Sildenafil for Severe Lymphatic Malformations – NEJM

Sildenafil for Severe Lymphatic Malformations.
N Engl J Med 2012; 366:384-386 January 26, 2012 DOI: 10.1056/NEJMc1112482.
To the Editor:
Lymphatic malformations are uncommon congenital vascular anomalies that can cause complications including obstruction of vital organs and their function, recurrent infection, and disfigurement. 1 Current procedural treatments are only partially successful, and lymphatic malformations often recur. We report marked regression of lymphatic malformations in three children after treatment with oral sildenafil.
A 10-week-old girl presented with a congenital, nonpulsatile, violaceous, nodular plaque causing massive enlargement of the right chest and arm. A scan obtained with magnetic resonance imaging (MRI) revealed microcystic venolymphatic malformation with intrathoracic extension ( Figure 1A Figure 1 MRI of the Chest, Performed with the Use of Contrast Material, before and after Treatment of the Index Patient with Sildenafil, and Photographs of Subject 2 before and after Treatment. An MRI scan of the chest obtained before the index patient received sildenafil shows an enhancing, low-flow malformation (Panel A). This transverse section shows involvement of the subcutaneous chest wall (white arrows) in addition to pleural, paravertebral, mediastinal, and paraaortic involvement (black arrows), without extension into bone. After therapy with sildenafil, the malformation is almost completely resolved (Panel B). The use of contrast material highlights the heart, showing right ventricular enlargement (dashed arrow), the aorta, and the pulmonary vessels, but the malformation is difficult to discern. Subject 2 is seen at 9 weeks of age, before any intervention (Panel C), and at 14 months of age, after five sessions of sclerotherapy (Panel D). Although the malformations diminished with sclerotherapy, the malformation on the back remained tense and extended over the shoulder to involve the anterior clavicle. After a 12-week course of oral sildenafil (target dose, 1.0 mg per kilogram of body weight, three times per day), the lymphatic malformation became soft and was sagging (Panel E). Mild reenlargement of the malformations could be seen 4 weeks after sildenafil was discontinued (Panel F). ). At 5 months, congestive heart failure developed. An echocardiogram showed pulmonary hypertension without congenital anomalies. Despite initial improvement after treatment with conservative measures, the patient’s cardiorespiratory condition worsened. At 9 months, cardiac catheterization confirmed the presence of idiopathic pulmonary hypertension, and sildenafil was initiated. The malformation gradually diminished, and 4 months later a thin, blue plaque and redundant tissue were seen. A subsequent MRI of the heart confirmed the presence of only minimal residual lymphatic malformation ( Figure 1B ).
On the basis of this observation, a pilot study was approved by the institutional review board at Stanford University. Two children with disabling lymphatic malformations received sildenafil for 12 weeks.
In Subject 1, a 12-month-old boy, the lymphatic malformation involved the orbit and upper eyelid and obstructed visual input. Although improved eye opening was noted after 3 weeks, debulking was performed because of concerns about amblyopia. At the study’s end, the child’s ability to open the affected eye had increased by 25%. Tissue enlargement recurred after sildenafil was discontinued. Subject 2, a 15-month-old girl, had three large lymphatic malformations and had undergone sclerotherapy with partial improvement ( Figure 1C and 1D ). After administration of a 12-week course of sildenafil, the malformations had diminished by about 75%, with the malformation on her back appearing deflated, leaving sagging skin ( Figure 1E ). Sildenafil was stopped, and mild enlargement was noted 4 weeks later ( Figure 1F ).
Neither child had significant adverse effects from treatment. Both families elected to continue administration of sildenafil after study completion.
Sildenafil selectively inhibits phosphodiesterase-5, preventing the breakdown of cyclic guanosine monophosphate. 2 Inhibition of phosphodiesterase-5 decreases the contractility of vascular smooth muscle, producing vasodilation. The drug has been approved for the treatment of pulmonary hypertension in adults; it is used off-label in children with pulmonary hypertension and appears to be safe and effective. 3.
Lymphatic malformations are hypothesized to develop from primitive lymphatic sacs that arise from mesenchyma or embryologic endothelial networks. The contraction of thickened muscular linings may increase intramural pressure and cause cystic dilatation. 4 A potential explanation for the therapeutic effect seen in this series is the relaxation of smooth muscle followed by cystic decompression. Alternatively, relaxation may allow secondary lymphatic spaces to open, or sildenafil may normalize lymphatic endothelial dysfunction. 5.
The observations described suggest that sildenafil represents an encouraging, propitious treatment for lymphatic malformations, used as monotherapy or with other treatments. A double-blind, placebo-controlled trial is under way.
Glenda L. Swetman, M.D.
Stanford University School of Medicine, Stanford, CA.
David R. Berk, M.D.
Washington University School of Medicine, St. Louis, MO.
Shreyas S. Vasanawala, M.D., Ph.D.
Jeffrey A. Feinstein, M.D., M.P.H.
Alfred T. Lane, M.D., M.A.
Stanford University School of Medicine, Stanford, California.
Anna L. Bruckner, M.D.
University of Colorado School of Medicine, Aurora, CO.
Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.
Blei F . Congenital lymphatic malformations. Ann N Y Acad Sci 2008;1131:185-194.
Lin CS , Lin G , Xin ZC , Lue TF . Expression, distribution and regulation of phosphodiesterase 5. Curr Pharm Des 2006;12:3439-3457.
Karatza AA , Bush A , Magee AG . Safety and efficacy of sildenafil therapy in children with pulmonary hypertension. Int J Cardiol 2005;100:267-273.
Whimster IW . The pathology of lymphangioma circumscriptum. Br J Dermatol 1976;94:473-486.
Muthuchamy M , Zawieja D . Molecular regulation of lymphatic contractility. Ann N Y Acad Sci 2008;1131:89-99.
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Milton Waner, Teresa M. O. . (2018) Multidisciplinary Approach to the Management of Lymphatic Malformations of the Head and Neck. Otolaryngologic Clinics of North America 51 :1, 159-172.
Denise M. Adams, Leonardo R. Brandão, Caitlin M. Peterman, Anita Gupta, Manish Patel, Steven Fishman, Cameron C. Trenor. . (2018) Vascular anomaly cases for the pediatric hematologist oncologists-An interdisciplinary review. Pediatric Blood & Cancer 65 :1, e26716.
Ilaria Amodeo, Mariarosa Colnaghi, Genny Raffaeli, Giacomo Cavallaro, Fabrizio Ciralli, Silvana Gangi, Ernesto Leva, Lorenzo Pignataro, Irene Borzani, Lorenza Pugni, Fabio Mosca. . (2017) The use of sirolimus in the treatment of giant cystic lymphangioma. Medicine 96 :51, e8871.
Joanna H. Tu, Elidia Tafoya, Michael Jeng, Joyce M. Teng. . (2017) Long-Term Follow-Up of Lymphatic Malformations in Children Treated with Sildenafil. Pediatric Dermatology 34 :5, 559-565.
Shengcai Wang, Jie Zhang, Wentong Ge, Yuanhu Liu, Yongli Guo, Yue Liu, Ning Wang, Yuzhu He, Jun Tai, Xin Ni. . (2017) Efficacy and safety of oral sildenafil in treatment of pediatric head and neck lymphatic malformations. Acta Oto-Laryngologica 137 :6, 674-678.
Cynthia Reyes, Taylor Parnall, Tania Kraai, Linda Butros, Anna Fabre, Jimmy Windsor, Jason McKee, Gresham Richter. . (2017) Multimodality treatment of a massive cervicothoracic lymphatic-venous malformation in a 13-year-old boy. Journal of Pediatric Surgery Case Reports 21 , 15-18.
John Rocke, Gavin Quail, Graeme Copley. . (2017) Using sildenafil (viagra) to treat congenital lymphatic malformations of the head and neck, our experience. International Journal of Pediatric Otorhinolaryngology 96 , 25-27.
R. Gabeff, G. Lorette, D. Herbreteau, A. le Touze, D. Goga, A. Maruani. . (2017) Malformations lymphatiques kystiques superficielles. Annales de Dermatologie et de Vénéréologie 144 :5, 389-397.
Xiaopo He, Yiran Liu, Kai Li, Aijun Yang, Rui Wang, Shaohua Liu. . (2017) Sildenafil suppresses the proliferation and enhances the apoptosis of hemangioma endothelial cells. Experimental and Therapeutic Medicine .
Nirav D. Raichura, Md Shahid Alam, Veena Olma Noronha, Bipasha Mukherjee. . (2017) A prospective study of the role of intralesional bleomycin in orbital lymphangioma. Journal of American Association for Pediatric Ophthalmology and Strabismus 21 :2, 146-151.
M. Barreau, A. Dompmartin. . (2017) Anomalías vasculares superficiales: malformaciones vasculares. EMC – Dermatología 51 :1, 1-10.
Ilaria Amodeo, Giacomo Cavallaro, Genny Raffaeli, Lorenzo Colombo, Monica Fumagalli, Riccardo Cavalli, Ernesto Leva, Fabio Mosca. . (2017) Abdominal cystic lymphangioma in a term newborn. Medicine 96 :8, e5984.
Diana H. Lee, Elena B. Hawryluk. . 2017. Vascular Disorders and Anomalies. Therapy in Pediatric Dermatology, 183-188.
Young Jun Woo, Chang Yeom Kim, Bradford Sgrignoli, Jin Sook Yoon. . (2017) Orbital Lymphangioma: Characteristics and Treatment Outcomes of 12 Cases. Korean Journal of Ophthalmology 31 :3, 194.
Jovan N. Markovic, Cynthia K. Shortell. . 2017. Lymphatic Malformation (LM) (Extratruncular): Lymphangioma. Congenital Vascular Malformations, 113-120.
Iris Baumgartner, Byung-Boong Lee. . 2017. Conservative/Medical Treatment of CVM. Congenital Vascular Malformations, 323-327.
Sophie E.R. Horbach, Folkert Jolink, Chantal M.A.M. van der Horst. . (2016) Oral sildenafil as a treatment option for lymphatic malformations in PIK3CA-related tissue overgrowth syndromes. Dermatologic Therapy 29 :6, 466-469.
Junji Shimizu, Takashi Taga, Takuma Kishimoto, Motoki Ohta, Kouji Tagawa, Tomoaki Kunitsu, Tetsunobu Yamane, Yasuyuki Tsujita, Yoshihiro Kubota, Yutaka Eguchi. . (2016) Airway obstruction caused by rapid enlargement of cervical lymphangioma in a five-month-old boy. Clinical Case Reports 4 :9, 896-898.
Ann M. Defnet, Naina Bagrodia, Sonia L. Hernandez, Natalie Gwilliam, Jessica J. Kandel. . (2016) Pediatric lymphatic malformations: evolving understanding and therapeutic options. Pediatric Surgery International 32 :5, 425-433.
Peter A. Lio. . (2016) Herbal Remedy for Lymphatic Malformations: Will This Join Our Treatment Armamentarium?. Pediatric Dermatology 33 :2, 234-235.
S. Wiegand, J. A. Werner. . (2016) Lymphatische Malformationen im Kopf-Hals-Bereich. HNO 64 :2, 133-142.
Teresa Min-Jung O, Man Si Lou, Yupo Ma. . (2016) Zinc effect on human lymphatic malformation cells in vitro. International Journal of Pediatric Otorhinolaryngology 80 , 33-38.
James Wall, Karl Sylvester, Craig Albanese. . 2016. Lymphatic Malformations in Children. Pediatric Surgery, 1-8.
Hannah Rankin, Kelley Zwicker, Cameron C. Trenor. . (2015) Caution is recommended prior to sildenafil use in vascular anomalies. Pediatric Blood & Cancer 62 :11, 2015-2017.
Bin Yang, Li Li, Li-xin Zhang, Yu-juan Sun, Lin Ma. . (2015) Clinical Characteristics and Treatment Options of Infantile Vascular Anomalies. Medicine 94 :40, e1717.
Aliza Olive, Julie S. Moldenhauer, Pablo Laje, Mark P. Johnson, Beverly G. Coleman, Teresa Victoria, Alan W. Flake, N. Scott Adzick. . (2015) Axillary lymphatic malformations: Prenatal evaluation and postnatal outcomes. Journal of Pediatric Surgery 50 :10, 1711-1715.
Ahmet Kaan Gündüz, Yağmur Seda Yeşiltaş, Carol L Shields. . (2015) Orbital tumors: a systematic review: part I. Expert Review of Ophthalmology 10 :5, 465-483.
Nariman Nassiri, Jack Rootman, Daniel B. Rootman, Robert A. Goldberg. . (2015) Orbital lymphaticovenous malformations: Current and future treatments. Survey of Ophthalmology 60 :5, 383-405.
Lisa S. Foley, Ann M. Kulungowski. . (2015) Vascular Anomalies in Pediatrics. Advances in Pediatrics 62 :1, 227-255.
David Kim, Latanya Benjamin, Ashley Wysong, David Hovsepian, Joyce Teng. . (2015) Treatment of complex periorbital venolymphatic malformation in a neonate with a combination therapy of sirolimus and prednisolone. Dermatologic Therapy 28 :4, 218-221.
John C. Koshy, Bradley S. Eisemann, Nikhil Agrawal, Sheena Pimpalwar, Joseph L. Edmonds. . (2015) Sildenafil for microcystic lymphatic malformations of the head and neck: A prospective study. International Journal of Pediatric Otorhinolaryngology 79 :7, 980-982.
Naina Bagrodia, Ann M. Defnet, Jessica J. Kandel. . (2015) Management of lymphatic malformations in children. Current Opinion in Pediatrics 27 :3, 356-363.
D T Malleske, B A Yoder. . (2015) Congenital chylothorax treated with oral sildenafil: a case report and review of the literature. Journal of Perinatology 35 :5, 384-386.
Eric Tranvinh, Kristen W. Yeom, Michael Iv. . (2015) Imaging Neck Masses in the Neonate and Young Infant. Seminars in Ultrasound, CT and MRI 36 :2, 120-137.
Ryan George, Rahul Shah, Dorothy Bulas, Shannon Kline, Sean Alexander, Brian K. Reilly. . (2015) The delivered promise of prenatal imaging and a challenge to the utility of sildenafil for severe lymphatic malformations. International Journal of Pediatric Otorhinolaryngology 79 :2, 89-93.
Andrew W. Stacey, Joseph J. Gemmete, Alon Kahana. . (2015) Management of Orbital and Periocular Vascular Anomalies. Ophthalmic Plastic and Reconstructive Surgery 31 :6, 427-436.
Maurice Beghetti, Julie Wacker Bou Puigdefabregas, Sausan Merali. . (2014) Sildenafil for the treatment of pulmonary hypertension in children. Expert Review of Cardiovascular Therapy 12 :10, 1157-1184.
Cameron C. Trenor, Gulraiz Chaudry. . (2014) Complex lymphatic anomalies. Seminars in Pediatric Surgery 23 :4, 186-190.
Ravindhra G. Elluru, Karthik Balakrishnan, Horacio M. Padua. . (2014) Lymphatic malformations: Diagnosis and management. Seminars in Pediatric Surgery 23 :4, 178-185.
Christina Danial, Andrea L. Tichy, Umar Tariq, Glenda L. Swetman, Phuong Khuu, Thomas H. Leung, Latanya Benjamin, Joyce Teng, Shreyas S. Vasanawala, Alfred T. Lane. . (2014) An open-label study to evaluate sildenafil for the treatment of lymphatic malformations. Journal of the American Academy of Dermatology 70 :6, 1050-1057.
M. Barreau, A. Dompmartin. . (2014) Les malformations cutanées vasculaires non syndromiques. Annales de Dermatologie et de Vénéréologie 141 :1, 56-67.
Jack Rootman, Manraj K.S. Heran, Douglas A. Graeb. . (2014) Vascular Malformations of the Orbit. Ophthalmic Plastic and Reconstructive Surgery 30 :2, 91-104.
Zerina Lokmic, Geraldine M. Mitchell, Nicholas Koh Wee Chong, Jacqueline Bastiaanse, Yi-Wen Gerrand, Yiping Zeng, Elizabeth D. Williams, Anthony J. Penington. . (2014) Isolation of human lymphatic malformation endothelial cells, their in vitro characterization and in vivo survival in a mouse xenograft model. Angiogenesis 17 :1, 1-15.
Scott C. Manning, Jonathan Perkins. . (2013) Lymphatic malformations. Current Opinion in Otolaryngology & Head and Neck Surgery 21 :6, 571-575.
Julie Blatt, Thomas W. McLean, Sharon M. Castellino, Craig N. Burkhart. . (2013) A review of contemporary options for medical management of hemangiomas, other vascular tumors, and vascular malformations. Pharmacology & Therapeutics 139 :3, 327-333.
Eric E. Berg, Steven E. Sobol, Ian Jacobs. . (2013) Laryngeal Obstruction by Cervical and Endolaryngeal Lymphatic Malformations in Children: Proposed Staging System and Review of Treatment. Annals of Otology, Rhinology & Laryngology 122 :9, 575-581.
Howard B. Pride, Megha Tollefson, Robert Silverman. . (2013) What’s new in pediatric dermatology?. Journal of the American Academy of Dermatology 68 :6, 899.e1-899.e11.
Francine Blei. . (2013) Medical and Genetic Aspects of Vascular Anomalies. Techniques in Vascular and Interventional Radiology 16 :1, 2-11.
Julie Blatt, Seth J. Corey. . (2013) Drug repurposing in pediatrics and pediatric hematology oncology. Drug Discovery Today 18 :1-2, 4-10.
S. Aractingi. . (2012) Quoi de neuf en thérapeutique dermatologique ?. Annales de Dermatologie et de Vénéréologie 139 , S223-S228.
S. Barbarot. . (2012) Quoi de neuf en dermatologie pédiatrique ?. Annales de Dermatologie et de Vénéréologie 139 , S202-S216.
Francine Blei. . (2012) Update March 2012. Lymphatic Research and Biology 10 :1, 33-41.