An overview of clinical and experimental treatment modalities for port wine stains

Abstract

Port wine stains (PWS) are the most common vascular malformation of the skin, occurring in 0.3% to 0.5% of the population. Noninvasive laser irradiation with flashlamp-pumped pulsed dye lasers (selective photothermolysis) currently comprises the gold standard treatment of PWS; however, the majority of PWS fail to clear completely after selective photothermolysis. In this review, the clinically used PWS treatment modalities (pulsed dye lasers, alexandrite lasers, neodymium:yttrium-aluminum-garnet lasers, and intense pulsed light) and techniques (combination approaches, multiple passes, and epidermal cooling) are discussed. Retrospective analysis of clinical studies published between 1990 and 2011 was performed to determine therapeutic efficacies for each clinically used modality/technique. In addition, factors that have resulted in the high degree of therapeutic recalcitrance are identified, and emerging experimental treatment strategies are addressed, including the use of photodynamic therapy, immunomodulators, angiogenesis inhibitors, hypobaric pressure, and site-specific pharmaco-laser therapy.

Fig 1

Overview of endovascular laser-tissue interactions in pulsed dye laser (PDL) treatment of refractory port wine stain (PWS) skin. Yellow light-emitting PDL is used to selectively photothermolyze ectatic venules (blue structures) in predominantly papillary dermis. Affected dermal segment is encircled, and acute and chronic responses are depicted in chronological order in panels from top to bottom. An approximate time frame in which events occur is indicated in upper left corner of each panel. Upon irradiation, photons are absorbed by hemoglobin-containing erythrocytes and converted to heat, resulting in thermal denaturation of blood and formation of thermal coagulum (photothermal response).^,,,,, In refractory PWS vessels, one fraction of the vascular lumen is completely photocoagulated and another fraction is incompletely occluded by thermal coagula. Thermal coagula in latter trigger thrombosis (hemodynamic response). It is believed that these processes induce an inflammatory reaction that culminates in vascular remodeling, whereby completely photo-coagulated vasculature is removed and replaced by normal-sized capillaries through angio-genesis and/or neovasculogenesis. Because remodeled vasculature contains lower blood volume, PWS either lightens in redness or disappears entirely. In contrast, thermal coagula and thrombi in incompletely occluded structures are thought to be remodeled into restructured vascular lumen. Image of skin and vascular anatomy courtesy of Libuše Markvart, used with permission.

Fig 2

Overview of port wine stain treatment outcomes achieved by laser and intense pulsed light (IPL) systems from 1990 to present. Data are categorized by laser treatment modality, plotted as percentage of clearance (cl ) (generally classified into 0%–24%, 25%–49%, 50%–74%, and 75%–100%), and color coded according to level of cl. Solid circle on right side of chart indicates different classification system as described in legend (top), which has been color coded in yellow/orange as indicated in legend. Each horizontal bar set represents entire patient population of study, referenced on left side of chart, whereby patient percentages are provided on bottom x-axis. Complete data set is presented in Table I. CSC, Cryogen spray cooling; Nd:YAG, neodymium:yttrium-aluminum-garnet; PDL, pulsed dye laser; →, followed by IPL.

Fig 3

Overview of port wine stain treatment outcomes achieved with photodynamic therapy from 1990 to present. Data are plotted as percentage of clearance (cl) classified according to figure legend. Solid circle on right side of chart indicates type of classification system, which has been color coded according to level of cl as provided behind every legend entry. Each horizontal bar set represents entire patient population of study, referenced on left side of chart, whereby patient percentages are provided on bottom x-axis. Complete data set is presented in Table II. CVL, Copper vapor laser.

Fig 4

Pulsed dye laser-induced (585 nm) purpura on inner forearm in absence of and after application of pressure cuff in healthy volunteer (A) and on back upper aspect of arm in patients with port wine stain (PWS ) at increasing vacuum pressures and suction times (B). A, Healthy volunteers with Fitzpatrick skin types II and III were subjected to laser irradiation at radiant exposure as indicated in legend, and extent of purpura was imaged at indicated times after laser irradiation. Purpura induced without use of suction device (top row) or obtained after suction device was applied at 10 inHg for 3 minutes before laser irradiation (bottom row). B, Laser-induced purpura directly after laser irradiation, 1 day, and 7 months after laser irradiation of PWS skin at 6-J/cm² radiant exposure. Rows show hypobaric pressures applied before laser irradiation and columns indicate duration of applied vacuum (see legend). Column right of grid shows induced purpura without vacuum at same radiant exposure. Note obvious clearing in upper two rows after single laser pulse. Data modified and used with permission. CTRL, Control.

Fig 5

Schematic representation of principles of site-specific pharmaco-laser therapy (SSPLT) for treatment of port wine stains (PWS). After intravenous (iv) administration of liposomes containing prothrombotic and/or antifibrinolytic agents, PWS vasculature will contain liposomal drug carriers and cells that are instrumental in SSPLT: red blood cells (nucleation centers during selective photothermolysis, required for triggering hemodynamic response via thermal coagulum formation) and platelets (mediators of thrombosis, required for targeting of liposomes) (top). First step of envisaged modality comprises induction of thermal coagulum by laser irradiation according to current clinical practice. Direction of blood flow (→). This leads to subsequent induction of thrombosis in semiphotocoagulated blood vessels, whereby circulating liposomes are targeted to activated platelets in developing thrombus (step 2). Subsequently, irradiation of laser-treated PWS using near infrared light will locally generate heat that causes liposomes to release encapsulated pharmaceutical agents (step 3, arrows and dots) in vicinity of laser-induced, semiobstructive thermal coagulum. Release of prothrombotic and antifibrinolytic agents promotes hyperthrombosis and deterrence of fibrinolysis, culminating in thrombotic occlusion and hemostasis of blood vessel that otherwise would have remained incompletely photo-occluded (—X→). Because this damage profile is comparable to completely photocoagulated vasculature, SSPLT may prove promising in improving lesional clearance rates.