Angiomas
Kristen Renee Aguirre
Macrene Alexiades
John Stuart Nelson
OVERVIEW
The presence of vascular tumors or proliferations in the skin is a common reason for patients to seek cosmetic or medical treatment. There is a large number of vascular tumors with wide-ranging clinical presentations and clinical behavior. The most common vascular tumors for which treatment is sought will be discussed in this chapter with discussion of the clinical interventions that should be taken. Table 3.3.1 provides a summary of recommended treatments for the various vascular disorders.
INFANTILE HEMANGIOMA
BACKGROUND
Infantile hemangiomas (IHs) are defined as vascular tumors or proliferations presenting at or near birth, which proliferate rapidly over the first year of life and then spontaneously involute.1,2,3 IHs are an anomalous localized proliferation of vasculature which are generally thought to arise sporadically, although up to 10% can be familial. These lesions are seen in 4% to 5% of infants, more commonly in girls (2-5:1), premature, low-birth-weight infants, as well as in multiple births, and in the setting of maternal amniotic sampling.3,4,5,6,7 Synonyms include benign infantile hemangioendothelioma, cellular hemangioma of infancy, juvenile hemangioma, and strawberry nevus.
PRESENTATION
IHs present as vascular tumors or proliferations presenting at or near birth; they proliferate rapidly over the first year of life and then spontaneously involute. The lesions may initially present as a cluster of telangiectasias with a halo of pallor, erythematous macules, bruise-like patches, or even areas of ulceration on the lips or perineum.8,9
DIAGNOSIS
Clinical Diagnosis
IHs range in size from 0.1 to 6.0 cm and appear as red to purple nodules. IHs are typically found on the face or limbs that appear in the newborn period.
The presence of large segmental hemangiomas on the face or lumbosacral regions should raise suspicion for a hemangioma syndrome with defects in multiple organ systems such as PHACE(S) or LUMBAR syndromes. These syndromes are seen more frequently in segmental hemangiomas and in female infants (6:1 female to male). PHACE(S) syndrome represents a constellation of symptoms associated with facial segmental hemangiomas. The acronym encompasses posterior fossae abnormalities and other structural brain malformations; hemangioma (particularly segmental facial lesions); arterial abnormalities of cerebral and cervical vessels; cardiac defects (particularly coarctation of the aorta); eye abnormalities; and sternal defects and supraumbilical raphe. Diagnostic criteria for this syndrome were recently established by a multidisciplinary group of PHACE(S) experts.10 In a prospective study of 108 infants with large facial segmental hemangiomas, 31% were found to have PHACE(S) syndrome, and 91% of those infants had more than 1 extracutaneous manifestation. Given the fact that cardiovascular and cerebrovascular changes can be progressive, it is important to seek out the appropriate specialty care to screen and monitor for associated abnormalities.6,10,11,12
Midline lumbosacral hemangiomas >2.5 cm carry a 35% risk of underlying spinal dysraphism, and should also be considered a marker for possible underlying LUMBAR syndrome. LUMBAR syndrome is a similar syndrome to PHACE(S) involving large segmental hemangiomas of the lower body. The acronym LUMBAR syndrome: lower body/lumbosacral hemangioma and lipomas or other cutaneous anomalies (eg, “skin tags”); urogenital anomalies and ulceration; myelopathy (spinal dysraphism); bony deformities; anorectal and arterial anomalies; and renal anomalies. Similar to PHACE(S) syndrome, this constellation of abnormalities can be
progressive, and it is important when an infant is noted to have a large segmental hemangioma in the lower body, particularly the lumbosacral region, to refer for evaluation by the appropriate specialties. Early intervention can help prevent and/or manage possible complications.13
progressive, and it is important when an infant is noted to have a large segmental hemangioma in the lower body, particularly the lumbosacral region, to refer for evaluation by the appropriate specialties. Early intervention can help prevent and/or manage possible complications.13
TABLE 3.3.1 Disorders and Recommended Treatments | ||||||||||||||||
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A number of other instances exist in which further systemic workup is warranted in an infant with hemangioma, including lower facial or “beard hemangiomas,” which can be a marker of laryngeal hemangiomatosis leading to airway obstruction. Symptoms include biphasic stridor and noisy breathing presenting within the first weeks to months of life. Evaluation by an otolaryngologist is warranted in these cases. Rarely airway hemangiomas can also be seen in large upper face segmental hemangiomas and small “beard area” hemangiomas, so a low threshold for referral is warranted when symptoms are present.14
Last, in infants with multiple cutaneous hemangiomas, visceral hemangiomatosis should be considered, particularly when more than 5 small superficial cutaneous hemangiomas are present. The liver is the most common site for internal hemangiomas; however, they can also be found elsewhere in the gastrointestinal (GI) tract, in the central nervous system (CNS), in other mucosal surfaces, and within the eyes.15
Histopathology
Early lesions display solid, cellular lobules consisting of plump endothelial cells lining tiny rounded vascular spaces with inconspicuous lumina. At this stage, a reticulin stain is useful in demonstrating the connective tissue fibers encircling the vessels. Moderate numbers of mitotic figures are present. Numerous mast cells may be observed in the stroma. Vascular proliferation may involve subcutaneous tissue and may replace the fat lobules and may be noted around eccrine glands. Perineurial invasion in IH is a relatively common finding.
Maturation typically commences at the periphery of the lobules and evinced by enlargement of vascular spaces and flattening of the endothelium.
Regressed lesions display progressive fibrosis, absence of vascular elements, and fatty replacement of vascular tissue in the subcutis.
High endothelial immunoreactivity for the erythrocyte-type glucose transporter protein GLUT1 is a specific feature of IH during all phases.
Differential Diagnosis
Congenital hemangioma
Kaposiform hemangioendothelioma (KHE)
Tufted angioma (TA)
Pyogenic granuloma (PG)
PATHOGENESIS
There are several proposed mechanisms for the etiology of IHs, including somatic mutations in genes involved in vascular endothelial growth factor signaling
(VEGF receptors), as well as the genes involved in vascular development (eg, dual specificity phosphatase 5 [DUSP5]), which leads to clonal expansion of endothelial cells. Germline mutations have been found in familial cases and include VEGFR2, TEM8, and mutations on 5q. The placental theory of IHs postulates that the immunohistochemical similarities between IH cells and placental cells (GLUT-1, FcγRII, and Lewis Y antigen expression specifically) infer that IHs are either placental in origin or undergo differentiation toward the placental microvascular phenotype. There is further evidence that the placenta or, possibly, chorioangiomas within the placenta secrete substances that prepare the hemangioma sites for implantation. The approximately 9-month growth phase followed by stabilization and involution also lends credence to this hypothesis. This metastatic niche theory could provide possible future avenues for prevention and therapy.16 Finally, there is discussion regarding the role of hypoxia in the etiology of these lesions. This is supported by their association with hypoxic placental changes, placental insufficiency, low birth weight, regional arterial insufficiency seen in PHACE(S) and LUMBAR syndromes, and retinopathy of prematurity (GLUT-1-positive neovascularization). Estrogen may also play a role as IHs show such a significant predilection for female infants.17,18
(VEGF receptors), as well as the genes involved in vascular development (eg, dual specificity phosphatase 5 [DUSP5]), which leads to clonal expansion of endothelial cells. Germline mutations have been found in familial cases and include VEGFR2, TEM8, and mutations on 5q. The placental theory of IHs postulates that the immunohistochemical similarities between IH cells and placental cells (GLUT-1, FcγRII, and Lewis Y antigen expression specifically) infer that IHs are either placental in origin or undergo differentiation toward the placental microvascular phenotype. There is further evidence that the placenta or, possibly, chorioangiomas within the placenta secrete substances that prepare the hemangioma sites for implantation. The approximately 9-month growth phase followed by stabilization and involution also lends credence to this hypothesis. This metastatic niche theory could provide possible future avenues for prevention and therapy.16 Finally, there is discussion regarding the role of hypoxia in the etiology of these lesions. This is supported by their association with hypoxic placental changes, placental insufficiency, low birth weight, regional arterial insufficiency seen in PHACE(S) and LUMBAR syndromes, and retinopathy of prematurity (GLUT-1-positive neovascularization). Estrogen may also play a role as IHs show such a significant predilection for female infants.17,18
TREATMENT
Over the last century, there have been numerous therapies attempted for the treatment of IHs. The rationale behind treating a lesion which by its very nature will spontaneously involute involves the assessment of location of the lesion, cosmetic sensitivity versus potential for functional impairment, associated morbidity (pain and increased infection risk associated with ulceration), potential for residual fibrofatty remnant, and familial and patient wishes (Table 3.3.2).19,20,21
In most cases, active nonintervention is the treatment of choice. Close monitoring and support of the patient and family is all that is required. However, in cases that warrant treatment, the following therapies can be considered (Algorithm 3.3.1). Goals of therapy should be to stop the growth of the IH, to shrink the size of the IH, and to prevent or stop related complications and sequelae.22
Historical Therapies
A number of therapies have been used in the past but are no longer utilized secondary to side effects, undesirable safety profiles, suboptimal clinical outcomes, or better available options. We will mention some of the previously used methods of interest.
Scarification
Before current therapies for hemangiomas, it was noted that involution was often induced by trauma or infection. This led to the use of needle-radiofrequency scarification. This technique is no longer used owing to the high risk of residual scarring, massive bleeding (especially in proliferating hemangiomas), and associated pain with the procedure. The carbon dioxide (CO2) laser has also been used in the scarification technique, which not only destroyed tissue but also induced inflammation; however, the results were similar.23
TABLE 3.3.2 Reasons to Consider Active Interventions for Infantile Hemangiomas | |
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 ALGORITHM 3.3.1 Treatment algorithm for infantile hemangiomas. A, Treatment algorithm for infantile hemangiomas based on depth of the tumor. B, Treatment algorithm for infantile hemangiomas based on clinical characteristic of the tumor. IL, intralesional; IV, intravenous; KTP, potassium-titanyl-phosphate; PO, per oral; PDL, pulsed dye laser. |
Radiation Therapy
Radiation therapy (XRT) has been used to induce inflammation in the hemangioma and therefore induce regression. XRT has the advantage over scarification of sparing the overlying epithelial layer and therefore limiting scarring. This therapy was most effective in rapidly proliferating hemangiomas for obvious reasons. The most important side effect and primary reason it is no longer used is the presence of ionizing radiation and subsequent mutagenicity and carcinogenicity of the treated tissue. Additionally, secondary cataract formation was a serious side effect of any periorbital exposure.
Ligation and Embolization
Ligation and embolization have also been used to treat IHs, with extremely limited results. This ineffectiveness is due to the nature of the proliferating vascular tumor. Ligation and embolization are rapidly compensated for by arborizing and proliferating collaterals. The only exception to this is in infantile liver hemangiomas with high-output cardiac failure or in Kasabach-Merritt syndrome (KMS) that is unresponsive to other therapies.
Cryotherapy
Although generally not used, localized cryotherapy (electrical or liquid nitrogen) has been shown to be effective in the treatment of small superficial hemangiomas (<1 cm). Because of the nonselectivity of the cryotherapy, destruction is accomplished through crude frostbite and subsequent necrosis of the treated tissue. Side effects include scarring, hypopigmentation, and atrophy, in addition to the immediate pain and blistering that occurs at the time of treatment. This treatment is not appropriate for infiltrative, subcutaneous, or large hemangiomas.
Sclerotherapy
There are a number of case reports on the use of polidocanol sclerotherapy to treat IHs, with variable results. The primary contraindication to the continued use of polidocanol sclerotherapy is the significant risk of inducing myocarditis in the newborn. Owing to the diffuse microcirculation of the hemangioma complete compression is not attainable to prevent outflow of the drug into the systemic circulation. In infants, even relatively low concentrations of polidocanol, leaking into the systemic circulation, can lead to myocarditis. Given the existence of more effective and safer therapies, the use of sclerotherapy is not recommended for the treatment of IHs.24,25
Compression
Medical
Medical therapies for angiomas include topical, intralesional (IL), and systemic medications.
Localized Therapy
Topical Imiquimod. Topical imiquimod is another therapy that is proposed to work by inducing inflammation of the overlying epidermal layer, therefore inciting inflammation and, hopefully, inducing regression of the hemangioma. There are numerous case reports, randomized trials, and systematic reviews citing the efficacy and relative safety profile of this treatment in hemangiomas where the superficial component predominates.27,28,29,30,31
Topical Timolol. Topical timolol maleate, a nonselective β-blocker, available in concentrations of 0.25% and 0.5% and in formulations of droppered solution or gel has emerged as an effective and safe therapy to treat thin, superficial, and rapidly proliferating IHs. The overall improvement is modest and is seen over weeks to months. The safety profile of this medication is excellent, and it should be considered in infants and children whose hemangiomas warrant treatment but systemic treatments are either not wanted or are contraindicated. The usual treatment regimen uses topical timolol malate 0.5% gel applied twice daily (no more than 0.5 mg/d) for more than 3 months. Predictors of good outcome include smaller size, predominantly thin, superficial hemangiomas, longer treatment courses, and use of the 0.5% concentration (over the 0.1%). Side effects are rare and include sleep disturbance and topical irritation. Changes in blood pressure and heart rate were not seen when applied to nonulcerated lesions away from mucosal surfaces. This is not the treatment of choice for ulcerated or deep hemangiomas and is neither effective enough nor fast enough for lesions which pose a possible functional issue for the child. For smaller periorbital lesions, that do not pose immediate complications, timolol is the ideal treatment. Timolol has been used to treat pediatric glaucoma, so the safety is well established if medication gets into eyes.32,33,34,35,36,37,38,39,40
Topical Becaplermin Gel (for Ulcerated Lesions). Topical becaplermin 0.1% gel (a recombinant platelet-derived growth factor) has been used in IHs with deep recalcitrant ulcerations with excellent success. The primary limiting factor to this products use is its expense. At the time of printing, a 15 g tube retails for around $1000.41
Intralesional Glucocorticoids. Intralesional glucocorticoids have also been studied for the treatment of IHs. This therapy has been found to be moderately effective with a moderate safety profile. Intralesional triamcinolone was the most common steroid used with dosages (1-5 mg/kg) and frequencies (every 1-6 weeks, most commonly monthly) varying considerably in the literature. Owing to the fact that the effects of intralesional glucocorticoids wane in 3 to 4 weeks, repeated injections are required during the proliferative phase to prevent rebound. In a meta-analysis of the literature, intralesional glucocorticoids were found to be inferior to oral propranolol and topical timolol, but superior to oral glucocorticoids and intralesional propranolol. The most common side effects reported include pain, bleeding and ulceration, with infection, irritability, skin dyspigmentation, skin atrophy, and cushingoid appearance also reported.42,43
Intralesional Bleomycin. Intralesional bleomycin is proposed to induce involution of hemangiomas by cleaving DNA during the S cycle via oxidative damage from free radicals. Bleomycin also induces apoptosis in rapidly proliferating cells and has a sclerosing effect on the vascular endothelium which makes it particularly effective during the proliferating stage of hemangioma growth. Additional mechanisms include degrading cellular RNA, and inducing tumor necrosis factor. Bleomycin should especially be considered when a periocular hemangioma could lead to amblyopia or visual impairment.44 Reported treatment regimens were 0.5 mg/kg diluted to the needed size of the hemangiomas and injected monthly for 5 to 9 injections. However, general anesthesia is required to make the therapy tolerable for infants. Potentially serious side effects of systemic bleomycin include dose-dependent pulmonary fibrosis; however, this has never been reported in association with intralesional bleomycin. The most common side effects included pain, swelling erythema, cutaneous atrophy, bleeding, infection, eschar formation, hypopigmentation, temporary alopecia, and flu-like symptoms. More rare adverse effects that have been reported include lymphangitis, flagellate hyperpigmentation, and Raynaud phenomenon. Intralesional bleomycin is an effective option for the rapid treatment of periocular IHs in combination with oral propranolol or as monotherapy when systemic β-blockers are contraindicated.44,45,46,47,48,49
Systemic
Systemic Glucocorticoids. Once the mainstay of IH treatment, systemic glucocorticoids are now only recommended in propranolol-resistant cases or if β-blockers are contraindicated. Corticosteroids are only effective in the proliferative phase and have been shown to stabilize growth and promote involution through VEGF-A expression in the NF-κβ pathway, among others. Optimal dosing regimens for prednisolone are 2 to 3 mg/kg/d for approximately 4 to 12 weeks, depending on response, age of child, and stage of the hemangioma. The dose can then be slowly tapered over several months, with completion of therapy between 9 to 12 months of age. Side effects are common and include irritability, hypertension, immune suppression, adrenal suppression, cushingoid appearance, growth retardation, pseudotumor cerebri, and pneumocystis pneumonia.2,4,48,50,51,52,53,54
Systemic Interferon α. The use of both interferon-α (INF-α) 2a and 2b has been reported for the treatment of IH, although this medication should only be considered as a last resort owing to its significant systemic side effect profile. Response rates of up to 90% have been reported in steroid-resistant cases, with gradual onset of effect. As with the majority of IH treatments, rebound can occur upon discontinuation. INF-α is given as a subcutaneous injection, at an initial dose of 1 million IU/m2, increasing to 3 million IU daily over the first month while monitoring neurologic status, white blood cell count, and liver enzymes. The average duration of therapy is 2 to 12 months. As mentioned previously, significant systemic side effects are the primary limiting factor for this therapy and include flu-like symptoms, neutropenia, transaminitis, rash, GI upset, and spastic diplegia. Up to 20% of children treated with INF-α will develop spastic diplegia, which may be irreversible.48
Intravenous Vincristine. The Vinca alkaloid, vincristine, has also been used intravenously to treat steroid-resistant cases of IH. Vincristine is antiangiogenic through by inhibiting of vascular endothelial growth factor. Vincristine also interferes with the
mitotic spindle by binding to tubulin. Vincristine has been shown to induce rapid and dramatic clearance of IHs, particularly when combined with systemic corticosteroids. Suggested dosage regimens are 0.75 to 1.5 mg/m2 intravenously at weekly intervals for 5 weeks and then slowly tapering by increasing dosing intervals based on treatment response. Caution must be used to prevent extravasation as this can lead to skin necrosis. Additional adverse effects include dose-limiting neurotoxicity, autonomic neuropathy resulting in abdominal pain, constipation, and ileus, and a peripheral mixed sensory motor neuropathy is common. Hematologic toxicity is rarely seen.48,50,54,55,56
mitotic spindle by binding to tubulin. Vincristine has been shown to induce rapid and dramatic clearance of IHs, particularly when combined with systemic corticosteroids. Suggested dosage regimens are 0.75 to 1.5 mg/m2 intravenously at weekly intervals for 5 weeks and then slowly tapering by increasing dosing intervals based on treatment response. Caution must be used to prevent extravasation as this can lead to skin necrosis. Additional adverse effects include dose-limiting neurotoxicity, autonomic neuropathy resulting in abdominal pain, constipation, and ileus, and a peripheral mixed sensory motor neuropathy is common. Hematologic toxicity is rarely seen.48,50,54,55,56
Oral Propranolol. In 2008, it was serendipitously discovered by a French cardiologist that the use of a systemic nonselective β-blocker, propranolol, led to the rapid involution of IHs. Since that time, a large randomized controlled trial, as well as several large series and numerous case reports have proven oral propranolol to be a safe and effective therapy for the treatment of IHs. Now considered to be the first-line therapy for IH, propranolol can be used to treat severe IHs or less severe hemangiomas located in critical locations.57,58 The effects of propranolol include vasoconstriction of the blood vessels, decreased expression of VEGF and bFGF, induction of endothelial cell apoptosis, and inhibition of renin production.2,54,59,60,61,62,63,64,65
Unlike many of the aforementioned treatments, propranolol not only works during the proliferative stage of IH but has also shown benefit for infants and young children in the late proliferative and involution stages. Standard treatment regimens begin at a dose of 0.5 to 1 mg/kg/d divided into BID or TID dosing, which is titrated up to 2 to 3 mg/kg/d, depending on patient tolerance and response to therapy. For an IH in the proliferative stage, treatment is continued until the child is between 9 to 15 months of age and is then tapered slowly, over weeks to months, to prevent rebound. Dosing should be suspended for illness or poor oral intake, given the risk of masking tachycardia (hypoglycemia induced or otherwise).40,41,49,51,52,66
The side effect profile for propranolol is more favorable than previously mentioned systemic therapies. Remarkably, cardiac side effects such as hypotension (<0.5%) and bradycardia (<0.1%) are extremely rare. Other side effects such as sleep disturbance (10%), hypoglycemia (<0.5%), and bronchospasm (˜3%) are more common. Side effects are generally mild and well tolerated. Many practitioners will require cardiac clearance before initiation, and blood pressure, heart rate, and blood glucose are often monitored at each dose escalation. Within the cardiac clearance, an electrocardiogram (ECG) and echocardiogram (ECHO) should be completed to rule out preexisting bradycardia, arrhythmia, congenital heart defects, or congenital heart black. If the patient is at risk for PHACE(S) syndrome then magnetic resonance imaging (MRI)/magnetic resonance angiography (MRA) of the head, neck, and aortic arch should also be evaluated. The risk of hypoglycemia can be mitigated by regular feedings (at least every 4 hours in infants <6 weeks, every 5 hours in 6 weeks-4 months, and every 6-8 hours in >4 months). It is also important to suspend therapy during illness, especially if decreased oral intake.32,58,67
Oral Captopril. Captopril is a member of the angiotensin-converting enzyme (ACE) inhibitor class of antihypertensive medications. It was first discovered to have an effect on IHs after being used to treat systemic corticosteroid induced hypertension. Since that time, it has been postulated that the renin-angiotensin pathway may play a significant role in the pathogenesis and inhibition of IHs. This has been supported by the observation that inhibition of either renin activity by propranolol or ACE activity by captopril leads to decreased production of angiotensin II and accelerated involution of IHs. The use of this medication in the treatment of IH is still under investigation and may represent a future option for patients intolerant to β-blockers. Oral atenolol has also been examined as another alternative.68 Further studies will be needed to evaluate optimal dosages and safety.60,65,69,70
Cosmetic
Lasers
Laser therapy offers an excellent option for localized IH therapy owing to its very specific and predictable tissue interactions, as well as its ability to spare the overlying epithelium. In addition to the different wavelengths, with their respective absorption profiles, a number of other parameters can be manipulated to create a variety of tissue interactions tailored to a specific lesion.71
Treatment with lasers and noncoherent light sources, such as intense pulsed light (IPL), is based on the principle of selective photothermolysis. In IHs and other vascular lesions, the target chromophore is hemoglobin. Hemoglobin has 3 main absorption peaks at 418, 542, and 577 nm with optimal absorption occurring between
577 to 600 nm. Upon absorption of the laser light by hemoglobin, the incoming photon energy is converted to thermal energy which diffuses within the vessels leading to endothelial cell apoptosis, and vessel inflammation and obstruction. If the pulse duration is greater than the thermal relaxation time of the vessels (which is directly proportional to the squared diameter of the target vessels), nonselective thermal damage occurs to the adjacent tissue leading to unwanted destruction and scarring.72,73,74
577 to 600 nm. Upon absorption of the laser light by hemoglobin, the incoming photon energy is converted to thermal energy which diffuses within the vessels leading to endothelial cell apoptosis, and vessel inflammation and obstruction. If the pulse duration is greater than the thermal relaxation time of the vessels (which is directly proportional to the squared diameter of the target vessels), nonselective thermal damage occurs to the adjacent tissue leading to unwanted destruction and scarring.72,73,74
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