Laser treatment of infantile hemangioma

Infantile hemangiomas (IH) are common benign tumors of infancy. Most IH either involute spontaneously or respond to treatment with systemic Beta‐ blockers, but unfortunately not in all cases. In poor responses or in cases of contra indications for pharmacological treatment, laser treatment poses a very good solution.


| INTRODUC TI ON
Infantile hemangiomas (IH) are the most common soft-tissue tumors of childhood. IH is not a rare condition, and the incidence vary from 3% to 10% of the population with higher prevalence in females and Caucasians. [1][2][3][4] IHs are commonly located on the head, neck, and trunk, but in fact they can occur almost anywhere throughout the body, including the extremities, the spine, and visceral organs. [5][6][7] Although the exact natural history of IHs is unclear, the growth cycle of IH can be divided into early and late proliferative stages, followed by a slow involution phase. 8,9 Multiple studies had shown that IHs can result in infection, bleeding, ulceration, functional impairment of internal organs, pain and without intervention, approximately 15%-40% of IHs will involute with resultant textural skin changes. [10][11][12][13] IHs situated in areas of particular concern (i.e., periorbital, oropharyngeal, preauricular, or parotid regions), or those typified by a large size, segmental distribution, or prominent deep component often indicate rapid treatment to prevent permanent sequelae. for example, lesions of the lip or nose, may result in scarring if untreated and orbital lesions may result in persistent visual deficits that may necessitate corrective treatment. 14 Historically, medical care of clinically significant hemangiomas had been limited to a few medications, including glucocorticosteroids (topical, intralesional, and oral), interferon alfa, and, rarely, vincristine and topical imiquimod. Since 2008, propranolol emerged as a promising first-line therapy for IH that requires treatment. 15 Since the incidental repurposing of propranolol as a treatment of IH in 2008, 16 multiple lines of evidence had accumulated to substantiate its efficacy and safety. [17][18][19] As experience with propranolol for IH accumulates, rebound growth following propranolol discontinuation was repeatedly reported, also at ages when the proliferative phase is expected to be completed. [20][21][22][23][24] However, predictors of this phenomenon remain to be decisively determined. While propranolol demonstrates satisfying outcomes in the majority of patients, interindividual variation in drug response exists, and some patients are more likely to favorably respond more than others.
The use of propranolol revolutionized the treatment of IHs and became the standard of care, with high efficacy rates and minimal side effects. However, many IHs involute only partially, even after systemic treatment of propranolol. The exact cause of partial resolution of IHs after systemic propranolol treatment has not been established, although some theories have been suggested. 24 Residual hemangioma often leads to cosmetic disfigurement and dissatisfaction, and the patients' legal guardians often seek additional individualized treatments.
Energy-based devices and surgical interventions for IH may be used for residual hemangioma or for primary management of high risk lesions and include resection or ablation using laser or radiofrequency. Pulsed dye laser (PDL) is typically used with IH and is often intended to arrest growth of the lesion. Diverse opinions exist about what type of surgical treatment to use, when in the disease course to treat, and how the disease site informs treatment decisions.
Interventions for IH are varied, involved, and not without risk (e.g., risk of permanent hypopigmentation, scarring from PDL therapy, and potential harms of anesthesia); therefore, universal treatment is not recommended.
The laser therapy option is especially important in providing additional treatment modalities for residual and recurrent hemangiomas as well as for patients with contraindications or at risk of side effects to propranolol. Laser treatment for residual IHs and vascular malformations has been routinely practiced since 1980, including argon, diode, erbium-doped yttrium aluminum garnet (Er:YAG), potassium-titanyl-phosphate (KTP), pulsed dye laser (PDL), and neodymium-doped yttrium aluminum garnet (ND:YAG) lasers.

| Pulse dye laser(PDL)
Pulsed dye laser with epidermal cooling was the most commonly used laser for cutaneous vascular lesions. This type of laser has 2 wavelengths of 585 and 595 nm. Basing at the concept of selective photothermolysis, this laser can induce thrombosis within the vessels without damage to the dermis. With the use of a 585 nm laser, penetration depth is expected to range 0.8-1.2 mm which would be enough for treating superficial hemangioma, yet its use has no benefit in deeper procedures. [25][26][27] Numerous studies on PDL treatments for IHs have shown response rates of 80%-90%. 28,29 Reddy et al. 30 compared three treatments for facial segmental IH: concurrent propranolol and PDL (n = 12), propranolol followed by PDL (n = 5), and propranolol alone (n = 8). The difference in effectiveness between combined therapy, either concurrently or sequentially, and propranolol alone was statistically significant. The number of days of propranolol treatment until near-complete clearance was significantly lower (p < 0.001) for those receiving concurrent or sequential therapy than those receiving propranolol alone. Tay et al. 31 compared short and longer pulse PDL and similarly reported no significant differences in the number of children with complete or nearcomplete resolution by age 3-3.5 years.
Immediately after laser radiation, the color of the treated area turns to purpuric color, with surrounding erythematous flare which resolves in 7-14 days after laser therapy. The side effects comprise edema, especially in the periorbital area. If the epidermis turns blanch or gray during application, the energy fluences should be reduced to avoid blisters. After treatment, the treated areas are covered with panthenol ointment in order to improve hydration, reduce itching and inflammation of the skin, and accelerate epidermal wound healing. In a condition were blistering or crusting occurs, povidone-iodine solution is recommended.
The dermis of facial skin is approximately 0.6 mm deep in children and 0.9 mm in adults. Therefore, PDL was proved to be safe and effective for the facial area. Given that PDL is characterized by selective absorption by hemoglobin, it can achieve effective photothermolysis of vascular lesions.

| Nd: YAG laser
Yet, the maximum penetration depth of PDL is up to 1.2 mm. 37 40%-50% of IHs extend into the subcutis, namely in our sample, almost all (IH) were much deeper than 0.8 mm (MW: 10.2 mm; 71.1% with a subcutaneous component), emphasizing the need for a deeply penetrating laser, such as Nd:YAG laser (1064 nm, penetration depth of up to 6 mm) to effectively treat IHs. 37,38 The therapeutic result of LP 1064 nm laser treatment for residual IH is dependent upon the response of the individual residual hemangioma. The results vary from patient to patient, and depend upon the size and type of the residual hemangioma lesion.

| Argon laser
The Argon laser is observed as green light with a wavelength of 514 nm. The penetration depth of this laser is about 0.5 mm; thus, it was used for superficial hemangioma and superficial telangiectasia, but in deeper and larger hemangioma it has a variable response and it has recently been replaced with pulsed lasers. 41,42

| Intense pulsed light
Intense pulse light (IPL) is not considered a laser as it has highintensity light sources that can emit polychromatic light and radiate a non-coherent light in a spectrum ranging from 500 nm to over 1100 nm with energies up to 90 J/cm 2 . By using filters, we could minimize the emitted light in range of 515 and 590 nm, and could be used in single or more pulses in the millisecond range. In order to minimize side effects such as erythema, IPLs system has a cooling device. According to the properties of this technology, we can use it for treatment of benign venous malformations, telangiectasia port wine stains, and hemangioma. 43,44 Dong-Ni Li et al 45 found that the IPL with OPT (optimal pulse technology) may become a new standard for the treatment of hemangiomas. With its squared pulse technology, leading to safer and more effective treatments and conforming to the principles of selective photothermolysis, 46,47 the IPL with OPT targets hemoglobin as the endogenous chromophore in hemangiomas-again making it an effective therapeutic modality for these lesions.

| KTP laser
The KTP laser has a solid medium, emitting a wavelength of 532 nm (double the frequency of Nd:YAG) and observed as green light, and is almost at the hemoglobin absorption peak. The indication of this laser is mainly superficial hemangiomas. It has a wide range of pulse duration, ranging from 1 to 100 ms which leads to longer pulse duration and slow heat conduction to blood vessel without rupture of blood vessel walls. However, this laser has many side effects such as edema, purpura, and crusting. 48,49

| Alexandrite laser
Comparing to PDL, we can identify several differences: First, the 755-nm alexandrite laser needs a relative energy density, when compared with PDL, due to the relatively low absorption parameters of methemoglobin and deoxygenated hemoglobin at a wavelength of 755 nm. 50 Second, the alexandrite laser has approximately twice the tissue penetration.
Comparing to Nd:YAG, at 755 nm, the photon absorption of hemoglobin is twice of that at 1064 nm. Therefore, the heating ratio of effective containers in J/cm 2 is more effective at 1064 nm.
Long-pulse Alexandrite laser (755 nm) has been proven to be effective for treating localized angiokeratoma, 51 telangiectasias of the face, 52 and superficial basal cell carcinoma. 53 When we dealing with deep hemangioma, sequential therapy with 755-nm pulsed dye laser and 595-nm long-pulsed alexandrite laser could be a safe and effective treatment. 54

| DISCUSS ION
Infantile hemangiomas (IHs) are common benign tumors of infancy, most of them resolve during early infancy, some persist and require treatment with systemic propranolol oral solution, which mostly leads to significant improvement. However, in our recent studies we note that some IHs remain with unsatisfactory results. 18,19 In addition, after initial successful propranolol treatment, recurrent IHs occur in up to 25% of treated children. In 10%-15% of these patients, repeated treatment with propranolol was required. 23,24,[55][56][57][58][59][60][61][62][63][64] Furthermore, in rare instances, propranolol can cause side effects such as hypoglycemia, hypotension, bradycardia, diarrhea, and hyperkalemia. Therefore, in such cases, there is an unmet need for additional management following the propranolol treatment.
The laser therapy option is especially important in providing additional treatment modalities for residual and recurrent hemangiomas as well as for patients with contraindications or at risk of side effects to propranolol. Historically, lasers provided a fair benefit in primary management of IH. PDL is often used for residual refractory hemangioma after propranolol treatment.
Nd:YAG laser is often used for medically refractory lesions with a significant subcutaneous component, and there are several studies reported significant resolution of lesion size, and particular usefulness as an adjunct to propranolol treatment in managing lesions with a significant deep extent.

| Comparisons of lasers
In general, the strength of the evidence for outcomes after laser treatments have insufficient or low for effectiveness outcomes.
Most laser treatment studies of IH primarily addressed different laser modalities compared with observation, steroids, or other laser. In some studies, the KTP laser is still considered as an efficient treatment of deep hemangiomas, because this laser system can be used with the low output power 2-5 W and the ulceration rate is decreased from 20% to 2%. 65

| Contraindication for using laser in hemangioma treatment
There are some contraindications for using laser in hemangioma treatment: The absolute contraindications are photo-aggravated skin diseases and active local infection. Relative contraindications are reported to be psoriasis and vitiligo due to the possibility of Köbner phenomenon, keloidal tendencies, patient treated with isotretinoin or patient who is not cooperative or has unrealistic expectations. 69

| Personal experience
Our experience in the treatment of IH is of 14 years, in which our center had treated over 420 patients. Up until 2017, the main and almost sole treatment suggested to our IH patients was a systemic use of Propranolol. Due to the fact that a high percent of children with hemangioma had partial response, rebound growth, or contraindication to propranolol, we offered a treatment of LP Nd:YAG laser (Harmony XL Pro, Alma lasers LTD). During this 5-year period, we had treated 150 IH patients successfully (fig-1). The decision to use the LP Nd:YAG over the other technologies previously mentioned is due to the deeper penetration that characterizes this wavelength, the fact that it is of internal contact cooling and that the platform can also mound a 500-600 nm IPL, targeting the superficial portion of the skin. Usually my parameters for treating hemangioma with LP Nd:YAG laser are either with a 6 mm spot size in a fluence ranging from 40 to 100 mJ per pulse and a pulse duration of 45 ms, or 2 mm spot size in a fluence ranging from 300 to 400 mJ per pulse and a pulse duration of 10 ms. As the number of sessions progress, more fluence is needed to reach the endpoint.
Although Propranolol still remains our first line of treatment for our patients, it became increasingly important to offer a solution for the cases which cannot be treated using Propranolol.
The treatment with long-pulsed Nd:YAG 1064 nm laser for residual IH, which were resistant to systemic propranolol treatment, is safe and effective. Thus, we suggest its use as a second-line treatment for patients with sub-optimal aesthetic results following systemic propranolol.

| CON CLUS ION
Infantile hemangiomas are common benign tumors of infancy. Most IH involute, either spontaneously, or secondary to pharmacological treatment with systemic propranolol. Propranolol treatment mostly leads to regression of hemangiomas with satisfactory aesthetic results, but unfortunately not in all cases. In such cases or in cases of contra indications for pharmacological treatment laser is the best option. There are many laser systems used in the treatment of hemangioma and vascular tumors. These laser systems have different wavelengths and penetration depths; however, they have similar mechanisms, and in some cases, two or more lasers can be applied during the course of treating these lesions. PDL followed by Nd:YAG laser were the most common studied but multiple variations in treatment protocols did not allow for demonstration of superiority of a single method. In our opinion, in the era of β-blocker therapy, laser treatment still has an important role in the treatment of residual and refractory lesions.

AUTH O R CO NTR I B UTI O N S
All authors have read and approved the final manuscript. Z.k. wrote the paper. E.A., R.Z., and B.J contributed essential review of the literature.

CO N FLI C T O F I NTE R E S T S TATE M E NT
There was no conflict of interest. The principal investigator and the medical resident did not receive any fees or compensations for this study.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.

E TH I C A L A PPROVA L
There were no ethical issues.