During the past decade, there have been great advances in the biology, classification, terminology, diagnosis, and treatment of vascular anomalies (VAs). The International Society for the Study of Vascular Anomalies (ISSVA; https://www.issva.org) published the ISSVA classification for VA in 2014 and revised version in 2018, which classifies VA into 2 large categories of vascular tumors and vascular malformations [1-7]. Vascular tumors are defined as vascular neoplasms caused by the proliferation and hyperplasia of abnormal endothelial and other vascular cells, while vascular malformations are defined as congenital developmental disorders consisting of capillary, lymphatic, venous, and arterial vessel formation [2-10]. Vascular tumors feature increased endothelial turnover (mitosis), while vascular malformations do not [3].

Infantile hemangiomas (IHs) are the most common vascular tumor and the most common benign tumor of infancy, developing in 5%–10% of infants [5,8-13]. Pathologically, IHs are glucose transporter-1 protein (GLUT-1)–positive, the expression of which distinguishes them from other vascular tumors or vascular malformations [5,7,8,10,11]. IHs are clinically characterized by a proliferative phase followed by an involutive phase [10,14,15]. Because of the spontaneous involution, most IHs do not require treatment, but about 10% of cases require early treatment due to size, location, and complications [9,11-13]. Since 2015, IH management guidelines have been published in Europe, America, Australia, and Japan [12,13,16-18]. The American Academy of Pediatrics (AAP) published its first clinical practice guideline (CPG) for the management of IHs in 2019, which recommends that pediatricians and other primary care clinicians frequently monitor infants with IHs during the first few weeks and months of life to screen for growth and complications, educate the parents about the clinical course, and refer infants with potentially problematic IHs to IH specialists as early as 1 month of age [11]. Potentially problematic or high-risk IHs include those with life-threatening complications, functional impairment, ulceration, associated structural anomalies, and disfigurement [11-13]. Primary care clinicians are also recommended the referral to IH specialists when the IH diagnosis is uncertain and requires differentiation from other vascular tumors or vascular malformations [9,11,13]. Imaging modalities such as ultrasonography (US) with Doppler, magnetic resonance imaging (MRI), and/or magnetic resonance angiography (MRA) may be used to diagnose IHs and monitor their treatment response [9,11-13]. In Korea, IHs are usually treated by pediatric hematology-oncologists with the cooperation of pediatric cardiologists, radiologists, dermatologists, and plastic surgeons [19-22].

The AAP CPG for the management of IHs recommends oral propranolol, an oral nonselective beta-adrenergic antagonist, as the present gold standard treatment for high-risk IHs at a dosage of 2–3 mg/kg/day divided into 2 daily doses maintained for at least 6 months [11]. This AAP CPG also approves topical timolol maleate, a topical nonselective beta-blocker, for the treatment of some small, thin, superficial IHs at a dose of 1–2 drops of 0.5% gel-forming ophthalmic solution applied twice daily [11]. Pulse-dye laser therapy (PDL) or surgery are recommended for the treatment of residual skin changes after IH involution but may be used earlier to treat selected cases of IHs [9,11,12,16].

The ISSVA classification of VA better explains the terminologies, biology, and clinical characteristics of VA, including vascular tumors and vascular malformations, and is now considered the clinical gold standard for the care of patients with VA [1]. The 2018 ISSVA classification for VA is summarized in Table 1 [1]. Vascular tumors are classified as benign, locally aggressive or borderline, or malignant [1,5]. Benign vascular tumors include IHs, congenital hemangiomas (CHs), tufted hemangioma, spindle-cell hemangioma, epithelioid hemangioma, and pyogenic granuloma (also known as lobular capillary hemangioma). CHs are further classified as rapidly involuting CH (RICH), noninvoluting CH (NICH), and partially involuting CH (PICH) depending on their clinical progression. Locally aggressive or borderline vascular tumors include Kaposiform hemangioendothelioma, other hemangioendotheliomas, and Kaposi sarcoma. Malignant vascular tumors include angiosarcoma and epithelioid hemangioendothelioma. Vascular malformations are classified as simple or combined vascular malformations, of the major vessels, and vascular malformations associated with other anomalies [1,2]. Simple vascular malformations are subgrouped as slow blood flow (capillary, lymphatic, venous malformations [VMs]) or fast blood flow (arteriovenous malformations [AVMs], arteriovenous fistula) depending on the blood flow [1,2].

VA can be associated with hematologic disorders such as thrombocytopenia and/or consumption coagulopathy, some of which cause life-threatening Kasabach-Merritt phenomenon (KMP; the combination of rapidly enlarging hemangioma, thrombocytopenia, microangiopathic hemolytic anemia, and acute or chronic consumption coagulopathy with D-dimer elevation) (Table 2) [1]. Tufted angioma or Kaposiform hemangioendothelioma, rather than IHs, cause KMP and require emergency referral [5,8,23-25].

IH is a benign vascular tumor with abnormally increased proliferation of vascular endothelial cells and aberrant blood vessel architecture [5,11-13,16,26].

IH is the most common vascular tumor and most common benign tumor of infancy, developing in 5% of infants and in up to 10% of Caucasian infants [5,11-13,16,26]. IHs develop more commonly in cases of female infants (female to male ratio, 1.4:1 to 3:1), twins, Caucasians, premature infants, low birth weight infants (up to 30% of infants with a birth weight < 1 kg), multiple pregnancies, increased maternal age, preeclampsia, placental anomalies (placenta previa, placental abruption, abnormal insertion of the umbilical cord), and a family history of IH in a first-degree relative [9,11-13,16,27].

The pathogenesis of IH has not yet been completely defined, and current studies support several hypotheses. The first hypothesis is the somatic mutation of hemangioma stem cells (HemSC) and upregulation of angiogenic vascular endothelial growth factor receptor (VEGFR) signaling. This theory suggests that IH is derived from CD34+/CD133+ endothelial progenitor cells (EPCs) or HemSC, which differentiate into GLUT-1–positive endothelial cells under the influence of mediators of EPCs and vasculogenesis (e.g., VEGF-A, VEGFR-2, and hypoxia-inducible factor [HIF-1α]) [11,13,16,28-30]. Increased VEGF and HIF-1α levels are observed in IH patients [13,27]. The second hypothesis is the placental theory, which suggests that IH is derived from embolized placental cells [13,28,29]. GLUT-1 expression in IHs, placental syncytiotrophoblast microvilli, and placental basement membranes and the clinical characteristics of rapid proliferation followed by gradual involution in IHs, which are similar to placentae, support this placental cell embolization theory [13,28,29]. The third hypothesis is the tissue hypoxia-induced vascular proliferation theory, which suggests that the induction and proliferation of EPCs are stimulated by hypoxic conditions (preterm, low birth weight, increased maternal age, placental anomalies) mediated by HIF-1α [13,28-30]. Tissue hypoxia induces neovascularization and angiogenesis by stimulating the expression of angiogenic factors such as VEGF and basic fibroblast growth factor (bFGF), on EPCs [5,7,11,21,27]. VEGF may be the most potent angiogenic factor involved in the pathogenesis of IH, stimulating endothelial cell proliferation and mobilization through matrix metalloproteinases [27]. The fourth hypothesis is the renin-angiotensin system theory, which suggests that the proliferation of IH-derived blast cells is induced by angiotensin (AT) II stimulated indirectly by high renin levels. Renin converts angiotensinogen to AT I, which leads to high levels of AT II [7,28]. High renin levels in infants and high-risk groups of IH patients and the expression of angiotensin-converting enzyme and AT II receptor 2 on the endothelium of proliferating IHs support this theory [28]. The mechanism of β-adrenergic blockers inducing the accelerated involution of IHs may be associated with the blocking of β1-adrenergic receptors in the kidney, leading to the inhibition of renin release [7,28].

IHs are not present at birth, usually develop during the first 1–2 weeks of age, rapidly proliferate during the first 1–3 months of age, finish proliferating at 5 months of age, and then spontaneously and slowly involute into the adipose and fibrous tissue until around 4 years of age but sometimes up to 10 years of age [9,11-15,26,31,32]. Segmental IHs and large focal IHs, especially the deep type or those located in the parotid gland, may show an extended growth period late during the second and third years of age [11,13].

IHs are most frequently located in the head and neck region (60%), followed by the trunk (25%) and the extremities (15%) [26]. IHs usually develop in the skin involving the epidermis, dermis, and subcutaneous fat but rarely in the internal organs such as the liver, gastrointestinal tract, respiratory tract, brain, or other organs. Large visceral IHs, especially hepatic IHs, may be complicated by hypothyroidism due to inactivation of thyroid hormones by type 3 iodothyronine deiodinase in IH tissues [33]. Visceral hemangiomas are usually associated with large segmental or multifocal cutaneous IHs [16].

Depending on the depth of the lesion from the skin’s surface, IHs are classified as superficial, deep, or mixed (superficial+deep) types or reticular/abortive/minimal growth types [1,11,16,26]. Superficial IHs are usually located in the epidermis and dermis with little or no involvement of the subcutaneous fat, bright red in color, and formally termed “strawberry hemangiomas.” [11] Deep IHs are located deep below the skin’s surface, more diffuse, and less well-defined than the superficial type, covered with skin, may be a normal skin color or have a bluish hue, and are formally termed “cavernous hemangiomas.” [11] The terms “strawberry hemangiomas” or “cavernous hemangiomas” are not used to describe IHs anymore [11]. Mixed or combined type IHs are hemangiomas containing both superficial and deep components. Deep type IHs or mixed type IHs with deeper soft tissue components often present at later age such as 1-2 months of age or later [11]. There is a subset of IHs with minimal or arrested growth (IH-MAGs) that typically present as a patch of reticulated telangiectasia and can be misdiagnosed as a port-wine stain or other vascular birthmark [11,34]. IH-MAGs can be complicated by ulceration or even structural anomalies if showing segmental patterns [11].

Depending on the anatomic appearance, IHs are described as having localized or focal, segmental, indeterminate, or multifocal patterns [1,11,16,26]. Localized or focal IHs are the most common pattern, well-circumscribed focal lesions appearing to rise from a point, and segmental IHs are plaque-like extensive IHs measuring often larger than 5 cm in diameter [16]. Indeterminate IHs are not clearly localized or segmental and often called partial segmental [16]. Multifocal IHs are multiple discrete IHs located at multiple distant sites [16].

Primary care clinicians should identify the high-risk IH group before 3 months of age, ideally at 1 month of age, and transfer them to hemangioma specialists for further evaluation and early treatment. Potentially problematic or high-risk IH groups with consideration for early treatment are IHs those with: (1) life-threatening complications, (2) functional impairment, (3) ulceration, (4) associated structural anomalies (upper body [PHACE syndrome], lower body [LUMBAR syndrome]), or (5) possible permanent disfigurement (Table 3) [9,11-13].

IHs with life-threatening complications include obstructive airway hemangiomas such as subglottic hemangiomas (Fig. 1) [35-38], hepatic IHs associated with high-output congestive heart failure and hypothyroidism [39,40], and profuse bleeding from ulcerated IHs [11]. Subglottic hemangiomas are diagnosed at mean age of 4 months, and patients present with progressive biphasic stridor, a barking cough, and dyspnea, and they may be misdiagnosed with congenital laryngeal stridor or infectious croup [11,13,16]. Approximately 50% of subglottic hemangiomas have a cutaneous hemangioma [11]. Segmental IHs of the lower face (“beard distribution”) or anterior neck and oral and/or pharyngeal mucosal IHs are risk factors for obstructive airway hemangiomas [11-13,16]. Hepatic hemangiomas present as focal, multifocal, or diffuse types [8,11]. Hepatic IHs usually present as a multifocal or diffuse hepatic distribution, whereas congenital hepatic hemangiomas present as a focal hepatic lesion [8]. Multiple IHs are usually asymptomatic, but some are associated with high-flow macrovascular shunting causing high-output cardiac failure [8,11,13]. Diffuse hepatic IHs are rare but present as severe hepatomegaly leading to abdominal compartment syndrome causing abnormal ventilation and renal failure due to renal vein compression [11-13,39-41]. In cases of multiple or diffuse hepatic IHs, hypothyroidism can occur due to inactivation of the thyroid hormones by type 3 iodothyronine deiodinase in the IH tissue; therefore, thyroid function testing is required [8,11,13,16]. Hepatic IHs are usually associated with ≥5 multifocal cutaneous IHs [8,13,16].

IHs with possible functional impairments are periocular, nasal, neck, lip, or oral cavity IHs (Fig. 2) [11,13,16]. Functional impairments such as visual disturbances, including mechanical ptosis, strabismus, anisometropia, or astigmatism, leading to the development of amblyopia, may occur in periocular IHs, especially in cases of upper eyelid IHs larger than 1 cm [11-13,42-44]. Functional impairments such as feeding problems may occur in cases of lip, oral cavity, or airway IH, leading to failure to thrive [11,13,16,45].

Skin or mucosal ulceration is the most common complication of IHs, occurring in 5%–21% of referred IHs and causing pain, bleeding, secondary infection, scarring, and disfigurement [46,47]. Ulceration is the most common complication of IHs, occurring in 10% of IHs and 15%–25% of referred IHs [11,13,16]. Ulceration usually develops in infants younger than 4 months of age during the period of rapid proliferation, frequently in superficial or mixed types or segmental IHs located on the scalp, neck, ear helix, perioral, perineal, perianal, and intertriginous areas and can cause pain, bleeding, infection, and scarring [11,13,16].

IHs with structural anomalies include PHACE syndrome and LUMBAR syndrome [11,16]. PHACE syndrome or PHACES is a congenital anomaly with IHs characterized by posterior fossa brain malformations such as Dandy-Walker malformation or cerebellar hypoplasia (52%), hemangioma of large (diameter >5 cm) segmental IHs involving the face, scalp, and/or neck (100%), arterial anomalies such as cerebrovascular aneurysms or stroke (90%), cardiac anomalies or coarctation of the aorta (67%), eye anomalies, and midline defects such as sternal cleft and/or supraumbilical raphe [11-13,16,48,49]. LUMBAR syndrome is another congenital anomaly with large segmental IHs involving the lower half of the body, such as the perineal, gluteal, or lumbosacral skin, often extending onto a unilateral lower extremity, undergrowth or overgrowth of the affected extremity, urogenital anomalies and ulceration, myelopathy, bony deformities, anorectal malformations, arterial anomalies, and renal anomalies [11-13,16,50].

IHs with permanent disfigurement usually occur in large-sized and facial IHs via rapid proliferation of IHs and scarring or distortion of landmarks such as the nose or lip [11-13]. Segmental IHs on the face and scalp; facial IHs in the nose or lips; any facial IHs ≥2 cm or > 1 cm in an infant ≤3 months of age; those >2 cm on the scalp, neck, trunk, or extremity; superficial IH ≥2 mm in thickness; or on the breast in female infants requires treatment to prevent permanent disfigurement (Fig. 3) [11-13].

Most IHs can be diagnosed clinically through history taking and physical examinations. At the first clinic visit, the documented history should include birth history (gestation age, delivery type, birth weight, parity, single or twin pregnancy, maternal age), date (age) of onset or detection of hemangioma, period of proliferative growth, age at when the hemangioma stopped growing and started to regress, and the occurrence of complications such as ulceration or bleeding or infection (oozing) [11,16,19-22]. A physical examination should be performed initially and at every outpatient clinic visit at 1- to 3-month intervals and include vital signs, body weight and height, systemic physical examinations, and the details of the hemangiomas such as location, number, color, long diameter, thickness, consistency, and signs of involution to the adipose and fibrous tissue [12,19-22,51]. Hemangiomas should be photographed serially at the first visit, at every follow-up visit, and at 3 and 6 months after the discontinuation of treatment for comparison [12-14,19-22]. Response to treatment can be evaluated clinically using the visual analogue scale (VAS) for superficial IHs for color, longest diameter, and thickness, with each score ranging from 0 (indicating no change) to 3 (indicating complete resolution) (Table 4) [16,21,22,52]. Therapeutic outcomes are graded as excellent response (VAS 7–9), good (VAS 4–6), poor response (VAS 1–3), and no response (VAS 0) [21,22]. The VAS scores are evaluated during treatment and at the last follow-up [21,22].

US with Doppler is the imaging modality of choice for IH assessment and is recommended when the diagnosis of IH is uncertain, when IHs show explosive or prolonged growth without involution, to differentiate IHs from malignant vascular tumors or vascular malformations, when there are 5 or more cutaneous IHs, or when the association with anatomic abnormalities such as PHACE syndrome or LUMBAR syndrome is suspected [5,11-13,16]. US with Doppler, a noninvasive modality without ionizing radiation exposure, can be performed on neonates and infants without sedation to efficiently assess IH size, extent, characteristics (cystic or solid), and vascularity [11,16].

On US with Doppler, IHs appear as well-defined solid masses with high-flow vascularity but without arteriovenous shunting (Table 5) [3,5]. US with Doppler is also the imaging modality of choice for screening hepatic IHs, especially in cases of 5 or more cutaneous IHs, and for monitoring involution response to treatment [5,8,11-13,16,41,53].

MRI is recommended for infants with associated anatomic abnormalities such as PHACE syndrome or LUMBAR syndrome. Infants with a large (>5 cm in diameter) segmentally patterned facial or scalp IHs are at risk for PHACE syndrome, and MRI and/or MRA of the head and neck (including the aortic arch and brachiocephalic origin) and echocardiography are recommended for further evaluation [5,16,48]. Infants with large segmental IHs on the lower half of the body are at risk for LUMBAR syndrome, for which spine MRI is recommended, especially in the presence of sacral dimples, skin appendages, hair tufts, or lipomas. US and Doppler of the spine, pelvis, and abdomen can be performed to initially screen for LUMBAR syndrome in young infants with a corrected age of less than 6 months, but ultimately more sensitive MRI will be required to ensure the accurate diagnosis of spinal abnormalities [5,50]. On MRI, IHs appear as well-delineated homogeneous solid masses with iso- to intermediate signals on T1-weighted images and intermediate to bright signal intensity on T2-weighted and proton density-weighted images (Table 5) [5,11-13,16].

Biopsy and pathological diagnosis are rarely required when the hemangioma lesion is differentiated from a borderline or malignant vascular tumor [8,11].

IHs must be differentiated from other vascular tumors, including benign vascular tumors such as CHs, borderline vascular tumors such as Kaposiform hemangioendothelioma (Fig. 4), and malignant tumors such as angiosarcoma; their differences in pathology, clinical findings, imaging, and treatment are summarized in Table 5 [3,5,25,26]. IHs must also be differentiated from vascular malformations; their differences in clinical characteristics, imaging, pathology, and treatment are summarized in Table 6 [3,8,25,26].

The majority of IHs involute spontaneously and do not require treatment, especially when small, superficial, located in areas covered by hair or clothing, or unlikely to cause disfigurement or other complications [5,11]. However, primary care clinicians should actively observe neonates or infants with hemangioma at frequent intervals during the first few weeks and months of life and educate parents about the natural course, complications, and psychosocial impact of IHs [11-13]. As recent studies show that most IHs complete the proliferative phase by 5 months of age, the 2019 AAP CPG for IH management recommends that primary care clinicians refer infants with high-risk IHs to IH specialists by 1 month of age [11,14,15]. The IH management guideline from Europe, the US, Australia, and Japan all recommend oral propranolol as the first-line treatment for high-risk IHs [11-13]. The 2019 AAP CPG for IH management recommends topical timolol maleate application for small superficial IHs. In the Agency for Healthcare Research and Quality review of 2 large prospective multicenter randomized controlled trials (RCTs) and 4 cohort studies, the efficacy or estimated expected clearance of IHs was 96% when treated with propranolol, 62% when treated with topical timolol, 58% when treated with intralesional triamcinolone, and 43% when treated with oral steroids compared to 6% in the control group [9,11].

Approximately 10%–20% of IHs may develop serious complications requiring treatment such as ulceration, infection, bleeding, functional impairment, permanent disfigurement, hypothyroidism, and airway obstruction [11-13,16]. An estimated 85%–90% of IHs involute spontaneously and do not need treatment, but 50%–70% of involuted IHs may leave behind residual skin changes such as telangiectasia, fibrofatty tissue, redundant skin, atrophy, scarring, hypopigmentation, or alopecia [11-13,16]. Among the referred untreated IH patients, 55%–69% show permanent disfigurement [11].

Rebound growth may occur in 10%–25% of treated IHs during tapering or after stopping propranolol, but they usually respond if treated again with propranolol [22,59,92]. Risk factors for IH relapse include discontinuation of therapy before 12 months of age, mixed or deep type, and female sex [92]. The best responses are observed when IHs are superficial, thin (<1 mm thickness), and in infants 6 months old or younger [9,11,59]. An estimated 7% of infants require subsequent treatment with oral propranolol [85].

As IHs are the most common benign tumor of infancy, developing in up to 10% of infants, and best diagnosed at 1 week to 1 month of age, primary care pediatricians are the first doctors to recognize and diagnose them. It is recommended that primary care pediatricians understand IHs and other VAs, monitor patients monthly during early infancy for IH growth and complications, and refer high-risk patients to IH specialists (pediatric hematology-oncologists in Korea) for treatment as early as 1 month of age. Oral propranolol therapy is currently the gold standard therapy for high-risk IHs.

See the commentary on "Infantile hemangioma: timely diagnosis and treatment" via https://doi.org/10.3345/cep.2021.00752.