomalies: a systematic review. J Vasc Surg 2020; 71 (01) 318-327
• 83 Mansur A, Radovanovic I. Vascular malformations: an overview of their molecular pathways, detection of mutational profiles and subsequent targets for drug therapy. Front Neurol 2023; 14: 1099328
• 84 Queisser A, Seront E, Boon LM, Vikkula M. Genetic basis and therapies for vascular anomalies. Circ Res 2021; 129 (01) 155-173
• 85 Bertino F, Braithwaite KA, Hawkins CM. et al. Congenital limb overgrowth syndromes associated with vascular anomalies. Radiographics 2019; 39 (02) 491-515