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Vascular Anomalies and Other Cutaneous Congenital Defects
Key Points
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Infantile hemangiomas (IHs) are the most common soft tissue tumor of infancy, with a reported incidence of 4% to 5% in mature newborns and up to 23% in extremely preterm infants.
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There is often parental concern regarding the risk of hemorrhage in IHs, but serious bleeding rarely occurs, and there is not a risk of coagulopathy or Kasabach-Merritt phenomenon.
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Propranolol is a nonselective beta blocker that was serendipitously discovered to effectively treat IHs.
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Port-wine stains can occur in isolation but also can be related to an underlying genetic disorder, of which Sturge–Weber syndrome is the most common. Laser therapy can yield remarkable improvement for many port-wine stains, minimizing the emotional pain that accompanies facial disfigurement.
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Localized areas of hypopigmentation on the skin of the newborn may be isolated phenomena, or they may be markers of extracutaneous abnormalities.
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Congenital melanocytic nevi are hamartomas derived from neural crest cells that form in utero and are often classified by the largest diameter of their adult projected size. The risk of melanoma in small and intermediate-sized nevi is low, but for large and giant congenital melanocytic nevi, the risk of melanoma is higher, ranging from 4.5% to 10%.
The spectrum of congenital cutaneous defects can be organized by the type of tissue or cell of origin or on the basis of their location within the skin. This chapter presents information on the most common and clinically significant vascular anomalies and other congenital cutaneous defects.
Vascular Anomalies
There has been long-standing confusion regarding the nomenclature and pathogenesis surrounding cutaneous vascular anomalies, which has led to delays in diagnosis and improper treatment and management. Terms such as cavernous hemangioma were used to describe both vascular tumors and vascular malformations, and terms such as hemangioma have been used indiscriminately to encompass various vascular tumors of differing behavior, prognosis, morphology, and treatment. A classification system for vascular anomalies was originally proposed by and was most recently updated in 2015 by the International Society for the Study of Vascular Anomalies to allow more precise diagnosis, categorization, and management. Vascular anomalies can be largely divided into two groups—vascular tumors and vascular malformations—with a smaller third group of provisionally unclassified vascular anomalies ( Table 95.1 ). Vascular tumors demonstrate cellular hyperplasia, while vascular malformations comprise a single malformed and dysplastic vessel or a combination of such vessels. Vascular tumors can be further subdivided into benign, locally aggressive, and malignant tumors. Vascular malformations are subdivided into categories based on the predominant type of anomalous channel, arising either from a single abnormal channel type or a mixed malformation comprising a combination of capillary, venous, lymphatic, or arterial vessel involvement. Simple and combined vascular malformations can be further divided according to their flow characteristics. Vascular malformations can also be classified by their association with other clinical features or associated syndromes ( Table 95.2 ). A complete list of the various vascular tumors and malformations is given in Table 95.1 , with highlighting of the most common vascular anomalies described within the text.
Table 95.1
Classification of Vascular Anomalies
| Vascular Tumors | Vascular Malformations |
|---|---|
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ISSVA Classification of Vascular Anomalies ©2018 International Society for the Study of Vascular Anomalies Available at https://www.issva.org/UserFiles/file/ISSVA-Classification-2018.pdf Accessed October 2022.
a May be associated with thrombocytopenia or consumptive coagulopathy.
b Expert consensus is that these lesions lie along a spectrum, rather than being distinct entities.
Table 95.2
Syndromes Associated With Vascular Malformations
| Vascular Malformation Type | Associated Syndrome | Clinical Features | Other Features |
|---|---|---|---|
| Capillary malformation/port-wine stain | Sturge-Weber syndrome |
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Mutations in GNAQ in syndromic and nonsyndromic port-wine stains identified |
| Nova syndrome |
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| Phakomatosis pigmentovascularis |
Classification into five subtypes:
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Phakomatosis pigmentovascularis has been associated with other vascular anomaly syndromes, including Sturge–Weber syndrome and Klippel-Trenaunay syndrome | |
| Beckwith–Wiedemann syndrome |
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Intelligence is often not impaired. Overgrowth syndrome, therefore increased risk of Wilms tumor—screening is recommended. | |
| Macrocephaly–capillary malformation syndrome/megalencephaly–capillary malformation–polymicrogyria syndrome |
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Overgrowth syndrome, therefore increased risk of Wilms tumor—screening is recommended. AKT3, PIK3CA, PIK3R2 mutations detected. Developmental delay and seizures often occur. | |
| Venous malformations | Blue rubber bleb nevus syndrome (Bean syndrome) | Multifocal venous malformations of the skin, mucosa, and gastrointestinal tract. Present as small black-blue papules and skin-colored nodules. Involvement of the palms and soles is common. Gastrointestinal bleeding is common. | Gastrointestinal bleeding is common and is a unique feature of blue rubber bleb nevus syndrome. Bleeding can result in chronic anemia and can require transfusions. |
| Glomuvenous malformation syndrome | Small to large segmental venous malformations with cobblestoned appearance and bluish-purple color. Often painful to palpation. | Autosomal dominant inheritance or sporadic, mutations in glomulin gene ( GLMN ) | |
| Familial venous malformation cutaneous and mucosal | Small venous malformations mainly involving skin and mucosa but can also involve gastrointestinal tract, brain, and skeletal muscle. Usually asymptomatic. | Autosomal dominant inheritance. Often associated with Tie2 mutation. | |
| Maffucci syndrome |
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Malignant transformation of the enchondromas can occur over time. Somatic mosaic mutations in IDH1 and IDH2 have been identified in cases. | |
| Cutis marmorata telangiectatica congenita |
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Other reported abnormalities: glaucoma and other ocular anomalies, cardiac defects, syndactyly, brain and spinal cord abnormalities | |
| Lymphatic malformation | Gorham syndrome |
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| Arteriovenous malformation | Capillary malformation–arteriovenous malformation syndrome |
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| Cobb syndrome |
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| Hereditary hemorrhagic telangiectasia |
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| Vascular malformation and overgrowth syndromes | Beckwith-Wiedemann syndrome |
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Intelligence is often not impaired. Overgrowth syndrome, therefore increased risk of Wilms tumor—screening is recommended. |
| Macrocephaly–capillary malformation syndrome/megalencephaly–capillary malformation–polymicrogyria syndrome |
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Overgrowth syndrome, therefore increased risk of Wilms tumor—screening is recommended. AKT3, PIK3CA , and PIK3R2 mutations detected. Developmental delay and seizures often occur. | |
| Klippel-Trenaunay syndrome |
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At risk of coagulopathy, pulmonary embolism, contractures | |
| Parkes Weber syndrome |
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Can occur as part of capillary malformation–arteriovenous malformation syndrome due to RASA1 mutation, therefore family history should be obtained | |
| CLOVES syndrome |
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PIK3CA mutation. Risk of Wilms tumor. | |
| Proteus syndrome |
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Growth is progressive | |
| PTEN hamartoma tumor syndrome (Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome) |
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Segmental overgrowth. At risk of internal malignancies such as breast, thyroid, and endometrial cancers. Syndrome has characteristics of penile lentigines, developmental delay, and macrocephaly. |
Vascular Tumors
Infantile Hemangiomas
Infantile hemangiomas (IHs) are the most common soft tissue tumor of infancy. They have a reported incidence of 4% to 5% in mature newborns, and incidence rates of up to 23% have been reported in preterm infants weighing less than 1000 g. Infantile hemangiomas have a female (2.3 to 2.9 times higher) and white predominance. The most significant risk factor for the development of IHs is low birth weight, with the risk increasing by 40% for every 500-g decrease in birth weight. Additional risk factors include prematurity, multiple gestation, preeclampsia, placental abnormalities, advanced maternal age, and in vitro fertilization.
Clinical Features
IHs have a characteristic and unique growth pattern that is similar in both full-term and premature infants. At birth, IHs are either absent or barely evident. Within the first few weeks after birth, a precursor lesion is present, which can appear as either a pale area of vasoconstriction or a telangiectatic red macule or a “bruise-like” area ( Fig. 95.1 ). There is a short latency period of 1 to 3 weeks before initiation of a rapid proliferation phase in most hemangiomas. This rapid growth phase occurs within the first 3 months after birth, with most of the growth occurring between 5 and 8 weeks of age. It is important to note that up to 80% of IHs have completed their growth by 3 months of age. Their growth is also limited to increasing volume within a predefined area rather than exhibiting a true radial growth phase, which is seen more characteristically in other neoplasms. After a more rapid growth phase, IHs can continue to grow more slowly up until 9 to 12 months of age. There is then an observed phase of relative stabilization followed by spontaneous regression. Regression of a hemangioma occurs slowly over many years, with approximately 90% regression noted by 4 years of age. Clinical signs of regression include dulling of the bright red color to a more purple color and a central gray-white discoloration that spreads centrifugally. If the white discoloration occurs in infants younger than 3 months, it can sometimes be a marker of impending ulceration. Regression does not indicate complete resolution and normalization of the underlying skin in all cases. There can be remaining telangiectasias, anatomical distortion most notable in facial lesions, and permanent textural changes characterized by residual fibrofatty tissue and skin laxity because of loss of elastic fibers causing fine wrinkling of tissue. Permanent scarring can also result from hemangiomas that were previously ulcerated.
While proliferation is often a key characteristic of IHs, it should not be considered an absolute defining feature. There is a unique subset of IHs known as abortive hemangiomas or infantile hemangiomas with minimal or absent growth in which the proliferation phase is absent ( Fig. 95.2 ). These hemangiomas present preferentially on the lower extremities and sometimes can be confused with capillary malformations (CMs). Although they lack the proliferation phase, they do spontaneously regress.
The clinical appearance of an infantile hemangioma is dictated by the depth of involvement, which can also lend itself to differences in the timing of growth. Superficial hemangiomas ( Fig. 95.3 ) are located in the upper dermis and present as elevated bright-red, well-demarcated papules or plaques, which are sometimes in lay language referred to as strawberry hemangiomas . In their early proliferation phase, small bright-red papules can be seen arising from fine telangiectatic vessels, which can be a distinguishing feature between IHs and CMs that have a similar appearance in early infancy. Deep infantile hemangiomas ( Fig. 95.4 ) are confined to the deep dermis and subcutis and present as bluish, dome-shaped tumors or nodules, with ill-defined borders. They can present in isolation or more commonly as a mixed infantile hemangioma ( Fig. 95.5 ) with both superficial and deep components. The deep component of IHs often has a distinct growth pattern in which they tend to appear later, around 2 to 3 months of age, and grow for a longer period, sometimes even over years, as compared with their superficial counterparts. Hemangiomas are further characterized by their shape, pattern, and extent of involvement—whether focal or segmental. Focal hemangiomas seem to grow from a single point, whereas segmental hemangiomas are thought to arise from an embryonic developmental unit or placode and comprise a pattern on the skin correlating with these developmental units. Segmental hemangiomas are at risk of associated anomalies and syndromes. Large facial or scalp hemangiomas should be evaluated for the possibility of PHACE ( p osterior fossa abnormalities, infantile h emangioma, a rterial abnormalities, c oarctation of the aorta, e ye abnormalities) syndrome, which can also have associated midline defects such as supraumbilical raphe and sternal cleft abnormalities and therefore are sometimes referred to as PHACES . Perineal hemangiomas or segmental hemangiomas in the lumbosacral area should be evaluated for the possibility of underlying spinal and genitourinary abnormalities with possible LUMBAR ( l ower body hemangioma, u rogenital abnormalities, u lceration, m yelopathy, b ony deformities, a norectal malformations, and r enal abnormalities) syndrome, also known as SACRAL ( s pinal dysraphism, a nogenital abnormalities, c utaneous, r enal and urologic abnormalities, associated with a ngioma of the l umbosacral localization) or PELVIS ( p erineal hemangioma, e xternal genitalia malformations, l ipomyelomeningocele, v esicorenal abnormalities, i mperforate anus, and s kin tag) syndrome. Segmental hemangiomas, like deep IHs, can sometimes have a prolonged growth phase, which in rare cases may last for years.
There is often parental concern regarding the risk of hemorrhage in IHs, and parents should be reassured that serious bleeding rarely occurs. Coagulopathy and risk of Kasabach-Merritt phenomenon (KMP) was originally thought to be associated with large infantile hemangioma, but it has been shown that KMP does not occur with IHs and is seen only with other vascular tumors, such as tufted angiomas and kaposiform hemangioendotheliomas.
Pathogenesis
IHs form as a result of dysregulation of both vasculogenesis and angiogenesis. There are many proposed theories as to the trigger that initiates this dysregulation, without any one unifying cause, but it is likely that hypoxia plays an important role. There is strong evidence in support of IHs being derived from endothelial stem and progenitor cells. Isolation of CD133 + endothelial progenitor cells from infantile hemangioma tissue and injection of these progenitor cells into nude mice lead to formation of tumors with the unique immunohistochemical and growth characteristics of IHs. The endothelial cells that were isolated from IHs were also found to be clonal in nature, suggesting that these tumors were caused by a somatic mutation in one or more genes regulating endothelial cell proliferation. The endothelial cells in infantile hemangioma express a unique phenotype of cell surface markers with positive staining for glucose transporter 1 (GLUT1), merosin, and antigen Lewis Y, which is also expressed by placental endothelial cells, but are not present in any other tumor or vascular malformation. Histologically, IHs have increased cellularity and form small sinusoidal vascular channels. It has been suggested that IHs may result from ectopic placental tissue given the similarity in their endothelial cell profiles and the fact that the placenta and IHs share a similar life cycle. Further evidence suggestive of this link relates to the increased risk of development of IHs in low birth weight infants—particularly those whose mothers had preeclampsia or placenta previa, both of which are associated with placental hypoxia. Hypoxia likely plays a large role in the development of IHs and is thought to be an important triggering signal for their development, with in utero hypoxia as a risk factor for localized hemangiomas and regional hypoxia from arterial abnormalities as a risk factor for segmental hemangiomas. It is likely that this hypoxic stress acts as a triggering signal and leads to overexpression of vascular endothelial growth factor via the hypoxia-inducible factor α pathway, which then leads to proliferation of CD133 + endothelial progenitor cells that are present in fetal tissue and causes them to differentiate into immature endothelial cells, along with pericytes, dendritic cells, and mesenchymal cells with adipogenetic potential. The adipogenetic potential may play a role during regression—when blood vessels are replaced with fibrofatty tissue. During the involution phase, endothelial cells are also noted to express caspases, which are known markers of apoptosis.
Diagnosis
In most cases, a hemangioma can be diagnosed by its clinical appearance and characteristic pattern of evolution. A lesion that deviates from this typical picture presents a diagnostic dilemma. Doppler ultrasound examination can be easily performed and may be helpful in distinguishing between an infantile hemangioma and low-flow malformation or nonvascular tumor. Other imaging modalities—magnetic resonance imaging (MRI) or angiography—may be indicated for large or obstructive lesions (e.g., ocular, upper airway) to help define the extent of involvement or associated abnormalities (e.g., PHACE or LUMBAR syndrome). Skin biopsy is diagnostic for nonvascular tumors, which can mimic vascular birthmarks (e.g., pilomatricoma, juvenile xanthogranuloma [JXG], Langerhans cell histiocytosis, infantile myofibromatosis, rhabdomyosarcoma). IHs can also be differentiated from other vascular tumors by staining with GLUT1, an immunohistochemical marker that is highly selective and specific for IHs. GLUT1 is also expressed at the blood–brain barrier and in placental tissue but has not been found in any other vascular tumors, including congenital hemangiomas. Its discovery has helped in making the correct diagnosis of these vascular tumors, especially in cases with atypical presentations. It should be noted that congenital hemangiomas (NICH, RICH, PICH) are Glut-1 negative.
Complications
While the majority of IHs are uncomplicated and spontaneously regress without any need for intervention, in approximately 10% to 15% of cases, complications can arise requiring treatment.
Local Complications
Ulceration.Ulceration is the most common complication observed in IHs and can be seen in up to 30% of cases ( Fig. 95.6 ). It can cause significant pain and discomfort and permanent scarring in the area of ulceration. Ulceration has been described to be more likely to occur during two points during the life cycle of the hemangioma: either just before the rapid proliferation phase, which can be the presenting sign of the hemangioma, or at the end of the growth phase (usually around 4 months of age). The exact mechanism causing ulceration is unknown but is thought to be related to tissue hypoxia, with the tumor outgrowing its blood supply. Ulceration is more commonly seen in large hemangiomas, those with segmental distribution, and those with mixed morphology with both superficial and deep components. Areas of friction or those exposed to moisture for a long time, such as the lower lip, neck, intertriginous areas, and anogenital and diaper region, are at high risk of ulceration. Nearly one-third of all ulcerated hemangiomas are found in the diaper region. Various treatment modalities have been shown to be effective in treating ulcerated hemangiomas, but all ulcerated hemangiomas benefit from local wound care, and combination therapy is more effective than monotherapy. Treatment options included topically administered brimonidine, 0.2% or timolol, 0.5%, topical antibiotics with mupirocin or metronidazole, pulsed dye laser treatment, and systemic therapy with propranolol. Topical analgesics can also be useful to minimize pain and discomfort.
Disfigurement
In addition to the transient disfigurement (hemangiomas located on the central face), large hemangiomas, and those with a significant superficial component, can predispose the affected child to permanent scarring. IHs involving the nasal tip are at risk of a bulbous nasal tip or a “Cyrano” deformity ( Fig. 95.7 ). This is caused by splaying of the alar cartilage during the proliferative growth phase. Early intervention with initiation of propranolol therapy can preserve the contour of the nose. If a persistent deformity develops, surgical debulking may be needed. Similarly, IHs located on the lip are at risk of deformity and disruption of the natural contours of the lips, in addition to being at high risk of ulceration and permanent scarring ( Fig. 95.8 ). Large hemangiomas of the central chest or hemangiomas involving the breast tissue in females can also be quite disfiguring, leading to permanent breast hypoplasia in some cases ( Fig. 95.9 ). Disfigurement alone, regardless of threat to function, is a reasonable indication for medical therapy in certain cases, and should be considered. Regression of hemangiomas does not always ensure complete normalization of the underlying skin and therefore can lead to lifelong psychosocial and emotional sequelae experienced by both the family and the patient.
Functional Complications
Periocular Hemangiomas . Hemangiomas located on the lid or around the orbit are at risk of causing visual impairment and can lead to amblyopia in severe cases. Amblyopia can be caused by direct pressure on the globe, causing astigmatism or myopia, or because of the size of the hemangioma there can be visual axis obstruction or strabismus. Larger and segmental hemangiomas in the periorbital area pose the greatest risk of ocular complications. Deep retrobulbar IHs may present with proptosis and can also cause strabismus and visual acuity changes. Deep and mixed infant hemangiomas can also cause tear duct obstruction and exposure keratopathy. Aggressive and early initiation of treatment along with evaluation by a pediatric ophthalmologist can help prevent some of these complications. Further imaging, such as MRI, may be needed to assess the extent of the hemangioma or the presence of a deeper component.
Auricular Hemangiomas . With infantile hemangiomas of the ear there is high risk of physical deformity of the ear, cartilage destruction, ulceration, potential infection when ulceration is present, and potential hearing alterations. Segmental hemangiomas in this region have a higher rate of complications, and with them there can also be a risk of sensorineural and conductive hearing loss.
Potential Life-Threatening Complications
Airway Hemangiomas . Airway obstruction by an infantile hemangioma is a life-threatening complication that requires immediate evaluation and treatment. Airway hemangiomas can occur with or without the presence of cutaneous IHs. The highest risk occurs with hemangiomas located in a “beard distribution” specifically involving the left or right preauricular areas, chin, lower lip, and anterior part of the neck. Involvement with IHs at four or more of these sites is associated with a 63% risk of a symptomatic airway hemangioma. A greater number of lesions in the beard distribution leads to a higher risk of airway involvement. Segmental hemangiomas involving facial segment 3 have a 29% risk of airway involvement. Clinically, airway hemangiomas present most commonly between 6 and 12 weeks of age with biphasic stridor or a hoarse, croup-like cry. The subglottis is the most common site of involvement, but the oral cavity, oropharynx, hypopharynx, larynx, and upper trachea can also be involved. Referral to a pediatric otolaryngologist is important for evaluation of the airway, and systemic treatment should be started immediately. Treatment of airway hemangiomas may require a combination of multiple medical and surgical treatments depending on the extent of involvement, which may include propranolol, oral and intralesional corticosteroids, vincristine, interferon alpha, surgical excision, and laser therapy.
Hepatic Hemangiomas . The presence of an IH in the liver can lead to potential serious complications such as congestive heart failure and consumptive hypothyroidism. Individuals with five or more cutaneous IHs ( Fig. 95.10 ) of any size and in any location should be screened for the possibility of hepatic IH. This study showed that in patients with five or more cutaneous hemangiomas, 16% of them had evidence of a hepatic hemangioma versus none in the group with fewer than five cutaneous hemangiomas. Individuals with large or segmental IHs do not seem to be at greater risk of hepatic IHs.
Parotid Hemangiomas . Parotid hemangiomas can be isolated to the parotid gland or can be present as part of a segmental IH in the maxillary distribution of facial segment 3. Parotid hemangiomas have a unique pattern of growth as they can have a longer proliferative growth phase than typical IHs. This can lead to longer treatment courses. They have also been associated with functional complications relating to deformity of adjacent structures such as the ear and lip and conductive hearing loss caused by narrowing of the external auditory canal. Life-threatening complications can also arise, including an association with subglottic hemangiomas and, less commonly, congestive heart failure and consumptive hypothyroidism.
Treatment
Most IHs are uncomplicated and spontaneously regress, but there is a subset of approximately 10% to 15% of IHs that result in complications requiring treatment. Treatment is indicated in cases complicated by disfigurement or risk of disfigurement, ulceration, or functional compromise. There are various treatment modalities, including topical or systemic medications, surgery, or laser therapy, that are chosen on the basis of various factors, including the stage of growth, location, potential complications, and associated conditions. The various treatment modalities are outlined in the following sections. In general, pharmacologic treatment is the first-line treatment, with surgical and laser therapies being considered as adjunctive or second-line treatment following medical interventions.
Active Nonintervention . For most lesions the initial treatment of choice is “active nonintervention.” This is reserved for hemangiomas that are not at risk of causing disfigurement, ulceration, or causing any functional impairment. These often tend to be small focal hemangiomas in nonfacial locations. Anticipatory guidance should be discussed with the family in regard to the natural course of IHs: the initial period of rapid growth in the first few months of life and the slow rate of involution over many years. Demonstration of before-and-after photographs of growing and involuted hemangiomas in other children can help demonstrate the natural course and diminish parental concern. There is also a common concern of risk of significant hemorrhage. This is rare in IHs. Minor episodes of bleeding can result from trauma and, like any superficial wound, respond to short-term compression.
Although the large majority of IHs do not require treatment and spontaneously regress, the disfigurement associated with the residua of IHs should not be underestimated, and treatment should be considered on the basis of the location and size of the infantile hemangioma. Up to 40% of hemangiomas leave permanent skin changes that can be disfiguring. Psychological and social problems may result from facial or other visible deformities. A small study found that patients with untreated involuted facial hemangiomas had higher levels of social anxiety and decreased social initiative as compared with children with treated facial IHs. Therefore, early intervention should be considered for lesions with a higher potential for complications.
Topical Therapies
Topically administered timolol maleate is a nonselective β-adrenergic receptor blocker that was first reported to be used in IHs in 2010 and has been shown to be most effective for superficial and thin hemangiomas. It is approved for use in pediatric glaucoma, but its use topically on the surface of the IHs is off-label. The preferred formulation is timolol gel forming solution, 0.5%. In general, timolol is well tolerated, without significant systemic side effects. However, a recent prospective study showed systemic absorption with use of one drop twice a day—although the concentrations detected were below 0.2 ng/mL, which is below the level at which systemic effects may begin to be seen. Caution should be used in preterm infants with postmenstrual age less than 44 weeks and low birth weight infants weighing less than 2500 g at the time of initiation of treatment, as there have been a few case reports of symptomatic bradycardia in this group. However, in these reported cases, the doses of timolol being used exceeded 0.2 ng/mL, and the treatment areas had variable or increased absorption (e.g., thin-skinned areas such as eyelids, mucosal surfaces, and ulcerated sites). Absorption within mucosal sites and ulcerated hemangiomas is variable, and therefore caution should be used, but there have been reports of use in these areas without any adverse side effects. A recent randomized controlled trial showed that timolol, though well tolerated, did not differ from placebo at 24 weeks in terms of complete or nearly complete hemangioma resolution.
Systemic Therapies
Propranolol . Propranolol is a nonselective β-adrenergic receptor blocker that in 2008 was discovered by chance to treat IHs. It had been used at higher doses in children with cardiac disease for many decades previously. In 2014, Hemangeol (propranolol hydrochloride, Pierre Fabre, Parsippany, New Jersey, United States) was approved by the U.S. Food and Drug Administration as the only approved systemic treatment for IHs, and propranolol become first-line systemic treatment for IHs. The dosages for IHs range from 1 to 4 mg/kg per day in divided doses (two or three times daily), with a 98% response rate at a mean dosage of 2.1 mg/kg per day. There have now been three randomized controlled trials examining the efficacy of propranolol for IHs, with the largest trial showing the highest efficacy at dosages of 3 mg/kg per day for a 6-month course. Despite this, most practitioners use maintenance dosages of 2 mg/kg per day because dosing regimens of more than 2 mg/kg per day did not show a significant increase in effect but did show an increase in the rate of adverse events. The most common adverse side effects of the medication reported are gastrointestinal disturbance, sleep disturbance, and acrocyanosis. These side effects were overall mild and reversible. Serious adverse effects such as symptomatic hypotension, hypoglycemia, bradycardia, and bronchospasm occurred infrequently and, in a randomized control trial, were reported at a similar frequency in the placebo group. Once the medication is discontinued, rebound growth can occur, but this was more likely if the hemangioma was treated for less than 9 months versus a course of 12 to 15 months.
Corticosteroids . Oral corticosteroids were the first-line treatment before the discovery of propranolol. Prednisone or prednisolone dosages of 2 to 5 mg/kg per day were used, with the most optimal effects reported at a dosage of around 3 mg/kg per day. Within 1 to 2 weeks, 30% of hemangiomas would show a dramatic response, but 40% would respond equivocally. Many side effects were noted in these patients, most notably cushingoid appearance, gastroesophageal reflux, insomnia, irritability, transient growth retardation, hyperglycemia, and, rarely, adrenal insufficiency, hypertension, and osteoporosis. Studies comparing propranolol with oral corticosteroids showed that clinical response to propranolol was more rapid and effective, with need for fewer surgical interventions, and that, overall, propranolol was better tolerated. Corticosteroids as a monotherapy are no longer used for IHs but rather are now reserved for complex and refractory cases and can be used in conjunction with propranolol or other therapies.
Intralesional corticosteroid injections may be used in small, localized hemangiomas in cosmetically sensitive areas with high rates of morbidity such as the lip, nasal tip, and eyelid. This can be used as a therapy adjuvant to other topical or systemic treatments. Complications include cutaneous atrophy, skin necrosis, and, for intralesional periocular injections, ophthalmic artery occlusion and blindness. Thus, periocular intralesional steroid injection should be performed only by experienced pediatric ophthalmologists.
Other Therapies . Historically, interferon alpha and vincristine were used with variable effect for treatment of IHs. These therapies have potential adverse effects and are now reserved only for refractory lesions. Orally administered sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has now been considered in a few such cases.
Surgical Therapies
Laser Therapy . Pulsed dye laser treatment has been used in various settings with IHs. There have been some controversial data regarding its use as a monotherapy for uncomplicated hemangiomas, and it seems to be more efficacious when used in conjunction with propranolol or timolol. It has also been used to heal ulcerations and to decrease residual erythema and telangiectasias in an involuting hemangioma. However, a randomized prospective controlled trial of 121 infants found that pulsed dye laser treatment in uncomplicated hemangiomas is no better than watchful waiting. Pulsed dye laser treatment cannot prevent the preprogrammed growth pattern of hemangiomas and has a limited role during the proliferative phase. One risk of laser use during the proliferative phase can be ulceration. In contrast, it can be useful during involution, if there is residual redness or telangiectasias, which may be resolved faster than with the natural course of involution but has no effect on fibrofatty residuum.
Surgical Excision . Surgical excision can be done in cases of medically refractory hemangiomas that are symptomatic and proliferating, in an emergency situation where there is life-threatening functional compromise, or in situations with recurrent profuse bleeding. It may also be beneficial in situations where there is a large disfiguring pedunculated lesion that will leave behind significant fibrofatty residual or scar.
Wound Care . Ulceration is a therapeutic challenge, but all ulcers benefit from local wound care and potential occlusive dressings. The type of dressing chosen depends on the amount of exudate and on the location of ulceration. For sites that are difficult to dress, for example the diaper area, frequent and liberal application of petrolatum jelly is effective. Various dressing materials, including petrolatum-impregnated gauze and seaweed-derived alginate dressings, are often recommended. Off-label use of becaplermin gel, a recombinant human platelet-derived growth factor, has reportedly shown dramatic healing in a small case series. The product now carries a warning from the Food and Drug Administration, which must be taken into consideration before its use. Agents for pain control should be considered, including topical anesthetics (being mindful of the percentage of body surface area covered) and oral analgesics such as acetaminophen or ibuprofen. A high index of suspicion should be maintained for secondary infection, with appropriate use of topical or oral antibiotics as needed. If conservative therapy is unsuccessful, pulsed dye laser treatment may relieve pain and speed reepithelialization. The ulcers will heal but will inevitably leave scars.
Work-Up and Associations . A complete list of associations and the work-up needed for specific hemangiomas on the basis of their size and location is given in Table 95.3 . Here we will highlight a few other special circumstances.
Table 95.3
Indications for Work-Up of Extracutaneous Anomalies Associated With Infantile Hemangiomas
| Clinical Presentation of Hemangioma | Association | Evaluation |
|---|---|---|
| Large facial hemangioma/segmental facial hemangioma >5 cm | PHACE syndrome | MRI/MRA of the brain and neck, echocardiogram, ophthalmology evaluation |
| Multifocal hemangiomas ≥5 cm | Extracutaneous hemangiomas, especially hepatic hemangiomas | Abdominal ultrasound examination with Doppler imaging |
| Periocular hemangioma | Ocular complications | Ophthalmology evaluation |
| Parotid hemangioma | Consumptive hypothyroidism, congestive heart failure, airway hemangioma | |
| Lumbosacral hemangioma >2.5 cm | LUMBAR syndrome | MRI of lumbar spine and pelvis, neurosurgical evaluation |
| Large lower trunk or lower extremity hemangioma | PELVIS syndrome | MRI of lumbar spine and pelvis, neurosurgical evaluation, urologic evaluation |
| Beard distribution hemangiomas | Evaluation for respiratory distress | Otolaryngology evaluation and MRI of the neck |
| Breast hemangioma/large segmental chest hemangioma | Breast hypoplasia | Consider systemic treatment |
| Midline hemangiomas (with other cutaneous markers) | Spinal dysraphism | Spinal ultrasound examination at <3 months of age, MRI of the spine |
| Segmental proximal upper extremity hemangioma with extension onto the chest | PHACE syndrome or cardiac abnormality | Echocardiogram |
MRA , Magnetic resonance angiography; MRI , magnetic resonance imaging.
Visceral Involvement/Hepatic Hemangiomas . Diffuse neonatal hemangiomatosis (see Fig. 95.10 ) manifests itself as widely scattered, small superficial hemangiomas. Infants with this pattern of cutaneous involvement may have lesions limited to the skin, known as benign neonatal hemangiomatosis . However, associated hemangiomatosis of the liver, gastrointestinal tract, lungs, and/or central nervous system (CNS) can be complicated by visceral hemorrhage, hepatomegaly, high-output cardiac failure, or unexplained anemia or thrombocytopenia, with a significant mortality rate. Congestive heart failure can also occur with a large, isolated hepatic hemangioma.
Segmental Hemangiomas
PHACE Syndrome . PHACE syndrome is characterized by a large (>5 cm) segmental hemangioma of the face, scalp, or neck with associated anomalies and developmental defects. The acronym PHACE is used to describe the constellation of anomalies related to this syndrome: posterior fossa malformations, hemangioma, arterial anomalies, cardiac anomalies/coarctation of the aorta, and eye abnormalities. Midline defects such as sternal cleft and supraumbilical raphe can also be seen, and therefore sometimes this disorder is referred to as PHACES . The diagnostic criteria for PHACE syndrome were formalized by a consensus panel, and clinical features were grouped into major criteria. Definitive diagnosis of PHACE syndrome requires a facial segmental IH or an IH larger than 5 cm on the face or scalp in addition to one major or two minor criteria. This was revised in 2016 to also include a segmental hemangioma of the neck, upper trunk, or trunk and proximal upper extremity plus two major criteria. The exact incidence of PHACE syndrome is unknown, but it may be more common than Sturge-Weber syndrome (SWS). There is a striking female predominance in PHACE syndrome, with a female-to-male ratio of 9:1. A prospective study for PHACE syndrome found that 31% of infants with facial IHs with a surface area of 22 cm 2 or greater met the PHACE diagnostic criteria, which is based on expert consensus, and approximately 90% of affected infants had more than one extracutaneous finding. Children with frontotemporal and frontonasal IHs (known as segments 1 and 4) have a higher correlation with structural cerebral and cerebrovascular anomalies. Those with mandibular (segment 3) or beard distribution lesions are at higher risk of cardiac abnormalities and IHs in the airway. The maxillary face (segment 2) appears to be a lower-risk segment for association with PHACE syndrome. The most common and potentially devastating sequelae of PHACE syndrome are neurologic, including structural brain anomalies and abnormalities of cerebral vasculature. Progressive stenoses and occlusions of cerebral arteries can also be seen. Both moyamoya-like vasculopathy and arterial ischemic strokes have been reported. Other comorbidities have recently been reported in patients with PHACE syndrome, including headaches, endocrine abnormalities, hearing abnormalities, speech delay, dysphagia, and dental anomalies.
Because of the associated anomalies, patients suspected of having PHACE syndrome require the following:
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Echocardiogram to assess the patient for coarctation of the aorta or other structural cardiac abnormalities with possible cardiac MRI/magnetic resonance angiography (MRA) if the echocardiogram is abnormal
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MRI with contrast medium and MRA of the head and neck evaluating the patient for cerebrovascular and structural anomalies
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Ophthalmology examination of the retina
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Complete physical examination with particular focus on ventral midline defects
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Additional studies as indicated on the basis of signs and symptoms
Lumbar/Sacral/Pelvis Syndrome . Similarly to PHACE syndrome, large hemangiomas of the lower body may be associated with underlying structural abnormalities. Sacral and lumbar hemangiomas may reveal spinal dysraphism, including tethered spinal cord, lipomyelomeningocele, imperforate anus, renal anomalies, or abnormal external genitalia. Many acronyms have been coined, all describing a similar entity of a segmental hemangioma in the lumbosacral or perineal region with associated regional abnormalities. These include LUMBAR, SACRAL, and PELVIS.
Exact diagnostic criteria have not yet been defined, but IHs in the lumbosacral or perineal area that are large, midline, segmental, or present with other cutaneous markers (i.e., lipoma, gluteal cleft deviation, skin tag, aplasia cutis) should be screened for underlying abnormalities. One prospective study noted that 35% of patients with lumbosacral hemangiomas larger than 2.5 cm had evidence of spinal dysraphism on MRI. Segmental hemangiomas in the lumbosacral region typically present with minimal or absent growth and persist as a patch with coarse telangiectasias, which can lead to delays in diagnosis. These are also at high risk of ulceration.
Congenital Hemangiomas . Congenital hemangiomas are an uncommon and distinct type of vascular proliferation that are fully formed at birth. They do not undergo the characteristic proliferative growth pattern in postnatal life as seen with IHs, but rather their proliferative phase occurs in utero. They are also GLUT1 negative, unlike IHs. Congenital hemangiomas can be divided into three major subtypes of rapidly involuting congenital hemangiomas (RICHs), noninvoluting congenital hemangiomas (NICH), and partially involuting congenital hemangiomas (PICHs) on the basis of their clinical progression. Congenital hemangiomas are usually solitary in nature and are more common on the extremities and head and neck.
Rapidly Involuting Congenital Hemangiomas . RICHs can present clinically in three distinct ways: (1) a raised violaceous tumor with prominent peripheral vasculature, (2) a raised tumor with coarse overlying telangiectasias with a peripheral halo of vasoconstriction or pallor, or (3) a pink-purple tumor with deep infiltrative nodules. There can sometimes be overlying hypertrichosis. Rapid involution often begins in the first few weeks of life and is completed by 14 months of age. After involution there may be some residual atrophy, telangiectasias, persistent and prominent vessels, or milia present. There is a rare subtype of RICH where complete involution occurs in utero called RICH fetal involution type . Complications of RICHs are that they can undergo ulceration and bleeding shortly after birth, which can be painful and leave a permanent scar in the area of ulceration. There have also been reports of transient coagulopathy with thrombocytopenia occurring. The decrease in platelet count is brief and not progressive as seen in KMP. The presence of this phenomenon can lead to misdiagnosis of RICH with tumors associated with KMP, such as tufted angiomas and kaposiform hemangioendothelioma, and, therefore, biopsy may be required to confirm the diagnosis.
Noninvoluting Congenital Hemangiomas . NICHs ( Fig. 95.11 ) present as vascular patches, plaques, or nodules with blue or pink-purple color with overlying coarse telangiectasias and peripheral rim of pallor and vasoconstriction. They persist over time and grow proportionally with the child, without spontaneous regression. Some can become more protuberant or develop an increase in draining veins over time. Symptoms may develop during pregnancy or puberty, most notably that of pain.
Partially Involuting Congenital Hemangiomas . There is a small subset of congenital hemangiomas that begin a phase of involution that lasts until 12 to 30 months of age, at which time the involution halts. The residual vascular lesion then persists lifelong morphologically, resembling a NICH. There have been no reported complications in patients with PICH. The existence of PICH suggests that all congenital hemangiomas may exist along a spectrum.
Kaposiform Hemangioendotheliomas and Tufted Angiomas . Kaposiform hemangioendotheliomas (KHEs) and tufted angiomas are rare vascular tumors with locally aggressive and benign growth potential, respectively. They are thought to exist along a spectrum and are associated with life-threatening KMP. KMP is a profound and life-threatening thrombocytopenia that results from intralesional platelet trapping with a consumptive coagulopathy evidenced by elevation of D-dimer levels, reduction in fibrinogen levels, and prolongation of prothrombin time and partial thromboplastin time. The severity of the coagulopathy is variable.
Tufted angiomas ( Fig. 95.12 ) typically present in infancy or early childhood as a solitary dusky erythematous indurated vascular plaque with overlying hypertrichosis, hyperpigmentation, and/or telangiectasias. Tufted angiomas tend to not be as aggressive and do not have as deep an infiltration as their counterpart kaposiform hemangioma. Spontaneous regression has been reported in some congenital cases or cases with earlier onset.
KHE presents as a solitary ill-defined red-purple plaque during infancy or early childhood. It can extend to involve the viscera, chest wall, and retroperitoneum and may present without cutaneous findings. KHE is more commonly seen in neonates and infants, as compared with older children, and may be associated with an increased risk of KMP. Treatment can be either medical or surgical. A recent randomized controlled trial showed that sirolimus plus prednisolone was superior to sirolimus monotherapy for KHE complicated by Kasabach-Merritt phenomenon.
Pyogenic Granulomas . Pyogenic granulomas, also known as lobular capillary hemangiomas because of their histologic appearance, are benign acquired vascular tumors that are commonly seen in infants and children ( Fig. 95.13 ). They have also been seen to develop within an existing port-wine stain. They present clinically as a rapidly growing solitary, red papule that can sometimes be exophytic or pedunculated in nature. They often present with a crusted or eroded surface because of their friable nature. They do not spontaneous involute, and treatment is often pursued because of recurrent episodes of bleeding and their friability. Treatment options include simple curettage or shave excision with electrocautery of the base, which is most definitive and curative. Other treatment options include topical therapies, such as topically administered timolol therapy, a beta blocker, imiquimod therapy, or pulsed dye laser treatment, which have variable success with prolonged treatment courses. Recurrence is possible.
Vascular Malformations
Nevus Simplex
Nevus simplex, also known as a salmon patch or fading capillary stain and colloquially referred to as angel's kiss when it occurs on the forehead or eyelids and as stork bite when it occurs on the nape of the neck, is a very common capillary malformation that almost always spontaneously fades by 1 to 2 years of age ( Fig. 95.14 ), although some malformations persist, most notably those at the nape of the neck ( Fig. 95.15 ). It typically presents as a bilateral and symmetric faint pink patch with a feathery border and a midline predilection and most commonly occurs on the central forehead, glabella, upper eyelids, nose, upper lip, nape of the neck, posterior occiput, and the lower back. Nevus simplex located at the midline in the lumbosacral area is usually a benign finding in isolation and not associated with underlying spinal dysraphism, but if there are any other cutaneous findings in this area (i.e., lipoma, hypertrichosis, faun tail, aplasia cutis) or abnormalities noted (i.e., gluteal cleft deformity), then further work-up is warranted. Prominent and persistent nevus simplex can be associated with underlying syndromes such as Beckwith–Wiedemann syndrome, macrocephaly–capillary malformation syndrome, and Nova syndrome (see Table 95.2 ).
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