Continued research has resulted in new and improved treatment methods. Port wine stain” (PWS) is a descriptive term, adopted to describe a vascular lesion present at birth with an underlying capillary malformation. Due to nomenclature misuse regarding various types of vascular malformations, the Hamburg classification system was developed based on the predominant vascular structure of the malformation. Classifying these malformations has been useful for understanding the etiology and pathogenesis, which has subsequently led to several advancements in treatment. PWSs exhibit an equal sex distribution and carry a birth prevalence of 0.3%, making these the most common vascular malformation. 1 Familial cases have been identified, but are generally uncommon. These lesions remain throughout life and may appear anywhere on the body; however, PWSs appear most frequently on the head and neck. Since they typically darken and may become hyperkeratotic and nodular with age, it is important to identify PWSs as early as possible, as they may become more difficult to treat with time. Early treatment may help prevent possible psycho-social effects as well. 2 The diagnosis of a capillary malformation is not only important in determining treatment, but can also lead to the successful prognostication of associated complications.
Although the pathogenesis of capillary malformations (CM) remains uncertain, there is an obvious defect in the angiogenesis, vasculogenesis, and remodeling of blood vessels that occur during embryogenesis. Histopathology depicts CMs to have increased numbers of ectasias in the papillary and reticular dermis, with varying depth based on location. A study by Vural and colleagues found a significant over-expression of vascular endothelial growth factor (VEGF) and its receptor in PWS, which play a critical role in angiogenesis. CMs may be due to hyperplasia, rather than hypertrophy. 3 A confocal microscopy study found a significant decrease in neuron density and increase in vessel diameter in affected skin compared to unaffected skin. The study also found a correlation between neuron density and vessel diameter. That is, as neuronal density decreased, vessel diameter increased. 4 Thus, a decrease in neuronal density may lead to the ectasia of vessels and abnormal vasculature. There may be a genetic predisposition to CMs. Past studies have found RASA1 gene mutations to be associated with arteriovenous malformations (AVMs). RASA1 encodes for p120-RasGAP (RasGAP), which normally down regulates Ras signaling cascade, a mutation of this gene interferes with normal cellular growth, differentiation and proliferation. 5 After sequencing the gene, a recent study identified the presence of RASA1 heterozygous mutation in three families containing several members with CM without AVMs. 6 The RASA1 autosomal dominant gene mutation is also present in Parkes-Weber syndrome (AVM with limb hypertrophy).
PWSs are generally diagnosed based on clinical presentation. They may present as single or multiple lesions, as localized or extensive. At birth, they appear pink or blue in color, and may be mistaken for a bruise as a result of delivery trauma. With age, these lesions become darker and more violaceous — hence the term “port wine stains” — as well as thicker and hyperkeratotic. Although generally diagnosed based on clinical appearance, other vascular malformations may present similarly to PWS, including nevi simplex, cutis marmorata telangiectatica congenita, hemangiomas, and AVMs. Some clinical pearls for differentiating these vascular lesions from PWS: • Nevi simplex generally lighten within the first few years. • Cutis marmorata telangiectatica congenita accentuates with cold. • Hemangiomas grow rapidly and may exhibit overlying telangiectasias. • AVMs have a palpable thrill and are warm to touch. In order to differentiate pure CMs from CMs with AVMs, doppler ultrasound may be used, since pure CMs are slow-flowing malformations. 7 Due to PWS association with other medical complications, MRI and arteriography may be utilized in the diagnostic process as well.
The incidence of Sturge-Weber Syndrome (SWS) in patients with PWS involving V1 is 3%.8 SWS is characterized by facial CM, glaucoma, and leptomeningeal vascular anomaly. However, knowing the association between SWS and glaucoma, recent literature has emphasized the importance of screening all patients for glaucoma with PWS in any trigeminal dermatome, not just V1. 9 CMs associated with both deeper venous and lymphatic anomalies are oftentimes found on the extremities. These types of stains are part of the classic triad of symptoms present in Klippel-Trenaunay Syndrome (KTS), also including soft tissue/bone hypertrophy, and venous varicosity. Early identification of this PWS allows for early diagnosis of KTS, resulting in closer observation of these patients for orthopaedic complications. 10 As mentioned above, Parkes-Weber Syndrome is identical to KTS, except AVMs are present along with CMs, and can be diagnosed using MR projection angiograpy. 11 CMs may also be associated with underlying neurological conditions when overlying areas of the central nervous system. Cobb Syndrome is characterized by a cutaneous vascular nevus, such as a CM, and a spinal canal hemangioma at the same dermatomal level. 12
Pulsed Dye Lasers Originally, argon pumped dye lasers were used in the treatment of port wine stains; however, flash-lamp pulsed dye lasers (PDL) have shown significantly better lightening. 13 Recent literature has found newer, long-pulse-duration dye lasers to be equally effective when compared to PDL in treating PWS. 14 PDL has become the gold standard of treatment for PWS. Mathematical models have determined the optimal pulse duration and wavelength to use based on the size and depth of targeted vessels. As will be discussed below, the literature generally supports a PDL wavelength of 585 nm or 595 nm as safe and effective, as these are the wavelengths optimally absorbed by oxyhemoglobin present in vessels, resulting in intravascular coagulation with minimal damage to surrounding tissues. Greater utilization of videomicroscopy may result in improved outcomes by determining the depth of the CM prior to selecting treatment laser parameters. 15 Other noninvasive imaging, such as infrared and optical Doppler tomography, allow for visualization and determination of vessel size in order to optimize treatment parameters. 16,17 According to mathematical models, vessel diameters of 150 µm to 500 µm are ideally treated with a PDL at 595 nm wavelength with a radiant exposure of at least 12 J/cm2 and pulse time of 1.5 ms, delivered in 2 to 3 stacked pulses. Vessel diameters of 50 µm to 150 µm can be treated with 585 nm or 595 nm wavelength; however, it is projected that vessels smaller than 50 µm will not respond as well to PDL. 18 It is this author’s experience that even these smaller capillaries are quite responsive when pulse durations are increased slightly to 3 ms to 6 ms. In order to minimize pain and risks of side effects, such as scarring, pre-pulse epidermal cooling is highly recommended.
PWSs may be difficult to treat when they become hypertrophic or reach a response plateau after several treatments with PDL. Once PWS become resistant to PDL, they may be treated in combination with the Nd:YAG 1064 nm laser for more effective lightening. 19, 20 The Alexandrite 755 nm laser is efficacious in treating these lesion when used in conjunction with PDL, because it also targets deoxyhemoglobin.
Post-laser treatment, blanching is considered a good prognostic sign. In the confocal microscopy study mentioned above, a correlation between vessel size and blanching was found; superior blanching was noted in PWS with smaller vessel diameter post PDL treatment. 4 It is likely the vessels were larger prior to treatment, and thus the importance of choosing an appropriate wavelength and pulse duration. Age may be a prognostic factor, since a delay in treatment, and an insufficient number of treatments result in hypertrophy and nodularity, and thus a progression of PWS. 21 Increased thickness of the lesion results in decreased penetration of the laser; hence, for best results, PWS should be treated with high-energy PDL before 6 months of age, increasing chances of resolution. 2 Location may be another prognostic factor, as videomicroscopy has found dermatome V3, trunk and neck to have more superficial ecstatic vessels, where dermatomes V2 and extremities have deeper vessels with a lackluster response to treatment. 22
As mentioned above, VEGF and its receptor may play a significant role in the progression of PWS, and thus may be a potential target for future treatment therapies. Recent studies have found statistically significant over-expression of both VEGF and VEGF-R2 molecules when compared with control specimens; thus blockade of the VEGF receptor may be promising for targeted therapy. 3 As mentioned above, RASA1 gene mutations result in CM, as well as other vascular malformation, and may be the focus of future research for gene therapy. The fact that CM has been localized to a single gene mutation, and not as a multifactorial or multigenetic defect, makes it a hopeful candidate for gene therapy. Since PWS are present at birth, and may be associated with complicated syndromes, diagnosis in-utero may result in early treatment. A chart review found an association between umbilical cord hemangiomas, diagnosed via ultrasound, and fetal vascular birthmarks, including PWS. 23 Further research is needed to determine if both presentations are a result of the same etiology, such as an over-expression of VEGF and its receptor, and if this is the case, it may be possible to begin targeted therapy in-utero with the hope of preventing progression or even the development of PWS.
Port wine stains are capillary malformations, which may be related to associated syndromes such as Sturge-Weber, Klippel-Trenaunay syndrome, Parkes-Weber and Cobbs. They progress with age, becoming more intense in color, and hyperkeratotic. It appears there is a genetic component resulting in these capillary malformations, with a mutation of the RASA1 gene, and VEGF and its receptor playing a role as well. Aside from the complications that may be associated with the syndromes mentioned above, PWS are generally benign. However, they may cosmetically impact patients. If treated properly and in a timely fashion, resolution of PWS is possible. The gold standard of treatment is currently pulsed-dye lasers at a wavelength of 585 nm to 595 nm. Since these lesions progress and may become refractory to treatment, other lasers, such as the Nd:YAG and Alexandrite, may be used in conjunction to increase efficacy. New and improved methods are a result of the continuing research in treating PWS, and will contribute to the already promising prognosis of these lesions.n Dr. Buka is Section Chief, Department of Dermatology, Mount Sinai School of Medicine, New York, NY. Ms. Noce is a third year medical student at New York University School of Medicine, New, York, NY. Disclosures: The authors have no conflicts of interest with any material presented in this article.