Light‐based treatment of pediatric port‐wine birthmarks

Port‐wine birthmarks (PWBs) are progressive vascular malformations with significant disfigurement and psychosocial morbidity; early light‐based treatment has shown improved outcomes in the pediatric population. Somatic mosaic mutations underly the progressive nature of PWBs and explain the significant differences in response and heterogeneity of vessel architecture in the pediatric population when compared to the adult cohort. Here, we summarize a review of pediatric specific literature on the various light‐based treatment modalities, including pulsed dye laser, near‐infrared lasers, and intense pulsed light, providing the various indications, tips, advantages, and disadvantages for the pediatric dermatologist.

absorbed by the target structure and reach sufficient depth. Second, the pulse duration must be less than or equal to the thermal relaxation time (TRT) of the target PWB vessels, which is, in seconds, approximately equal to the square of the vessel diameter. PWB vessel diameters range from approximately 10 to 300 μm in diameter.
For PWB, this produces an optimal pulse duration ranging from 1 to 10 ms 10 Finally, sufficient fluence (energy per unit area) must be emitted to damage the target vessels, while minimizing collateral tissue damage. Vascular-selective laser wavelengths are absorbed by hemoglobin, converted to heat, resulting in photocoagulation, with injury and necrosis of the endothelial cells. Theoretically, these laser-tissue interactions lead to clearance of PWBs.

| Cooling modalities for light-based devices
Cooling modalities allow for the use of higher fluences to maximize thermal damage to the target chromophore while minimizing injury to normal skin, enhancing efficacy of light-based treatments by selectively cooling the epidermis. 11 The most common cooling strategies are contact cooling, cryogen spray, or forced air. Contact cooling and cryogen spray have the advantage of delivering cooling immediately before or after the light pulse, promoting rapid and spatially selective cooling without affecting the target chromophore temperature.
Forced air is the least selective of the cooling methods. Forced air or prolonged contact cooling has the risk of decreasing temperature in superficial vessels thus diminishing efficacy. Post-treatment cooling with ice packs can be used for patient comfort. This does not reduce the risk of thermal damage during laser, and should not be used as a primary cooling modality.

| L A S ER AND LI G HT-BA S ED MODALITIE S
The types of laser and other light-based modalities used in the treatment of pediatric PWB and efficacy results are discussed. Table 1 compares various modalities for pediatric PWB.

| Pediatric cutaneous anatomy and differences from adults
Significant heterogeneity in vessel architecture exists among PWBs and even within different regions of a single PWB, which may play a significant role in varied treatment responses. Many factors influence the efficacy of laser treatment of PWBs such as patient age, lesion size, color, localization, hypertrophy, and vessel architecture. [12][13][14][15] Infant skin is approximately 40%-60% thinner than adult skin, with relatively less melanin and fewer hair follicles relative to adults. 16 These properties, along with other hypothesized mechanisms including elevated hemoglobin F in infants and smaller vessel size, make pulsed dye laser the treatment of choice in young children with PWB. It is the safest laser modality for treatment in the pediatric population.

| Preoperative considerations in the pediatric patient
Laser safety is paramount to protect from ocular damage. All present in the laser treatment room need appropriate eye protection specific to the laser wavelength. For patients undergoing facial treatments, wavelength-specific adhesive pads that cover the eyes or laser safe metal corneal shields, which are inserted under the eyelids, should be utilized. 17,18 An assessment of an infant or child's ability to tolerate an in-office laser treatment with or without anesthesia (topical or general) is important for preoperative planning. Treatment with pulsed dye laser has been compared to the sensation of a rubber band snapped against the skin. For younger children, laser treatment may not be well tolerated and impractical without anesthesia, which provides both analgesia and immobility. While local anesthesia may be considered, it should be noted that topical anesthetics can result in blanching, and conversion of deoxyhemoglobin to methemoglobin, which may alter the chromophore target and make vascular lesions more difficult to view during treatment. However, the use of topical lidocaine 2.5% and prilocaine 2.5% (EMLA) cream has been effective as a topical anesthetic without adversely affecting efficacy of treatment. 19,20 General anesthesia (GA) results in vasodilation that can obscure the malformation. Prior to treatment, outlining the affected area with the use of a pen/pencil may be helpful, and our authors recommend the use of a white pen/pencil/eyeliner or yellow highlighter as black, blue or green will be absorbed by the 595 nm wavelength.
Infants treated early without GA may be given pacifiers dipped in sucrose syrup prior to treatment and during the procedure. A large Cochrane review meta-analysis found that this was effective in reducing procedure pain. 21 Sucrose mixed with sterile water works best if given two minutes before the procedure starts and can be repeated every 5 minutes during the procedure. Parents can often swaddle and cradle their child during the procedure. Additional staff may be needed to help stabilize the patient. Upon treatment completion, parents are recommended to comfort their child and encourage feeding.
Most infants will often cease crying seconds to minutes after treatment completion. Ice can be used for comfort following the procedure in older children.
General anesthesia in children under the age of 3 is controversial, with the FDA emphasizing avoidance due to concerns for abnormal neurocognitive development. 22 Because studies have demonstrated improved clearance of PWB with earlier initiation of laser, physicians often treat in infancy without anesthesia. 18 While further studies are needed to determine the long-term psychologic effects of serial laser treatments in infants, families and clinicians should continue to participate in shared decision-making, weighing the risks of early treatment against the social stigma and proliferative growth of PWBs over time. In this discussion, parents should be informed that numerous treatments (~8-10) are often needed for good clearance and that complete resolution may not be achieved. 13

| Pulsed dye laser
The pulsed dye laser (PDL) was the first laser specifically developed for the treatment of vascular lesions and is the gold standard for F I G U R E 1 Genotype-phenotype correlation exists for the most common mutations in vascular malformations

| Dosimetry
Laser tissue reactions result in end points that may be used as a guide for treatment. For PDL-treated PWBs, the therapeutic end point is usually purpura (Figure 3) limited to the laser spot size. Purpura is one end point, but does not guarantee complete vessel destruction, as regions of persistent perfusion can exist despite the presence of purpura.
If the immediate purpuric end point is not achieved, the laser calibration could be checked, adjusted, and exposure-repeated. However, it should be noted that in cases where longer pulse durations are used, purpura may not be visualized. Increasing the fluence may not be the solution and adjustments of other features may be necessary, such as pulse width, wavelength, or evaluation of skin type. 23 Immediate skin shrinkage and metallic-gray blanching indicate nonspecific dermal injury and should prompt immediate reduction in treatment fluence or better skin cooling. 11

| Efficacy
Given the proven safety and efficacy of PDL treatment in infants and young children, early treatment is recommended, with studies demonstrating 26%-32% complete clearance in infants <1 year of age, and 89%-100% of infants with greater than 50% clearance. 18,24 Pediatric PWBs have a better response to PDL treatment than adults with PWBs, often requiring fewer treatment sessions to achieve greater lightening, especially before the age of 1 year. 14,25 These results are attributed to smaller, more superficial vessels and thinner dermis in infants, enabling better accessibility of the vasculature to PDL and improved vessel destruction. 14,26 Among early-onset hypertrophic PWBs, complete clearance was rare (3%), but early treatment before the age of 2 resulted in higher response rates relative to later treatment (50% vs 24%; P < .001). 2 The general practice of our authors is to begin treatment as early as possible, optimally within the first few weeks of life. Regardless of age at initiation of treatment, the target chromophore (ie, hemoglobin) can be locally increased by utilizing several techniques, including increasing the ambient room temperature, application of heating pads or heated air from a hair dryer, brisk patting or rubbing, and improved patient positioning (eg, Trendelenburg for facial lesions).
Treatment intervals used in infants vary in the literature, and our authors treat every 4-6 weeks. Other clinicians found on retrospective review that with shorter intervals (2-, 3-, 4-week), efficacy results were equal or greater to 6-to 12-week intervals with no difference in complication rates in skin types I-III. 24 In contrast, a recent prospective study of East Asian infants found that frequent PDL treatments (2-week intervals) did not necessarily increase efficacy and resulted in more side effects such as eczematous dermatitis. 27

| Postoperative care
To reduce swelling post-treatment, ice packs can be used with application for 10-15 minutes each hour for four hours. A bland moisturizer, such as petrolatum, should be applied to the treated areas if blisters develop. In addition, photoprotection with sun avoidance and broad-spectrum SPF 50 sunscreen is recommended to reduce the effects of epidermal damage. The use of topical steroids may be considered to reduce acute adverse effects from treatment. 28

Savas et al summarized the factors that contribute to PDL-resistant
PWBs. These include age, size of lesion (>40 cm 2 ), anatomic location (peripheral limbs and centrally located lesions, ie, medial cheeks, upper lip, and nose), dermatomal distribution (V2 lesions), skin thickness (hypertrophic or nodular PWB), vessel depth (>400 μm), and vessel diameter (<40 μm). 13 In addition, many PWB lesions extend 3 to 5 mm deep, with depth of penetration of PDL at 585 to 600 nm limited to approximately 1 mm. 15 Deeper dermal capillaries from PWB are most likely inaccessible to PDL; those that escape complete photocoagulation will continue to proliferate and grow due to the genetic mutations underlying the birthmark. 13,15 Because of the differences between pediatric and adult cutaneous anatomy, these features are less likely to be seen in the pediatric population. Redarkening can also be seen in PWBs over time and is hypothesized to occur due to their progressive genetic etiology, lack of complete eradication of vessels, and suboptimal laser parameters. 30

| Near-infrared lasers (long-pulsed (LP) Alexandrite, 755 nm, and LP Nd:YAG, 1064 nm) for resistant PWB
The longer wavelength lasers, the long-pulsed 1064 nm Nd:YAG and long-pulsed 755 nm Alexandrite, penetrate 50%-75% deeper into skin than PDL, with less optical scatter and epidermal melanin absorption. For this reason, they are typically used for PDL-resistant PWB including those with nodular or hypertrophic change, and patients with the darkest skin phototypes due to decreased wavelength interaction with melanin. However, treatment should be reserved for laser surgeons with significant experience, as scarring can occur at or just above purpuric doses. Due to their lower hemoglobin absorption, they require higher fluences for sufficient vessel F I G U R E 3 Purpura immediately following treatment with pulse dye laser of a PWB that was delineated preoperatively with white marker F I G U R E 4 Small area of crusting following pulse dye laser treatment of a PWB. This resolved after a few days of emollient and did not lead to any scarring photocoagulation. Corneal damage has been reported with the LP Nd:YAG laser, even with metal corneal shields in place, and it should not be used near the periorbital region. 31 In addition, the LP Nd:YAG laser has a higher absorption for water, leading to nonselective bulk tissue heating that can result in significant scarring ( Figure 5). 32

| Dosimetry
With more deeply penetrating wavelengths of the near-infrared (IR) lasers, the appropriate therapeutic end point is different than PDL, and this recognition is critical to minimize the risk of epidermal damage. These lasers enable deeper penetration than PDL, but should be delivered at or barely above the lowest fluence that causes purpura.
The immediate end point of both the Alexandrite and the Nd:YAG is an immediate transient gray-blue that evolves over minutes to hours into a deep purple and a purple-blue color, respectively. In addition, the purpura threshold fluence for these lasers can vary widely between patients compared to PDL and should be determined individually through test spots. Overtreatment can result in a dermal burn, which is evidenced by a persistent gunmetal gray color, and invariably leads to scarring. 32,33

| Efficacy
The majority of studies with the near-IR lasers are in adults, most of whom have developed hypertrophy or recalcitrant PWB, with fewer cases of resistant pediatric PWBs. Even with the use of near-IR lasers in conjunction with PDL, complete PWB clearance is rare.
In a small case series of resistant PWBs treated with Alexandrite laser, only mild to moderate responses were achieved in pediatric patients, with no cases of complete clearance. Moreover, several cases were complicated by blistering, pigmentary changes, and isolated scarring. 34 The LP Nd:YAG (1064 nm) laser is typically used in the same refractory patient population, or for those with darker skin types (V-VI), as the 1064 wavelength has a lower relative affinity for melanin, with decreased risk for post-inflammatory change.
However, the LP Nd:YAG laser has a higher relative affinity for oxyhemoglobin than deoxyhemoglobin (in contrast to the Alexandrite), and this leads to a significantly higher risk for ulceration and scar- Cases with the poorest efficacy were in infants 6-9 months old with smooth, flat, pink lesions. 36 In summary, the use of near-IR lasers should be considered only for PDL-refractory or nodular/hypertrophic PWBs, and should be used with caution due to increased potential for adverse events including scarring. Potential side effects are similar to PDL with potential for epidermal or dermal injury, resulting in blistering and metallic-gray blanching, respectively. In general, we recommend against the use of near-IR lasers in infants and young children since this population is more likely to respond to PDL repeated at regular intervals, with appropriate parameters.

| Intense pulsed light
Intense pulsed light (IPL) may be used and considered for PDLresistant patients or when PDL is unavailable given that is has less adverse effects than the near-IR lasers and enables deeper pen- Discovery of the shared molecular basis between vascular anomalies and cancer has set the stage for repurposing targeted therapies originally developed for malignancy, unlocking the potential for pharmacologic blockade of activated pathways. Optimizing treatment will require a precision-based, multimodal approach with better imaging techniques to individualize parameters, improvements in laser technology, and targeted molecular therapy to prevent progression and recurrence.