Port wine stain (‘nevus flammeus’)

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[level-membership-for-dermatology-category]

Port wine stain (‘nevus flammeus’)

Andrew C. Krakowski and Lawrence F. Eichenfield

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Port wine stains (PWS), also known as ‘nevus flammeus’, are benign capillary malformations of the superficial cutaneous vasculature. These lesions are almost always congenital, though they may be acquired secondary to trauma and, thus, may rarely develop in adolescence or adulthood. The head and neck are sites of predilection, but any part of the integument can be affected. Morphologically, these lesions present as light pink to red patches that typically grow proportionately with the child’s somatic growth. Unlike the salmon patch (also known as nevus simplex, angel kiss), which usually disappears within 1 or 2 years, untreated port wine stains persist throughout a patient’s life and tend to darken with time. Confusing this clinical picture is the fact that PWS may appear to lighten during the first 3 to 6 months of life; this is a physiologic change most likely due to the decrease in blood hemoglobin concentration (typically 15–17 g/dL at birth to a nadir of 8–10 g/dL by age 3 months) and should not be interpreted as a sign of clinical resolution. Skin thickening and the development of surface irregularities (nodules or ‘blebs’) and soft tissue hypertrophy may also occur, especially in the V2 distribution. PWS may also present with an inflammatory component consisting of scaling, excoriations, oozing, and crusting, which resembles an eczematous dermatitis.

While the exact molecular pathogenesis of these capillary malformations has yet to be elucidated, it is believed that complex, localized defects in pathways controlling embryogenesis and angiogenesis play crucial roles. Several specific mutations have recently been identified that may shed light on the possible pathogenesis of capillary malformations. For example, mutations in RASA1, encoding p120-rasGTPase-activating protein (p120-rasGAP), along the Ras/MAPkinase pathway, have been identified in patients with atypical capillary malformations with or without concurrent arteriovenous malformations or arteriovenous fistulas; this protein appears to play a crucial role in controlling proliferation, migration, and cell death in a number of tissues including vascular endothelium. Likewise, developmental endothelial locus-1 (Del-1), an extracellular matrix protein adhered to by human umbilical vein endothelial cells, is another protein being investigated for its potential to induce formation of a vascular plexus with increased number of capillaries. Why certain PWS seem to follow a dermatomal distribution, like the V1 involvement classically seen in Sturge–Weber syndrome, remains unclear.

In addition to being potentially cosmetically distressing and at risk for long-term deformation, PWS may also be associated with serious physical, social, and psychological sequelae. The presentation of a PWS on the face in the V1 distribution, for example, has been classically linked to the development of ocular and/or neurologic complications in the form of glaucoma or Sturge-Weber syndrome (especially with complete unilateral involvement of V1; bilateral involvement of V1; or a combination of V1, V2, and V3). Of note, anatomic variation in the distribution of V1 and V2 at the medial and lateral canthus (the so-called ‘watershed’ areas) has resulted in considerable difficulty in definitively defining distribution of a PWS occurring in these areas. PWS may also be associated with limb overgrowth (Klippel–Trenaunay syndrome), or with other vascular malformations (e.g., capillary–venous, capillary–venous–lymphatic, capillary–arteriovenous); evaluation of non-facial PWS for limb overgrowth or evidence of complex malformations may warrant consideration of MRI/MRA if symptomatic, and/or referral to genetics for syndromic evaluation.

Management strategy

Because of the well-recognized, predictable physical and psychosocial comorbidities associated with PWS, many specialists advocate for treatment of port wine stains as soon as possible after birth. Support for early intervention is based on the fact that the lesions themselves are physically smaller in size and comprise vessels that are smaller in diameter and more superficial; thus, early treatment may improve responsiveness, decrease the overall number of treatments, and reduce the likelihood of long-term adverse outcomes.

Many therapeutic modalities have been used to treat PWS, including surgical excision and grafting, dermabrasion, cryotherapy, sclerotherapy, radium implants, X-ray therapy, electrocautery, tattooing, and cosmetic camouflage. Vascular-targeted photodynamic therapy has also been used for patients with darker skin types with long-term studies in the Chinese population demonstrating mixed results and several serious complications. These modalities have limited results and many – if not all of them – have been associated with unfavorable outcomes.

Various lasers have been used, including CO2, Nd:YAG, argon, and copper vapor lasers, but results have been unsatisfactory with the risk of scarring unacceptably high. Consequently, the flashlamp-pumped pulsed dye laser (PDL) is considered by most authorities to be the gold standard of treatment for PWS. A lack of controlled studies with single parameter differences has made it difficult to optimize treatment settings. In general, wavelengths of 585–595 nm, fluences of 4–12 J/cm2, spot sizes of 2–10 mm, and pulse durations of about 0.45 ms (short-pulse PDL characterized by the clinical end-point of immediate purpura) to 1.5 ms (long-pulse PDL) are utilized, allowing for a deep, safe, and specific action that is confined to the targeted vasculature. Lightening and/or reduction in size of the stain is directly related to the number of treatments. Initial treatments usually give the highest percentage of improvement. Generally, the smaller, more superficial vessels are targeted first, and deeper, larger caliber vessels may require longer pulse durations or longer wavelengths. Graying of tissue is an indication of possible overtreatment.

Swelling, erythema, and pain are frequently present immediately following treatment with the laser. Other potential adverse events include post-inflammatory skin dyspigmentation (especially in darker skinned patients), immediate post-laser purpura, and recurrence of the lesion itself. Rarely, blistering, crusting, scarring, and infection may also occur. For these reasons, a test area may be performed prior to a full treatment session. Sun exposure can drastically affect pigmentary changes, and sun avoidance/protection should be optimized between treatment sessions. ‘Before and after’ photos are a helpful tool for demonstrating clinical efficacy and for assuaging patient and family fears.

Cooling the skin via an attached cooling device utilizing a targeted cryogenic spray or by application of a cool air machine is crucial to minimizing damage to surrounding tissues and reducing the risk of post-operative complications. Cold compresses and/or bags of ice applied immediately to the treated area or also useful for preventing post-operative complications.

Measures to overcome the pain and anxiety associated with laser use include topical anesthetics such as lidocaine 4% gel, eutectic mixture of 2.5% lidocaine and 2.5% prilocaine, local lidocaine infiltration, nerve block, sedation, and general anesthesia.

Specific investigations

First-line therapies

image Pulsed dye laser B

Double pass 595 nm pulsed dye laser at a 6 minute interval for the treatment of port-wine stains is not more effective than single pass.

Peters MA, Drooge AM, Wolkerstorfer A, van Gemert MJ, van der Veen JP, Bos JD, Beek JF. Lasers Surg Med 2012; 44: 199–204.

This randomized, ‘within-patient’ controlled study examined the role of a second pass on PWS resistant to multiple single-pass PDL treatments. In each patient (n=16), two similar PWS areas were randomly allocated to PDL with either a single pass (595 nm; 12 J/cm2 fluence; 7 mm spot; 1.5 ms pulse duration) or, as a new treatment, a double pass (11 J/cm2). Test areas were treated two times, 8 weeks apart, and clearance was assessed by two blinded dermatologists and by color measurement using reflectance spectroscopy at 3 months’ follow-up. No significant difference was noted in any of the outcomes between single- and double-pass PDL.

Pain relief measures and cooling devices

Second-line therapies

image Intense pulsed light source B
image Alexandrite 755 nm laser B
image Neodymium:yttrium–aluminum–garnet (Nd:YAG) laser B

Split-face comparison of intense pulsed light with short- and long-pulsed dye lasers for the treatment of port-wine stains.

Babilas P, Schremi S, Eames T, Hohenleutner U, Szeimies RM, Landthaler M. Lasers Surg Med 2010; 42: 720–7.

This study evaluated the efficacy and side effects of IPL treatment of PWS in a direct comparison to the short-pulsed dye laser (SPDL) and the long-pulsed dye laser (LPDL). Test spots were applied with IPL (555–950 nm; pulse duration 8–14 ms (single pulse); fluence 11–17.3 J/cm2) versus SPDL (585 nm; pulse duration 0.45 ms; fluence 6 J/cm2) versus LPDL (585/590/595/600 nm; pulse duration 1.5 ms; fluence 12/14/16/18 J/cm2) in a side-by-side modus. Subjects included those with both untreated (n=11) and previously treated (n=14) PWS, and lesion clearance was evaluated by three blinded investigators based on follow-up photography 6 weeks after treatment. In both untreated and previously treated PWS, IPL treatments were rated significantly better than SPDL; in both groups, IPL and LPDL treatments did not differ significantly. Side effects were rare with all modalities.

Treatment of hypertrophic and resistant port wine stains with a 755 nm laser: a case series of 20 patients.

Izikson L, Nelson JS, Anderson RR. Lasers Surg Med 2009; 41: 427–32.

Many PWS that respond well initially to PDL treatment may reach a response plateau, and many hypertrophic PWS are less responsive to PDL, in general. Based on the theory of selective photothermolysis, the deoxyhemoglobin and oxyhemoglobin in the deeper vessels within these lesions may be targeted with a 755 nm laser. This retrospective case review of 20 patients demonstrated the utility of the 755 nm laser for improving hypertrophic and treatment-resistant PWS in both adult and pediatric patients. Most commonly encountered complications included pain, edema, bullae, crusting, and rare scarring.

Some scarring with the 755 nm laser is inevitable if one uses the laser enough; however, the technique for PWS is difficult enough that these authors recommend its use by experienced laser specialists only.

Treatment endpoints for resistant port wine stains with a 755 nm laser.

Izikson L, Anderson RR. J Cosmet Laser Ther 2009; 11: 52–5.

Deeper vessels may be targeted with the near-infrared light from the 755 nm laser. It is more difficult to assess laser-induced changes within the deeper dermis, however, and adverse effects include deep dermal burns. The authors treated a resistant PWS with a 755 nm laser at high fluences (40–100 J/cm2; 1.5 ms pulse duration) with dynamic cooling device cooling. They presented their clinical observation that mild-to-moderate lightening of the PWS was associated with the immediate clinical end-point of a transient gray color that gradually evolved into persistent deep purpura within several minutes. The authors recommend judicious use of the 755 nm for resistant PWS.

Combined 595 nm and 1064 nm laser irradiation of recalcitrant and hypertrophic port-wine stains in children and adults.

Alster TS, Tanzi EL. Dermatol Surg 2009; 35: 914–19.

The purpose of this study was to evaluate the safety and efficacy of a novel device that delivers sequential pulses of 595 nm and 1064 nm wavelengths in the treatment of recalcitrant and hypertrophic PWS. Twenty-five subjects (aged 2–75) with skin types I–III were identified with recalcitrant or hypertrophic PWS showing incomplete clearance after 10+ (mean=16.9) prior PDL treatments. Nineteen patients had a PWS in a trigeminial location and six had involvement of the extremities. Using the novel device, subjects were treated at 6- to 8-week intervals, and two blinded evaluators assessed clinical improvement using independent evaluation of photographs at baseline and 3 months after treatment. Continued improvement was noted in these resistant lesions. Side effects included transient erythema, edema, mild purpura, and rare vesicle formation.

Third-line therapies

image Potassium titanyl phosphate laser B
image Imiquimod (as anti-angiogenic therapy) B
image Photodynamic therapy B
image Rapamycin (as anti-angiogenic therapy) B

Pilot study examining the combined use of pulsed dye laser and topical imiquimod versus laser alone for treatment of port wine stain birthmarks.

Chang CJ, Hsiao YC, Mihm MC Jr, Nelson JS. Lasers Surg Med 2008; 40: 605–10.

This retrospective review of 20 Asian subjects (aged 3–56 years) with PWS used three test sites on each subject for treatment assignments to the following regimens: (1) PDL + imiquimod; (2) PDL alone; and (3) imquimod alone. PDL sites were treated once with a 585 nm wavelength, 10 J/cm2 fluence, 1.5 ms pulse duration, 7 mm spot size, with cryogen spray cooling. For the PDL + imiquimod and imiquimod alone test sites, subjects applied imiquimod topically once a day for 1 month after PDL exposure or alone. Subjects were followed at 1, 3, 6, and 12 months after PDL exposure to evaluate all three test sites. The primary efficacy measurement was the quantitative assessment of blanching responses as measured by a DermoSpectrometer to calculate the hemoglobin index of each site at follow-up visits after PDL exposure. The authors report statistically significant differences in blanching responses over time favoring PDL + imiquimod as compared to either PDL alone or imiquimod alone. Some evidence of redarkening, thought to be related to revascularization of blood vessels, was noted at 12 months at test sites treated with PDL + imiquimod and PDL alone. Transient hyperpigmentation was noted but had resolved on all sites without medical intervention within 6 months. The authors note that clinical validation in larger patient samples is necessary.

Enhanced port-wine stain lightening achieved with combined treatment of selective photothermolysis and imiquimod.

Tremaine AM, Armstrong J, Huang YC, Elkeeb L, Ortiz A, Harris R, et al. J Am Acad Dermatol 2012; 66: 634–41.

This study sought to determine if application of imiquimod 5% cream after PDL to PWS could improve treatment outcomes. Twenty-four patients with PWS were treated with PDL and randomized to apply post-treatment placebo cream or imiquimod 5% cream for 8 weeks. Chromameter measurements were taken at baseline and compared with measurements taken 8 weeks post treatment. The change in erythema and the change in color between normal-appearing skin and PWS skin were the primary end-points. Both a greater reduction in erythema and a greater color improvement were noted with imiquimod. The authors note that the true clinical duration of effect is unknown. Likewise, minor skin irritation and other adverse events were noted.

Photodynamic therapy of port-wine stains: long-term efficacy and complication in Chinese patients.

Xiao Q, Li Q, Yuan KH, Cheng B. J Dermatol 2011; 38: 1146–52.

The authors profess that PDL is not suitable for PWS patients with Fitzpatrick skin type V or with nodular lesions. In this retrospective study, the authors studied 642 Chinese patients who had received PDT in a 5-year period (totaling 3066 treatment sessions; average of 2.6–8.2 sessions per patient). Seventy percent of patients had more than 25% of clearing and over 5% of patients had complete clearing. Ten percent of patients experienced complications that included hyperpigmentation (4.3%), scabbing (2.2%), blistering (1.4%), hypopigmentation (1.2%), prolonged blistering that persisted for >2 months (<0.7%), photoallergy (0.6%), and eczematous dermatitis (0.4%).

Long-term blood vessel removal with combined laser and topical rapamycin antiangiogenic therapy: implications for effective port wine stain treatment.

Jia W, Sun V, Tran N, Choi B, Liu SW, Mihm MC Jr, et al. Lasers Surg Med 2010; 42: 105–12.

Rapamycin, an anti-angiogenic agent, has been used to inhibit growth of pathological blood vessels. In this animal study, golden Syrian hamsters were divided into two groups: laser-only and laser + topical rapamycin. In both groups, blood vessels in the dorsal window chambers implanted on the hamsters were photocoagulated with laser; the combined treatment group also had topical rapamycin (with varying formulae and concentrations) applied to the epidermal side of the window daily for 14 days after last exposure. In the laser-only group, 23 out of 24 photocoagulated blood vessels reperfused within 5 to 14 days. In the combined treatment group, the reperfusion rates were lower (overall=36%) and were not linearly proportional to the rapamycin concentration.

Inhibition of revascularization of PWS is a ‘holy grail’ of therapy. Anti-angiogenic agents such as rapamycin could potentially open the door to a new frontier in the treatment of these lesions.

[/level-membership-for-dermatology-category][not-level-membership-for-dermatology-category]

Port wine stain (‘nevus flammeus’)

Andrew C. Krakowski and Lawrence F. Eichenfield

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Port wine stains (PWS), also known as ‘nevus flammeus’, are benign capillary malformations of the superficial cutaneous vasculature. These lesions are almost always congenital, though they may be acquired secondary to trauma and, thus, may rarely develop in adolescence or adulthood. The head and neck are sites of predilection, but any part of the integument can be affected. Morphologically, these lesions present as light pink to red patches that typically grow proportionately with the child’s somatic growth. Unlike the salmon patch (also known as nevus simplex, angel kiss), which usually disappears within 1 or 2 years, untreated port wine stains persist throughout a patient’s life and tend to darken with time. Confusing this clinical picture is the fact that PWS may appear to lighten during the first 3 to 6 months of life; this is a physiologic change most likely due to the decrease in blood hemoglobin concentration (typically 15–17 g/dL at birth to a nadir of 8–10 g/dL by age 3 months) and should not be interpreted as a sign of clinical resolution. Skin thickening and the development of surface irregularities (nodules or ‘blebs’) and soft tissue hypertrophy may also occur, especially in the V2 distribution. PWS may also present with an inflammatory component consisting of scaling, excoriations, oozing, and crusting, which resembles an eczematous dermatitis.

While the exact molecular pathogenesis of these capillary malformations has yet to be elucidated, it is believed that complex, localized defects in pathways controlling embryogenesis and angiogenesis play crucial roles. Several specific mutations have recently been identified that may shed light on the possible pathogenesis of capillary malformations. For example, mutations in RASA1, encoding p120-rasGTPase-activating protein (p120-rasGAP), along the Ras/MAPkinase pathway, have been identified in patients with atypical capillary malformations with or without concurrent arteriovenous malformations or arteriovenous fistulas; this protein appears to play a crucial role in controlling proliferation, migration, and cell death in a number of tissues including vascular endothelium. Likewise, developmental endothelial locus-1 (Del-1), an extracellular matrix protein adhered to by human umbilical vein endothelial cells, is another protein being investigated for its potential to induce formation of a vascular plexus with increased number of capillaries. Why certain PWS seem to follow a dermatomal distribution, like the V1 involvement classically seen in Sturge–Weber syndrome, remains unclear.

In addition to being potentially cosmetically distressing and at risk for long-term deformation, PWS may also be associated with serious physical, social, and psychological sequelae. The presentation of a PWS on the face in the V1 distribution, for example, has been classically linked to the development of ocular and/or neurologic complications in the form of glaucoma or Sturge-Weber syndrome (especially with complete unilateral involvement of V1; bilateral involvement of V1; or a combination of V1, V2, and V3). Of note, anatomic variation in the distribution of V1 and V2 at the medial and lateral canthus (the so-called ‘watershed’ areas) has resulted in considerable difficulty in definitively defining distribution of a PWS occurring in these areas. PWS may also be associated with limb overgrowth (Klippel–Trenaunay syndrome), or with other vascular malformations (e.g., capillary–venous, capillary–venous–lymphatic, capillary–arteriovenous); evaluation of non-facial PWS for limb overgrowth or evidence of complex malformations may warrant consideration of MRI/MRA if symptomatic, and/or referral to genetics for syndromic evaluation.

Management strategy

Because of the well-recognized, predictable physical and psychosocial comorbidities associated with PWS, many specialists advocate for treatment of port wine stains as soon as possible after birth. Support for early intervention is based on the fact that the lesions themselves are physically smaller in size and comprise vessels that are smaller in diameter and more superficial; thus, early treatment may improve responsiveness, decrease the overall number of treatments, and reduce the likelihood of long-term adverse outcomes.

Many therapeutic modalities have been used to treat PWS, including surgical excision and grafting, dermabrasion, cryotherapy, sclerotherapy, radium implants, X-ray therapy, electrocautery, tattooing, and cosmetic camouflage. Vascular-targeted photodynamic therapy has also been used for patients with darker skin types with long-term studies in the Chinese population demonstrating mixed results and several serious complications. These modalities have limited results and many – if not all of them – have been associated with unfavorable outcomes.

Various lasers have been used, including CO2, Nd:YAG, argon, and copper vapor lasers, but results have been unsatisfactory with the risk of scarring unacceptably high. Consequently, the flashlamp-pumped pulsed dye laser (PDL) is considered by most authorities to be the gold standard of treatment for PWS. A lack of controlled studies with single parameter differences has made it difficult to optimize treatment settings. In general, wavelengths of 585–595 nm, fluences of 4–12 J/cm2, spot sizes of 2–10 mm, and pulse durations of about 0.45 ms (short-pulse PDL characterized by the clinical end-point of immediate purpura) to 1.5 ms (long-pulse PDL) are utilized, allowing for a deep, safe, and specific action that is confined to the targeted vasculature. Lightening and/or reduction in size of the stain is directly related to the number of treatments. Initial treatments usually give the highest percentage of improvement. Generally, the smaller, more superficial vessels are targeted first, and deeper, larger caliber vessels may require longer pulse durations or longer wavelengths. Graying of tissue is an indication of possible overtreatment.

Swelling, erythema, and pain are frequently present immediately following treatment with the laser. Other potential adverse events include post-inflammatory skin dyspigmentation (especially in darker skinned patients), immediate post-laser purpura, and recurrence of the lesion itself. Rarely, blistering, crusting, scarring, and infection may also occur. For these reasons, a test area may be performed prior to a full treatment session. Sun exposure can drastically affect pigmentary changes, and sun avoidance/protection should be optimized between treatment sessions. ‘Before and after’ photos are a helpful tool for demonstrating clinical efficacy and for assuaging patient and family fears.

Cooling the skin via an attached cooling device utilizing a targeted cryogenic spray or by application of a cool air machine is crucial to minimizing damage to surrounding tissues and reducing the risk of post-operative complications. Cold compresses and/or bags of ice applied immediately to the treated area or also useful for preventing post-operative complications.

Measures to overcome the pain and anxiety associated with laser use include topical anesthetics such as lidocaine 4% gel, eutectic mixture of 2.5% lidocaine and 2.5% prilocaine, local lidocaine infiltration, nerve block, sedation, and general anesthesia.

Specific investigations