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International Society for the
Study of Vascular Anomalies


Scientific Articles


Junior ISSVA Member*/Scientific Committee Member

Karthik Balakrishnan, MD*/ Jonathan Perkins, DO - Otolaryngology
Michael Dellinger, PhD*/ Francine Blei, MD – Lymphatic Biology, Pathophysiology
Anne Dompmartin, MD – Dermatology
Israel Fernandez-Pineda, MD*/ Juan Carlos Lopez Guttierez, MD, PhD - Surgery
Dov Goldenberg, MD – Plastic Surgery
Ionela Iocobas, MD*/ Denise Adams, MD – Pediatric Hematology Oncology
Anna Lillis, MD*/ Gulraiz Chaudry, MD– Interventional Radiology
Zerina Lokmic Tomkins, PhD*/ Tony Penington, MD – Basic Science
Kristina W. Rosbe, MD - Otolaryngology

NOTE: Authors who are ISSVA members in bold



Ayturk UM, Couto JA, Hann S, Mulliken JB, Williams KL, Huang AY, Fishman SJ, Boyd TK, Kozakewich HP, Bischoff J, Greene AK, Warman ML.
Somatic Activating Mutations in GNAQ and GNA11 Are Associated with Congenital Hemangioma.
Am J Hum Genet. 2016 Apr 7;98(4):789-95.

Commentary: Ayturk et al have subjected eight congenital haemangioma (both rapidly involuting and non-involuting congenital haemangiomas) tissues to massively parallel mRNA sequencing to identify if somatic mutations play a role in the origin of these tumours. Employing various elimination criteria, the authors identified two mutually exclusive mosaic missense mutations. One mutation identified in 6/8 specimens was in the GNAQ gene whereas the second mutation identified in the remaining 2 specimens was in GNA11 gene. The GNAQ mutations identified are: GNAQ p.Gln209Leu (c.626A>T), GNAQ p.Gln209Pro (c.626A>C), GNAQ p.Gln209His (c.627A>C). The GNA11 somatic mutations identified is GNA11 p.Gln209Leu (c.626A>T). While these somatic mutations were mutually exclusive, the GNAQ mutations were present both in NICH and RICH. Although this mutation cannot be used as a diagnostic discriminatory factor, the authors suggest that the natural outcome of RICH and NICH may be due to other factors such as genetic, epigenetic or environmental factors may be at play. It is of note that not all NICH and RICH samples tested contained these gene mutations. The mutations identified in the congenital hemangioma GNAQ gene are distinctly different form the GNAQ mutation found in capillary malformations and in patients with Sturge-Weber Syndrome, where the mutation is GNAQ c.548G>A (p.Arg183Gln).  The work presents an interesting approach in methodology on how to identify the presence of a somatic mutation in the absence of patient’s blood and/or ‘normal’ tissue sample.  In the study design, the authors first removed variants with more than 40% variant allele frequency through an assumption that these most likely present germline variants rather than somatic changes, followed by all removal of all non-clinical variants and comparison to the variants found in arteriovenous malformations (n=3) and common infantile haemangioma (n=1). 

The study demonstrates an association between congenital haemangiomas and mutations in GNAQ and GNA11 genes. These mutations could not be used to distinguish between RICH and NICH and were not present in all RICH/NICH specimens examined. The mutations reported in the GNAQ gene of congenital haemangiomas are distinctly different from the GNAQ mutation identified in the capillary malformations and patients with Sturge-Weber Syndrome.
-Zerina Lokmic Tomkins, PhD/Tony Penington, MD

Castel P, Carmona FJ, Grego-Bessa J, Berger MF, Viale A, Anderson KV, Bague S, Scaltriti M, Antonescu CR, Baselga E, Baselga J.
Somatic PIK3CA mutations as a driver of sporadic venous malformations.
Sci Transl Med. 2016 Mar 30;8(332):332ra42.

Castillo SD, Tzouanacou E, Zaw-Thin M, Berenjeno IM, Parker VE, Chivite I, Milà-Guasch M, Pearce W, Solomon I, Angulo-Urarte A, Figueiredo AM, Dewhurst RE, Knox RG, Clark GR, Scudamore CL, Badar A, Kalber TL, Foster J, Stuckey DJ, David AL, Phillips WA, Lythgoe MF, Wilson V, Semple RK, Sebire NJ, Kinsler VA, Graupera M, Vanhaesebroeck B.
Somatic activating mutations in PIK3CA cause sporadic venous malformations in mice and humans.
Sci Transl Med. 2016 Mar 30;8(332):332ra43.

Couto JA, Huang L, Vivero MP, Kamitaki N, Maclellan RA, Mulliken JB, Bischoff J, Warman ML, Greene AK.
Endothelial Cells from Capillary Malformations Are Enriched for Somatic GNAQ Mutations.
Plast Reconstr Surg. 2016 Jan;137(1):77e-82e.

Harbi S, Wang R, Gregory M, Hanson N, Kobylarz K, Ryan K, Deng Y, Lopez P, Chiriboga L, Mignatti P.
Infantile Hemangioma Originates From A Dysregulated But Not Fully Transformed Multipotent Stem Cell.
Sci Rep. 2016 Oct 27;6:35811.

Commentary: Harbi et al report an extensive gene and cell surface marker expression profiles of hemangioma stem cells (HaemSc) relative to HUVECS or normal human stem and progenitor cells (references) and their derivatives grown in vitro. The study confirms that the HaemSc express genes highly associated with the processes of angiogenesis, vasculogenesis and tumour formation and suggests that the HaemSc are dysregulated immature stem cells arrested in their development.

The study further expands on our current knowledge of the HaemSc in vitro cell phenotype and gene expression and confirms tumorigenic potential of HemSc. More importantly it builds new branches in our understanding of the HaemSc heterogeneity and raises the potential that the immune system might play a significant role in the infantile haemangioma genesis.
-Zerina Lokmic Tomkins, PhD/Tony Penington, MD

Keppler-Noreuil KM, Parker VE, Darling TN, Martinez-Agosto JA.
Somatic overgrowth disorders of the PI3K/AKT/mTOR pathway & therapeutic strategies.
Am J Med Genet C Semin Med Genet. 2016 Nov 18. [Epub ahead of print]

Lim YH, Bacchiocchi A, Qiu J, Straub R, Bruckner A, Bercovitch L, Narayan D; Yale Center for Mendelian Genomics., McNiff J, Ko C, Robinson-Bostom L, Antaya R, Halaban R, Choate KA.
GNA14 Somatic Mutation Causes Congenital and Sporadic Vascular Tumors by MAPK Activation.
Am J Hum Genet. 2016 Aug 4;99(2):443-50.

Munabi NC, England RW, Edwards AK, Kitajewski AA, Tan QK, Weinstein A, Kung JE, Wilcox M, Kitajewski JK, Shawber CJ, Wu JK.
Propranolol targets hemangioma stem cells via cAMP and Mitogen-activated protein kinase regulation.
Stem Cells Transl Med. 2016 Jan;5(1):45-55.

Orbay, Hakan; Li, Yuanpei; Xiao, Wenwu; Cherry, Simon R.; Lam, Kit; Sahar, David E.
Developing a Nanoparticle-Delivered High-Efficacy Treatment for Infantile Hemangiomas Using a Mouse Hemangioendothelioma Model.
Plastic & Reconstructive Surgery. 138(2):410-417, August 2016.

Commentary: The authors present an experimental study and the main goal was to develop a novel, locally active, nontoxic treatment method for infantile hemangiomas using photodynamic therapy delivered by means of nanoparticles. A nanoporphyrin nanoparticle was used as a photosensitizer for photodynamic therapy in this study. The authors developed an animal model using mouse hemangioendothelioma cells and used their treatment in a group of animals, in a controlled randomized design. The experimental tumor responded to photodynamic therapy. The authors discussed in this study, the limitations of conventional propranolol treatment and considered using nanoporphyrin as a delivery vehicle for photodynamic therapy and potentially for propranolol. In conclusion, the authors stated that systemic injection of nanoporphyrin carrier leads to selective accumulation in the tumor model, predisposing to successful ablation by photodynamic therapy, suggesting that photodynamic therapy can be an effective treatment for infantile hemangiomas.
-Dov Goldenberg, MD

Soblet J, Kangas J, Nätynki M, Mendola A, Helaers R, Uebelhoer M, Kaakinen M, Cordisco M, Dompmartin A, Enjolras O, Holden S, Irvine AD, Kangesu L, Léauté-Labrèze C, Lanoel A, Lokmic Z, Maas S, McAleer MA, Penington A, Rieu P, Syed S, van der Vleuten C, Watson R, Fishman SJ, Mulliken JB, Eklund L, Limaye N, Boon LM, Vikkula M.
Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations.
J Invest Dermatol. 2016 Aug 9. pii: S0022-202X(16)32252-7. [Epub ahead of print]

Welsh JD, Kahn ML and Sweet DT.
Lymphovenous hemostasis and the role of platelets in regulating lymphatic flow and lymphatic vessel maturation.
Blood 2016; 128:1169-1173.

Wetzel-Strong SE, Detter MR, Marchuk DA.
The pathobiology of vascular malformations: insights from human and model organism genetics.
J Pathol. 2016 Nov 9. [Epub ahead of print]

Commentary: This outstanding manuscript provides a comprehensive, detailed overview of the genetic underpinnings and pathophysiology of vascular malformation syndromes, separating them by the predominantly or partially affected vascular bed: those abnormal small vessel integrity: Sturge Weber Syndrome, Klippel Trenaunay, Parkes Weber Syndrome, and CM-AVM; Cerebral Cavernous Malformations; Abnormal arterial bed vascular integrity: MoyMoya Disease, Hereditary Hemorrhagic Telangiectasia, CADASIL, CARDASIL, arterial tortuosity syndrome,  and those affecting maintenance of venous vascular integrity/vascular smooth muscle cell dysfunction: glomovenous malformations, mucocutaneous vascular malformations, and blue rubber bleb nevus syndrome. This thought-provoking review remarks that “these vascular malformation genes invariably encode components of the myriad signaling pathways that modulate normal endothelial or smooth muscle cell function”, rather than directly altering structural proteins of endothelial, smooth muscle, and/or extracellular matrix proteins. The authors underscore the need for improved models for studying these genes and the affected pathways, to better understand the pathobiology of vascular malformations, and ideally contribute to improved therapies.
-Michael Dellinger, PhD/Francine Blei, MD

Wilhelm K, Happel K, Eelen G, Schoors S, Oellerich MF, Lim R, Zimmermann B, Aspalter IM, Franco CA, Boettger T, Braun T, Fruttiger M, Rajewsky K, Keller C, Brüning JC, Gerhardt H, Carmeliet P, Potente M.
FOXO1 couples metabolic activity and growth state in the vascular endothelium.
Nature. 2016 Jan 14;529(7585):216-20.

Commentary: There is a growing interest in identifying how endothelial cell (EC) metabolism differs between normal and diseased/dysfunctional blood vessels. A better understanding of how EC metabolism is altered in diseased/dysfunctional blood vessels could lead to the identification of novel therapeutic targets and strategies to reverse or inhibit the growth of abnormal blood vessels. FOXO1 is a transcription factor that serves a critical role in regulating metabolism and is inhibited by the PI3K/AKT pathway. The objective of this study was to identify the role of FOXO1 in ECs. To attain this objective, the investigators genetically manipulated FOXO1 in ECs in mice. Conditional inactivation of FOXO1 in ECs induced EC proliferation and led to the formation of large irregular blood vessels. Conversely, forced activation of FOXO1 in ECs inhibited EC proliferation and restricted vessel growth. Next, the investigators tested whether FOXO1 regulates EC metabolism. They found that forced activation of FOXO1 inhibited glycolysis in ECs. They also found that FOXO1 suppressed the expression of Myc, a transcription factor that controls the expression of several genes involved in glycolysis. Importantly, restoration of Myc expression in FOXO1-active ECs normalized EC growth and metabolism. This study adds to our understanding of the regulation and role of metabolism in ECs. Interestingly, mutations in PIK3CA cause several different vascular anomalies. Importantly, these mutations lead to the activation of the PI3K/AKT pathway. In the future, it will be interesting to determine the effect of PIK3CA mutations on FOXO1 activity and EC metabolism in vascular anomalies. This may yield new therapeutic strategies to treat vascular anomalies caused by mutations that activate the PI3K/AKT pathway.
-Michael Dellinger, PhD/Francine Blei, MD

*Also see Martin-Almedina S et al in Lymphatic Disorders


Beijnen UE, Maclellan RA, Goss JA, Couto JA, Konczyk DJ, Greene AK.
Beckwith-Wiedemann Syndrome and Primary Lymphedema of the Lower Extremity.
Pediatr Dermatol. 2016 Oct 25. [Epub ahead of print]

Bjorklund, KA; Billmire, DA
Mandibular Body Resection and Setback for Severe Malocclusion in Lymphatic Malformations.
Journal of Craniofacial Surgery. 27(3):724-726, May 2016.

Defnet AM, Bagrodia N, Hernandez SL, Gwilliam N, Kandel JJ.
Pediatric lymphatic malformations: evolving understanding and therapeutic options.
Pediatr Surg Int. 2016 May;32(5):425-33. Epub 2016 Jan 27. Review.

Efe N; Altas E; Mazlumoglu MR; Aktan B; Ucuncu H; Eren S; Oner F.
Excellent Result With the Use of Single-Dose OK-432 in Cervical Macrocystic Lymphangioma.
Journal of Craniofacial Surgery. 27(7):1802-1803, October 2016.

Gardenier JC, Hespe GE, Kataru RP, Savetsky IL, Torrisi JS, Nores GD, Dayan JJ, Chang D, Zampell J, Martínez-Corral I, Ortega S, Mehrara BJ.
Diphtheria toxin-mediated ablation of lymphatic endothelial cells results in progressive lymphedema.
JCI Insight. 2016 Sep 22;1(15):e84095.

Commentary: Several animal models of secondary lymphedema have been created. However, the swelling observed in these models typically resolves overtime. The objective of this study was to develop and characterize a novel mouse model of chronic lymphedema. To attain this objective, the investigators generated mice that express the diphtheria toxin receptor (DTR) in their lymphatic endothelial cells (LECs). Diphtheria toxin (DT) triggered the destruction of lymphatic vessels and the deposition of collagen and adipose tissue in the limbs of DTR-positive mice. Importantly, DT-treated mice developed chronic lymphedema. Although lymphatic vessels regenerated in DT-treated mice, they were structurally and functionally abnormal. CD4+ T cells were found to accumulate in lymphedematous limbs of DT-treated mice. Interestingly, depletion of CD4+ T cells improved lymphatic function and reduced the swelling of affected limbs in DT-treated mice. These data suggest that the inflammatory changes that occur after lymphatic injury contribute to the pathophysiology of lymphedema. This study adds to our knowledge of the pathophysiology of secondary lymphedema. Additionally, the novel research tool described in this manuscript could be used to test new therapies for secondary lymphedema.
-Michael Dellinger, PhD/Francine Blei, MD

Inoue M, Nakatsuka S, Yashiro H, Tamura M, Suyama Y, Tsukada J, Ito N, Oguro S, Jinzaki M.
Lymphatic Intervention for Various Types of Lymphorrhea: Access and Treatment.
Radiographics. 2016 Nov-Dec;36(7):2199-2211.

Commentary: Inoue and colleagues present a concise review of lymphatic imaging and intervention for various types of lymphorrhea manifesting as chylothorax and chylous ascites related to leak or injury to either the thoracic duct (TD), aortoiliac lymphatic system or hepatic lymphatics.  This article provides a review of the anatomic variations of the TD and cisterna chyli, anatomy of the hepatic lymphatics, techniques of lymphatic imaging (lymphoscintigraphy, MR lymphangiography, intranodal and transhepatic lymphangiography), techniques for accessing the lymphatics and treatment strategies for lymphorrhea.  Following demonstration of the source of chyle or lymph leak, the authors outline several previously published techniques for addressing leak including trans-abdominal cannulation of the cisterna chyli or thoracic duct followed by embolization of leak with NBCA glue, retrograde cannulation of the ostium of the thoracic duct from the lymphovenous connection in the neck followed by embolization, direct percutaneous  access of site of leak followed by glue embolization, percutaneous drainage followed by sclerotherapy or hepatic lymphangiography followed by embolization using liquid embolic system (Onyx). This paper offers a nice overview of the lymphatic system, with illustrations and a summary of several previously published observations and techniques for treatment of these challenging disorders.
- Ann Illis, MD/Gulraiz Chaudry, MD

Itkin M, McCormack FX.
Nonmalignant Adult Thoracic Lymphatic Disorders.
Clin Chest Med. 2016 Sep;37(3):409-20.

Commentary: Excellent review from anatomy to genetics with clarifying nomenclature describing accurately physiopathology, diagnosis and current therapeutic options in the management of thoracic lymphatic anomalies. It includes recent discoveries in thoracic lymphatic malformations, lymphangioleiomyomatosis, GLA and GSD, KLA, chyloptysis and plastic bronchitis and yellow nail syndrome.  The article suggests the inclusion of two terms in the ISSVA classification: Primary pulmonary Lymphatic anomaly and Fatal neonatal lymphangiectasia.
-Israel Fernandez-Pineda, MD/ Juan Carlos Lopez Guttierez, MD, PhD

Kim SH, Kim HY, Lee C, Min HS, Jung SE.
Clinical features of mesenteric lymphatic malformation in children.
J Pediatr Surg. 2016 Apr;51(4):582-7. Epub 2015 Dec 9.

Martin-Almedina S, Martinez-Corral I, Holdhus R, Vicente A, Fotiou E, Lin S, Petersen K, Simpson MA, Hoischen A, Gilissen C, Jeffery H, Atton G, Karapouliou C, Brice G, Gordon K, Wiseman JW, Wedin M, Rockson SG, Jeffery S, Mortimer PS, Snyder MP, Berland S, Mansour S, Makinen T, Ostergaard P.
EPHB4 kinase-inactivating mutations cause autosomal dominant lymphatic-related hydrops fetalis.
J Clin Invest. 2016 Aug 1;126(8):3080-8.

Mori M, Dictor M, Brodszki N, López-Gutiérrez JC, Beato M, Erjefält JS, Eklund EA.
Pulmonary and pleural lymphatic endothelial cells from pediatric, but not adult, patients with Gorham-Stout disease and generalized lymphatic anomaly, show a high proliferation rate.
Orphanet J Rare Dis. 2016 May 18;11(1):67.

Nozawa A, Ozeki M, Kuze B, Asano T, Matsuoka K, Fukao T.
Gorham–Stout Disease of the Skull Base with Hearing Loss: Dramatic Recovery and Antiangiogenic Therapy.
Pediatr Blood Cancer. 2016 May; 63(5):931-4

O TM, Lou MS, Ma Y.
Zinc effect on human lymphatic malformation cells in vitro.
Int J Pediatr Otorhinolaryngol. 2016 Jan;80:33-8.

Commentary: These authors created an in vivo assay of lymphatic malformation cells and then tested zinc. Zinc has an apparent morphological effect on lymphatic malformation cells in vitro. Compared with other cell types, LM cells have a lower tolerance to zinc. This could have potential therapeutic implications but more studies are needed.
-Kristina W. Rosbe, MD

Ozeki M, Fujino A, Matsuoka K, Nosaka S, Kuroda T, Fukao T.
Clinical Features and Prognosis of Generalized Lymphatic Anomaly, Kaposiform Lymphangiomatosis, and Gorham–Stout Disease.
Pediatr Blood Cancer. 2016 May; 63(5):832-8.

Commentary: This is the largest reported series of complex lymphatic anomalies to date. It includes 35 Generalized Lymphatic Anomalies (GLA), 9 Kaposiform Lymphangiomatosis (KLA) and 41 Gorham-Stout Disease (GSD) cases. A few interesting features of the described population: 83.5% had pathological confirmation of the diagnosis, 18 patients were diagnosed <1 year old (most of them with GLA) and >80% of the total had clinical manifestations and were diagnosed in the first 2 decades of life. Low fat and medium chain triglyceride diet had no effect in the population. Overall, the mortality rate was 20% with the highest etiology being respiratory complications. All patients without thoracic involvement were alive at the time of report. GSD had a significantly better prognosis than GLA and KLA, while KLA had the highest mortality rate.
-Ionela Iocobas, MD/ Denise Adams, MD

Vlahovic A, Gazikalovic A, Adjic O.
Bleomycin sclerotherapy for lymphatic malformation after unsuccessful surgical excision: case report.
Acta Otorhinolaryngol Ital. 2015 Oct;35(5):365-7.

Commentary: The authors describe a case report of a facial lymphatic malformation with deep parapharyngeal component unsuccessfully resected four times with subsequent facial nerve paralysis. Sclerotherapy of the residual macrocysts with bleomycin achieved radiologic and clinical complete response.
-Kristina W. Rosbe, MD


Ali S, Weiss CR, Sinha A, Eng J, Mitchell SE.
The treatment of venous malformations with percutaneous sclerotherapy at a single academic medical center.
Phlebology. 2016 Oct;31(9):603-9.

Almesberger D; Manna F; Guarneri GF; Marchesi A; Parodi PC.
Arterio-Venous Malformations of the Nose: Combined Approach for a Successful Strategy.
Journal of Craniofacial Surgery. 27(6):1524-1526, September 2016.

Aronniemi J, Lohi J, Salminen P, Vuola P, Lappalainen K, Pitkäranta A, Pekkola J.
Angiomatosis of soft tissue as an important differential diagnosis for intramuscular venous malformations.
Phlebology. 2016 Sep 29. pii: 0268355516671463. [Epub ahead of print]

Azene E, Mitchell S, Radvany M, Agrawal N, Eisele D, Weiss C.
Foamed bleomycin sclerosis of airway venous malformations: The role of interspecialty collaboration.
Laryngoscope. 2016 Dec;126(12):2726-2732.

Commentary: This article reviews multidisciplinary treatment of 16 airway venous malformations. Sclerotherapy was performed with endoscopic airway guidance in 31% of the patients. The authors also note that ethanol was associated with a high rate of airway edema (7/8 versus Bleomycin (0/8) despite equivalent efficacy and that Bleomycin might be preferable to avoid complications of airway edema including prolonged intubation and overall hospital stay.
-Kristina W. Rosbe, MD

Chun R, Jabbour N, Balakrishnan K, Bauman N, Darrow DH, Elluru R, Grimmer JF, Perkins J, Richter G, Shin J.
Education on, Exposure to, and Management of Vascular Anomalies During Otolaryngology Residency and Pediatric Otolaryngology Fellowship.
JAMA Otolaryngol Head Neck Surg. 2016 Jul 1;142(7):648-51.

Couto JA; Maclellan RA; Greene AK
Management of Vascular Anomalies and Related Conditions Using Suction-Assisted Tissue Removal.
Plastic & Reconstructive Surgery. 136(4):511e-514e, October 2015.

Fowell C, Verea Linares C, Jones R, Nishikawa H, Monaghan A
Venous malformations of the head and neck: current concepts in management.
Br J Oral Maxillofac Surg. 2016 Nov 25. [Epub ahead of print] Review.

Commentary: This review provides a nice overview of current diagnosis and treatment of venous malformations. The authors emphasize a multidisciplinary approach and that treatment should be based on symptoms. They favor ultrasound or MRI as diagnostic study of choice and identification of phleboliths is pathognomonic for venous malformations. They discuss multiple therapeutic options including compression, anticoagulation agents, sclerotherapy, laser, and surgery. They review current sclerotherapy agents but mention that there are no current outcome studies declaring a superlative agent.
-Kristina W. Rosbe, MD

Harmoush S, Chinnadurai P, El Salek K, Metwalli Z, Herce H, Bhatt A, Steinkuller P, Vece T, Siddiqui S, Pimpalwar A, Marx D, Mawad M, Pimpalwar S.
Multimodality Image-Guided Sclerotherapy of Low-Flow Orbital Vascular Malformations: Report of Single-Center Experience.
J Vasc Interv Radiol. 2016 Jul;27(7):987-995.e4

Horbach, SE, Rigter, IM, Smitt, JH, Reekers, JA.; Spuls, PI, van der Horst, CM.
Intralesional Bleomycin Injections for Vascular Malformations: A Systematic Review and Meta-Analysis.
Plastic & Reconstructive Surgery. 137(1):244-256, January 2016.

Jafarian M, Dehghani N, Shams S, Esmaeelinejad M, Aghdashi F.
Comprehensive Treatment of Upper Lip Arteriovenous Malformation.
J Maxillofac Oral Surg. 2016 Sep;15(3):394-399.

Kulungowski AM, Hassanein AH, Foster CC, Greene AK, Fishman SJ.
Bevacizumab and interferon reduce venous recanalization following sclerotherapy.
J Pediatr Surg. 2016 Oct;51(10):1670-3.

Kim J, Sun Z, Leraas HJ, Nag UP, Benrashid E, Allori AC, Pabon-Ramos WM, Rice HE, Shortell CK, Tracy ET.
Morbidity and healthcare costs of vascular anomalies: a national study.
Pediatr Surg Int. 2016 Nov 22. [Epub ahead of print]

Kolokythas A.
Vascular Malformations and Their Treatment in the Growing Patient.
Oral Maxillofac Surg Clin North Am. 2016 Feb;28(1):91-104.

Commentary: Basic review of vascular anomalies including preferred diagnostic and therapeutic options based on areas of involvement and symptoms. Good to have this in the OMF literature since this specialty is not always part of multidisciplinary vascular anomalies centers but are asked to care for these patients and so it is important for them to understand the risks of bleeding, etc when operating near these lesions as well as expected progression and impact on maxillofacial growth and function.
-Kristina W. Rosbe, MD

Noguera-Morel L, Stein SL, Xirotagaros G, Hernández-Martín A, de Prada I, Frieden IJ, Requena L, Torrelo A.
Net-like superficial vascular malformation: clinical description and evidence for lymphatic origin.
Br J Dermatol 2016 Jul 175(1) 191-3.

Commentary: 3 cases presented large lesions irregularly shaped, angulated bright red to brown or purple patches with a finely reticulated pattern of net-like or arborizing vascular structures. The lesions started during infancy and progressed. Histology showed dilated vessels in the upper dermis without abnormal lesions of the deep dermis and subcutaneous tissue. Immunochemistry demonstrated positivity for the lymphatic marker podoplanin (D2 40) in the cells lining the dialted vessels. This malformation is clinically and histologically different from other superficial LM such as  hobnail hemangioma and angiokeratoma, and also different from verrucous hemangioma which is nonlymphatic anomaly.  The term of Lymphatic net-like malformation is proposed.
-Anne Dompmartin, MD

O'Mara DM, DiCamillo PA, Gilson WD, Herzka DA, Wacker FK, Lewin JS, Weiss CR.
MR-guided percutaneous sclerotherapy of low-flow vascular malformations: Clinical experience using a 1.5 tesla MR system.
J Magn Reson Imaging. 2016 Oct 31.

Salloum R, Fox CE, Alvarez-Allende CR, Hammill AM, Dasgupta R, Dickie BH, Mobberley-Schuman P, Wentzel MS, Chute C, Kaul A, Patel M, Merrow AC, Gupta A, Whitworth JR, Adams DM.
Response of Blue Rubber Bleb Nevus Syndrome to Sirolimus Treatment.
Pediatr Blood Cancer. 2016 Nov; 63(11):1911-4.

Commentary: The study presents four pediatric cases of Blue Rubber Bleb Nevus Syndrome (BRBNS) that were treated for more than 4 years with sirolimus orally after failing various other treatment modalities.  All patients had improvement in quality of life, became transfusion independent, had reduction in pain and stabilization in the size of the lesions. Recently there have been a few case reports of BRBNS responding well to sirolimus therapy.  This paper emphasizes the combination of venous and lymphatic elements in BRBNS, uses standardized definition of toxicity (Common Terminology Criteria for Adverse Events) and describes safe long-term use of sirolimus during childhood and adolescence in BRBNS.
-Ionela Iocobas, MD/Denise Adams, MD

Sohail M, Bashir MM, Ansari HH, Khan FA, Assumame N, Awan NU, Chatha AA.
Outcome of Management of Vascular Malformations of Lip.
J Craniofac Surg. 2016 Sep;27(6):e520-4.

Commentary: This is a study reviewing the outcomes of 38 lip vascular malformations. In this series, the lower lip was involved in 70% patients with 95% had difficulty in eating and 87% abnormal speech.  Referring diagnosis was incorrect in 35% patients. Twenty-one percent were high and 79% low-flow malformations (29% venous, 16% capillary, and 34% combined. The authors conclude that surgical debulking with adjuvant therapies including sclerotherapy or laser resulting in 95% of their patients satisfied with functional and cosmetic outcomes. 36/38 of the surgical sites were able to be closed primarily. Embolization was not required for the high flow lesions.
-Kristina W. Rosbe, MD

Triana P, Dore M, Cerezo VN, Cervantes M, Sánchez AV, Ferrero MM, González MD, Lopez-Gutierrez JC.
Sirolimus in the Treatment of Vascular Anomalies.
Eur J Pediatr Surg. 2016 Oct 10.

Wei T, Zhang H, Cetin N, Miller E, Moak T, Suen JY, Richter GT.
Elevated Expression of Matrix Metalloproteinase-9 not Matrix Metalloproteinase-2 Contributes to Progression of Extracranial Arteriovenous Malformation.
Sci Rep. 2016 Apr 14;6:24378.

Commentary: The authors demonstrated an increased levels of matrix metalloprotein-9 in patient serum as well as protein and RNA expression in AVM tissue compared to controls. They speculate that MMP-9 contributes to the formation of AVMs, and inhibitors of their protein

Wieck MM, Nowicki D, Schall KA, Zeinati C, Howell LK, Anselmo M.
Management of pediatric intramuscular venous malformations.
J Pediatr Surg. 2016 Sep 1. pii: S0022-3468(16)30295-0. [Epub ahead of print]

Zhao XP, Huang ZQ, Chen WL, Wang YY, Lin ZY.
Percutaneous sclerotherapy of arteriovenous of the face using fibrin glue combined with OK-432 and bleomycin after embolisation.
Br J Oral Maxillofac Surg. 2016 Feb;54(2):187-91.

Zhu JY, Ren JG, Zhang W, Wang FQ, Cai Y, Zhao JH, Chen G, Zhao YF.
Characterization of microparticles in patients with venous malformations of the head and neck.
Oral Dis. 2016 Sep 26. [Epub ahead of print]

Commentary: These authors discuss the potential utility of detection of microparticles (MP) for diagnosis and prognosis in venous malformations. Microparticles are 0.1- to 1-lm membrane- enclosed vesicles released from various cell types, including platelets, monocytes, endothelial cells, and erythrocytes. They are generated by budding of the plasma membrane during cellular activation or apoptosis in vitro and in vivo. MP can selectively inherit contents of parental cells, including surface receptors, cytosolic proteins, mRNA, and microRNA (miRNA), thus representing a miniature version of the MP-originating cells. This study found that circulating levels of total MP, platelet-derived MP, and endothelial MP were significantly elevated in VM patients and were consistently increased in VM patients with more extensive lesions.
-Kristina W. Rosbe, MD


Castrén E, Salminen P, Vikkula M, Pitkäranta A, Klockars T.
Inheritance Patterns of Infantile Hemangioma
Pediatrics. 2016 Nov 1; 138(5).

Commentary: This study used interviews with 40 IH index patients and their families to generate pedigrees to elucidate the inheritance patterns of IH. The study adds new evidence that IH may show an autosomal dominant inheritance pattern with incomplete penetrance as well as a possible maternal or mitochondrial inheritance pattern. This information adds more clarity to the existing evidence on positive family history being a risk factor for IH.
-Karthik Balakrishnan, MD/Jonathan Perkins, DO

Fernandez-Pineda I, Jenkins JJ, Santiago TC, Prajapati HJ, Pappo AS.
Awareness of intramuscular capillary type hemangioma in the differential diagnosis of soft-tissue tumors in children.
Pediatr Blood Cancer. 2016 Dec; 63(12):2252-2253.

Fowell C, Monaghan A, Nishikawa H.
Infantile haemangiomas of the head and neck: current concepts in management.
Br J Oral Maxillofac Surg. 2016 Jun;54(5):488-95.

Commentary: This is a good review article on infantile hemangiomas including a good cartoon of the classification system, description of the typical clinical course, discussion of Glut-1, and current state-of-the-art medical therapy including propranolol and timolol. Also discusses potential new therapies being investigated such as anti-VEGF antibody therapy.
-Kristina W. Rosbe, MD

Garzon MC, Epstein LG, Heyer GL, Frommelt PC, Orbach DB, Baylis AL, Blei FBurrows PEChamlin SL, Chun RH, Hess CP, Joachim S, Johnson K, Kim W, Liang MG, Maheshwari M, McCoy GN, Metry DW, Monrad PA, Pope E, Powell J, Shwayder TA, Siegel DHTollefson MM, Vadivelu S, Lew SM, Frieden IJ, Drolet BA.
PHACE Syndrome: Consensus-Derived Diagnosis and Care Recommendations.
J Pediatr. 2016 Nov;178:24-33.e2. Epub 2016 Sep 19.

Commentary: This manuscript reflects the efforts of a multidisciplinary group of physicians expert in PHACE Syndrome, providing updated consensus-derived guidelines for diagnosis, screening, risk stratification, and monitoring of patients with PHACE Syndrome. The resultant algorithm is helpful for health care providers as well as families of patients with PHACE Syndrome. Possible long-term sequelae such as hearing, speech, development, and psychosocial issues are also discussed.
-Michael Dellinger, PhD/Francine Blei, MD

Goldenberg DC; Hiraki PY; Marques TM; Koga A; Gemperli R
Surgical Treatment of Facial Infantile Hemangiomas: An Analysis Based on Tumor Characteristics and Outcomes.
Plastic & Reconstructive Surgery. 137(4):1221-1231, April 2016.
With Expert Discussion, PRS Journal Club Article, 2 Letters to Editor and Reply

Commentary: Surgical management of 74 patients with infantile hemangiomas was evaluated with a mean of 33 months of follow-up. Indications for treatment and an algorithm based on clinical features is presented. Phase, location, clinical conditions, reasons for surgical indication, surgical access and type of resection were the parameters considered for each type of approach. Anatomic location, extension and depth were also considered. From all possible locations, surgery was a real option for cervicofacial hemangiomas. Besides emergency indications, in cases with growth-related deformities removal of the tumor potentially allowed adequate facial development. The judicious selection of access, type of resection and reconstruction method was fundamental for obtaining the best scar. In summary, A clinical profile of candidates for surgery was defined: under elective circumstances, patients with proliferative localized eyelid, nasal, or lip hemangiomas with growth-related deformities are the best candidates for total resection under the direct (superficial or mixed infantile hemangiomas) or indirect (deep infantile hemangiomas) approach. For patients treated on an emergency basis, the best candidates are those non-responders to pharmacologic therapy presenting complications, with segmental lesions, treated by partial resection under a direct approach.
-Dov Goldenberg, MD

Granell J; Alonso A; Garrido L; Gutierrez-Fonseca R
Transoral Fully Robotic Dissection of a Parapharyngeal Hemangioma.
Journal of Craniofacial Surgery. 27(7):1806-1807, October 2016.

He A, Zampella JG, Kwatra SG.
Genotyping for CYP2D6 in Patients with Infantile Hemangiomas Refractory to Topical Timolol.
Pediatr Dermatol. 2016 Nov;33(6):686.

Léaute-Labrèze C, Boccara O, Degrugillier-Chopinet C, Mazereeuw-Hautier J, Prey S, Lebbé G, Gautier S, Ortis V, Lafon M, Montagne A, Delarue A, Voisard JJ.
Safety of Oral Propranolol for the Treatment of Infantile Hemangioma: A Systematic Review.
Pediatrics. 2016 Sep 29. [Epub ahead of print]

Commentary: Systematic reviews and other very high-level evidence are generally lacking in vascular anomalies. This study provides the highest-level evidence available on adverse effects on oral propranolol used for IH therapy. 83 studies were included, covering 3766 patients. Included studies were heterogeneous in design and dosing regimens, limiting pooling of data, and nearly 10% of included patients were from manufacturer’s studies.
-Karthik Balakrishnan, MD/Jonathan Perkins, DO

Li G; Xu D-P; Tong S; Xue L; Sun N-N; Wang X-K
Oral Propranolol with Topical Timolol Maleate Therapy for Mixed Infantile Hemangiomas in Oral and Maxillofacial Regions.
Journal of Craniofacial Surgery. 27(1):56-60, January 2016.

Li K, Wang Z, Liu Y, Yao W, Gong Y, Xiao X.
Fine clinical differences between patients with multifocal and diffuse hepatic hemangiomas.
J Pediatr Surg. 2016 Sep 16. pii: S0022-3468(16)30368-2.

Liang B, Zhan Y, Huang X, Gu E, Dai D, Cai J, Hu G.
Effect of 22 Novel Cytochrome P450 2D6 (CYP2D6) Variants Found in the Chinese Population on Hemangeol Metabolism In Vitro.
Eur J Drug Metab Pharmacokinet. 2016 Dec;41(6):759-765.

Ma EH, Robertson SJ, Chow CW, Bekhor PS.
Infantile Hemangioma with Minimal or Arrested Growth: Further Observations on Clinical and Histopathologic Findings of this Unique but Underrecognized Entity.
Pediatr Dermatol. 2016 Nov 22. [Epub ahead of print]

Commentary: “Abortive” hemangiomas, “infantile hemangioma with minimal or arrested growth (IH-MAG)” have been recognized for at least a decade. In this manuscript, five cased that were biopsied demonstrated GLUT-1 positivity. As the clinical course varies from congenital hemangiomas and typical hemangiomas of infancy, it is important to recognize the features of this unique subtype, marked by “telangiectasia, venules, and matte erythema with light and dark areas”, which resolved without intervention.
-Michael Dellinger, PhD/Francine Blei, MD

MacIsaac ZM; Nayar HS; Gehris R; Mehta D; Geisler S; Grunwaldt LJ
Treatment for Infantile Hemangiomas: Selection Criteria, Safety, and Outcomes Using Oral Propranolol During the Early Phase of Propranolol Use for Hemangiomas.
Journal of Craniofacial Surgery. 27(1):159-162, January 2016.

Mamlouk MD, Yu JP, Asch S, Mathes EF
PHACE syndrome and congenitally absent thyroid gland at MR imaging.
Clin Imaging. 2016 Mar-Apr;40(2):237-40.

Ng ZY; Kang GC-W; Chang C-S; Por YC
Efficacy of Topical Timolol as Primary Monotherapy in Cutaneous Facial Infantile Hemangiomas.
Journal of Craniofacial Surgery. 27(6):e516-e520, September 2016.

Phillips, JD, Zhang, H, Wei, Richter, GT.
Expression of β-Adrenergic Receptor Subtypes in Proliferative, Involuted, and Propranolol-Responsive Infantile Hemangiomas.
JAMA Facial Plast Surg. 2016. [Epub ahead of print]

Püttgen K, Lucky A, Adams D, Pope E, McCuaig C, Powell J, Feigenbaum D, Savva Y, Baselga E, Holland K, Drolet B, Siegel D, Morel KD, Garzon MC, Mathes E, Lauren C, Nopper A, Horii K, Newell B, Song W, Frieden I. Hemangioma Investigator Group.
Topical Timolol Maleate Treatment of Infantile Hemangiomas.
Pediatrics. 2016 Sep;138(3).

Reimer A, Hoeger PH.
Lesion Morphology in Multifocal Infantile Hemangiomas.
Pediatr Dermatol. 2016 Nov;33(6):621-626.

Commentary: This is a retrospective review of 103 infants with multifocal infantile hemangiomas (MIH) and compared them with 261 age-matched control infants with standard isolated focal hemangiomas (IH) Infants with multifocal hemangiomas had either small military lesions (MIH), larger irregular lesions, NMIH) or a combination of the 2 types. There was an inverse relationship between hemangioma size and number, and premature infants were more likely to have the multifocal infantile hemangioma (MIH) subtype. The cutaneous distribution of hemangiomas was mapped and correlated with clinical morbidity.  The authors propose there may be distinctive etiopathologies amongst the hemangioma subtypes, and the authors suggest incorporating hemangioma morphology be considered in identifying patients with increased morbidity from hemangioma-related complications (e.g. gastrointestinal bleeding and/or hepatic involvement).
-Michael Dellinger, PhD/Francine Blei, MD

Reimer A, Fliesser M, Hoeger PH.
Anatomical patterns of infantile hemangioma (IH) of the extremities (IHE).
J Am Acad Dermatol. 2016 Sep;75(3):556-63. Epub 2016 Apr 22.

Commentary: These authors performed a retrospective study, and mapped the anatomic distribution of hemangiomas of infancy affecting the extremities. The study was restricted to segmental hemangiomas and hemangiomas with minimal or arrested growth. 107 cases are subdivided into 22 categories, with photographs, anatomic descriptions, segmental vs IH-MAG type, and correlation with the underlying arterial anatomy of the respective extremity. The patterns of distribution appeared to correlate with embryologic arterial anatomy, and the authors postulate this may lead to focal tissue hypoxia, which triggers hemangioma stem cell growth.
-Michael Dellinger, PhD/Francine Blei, MD

Robertson SA, Kimble RM, Storey KJ, Gee Kee EL, Stockton KA.
3D photography is a reliable method of measuring infantile haemangioma volume over time.
J Pediatr Surg. 2016 Sep;51(9):1552-6. Epub 2016 Apr 23.


Duarte AF, Valera E, Chahud F and Velasco Cruz AA.
Infantile Primary Orbital Angiosarcoma.
Pediatr Blood Cancer. 2016 Apr; 63(4):752-3.

Swaika A and Jiang L.
Metastatic epithelioid angiosarcoma with bone marrow involvement.
Blood 2016; 127:1728.