Volume 24 Number 9| September 2018| Dermatology Online Journal || Review 24(9): 1 Infantile hemangiomas: our current understanding and treatment options Yssra S Soliman1 BA, Amor Khachemoune2,3 MD Affiliations: 1Albert Einstein College of Medicine, Bronx, New York, USA, 2State University of New York Downstate, Department of Dermatology, Brooklyn, New York, USA 3Veterans Health Administration, Department of Dermatology, Brooklyn, New York, USA Corresponding Author: Amor Khachemoune MD, FAAD, FACMS, Veterans Affairs Hospital & SUNY Downstate, Dermatology Service, 800 Poly Place, Brooklyn, NY 11209, Tel: 718-630-3725, Fax: 718-630-2881, Email: [email protected] or in visceral organs. Classically, the hemangiomas Abstract display rapid growth during the third month of life, Infantile hemangioma (IH) is the most common followed by slow involution [4]. By 48 months, vascular tumor of infancy, affecting up to 10% of all approximately 90% of cases will have regressed [5]. infants. Our understanding of IH and its management has greatly evolved. The etiology of IH is unclear but This article aims to review the epidemiology, clinical hypoxia is thought to play a key role. Furthermore, presentation, genetics, histopathology, associated GLUT1, IGF2, and HIF-1- syndromes, evolution without treatment, and important mediators. Current management options treatment options of infantile hemangioma. The include active observation, medical treatment, and primary database used was PubMed. We searched surgical intervention. The goals of treatment are , preventing cosmetic disfiguration, psychosocial , distress, and life-threatening complications. Infantile hemangioma should be managed with an individual, f patient-centered approach. Generally, uncompli- -1- cated IH can be observed up to 18 months. However, IH should be treated in the setting of bleeding, Historical note and evolving classification ulceration, functional compromise, or eventual Infantile hemangioma has been reported in the failure to regress. literature under a variety of names including strawberry nevus, capillary hemangioma, juvenile Keywords: infantile hemangioma, ISSVA, GLUT1, Table 1. Abbreviations. angiogenesis, propranolol GLUT1 Glucose Transporter 1 Abbreviations are listed in Table 1. IGF-2 Insulin-like growth factor 2 HIF-1- Hypoxia-inducible factor 1-alpha Introduction IH Infantile hemangioma Infantile hemangioma (IH) is the most common IH-MAG Infantile hemangioma minimal arrested vascular tumor of infancy. It is believed to occur in up growth to 10% of infants [1]. It is a benign, clinically ISSVA International Society for the Study of Vascular Anomalies heterogeneous vascular tumor [2]. Infantile EPC Endothelial Progenitor Cells hemangioma often appears by the second week of KMP Kasabach-Merrit Phenomenon life [3]. However, deeper hemangiomas may not be PG Pyogenic granulomas apparent to the eye until the 2nd to 4th month of life. PDL Pulsed Dye Laser Infantile hemangiomas commonly appear on the RICH Rapidly involuting congenital hemangioma head and neck but may appear anywhere on the skin NICH Non-involution congenital hemangioma - 1 - Volume 24 Number 9| September 2018| Dermatology Online Journal || Review 24(9): 1 hemangioma, and strawberry mark [6]. The term abortive growth, and even livedoid infantile hemangioma [14-17]. Bessis et al. proposed using by Patterson [7, 8]. However, it was Lister who first set reticular infantile hemangioma with minimal out to characterize them in a more specific manner. arrested growth (RIH-MAG) to emphasize the The lesions were common in infants but not in reticular morphology when discussing infantile adolescents or adults. He differentiated the growths hemangiomas that display minimal proliferation. based on depth into bright-red superficial lesions, RIH-MAG is significant in the literature owing to blue-tinged deep lesions, and mixed lesions with possible association with lipoatrophy [14]. central, superficial vasculature surrounded by a Epidemiology deeper base. The incidence of IH is believed to be between 4-10% Eighty-eight years later, Mulliken and Glowacki set to [18, 19]. It is difficult to determine the exact incidence differentiate IH from vascular malformations [9]. because of differing nomenclature [18]. They noted that the variety of nomenclature led to Furthermore, IH does not appear immediately at confusion among clinicians. For example, capillary birth, leading to misdiagnosis and under diagnosis. hemangioma was used interchangeably to refer to Several risk factors have been identified for IH both IH and non-regressive port-wine stains. including female sex and Caucasian race [18, 19]. Vascular tumors including IH differ from vascular Females have between a 3:1 to 5:1 increased risk of malformations based on pathophysiology. Simply, IH IH [18]. There is debate in the literature about are believed to be the product of increased whether family history is a true risk factor for IH. angiogenesis leading to proliferation of endothelial Some authors associate family history with a recall components [9]. Vascular malformations, including bias [19]. Others have identified potential genes port wine stains, are believed to be related to inherited on chromosome 5q [20]. It is unclear impaired innervation leading to poor, tortuous whether infants of mothers who underwent vessel tone [10]. transcervical chorionic villus sampling have a higher Mulliken and Glowacki differentiated IH based on risk of IH [21, 22]. two distinct histological phases [9]. The rapid, Etiology proliferating phase was defined by increased The etiology of IH is still being studied. However, endothelial hyperplasia. The slower, involuting several theories have been proposed. It has been phase was defined by fibrosis and fatty deposition. In speculated that hypoxia plays a key role [23]. Studies 1997, their findings were adopted by the have shown that prematurity, multiple gestations, International Society for the Study of Vascular Anomalies (ISSVA) and the nomenclature Table 2. Infantile Hemangioma Classifications. standardized [11]. The ISSVA classification was recently updated in 2014 [12]. Today, IH is Morphology considered a benign vascular tumor and classified Focal based on pattern, depth, association with other Multifocal lesions, and identified using immunohistochemical Segmental markers (Table 2). Indeterminate Depth Pattern is described as focal, multifocal, segmental, Superficial or indeterminate pattern. Types of IH are defined by depth such as superficial, deep, mixed, or Deep reticular/abortive/minimal growth. It is interesting to Mixed Reticular/abortive/minimal growth in 2007 [13]. Previous nomenclature included Immunohistochemical Markers -wine stain-like GLUT1 IGF-2 - 2 - Volume 24 Number 9| September 2018| Dermatology Online Journal || Review 24(9): 1 advanced maternal age, and, especially, low birth IGF-2 has been shown to increase levels of GLUT1 weight less than 1500 grams are risk factors for IH. expression. Further investigation is needed to Placental insufficiency is a known cause of low birth understand the exact roles of GLUT1 and IGF-2 in the weight. It is believed that an increase in angiogenic pathogenesis of IH. factors, such as HIF-1- xia in Emerging genetics utero leads to compensating, proliferating Most IH occurs sporadically. However, Walter et al. hemangiomas [23, 24]. attempted to delineate genetic factors by studying Histology and markers several families with seemingly autosomal dominant The histological characteristics of IH can be divided inheritance of IH [20]. They identified a possible into that of the proliferative versus involuting phase linkage to 5q31-33. This region corresponds to the [9]. The proliferative phase is characterized by following genes thought to contribute to increased endothelial cell activity and formation of angiogenesis: fibroblast growth factor receptor-4 syncytial masses lacking distinct vascular (FGFR4), platelet-derived growth factor receptor- architecture, especially decreased capillary lumina. beta (PDGRFB), and FMS-related tyrosine kinase-4 Then, laminated basement membranes are seen (FLT4). under endothelium. In the involuting phase, In one study, one-third of infants with large cellularity decreases while fatty deposits and fibrous segmental hemangiomas of the head and neck were tissue become evident. Hemangiomas that do not found to have posterior fossa malformations- completely regress show endothelial proliferation hemangioma-arterial anomalies-sternal cleft and intermingled with fibro-fatty infiltration. supraumbilical raphe (PHACE) syndrome and over One study aimed to understand whether mediators 90% had an accompanying cerebrovascular of endothelial progenitor cells (EPC) are increased abnormality (Table 3), [30]. The segmental during the proliferative phase of IH [24]. Specimens hemangioma may occur on the same side as the were obtained from patients with proliferating cerebrovascular abnormality [31]. Drolet and Frieden hemangiomas. Hypoxia induced factors, essential to postulate that the primary defect in PHACE post-natal angiogenesis, were measured. VEGF-A syndrome may relate to abnormal arterial and MMP-9 were measured in the blood and SDF-1- development, leading to vascular insufficiency [23]. -9, VEGF-A, and HIF-1- This localized hypoxic reaction may become the tissue sections. All factors were indeed increased in aggravating factor leading to segmental children with proliferating hemangiomas. hemangioma development. This is different from the Furthermore, it was