BJD

R EV IE W AR TI C LE British Journal of Dermatology

Pulsed dye laser-resistant port-wine stains: mechanisms of

resistance and implications for treatment
J.A. Savas, J.A. Ledon, K. Franca, A. Chacon and K. Nouri
Department of Dermatology and Cutaneous Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, U.S.A.

Summary

Correspondence Port-wine stains (PWS) are among the most common congenital vascular malfor-
Jessica Alexis Savas. mations. Unlike capillary haemangiomas, these lesions do not involute spontane-
E-mail: jsavas@med.miami.edu ously but rather become progressively more disfiguring as the patient ages.
While benign in nature, the cosmetic deformity and attendant psychological and
Accepted for publication
18 December 2012
emotional distress prompt the majority of those afflicted to seek treatment. The
pulsed dye laser (PDL) has long been considered the treatment of choice for
Funding sources these vascular lesions; however, very few patients achieve total clearance with
None. PDL therapy and a significant number of lesions fail to respond at all. In order to
address these recalcitrant cases, the mechanisms that contribute to treatment
Conflicts of interest
resistance must be understood and novel laser and light therapies must be
None declared.
employed. This review will address what is currently known about lesion-specific
DOI 10.1111/bjd.12204 characteristics of PDL-resistant PWS as well as discuss current and future treat-
ment options.

Congenital capillary malformations, or port-wine stains (PWS)
are among the most common congenital vascular lesions. It is
estimated that these vascular birthmarks are evident in 0Æ3–
0Æ5% of newborns in the U.S.A.1 The majority of lesions are
present at birth and, unlike capillary haemangiomas, do not
involute spontaneously; rather, they persist into adulthood
continuing to grow in size as the patient ages. Clinically, PWS
appear as pink macules or patches in infancy and over time
develop a deeper red or purple colour due to underlying pro-
gressive vascular ectasia. Diffuse thickening of the lesion grad-
ually occurs with approximately two-thirds of patients
developing hypertrophic or nodular lesions by age 50 years.2
PWS birthmarks are most commonly located on the face
and neck while lesions involving the trunk and extremities
occur less frequently. Facial lesions are usually found in a der-
matomal distribution, typically involving one or more
branches of the trigeminal nerve. Most lesions occur in isola-
tion and are not life-threatening; however their presence tends
to generate a great deal of emotional and psychosocial distress
in affected individuals and their families.3,4
The aetiopathogenesis of PWS remains largely unknown.
Histologically, PWS are characterized by clusters of ectatic cap-
illaries and venules located at varying depths within the mid
to upper dermis. Over time, the diameter of vessels increases,
resulting in a worsening clinical picture and a progressively
disfiguring lesion.5 Based on this observation, Smoller and
Rosen6 postulated that a dysregulation of blood flow might
account for this progressive vascular dilatation. They found a
significant decrease in nerve density and an increased vessel-
to-nerve ratio within PWS lesions when compared with nor-
mal skin, suggesting the possible role of dysfunctional neural
modulation.5,6 Mutations in RASA1 and vascular endothelial
growth factor (VEGF) expression have also been implicated in
the pathogenesis and progression of PWS lesions.7,8
Currently, the pulsed dye laser (PDL) is considered the gold
standard for the treatment of PWS lesions. The PDL was the
first laser system designed around the theory of selective
photothermolysis. According to Anderson and Parrish,9 by
matching the wavelength of the treating laser with the absorp-
tion peak of the target chromophore, one could improve the
efficacy of laser treatments while minimizing the nonspecific
thermal damage that had long complicated the use of lasers in
dermatology.
The improvement in lesional lightening and decrease in size
after PDL treatment is well documented; however, complete
clearance is achieved in < 10%, and roughly 20% of lesions
fail to lighten at all.10 Lesion re-darkening secondary to revas-
cularization is another possible limitation of treatment with
the PDL. Between 16Æ3% and 50% of patients noted re-darken-
ing of their PWS as early as 5 years after PDL treatment.11,12
Due to the heterogeneous nature of PWS, response to treat-
ment differs not only between affected individuals but also
within the same lesion. The factors that influence the unpre-
dictability and resistance of PWS to PDL treatment are many
and to date no true definition of ‘PDL-resistant PWS’ has been
established. This article will address the factors thought to

 2013 The Authors British Journal of Dermatology (2013) 168, pp941–953 941
BJD  2013 British Association of Dermatologists
942 Pulsed dye laser-resistant port-wine stains, J.A. Savas et al.
contribute to treatment resistance, as well as review currently
available treatment options for these more difficult cases.
Mechanisms of resistance
Age of patient and size of lesion
Early in infancy, PWS have not yet had adequate time to
develop into larger, thicker lesions and are thus more effec-
tively treated. Additionally, treating the lesion before the child
is aware of any abnormality may entirely prevent the psycho-
logical trauma known to be associated with PWS.13
One study with 83 patients aged between 2 weeks and
17 years compared treatment outcomes based on patient age
alone. They found that when treatment was initiated prior to
1 year of age, 32% achieved lesion clearance compared with
only 18% in older patients.14 Nguyen et al.15 also found that
patients aged < 1 year at the time of PDL treatment demon-
strated a 63% mean decrease in size vs. a 48% decrease in
children aged 1–6 years over the same number of treatments.
Furthermore, Chapas et al.16 reported an 88Æ6% average clear-
ance in 49 infants aged < 6 months who were treated with
the 595-nm PDL. The authors reported no increased incidence
of adverse effects in this young patient population despite the
use of more aggressive settings.
Several authors have also commented on lesion size as a
parameter closely related to age in terms of treatment out-
come. Independent of age, however, lesions < 20 cm2 were
associated with better treatment responses after five treatments
with the PDL than lesions > 40 cm2 (67% and 23% mean
decrease in size, respectively).15
Patients who are older at the time of treatment initiation
may have larger, more evolved lesions. Furthermore, older
children have thicker skin and possess a diminished capacity
for efficient wound healing when compared with young chil-
dren and infants, thus increasing their risk for resistance to
PDL treatment.
Anatomical location
While no PWS has predictable morphological features, there
are discernible trends in lesion characteristics and treatment
outcome based on anatomical location or dermatomal distri-
bution.
One study looking at mean decrease in lesion size based on
anatomical location found that central forehead lesions
responded best with 100% clearance after five treatments,
while peripheral facial lesions achieved 58% clearance, fol-
lowed by the central face at 48% and lastly, lesions with a
combination of central and peripheral components responded
with a 21% mean decrease in size.15
Renfro and Geronemus also compared lesion response with
treatment based on anatomical location; however, they used
percentage lightening as a primary endpoint. Periorbital, fore-
head ⁄temple, lateral aspect of the cheek, neck and chin
achieved a mean lightening of 82Æ3% while centrofacial
British Journal of Dermatology (2013) 168, pp941–953
lesions proved to be more resistant. Furthermore, when evalu-
ated by dermatomal distribution, V2 lesions displayed greater
resistance to treatment than V1 or V3 and C2 ⁄C3 lesions.17
PWS on the distal limb appear to be the most impervious to
treatment.18 Nguyen et al.15 concluded that anatomical location
was the most important predictor of treatment response,
followed by lesion size and patient age.
Skin thickness
Differences in skin thickness have been studied as a copredic-
tor of outcome in the treatment of PWS lesions in an effort to
explain the variable responses to treatment by anatomical loca-
tion and age.
Using video microscopy, Nagore et al. examined skin thick-
ness in children with and without PWS according to anatomi-
cal location, age and sex to determine their respective impact
on clinical outcome. Statistically significant differences were
found based on anatomical location and age, while no signifi-
cant difference was found between sexes.19 Skin in children
aged > 6 years was thicker than that in younger children, sup-
porting the current view that treatment at a younger age is
ideal. In regards to anatomical location, centrofacial areas were
thicker than peripheral areas, possibly due to a greater number
of sebaceous units found in the centrofacial region. When
examined by dermatomal distribution, the V1 dermatome
demonstrated the greatest thickness, followed by V2 and V3,
with C1–C2 dermatomes being the thinnest.19 The variation
in skin thickness was roughly consistent with the clinical
responses seen after PDL treatment to these areas.15,17,18
Skin thickness, much like lesion size, is not constant over
time. As the patient ages, PWS increase in both size and
thickness, often becoming hypertrophic and ⁄ or nodular.
The incidence of hypertrophic and nodular lesions has been
reported between 10% and 40% with a median age at
onset ranging from 20 to 39 years for hypertrophy,
39 years for nodules and as early as 12 years for the onset
of diffuse thickening.2,20–22 Despite the variability in inci-
dence and age at onset, most authors agree that increasing
age is strongly correlated with increased incidence of
hypertrophic PWS. No significant association has been
found between size or location and the development of
hypertrophy.22 PWS thickness, as a function of anatomical
location or age, is directly correlated with increasing resis-
tance to PDL treatment.
Characteristics of vessels (depth, diameter and wall
thickness)
Histologically, PWS demonstrate ectatic capillaries with dia-
meters ranging from 10 to 150 lm at a depth of 300–600 lm
within the dermis.23 While several studies have established a
correlation between lesional response to treatment with
patient age, lesion colour and anatomical location, Fiskerstrand
et al. hypothesized that vessel diameter, wall thickness and
depth in the dermis may also have a significant impact on
 2013 The Authors
BJD  2013 British Association of Dermatologists

treatment outcomes. They found that lesions with a good-
to-moderate clinical response were composed of vessels of
moderate size, located superficially within the dermis (red
macules clinically); whereas, vessels that were significantly
smaller and located deeper in the dermis displayed the poorest
clinical response (pink macules clinically). Vessel wall thick-
ness was found to increase with increasing depth, which sup-
ported the observation that lesions with more superficially
located vessels achieved greater blanching with treatment.24
The relationship between vessel diameter and depth was
found to vary with anatomical location, possibly explaining the
differences in clinical outcome based on location.17,25 The most
deeply located vessels were found in lesions on the face, pro-
viding a potential explanation as to why a lower percentage of
facial PWS achieve a good clinical response when compared
with lesions on the neck, trunk and proximal extremities.26 Fis-
kerstrand et al. also performed a histochemical analysis of the
vessels post-treatment to evaluate the degree of vessel wall
necrosis as determined by vessel depth, diameter and wall
thickness. These results followed a similar trend in that the ves-
sels found to be viable or partly viable (not coagulated) after
treatment had diameters < 20 lm and were located > 400 lm
from the dermoepidermal junction.26 Another study looked at
the predictive value of pretreatment capillary diameter on clini-
cal outcome and found that PWS with larger pretreatment
diameters (> 40 lm) were more likely to respond than those
with pretreatment diameters less than this.27 Based on these
data, one can extrapolate that treatment-resistant PWS may have
a greater composition of small, deeply located vessels that are
beyond the reach of coagulation by the PDL.
Number of treatments
Regardless of age, initial size or anatomical location, Nguyen
et al. found that the greatest clinical improvement in PWS size
was seen in the first five treatments with a 585-nm PDL (55%
decrease) when compared with the second five treatments
(additional 18% decrease).15 This diminished response to suc-
cessive PDL treatments may be secondary to an effect of laser
Skin thickness
(hypertrophic or
nodular lesions)
Anatomical location
(central face)
Size of lesion
(> 40 cm2)
Age
(> 1 year old)
Fig 1. Pictorial summary of factors contributing to pulsed dye laser (PDL)-resistance of port-wine stains (PWS).
 2013 The Authors
BJD  2013 British Association of Dermatologists
Pulsed dye laser-resistant port-wine stains, J.A. Savas et al. 943
treatment on vessel morphology. Several studies have docu-
mented that prior PDL treatment results in smaller and deeper
vessels post-treatment.24,28,29 Given that smaller, deeper ves-
sels are more difficult to treat, previous treatments with a PDL
may significantly contribute to resistance to subsequent treat-
ment.
There are multiple reasons why a PWS may reach a treat-
ment plateau or demonstrate resistance to PDL treatment
(Fig. 1). Variations of traditional PDL therapy and novel laser
and light therapies have been investigated to address these
recalcitrant cases.
Treatment options for pulsed dye laser-
resistant port-wine stains
Variations on traditional pulsed dye laser treatment
Over time, PDL treatment has evolved in an attempt to address
recalcitrant PWS lesions. The original 577 ⁄585-nm wavelength
was adjusted to 595 nm to achieve deeper penetration while
still maintaining vascular specificity. Pulse durations were
expanded to heat larger vessels more efficiently and adjuvant
technologies such as epidermal cooling were employed to
allow for the use of higher fluences without increasing the
risk of epidermal damage. Finally, techniques such as pulse
stacking, double-passes, and repetitive treatments have had
variable results on clinical outcomes in resistant PWS.30–34
Potassium-titanyl phosphate laser
The potassium-titanyl phosphate (KTP) laser uses a 1064-nm
Nd:YAG (neodymium:yttrium-aluminium-garnet) laser source
that is frequency-doubled with a KTP crystal to produce green
light at a wavelength of 532 nm.35 The KTP laser is also
capable of producing pulse durations up to 50 ms. While the
532-nm wavelength closely approximates the oxygenated hae-
moglobin absorption peak, providing for selective penetration,
the melanin absorption at this wavelength is higher than that
at 585 nm, resulting in an increased potential for epidermal
Vessel depth > 400 μm
from dermoepidermal
junction
Vessel diameter < 20 μm
PDL-
resistant
Number of
PWS
treatments (> 5)
British Journal of Dermatology (2013) 168, pp941–953
944 Pulsed dye laser-resistant port-wine stains, J.A. Savas et al.

injury. Conversely, when compared with the PDL, the KTP

laser does not illicit a purpuric response immediately post-

PWS can be further improved with

higher incidence of adverse effects

A small percentage of PDL-resistant

PDL-resistant PWS but results in a

treatment, making recovery more acceptable for the patient.36

The KTP laser can further lighten

One study comparing the PDL with the KTP laser found no

when compared with PDL

significant difference in PWS clearance and in fact found the
KTP laser to be significantly inferior to the PDL at certain
pulse durations and fluences. Additionally, patients experi-

the KTP laser

enced a greater severity of pain with the KTP laser treat-
ments.37 Woo et al. examined 22 patients with persistent PWS

Summary
after undergoing multiple treatments with the PDL. Only a
small percentage (three of the 22 patients) showed a > 25%
improvement with the 532-nm laser and no long-term com-
plications were reported.38 Chowdhury et al. also studied the

experienced hyperpigmentation, 3%
efficacy and tolerability of the KTP laser in 30 PDL-resistant

KTP laser compared with the PDL

immediate post-treatment effects

post-treatment purpura with the

experienced prolonged healing
PWS and found that overall, 21 patients showed > 25%

complications. No mention of

Patients reported less pain and

7% experienced scarring, 10%
improvement, one of whom actually achieved a 100%

No reported ‘long-term’
response. Side-effects were described in six patients and

Table 1 Summary of studies investigating the potassium-titanyl phosphate (KTP) laser for pulsed dye laser (PDL)-resistant port-wine stains (PWS)
included hyperpigmentation, scarring and prolonged healing,

(beyond 4 weeks)
in order of decreasing incidence.36

Adverse effects
The discrepancy in adverse effects and efficacy between the
studies of Woo et al. and Chowdhury et al. is quite striking but
upon closer observation may have been secondary to the laser
parameters employed by each investigator. Chowdhury et al.
reported enhanced outcomes with fluences ranging from 18 to
24 J cm)2 and a pulse duration of 9–14 ms vs. Woo and

16 (53%) patients showed > 25% response,

Facial PWS responded better than other sites

5 (17%) patients showed > 50% response
50–75% improvement, 1 patient achieved

50–75% improvement, 1 patient achieved

colleagues’ more conservative parameters of 7 J cm)2 and a

At 16 J cm)2 ⁄ 10 ms: 2 patients achieved

2-ms pulse duration or 16 J cm)2 with a 10-ms pulse duration. At 7 J cm)2 ⁄ 2 ms: 2 patients achieved
Additionally, Chowdhury et al. treated patients over one to four
sessions whereas Woo et al. treated patients only once.
The conflicting data reported by these two studies suggest
that further studies are needed to find the optimal treatment 25–50% improvement
parameters before the KTP laser can be recommended as a safe
and effective treatment for PDL-resistant PWS (Table 1).
n = 22 patients

n = 30 patients
25–50%
Results

Alexandrite (755 nm) laser

While alexandrite lasers are most commonly used for hair
removal, their efficacy in the treatment of leg veins and small
venous malformations is also well established.39–41 This latter
1 treatment, follow-up evaluation at

1–4 treatments, 2-month intervals

indication spurred interest in the alexandrite laser’s possible

Passes and overlap: not reported

use for the treatment of other vascular lesions, such as PWS.

Local anaesthetic as requested
Single pass with no overlap

In a direct comparison between the alexandrite laser and four

Pulse width: 2 or 10 ms
Fluence: 7 or 16 J cm)2

Fluence: 18–24 J cm)2

Spot size: not reported

other laser and light-based systems, the most significant

Pulse width: 7–14 ms
No local anaesthesia

response to treatment occurred in the test patches treated with

Spot size: 3 mm
Contact cooling

the alexandrite laser, both in terms of number of test patches

responding and degree of fading achieved. Unfortunately, the
Parameters

6 weeks

alexandrite laser also had the highest incidence of adverse

effects, namely hyperpigmentation and atrophic scarring;
however, these were limited to the test patches treated at a
higher fluence (70 vs. 50 J cm)2).27
Chowdhury et al.36

Tierney and Hanke performed a pilot study to assess the

degree of improvement in eight patients with refractory facial
38

PWS (mean of 25Æ9 previous treatment sessions with PDL)

Woo et al.

using the 755-nm millisecond pulsed alexandrite laser. Using

Study

a 3-ms pulse duration, 8–12-mm spot size, 40–60 J cm)2 and

dynamic cooling, they achieved a 56% mean improvement in

British Journal of Dermatology (2013) 168, pp941–953  2013 The Authors

BJD  2013 British Association of Dermatologists

skin colour, 60% mean improvement in skin texture and 59%
mean improvement in overall cosmetic appearance. All
patients noted postoperative purpura and oedema; however,
no incidence of blister formation, crusting, dyspigmentation
or scarring was reported at the settings used.42
Izikson et al. studied three patients with hypertrophic lesions
who were previously untreated, as well as flat PWS in 17
patients who had reached a treatment plateau with PDL.
Hypertrophic PWS treated with both the alexandrite laser and
PDL in the same session achieved greater clinical lightening
than when treated with alternating alexandrite and PDL. Resis-
tant PWS treated with the alexandrite alone or in combination
with PDL showed moderate lightening in 12 of 17 patients
after anywhere from 3 to 10 sessions. The side-effects were
mild and transient and occurred in only a minority of
patients.43
The efficacy of the alexandrite laser for treatment-resistant
PWS may be due primarily to two theoretical advantages
over other laser treatment modalities. The alexandrite laser
is capable of a greater depth of penetration allowing for
the treatment of PWS with deeper dermal components.
Secondly, the 755-nm wavelength has a higher absorption
coefficient for deoxygenated haemoglobin, the primary
chromophore in venous vessels. Other lasers more selec-
tively target oxyhaemoglobin, the primary chromophore in
arterial vasculature, making them less useful in predomi-
nantly venous malformations such as PWS.44 The alexandrite
laser can be considered for treatment of PWS lesions that
have become unresponsive to the PDL; however, further
studies are warranted to delineate the true role of this laser
in PWS treatment (Table 2).
The 1064-nm Nd:YAG laser
PDL-resistant and hypertrophic PWS may require the use of
lasers with deeper penetration and longer pulse durations
than the PDL, such as the 1064-nm Nd:YAG laser. Larger
calibre vessels possess longer thermal relaxation times and
therefore require lengthier pulse durations to target these
vessels when they become unresponsive to other laser sys-
tems. Additionally, the longer wavelength of the Nd:YAG
laser can achieve coagulation effects at a depth of 5–6 mm,
far beyond the 2 mm maximal penetration depth that limits
PDL therapy.45 Although the Nd:YAG laser has been shown
to be effective for deep vascular lesions, it must be used
with discretion when treating PWS. Treatment with this laser
at fluences slightly above the minimal purpuric dose has
been shown to carry an unacceptable potential for scarring
and dyspigmentation.45
In a study by Liu et al., > 90% clearance was achieved by
four of 20 patients with recalcitrant PWS treated with the
long-pulsed Nd:YAG laser. Another 12 patients showed
between 30% and 60% improvement. Notably however, eight
patients experienced pigmentary changes or scarring.46 A
combined approach using a 595-nm PDL followed by the
1064-nm Nd:YAG has also been investigated for improved
 2013 The Authors
BJD  2013 British Association of Dermatologists
Pulsed dye laser-resistant port-wine stains, J.A. Savas et al. 945
efficacy and tolerability in recalcitrant PWS. Initial treatment
with PDL induces a shift from haemoglobin to methaemo-
globin, which has an absorption coefficient that coincides
closely with 1064 nm. The synergistic effect of this dual
wavelength technique more selectively targets PWS vasculature
at lower fluences with fewer attendant adverse effects.47 A
study looking at the efficacy of a combined 595 and 1064 nm
irradiation technique in recalcitrant and hypertrophic lesions
found up to 50% additional clinical improvement in all 25
patients included in the study with only minimal side-effects
and no reports of scarring or pigmentary changes.47
In a 2011 study by Li et al., six different laser protocols
were used to compare the efficacy and epidermal effects of
sequential and single-wavelength irradiation on reducing ves-
sel number in a rooster comb model. Single- and double-pulse
595 nm, single- and double-pulse 1064 nm and sequential
595 nm with 1064 nm irradiation techniques were all com-
pared against an untreated control group using an optical
microscope to observe vessel and epidermal changes post-
treatment.48 While all treatment protocols resulted in a signifi-
cant decrease in vessel numbers compared with the control,
no significant difference was found among the laser-treated
groups. Similarly, there was no significant difference among
the laser-treated groups in regards to epidermal oedema or
damage. Although there was a lack of significant difference in
efficacy between PDL and sequential therapy, the same results
were obtained in both groups despite the use of subpurpuric
doses of both the PDL and Nd:YAG in the sequential protocol.
The authors concluded that given the increased epidermal
melanin content of the human skin compared with the rooster
comb, the ability to achieve the same therapeutic outcomes
with less aggressive laser parameters may confer a significant
advantage when treating human patients with PWS.48 While
further studies are needed, the 1064-nm Nd:YAG, when used
by experienced laser surgeons, may be a promising adjunct to
PDL when treating resistant PWS lesions (Table 3).
Intense pulsed light
Intense pulsed light (IPL) is a noncoherent light source that
produces wavelengths in the range of 500–1200 nm and has
the ability to produce longer pulse durations, variable pulse
durations and variable fluence energies. These characteristics
allow for the treatment of vessels of varying depths and dia-
meters, making IPL an attractive option for treating PWS.49 In
a study by Bjerring et al., 15 patients received four IPL treat-
ments at 2-month intervals with seven patients achieving 50%
lightening or better (average of 84%). The majority of side-
effects reported were minor and transient.50 Raulin et al.51
found that in 12 previously treated PWS, IPL resulted in a
58% good-to-excellent response rate in treatment-resistant
PWS. Despite the ability of IPL to further lighten resistant
lesions, it is still recommended that IPL be considered only
after PDL-treatment failure due to the less favourable side-
effect profile of IPL when compared with PDL, particularly in
skin of colour30 (Table 4).
British Journal of Dermatology (2013) 168, pp941–953
 Table 2 Summary of studies investigating the 755-nm alexandrite laser for hypertrophic or nodular port-wine stains (PWS) and pulsed dye laser (PDL)-resistant PWS

Study Parameters Results Adverse effects Summary

27
McGill et al. 1 treatment, evaluated at 2 months n = 16 patients Hyperpigmentation in 4 patients at The alexandrite laser was the most effective
Fluence: 50–70 J cm)2 Fading was achieved in 10 patients the higher fluence; 1 of these of the four lasers or light sources used
Pulse width: 3 ms The alexandrite laser was also the only patients also had evidence of when compared with a PDL control
Spot size: 8 mm laser test that resulted in a significant atrophic scarring
Dynamic cooling device used decrease in post-treatment capillary

British Journal of Dermatology (2013) 168, pp941–953

diameter
Tierney and 2–4 treatments, 6–8 week intervals n = 8 patients Transient purpura and oedema. No PDL-resistant PWS responded significantly to
Hanke42 Fluence: 40–60 J cm)2 56Æ3% mean improvement in skin col- blistering, crusting, a series of treatments with the alexandrite
Pulse width: 3 ms our, 60Æ0% mean improvement in skin dyspigmentation or scarring laser with no significant adverse effects
946 Pulsed dye laser-resistant port-wine stains, J.A. Savas et al.

Spot size: 8–12 mm texture, 59Æ4% mean improvement in reported

Dynamic cooling of 60 ⁄ 40 overall cosmetic appearance
Izikson et al.43 2–10 treatments, no mention of intervals n = 17 patients Transient and predictable erythema, Most PDL-resistant lesions showed moderate
Fluence: 35–100 J cm)2 12 patients showed moderate lightening, oedema, purpura and pain. 2 improvement with mild side-effects.
Pulse width: 3 ms 5 patients with alexandrite alone and 7 patients developed small Alexandrite laser may be a useful adjunct
Spot size: 8–12 mm patients with alexandrite + PDL hypertrophic scars and blistering. 1 to PDL therapy in PWS lesions that have
Single pass 3 patients showed mild lightening, 2 incident of hypopigmentation reached a treatment plateau. Further studies
Cryogen spray cooling or forced air cooling patients with alexandrite alone and 1 Permanent hair loss is also an are warranted to delineate the true role of
Children treated under general anaesthesia, patient with concurrent alexan- expected sequelae the alexandrite laser in PWS treatment
adults treated with local anaesthesia as drite + PDL
needed 1 patient showed significant improve-
ment with alexandrite alone
1 patient showed no response with alex-
andrite alone

BJD  2013 British Association of Dermatologists

 2013 The Authors
 Pulsed dye laser-resistant port-wine stains, J.A. Savas et al. 947

Photodynamic therapy

laser and its increased incidence of

narrow therapeutic window of the

epidermal damage compared with

improve PWS that have reached a

Caution must be used due to the

PDL-resistant PWS with minimal

Photodynamic therapy (PDT) is a relatively new modality used

The 1064-nm Nd:YAG laser can

treatment plateau with PDL.

primarily in the treatment of cancer. The successful use of

Dual 595-nm PDL ⁄ 1064-nm

Nd:YAG laser can improve
PDT requires oxygen, a photosensitizing agent and a wave-
length of light in the visible spectrum. When targeted by an
appropriate wavelength, the photosensitizer will react with

adverse effects
oxygen to produce singlet oxygen and other reactive oxygen
species (ROS). The cytotoxic effects of the ROS produced can
Summary

damage cellular components and eventually induce cell

PDL death.52 Studies have also shown that in regard to vascular
effects, PDT can cause endothelial damage, vasoconstriction,
thrombus formation and blood flow stasis.53,54 Theoretically,
to-moderate pain during treatment

alteration or scarring was noted in

these PDT-induced vascular changes could be advantageous in
Mild purpura and vesicle formation

the treatment of PWS lesions.

in 1 patient. No pigmentary
Most patients reported mild-

A long-term study conducted on 1385 patients with 1949

PWS lesions found that irradiation with a frequency-doubled
Nd:YAG laser after intravenous injection of a photosensitizing
agent resulted in the complete clearance or only slight residual
Adverse effects

colour in 874 (44Æ8%) lesions after one PDT treatment ses-

any patient

sion.55 Only minor adverse effects occurred, namely skin

Table 3 Summary of studies investigating the 1064-nm Nd:YAG laser for pulsed dye laser (PDL)-resistant port-wine stains (PWS)

photosensitivity and transient oedema, crusting or dyspigmen-

tation that resolved without consequence. The authors con-
cluded that all types of PWS lesions (from pink to purple with
proliferation) regardless of treatment history could safely
improvement, 13 showed 1–25%

achieve clinical lightening with PDT.

Another study assessing the efficacy of PDT in the treatment
4 showed > 90% clearance, 3
showed 61–90% clearance, 9
showed 31–60% clearance, 3

12 showed 25–50% clinical

of PWSs was conducted on 75 patients using a treatment pro-

showed < 30% clearance

tocol that consisted of copper vapour laser exposure after

administration of a photosensitizing agent. Complete clinical
remission was found in 57% of patients.56
n = 20 patients

n = 25 patients

improvement

Although PDT introduces the possibility of mild photosensi-

tivity reactions, it also offers the unique advantage of more
Results

selective vascular damage. The epidermis takes up little or no

photosensitizer during treatments, thus sparing the skin from
nonselective epidermal damage like that seen in PDL. By using
photosensitizers with faster clearance rates and refining the
technique of vascular-targeted PDT, one may be able to lower
the incidence of adverse effects and increase the efficacy of
3–6 treatments, 6–8 week intervals

2–7 treatments, 6–8 week intervals

Single laser pass with 10% overlap

Nd:YAG fluence ⁄ pulse width: 30–

PDT in the treatment of both recalcitrant as well as previously

untreated PWS lesions (Table 5).57
PDL fluence ⁄ pulse width: 6Æ5–

Local anaesthetic as requested

9Æ5 J cm)2 ⁄ 6 ms or 10 ms

Although current knowledge on the safety and efficacy of

Pulse width: 10–20 ms
Fluence: 65–95 J cm)2

Single pass, no overlap

PDT is improving and techniques and treatment protocols are

50 J cm)2 ⁄ 10–20 ms
No local anaesthesia

constantly being refined, most studies contributing to this

Spot size: 5–7 mm

Forced air cooling

Spot size: 10 mm
Contact cooling

knowledge come from China and few others have been able
to reproduce similarly favourable findings. Additional prospec-
Parameters

tive studies are warranted before any real conclusions can be

accurately drawn about PDT treatment of PWS.

Future directions
Alster and Tanzi47

Fractional ablative resurfacing

46
Liu et al.

Ablative fractional laser resurfacing utilizes narrow beams of

Study

high-energy light to create vertical cones of ablated tissue

within the skin, termed microscopic treatment zones (MTZ).58

 2013 The Authors British Journal of Dermatology (2013) 168, pp941–953

BJD  2013 British Association of Dermatologists
948 Pulsed dye laser-resistant port-wine stains, J.A. Savas et al.

These channels induce epidermal and dermal remodelling

IPL is safe and efficacious

through various mechanisms. It has been theorized that these

acceptable safety profile

PDL-resistant dark-type
except for those in the
PWS resistant to PDL

PWS lesions with an

treatment zones disrupt the vascular network of PWS through

for the treatment of

centrofacial region
direct physical damage to the vessels and extracellular matrix

IPL is particularly
efficacious with
or through modulation by cytokines released as part of an in-
flammatory response in the MTZs.59 Theoretically, these
Summary

changes could result in enhanced lightening of a PWS. Preli-

minary data for combined fractionated Er:YAG (erbium-doped:
YAG) laser with PDL on the same treatment day showed
promising results in a small case series involving three patients

Swelling and blisters were generally associated

immediate erythema observed in all patients.

with PDL-resistant facial PWS.59 To date, these are the only

Variable degrees of oedema observed in all

hyperpigmentation, 1 patient experienced

Heat damage and acute inflammation with

experienced hypopigmentation, 2Æ7% of

patients experienced hyperpigmentation
immediate purpura in 76% of sessions. data published on combined PDL and fractional photothermol-
hypopigmentation, 1 patient had mild

experienced crusting, 8Æ1% of patients

Immediate erythema in all sessions and

with higher fluences. 20% of patients

ysis for resistant PWS emphasizing the need for further studies
with larger cohorts to validate the efficacy of the Er:YAG laser
patients, 3 patients experience

in this context. Additionally, investigation into other fractional

slight epidermal atrophy

ablative devices, such as the carbon dioxide (CO2) laser, may

also be warranted based on favourable results obtained using
continuous wave CO2 ablative laser resurfacing for treatment-
Adverse effects

naive nodular and hypertrophic PWS.60

Indocyanine green-augmented diode laser therapy

Table 4 Summary of studies investigating intense pulsed light (IPL) for pulsed dye laser (PDL)-resistant port-wine stains (PWS)

To maximize selective thermal damage to smaller vessels,

All nonresponders had lesions in the V2 tri-

1 lesion achieved 100% clearance, 6 lesions

> 75% clearance, 14Æ3% achieved 50–74%
clearance, 8 patients did not respond to IPL
7 patients responded to IPL: 85Æ7% achieved

some authors have utilized indocyanine green (ICG) as an

exogenous target chromophore with subsequent diode laser
achieved 70–99% clearance, 4 lesions
achieved 40–69% clearance, 1 lesion

treatment (ICG + DL) for refractory PWS. ICG exhibits maxi-

mum absorption at 810 nm, making it an ideal target for the
n = 37 patients with 40 PWS

diode laser. This combined treatment technique was inspired

12 previously treated PWS

achieved < 40% clearance

by earlier observations of ICG + DL-induced irreversible pho-

tocoagulation of small (< 29 lm) blood vessels in an animal
geminal dermatome
(< 25% clearance)

model.61
n = 15 patients

ICG is a water-soluble dye that completely bypasses the en-

terohepatic circulation with a serum half-life of approximately
2Æ5–3 min.62 Given the rapid clearance of the dye, injection
Results

and laser treatment can be accomplished conveniently in one

session. While the ICG itself has a relatively favourable side-
effect profile, the administration of an intravenous dye as part
Single-, double- and triple-pulsed sequences used
Variable number of treatments, 4-week intervals

of the treatment protocol renders the procedure more invasive

than laser therapy alone and carries with it all the risks inher-
ent to venipuncture, such as nerve damage, haematoma for-
Cut-off filters used: 515, 550, 570 nm

mation, phlebitis and vasovagal episodes.63 Importantly

Emitted wavelength: 555–950 nm

No mention of epidermal cooling

however, the preparation does contain sodium iodide and its

4 treatments, 2-month intervals

use should therefore be avoided in patients with a history of

iodide allergy.64
Pulse width: 0Æ5–30 ms
Spot size: 10 · 48 mm
Fluence: 13–22 J cm)2

Fluence: 24–60 J cm)2

Local anaesthesia used

Pulse width: 8–30 ms

Spot size: 8 · 35 mm

In 28 patients with PDL-resistant PWSs, ICG given in a dose

No anaesthesia used

of 2 mg kg)1 of body weight plus diode laser therapy

Cooling gel use

(810 nm, 20–50 J cm)2, 10–25 ms pulse duration) proved to

Parameters

be safe with promising efficacy. Investigator ratings of PWS

clearance after therapy demonstrated a trend towards
ICG + DL over the flashlamp-pumped PDL, although it did
not reach statistical significance. No adverse events reported
Bjerring et al.50

were due to the ICG itself, suggesting that the addition of the
Raulin et al.51

dye might not add significant risk for patients.63

On histological analysis, blood vessels < 20 lm proved to
Study

be resistant to ICG + DL therapy and 3 months after treatment

compensatory angiogenesis occurred in ICG + DL-treated sites.

British Journal of Dermatology (2013) 168, pp941–953  2013 The Authors

BJD  2013 British Association of Dermatologists
  2013 The Authors
Table 5 Summary of studies investigating photodynamic therapy (PDT) for pulsed dye laser (PDL)-resistant port-wine stains (PWS)

Study Parameters Results Adverse effects Summary

55
Qiu et al. 1–4 treatments, 2-month intervals n = 1385 patients with 1949 PWS lesions Skin photosensitivity, PDT is effective, albeit
HMME or PSD-007 photosensitizer used at a 128 lesions achieved > 95% clearance, 746 lesions crusting and tempo- variable, in all
dosage of 3–7 mg kg)1 achieved 75–94% clearance, 923 lesions achieved rary pigmentation patients regardless of

BJD  2013 British Association of Dermatologists

Irradiation was initiated immediately after 25–74% clearance, 145 lesions achieved < 25% lesions colour or
intravenous administration of photosensi- clearance, 7 lesions showed no response treatment history.
tizer Of the lesions achieving an excellent response, Pink lesions were
Power density: 50–100 W cm)2 17Æ3% were pink lesions most sensitive to
Fluence: 90–540 J cm)2 No recurrences reported at follow-up 19 years later PDT treatment,
Spot size: 8–9 cm in diameter lesions which tend
to be resistant to
traditional PDL
therapy
Lu et al.56 1–4 treatments, 3-month intervals n = 75 patients with 22 treatment-resistant lesions Variable oedema and The majority of
PSD-007 photosensitizer used at a dosage of Complete clinical remission rate of 57Æ33% crusting in the major- patients can safely
5 mg kg)1 ity of patients. No achieve PWS
Irradiation with the argon laser began patients experienced lightening regardless
within 5 min after 1 ⁄ 3 of the photosensi- scar formation of treatment history
tizer was injected or lesion
Wavelengths: 510Æ6 and 578Æ2 nm characteristics
Power density: 80–100 W cm)2
Fluence: 160–360 J cm)2
Pulse width: 20–40 ms
Spot size: 2–8 cm

HMME, haematoporphyrin monomethyl ether; PSD-007, haematoporphyrin derivative.

Pulsed dye laser-resistant port-wine stains, J.A. Savas et al. 949

British Journal of Dermatology (2013) 168, pp941–953

950 Pulsed dye laser-resistant port-wine stains, J.A. Savas et al.
The authors asserted that a higher concentration of ICG
(4 mg kg)1) effectively coagulated all small vessels in an ani-
mal model and, therefore, a similar or higher dose of ICG
may be more effective on human vessels as well, albeit with
an increased potential for nonspecific epidermal damage.63
Further investigation is required to corroborate the safety and
efficacy of this experimental treatment modality for resistant
PWS.
Antiangiogenic agents
It has been postulated that the treatment failure of PWS lesions
is due in part to regeneration and revascularization of pho-
tocoagulated vessels.65 Antiangiogenic agents such as topical
rapamycin and imiquimod cream have shown encouraging
results for enhanced PWS lightening when used in combin-
ation with PDL therapy.
After laser photothermolysis-induced vessel coagulation,
blood supply to the skin is markedly reduced. Resultant local
hypoxia initiates the body’s normal wound healing response
and induces angiogenesis. Mammalian target of rapamycin
(mTOR) signalling via upregulation of hypoxia-inducible fac-
tor-1a is an important component of this cellular response to
hypoxia by increasing the expression of hypoxia-responsive
genes such as VEGF. VEGF expression has been implicated in
both the pathogenesis of PWS as well as the reappearance or
re-darkening of lesions after PDL treatment.66 Rapamycin is a
specific inhibitor of mTOR, and therefore a potent suppressor
of angiogenesis. Theoretically, concurrent administration of
rapamycin may prevent the reformation and reperfusion of
PWS after PDL treatment.66,67 In an animal model, the appli-
cation of topical rapamycin significantly reduced the frequency
of vessel reperfusion when compared with laser treatment
alone.65 Based on these and similar results in preliminary
studies on normal human skin,68 a clinical study performed
on a patient with PWS demonstrated an enhanced blanching
response of combined PDL and rapamycin vs. standard PDL
alone. The enhanced blanching response seen in the PDL–rapa-
mycin combined treatment sites was maintained at 13-month
follow-up and the treatment was well tolerated by the
patient.66 Enhanced blanching has also been documented with
the application of 5% imiquimod cream (a topical immune
response-modifying agent that inhibits neovascularization by
activating Toll-like receptor 7) after PDL therapy three times a
week for eight weeks.69 Larger, controlled trials are warranted
to confirm the safety and efficacy of antiangiogenic agents in
adults, children and infants with PWS.
Perioperative haemodynamic alterations in port-wine
stain vasculature
The size of blood vessels that have proven most resistant to
treatment fall within the range of 10–30 lm in diameter and
require a thermal relaxation time less than the 0Æ5–1Æ5 ms
pulse duration generated by most PDL devices.9,70 Further-
more, diminished blood volume compared with larger diame-
British Journal of Dermatology (2013) 168, pp941–953
ter vessels, as well as a nonuniform erythrocyte concentration,
may also contribute to the resistance of smaller vessels to PDL
treatment.71 Consequently, failure of PDL photocoagulation
occurs due to both insufficient heat production, as well as
decreased intraluminal target chromophore.72 Efforts have
been made to increase intravascular haemoglobin concentra-
tion and thus mitigate the influence of small vessel diameter
on PWS resistance through perioperative haemodynamic alter-
ation. This can be accomplished mechanically through the
obstruction of venous outflow via the application of hypobaric
pressure. Vacuum-induced vasodilation is one approach that
has been investigated to increase vessel diameter and blood
volume fraction while simultaneously decreasing vessel depth,
thus rendering small vessels more vulnerable to destruction
via selective photothermolysis with lower radiant energy
exposure.71
Pneumatic skin flattening (PSF) is a technique that exploits
these hypobaric pressure-related changes and has recently
found applications in the treatment of PWS. PSF involves the
generation of a vacuum over the skin while simultaneously
flattening the skin against a transmitting window. This tech-
nique has been shown to reduce pain significantly during
PDL treatment of PWS lesions.73 The same vacuum device,
without skin flattening against a window, has also been used
to increase the efficacy of PDL treatments in recalcitrant PWS
lesions based on observations that generating a vacuum over
the skin results in significant capillary dilatation and sub-
sequent blood enrichment in the treated area.74,75 Kautz et al.
conducted a within-patient comparison of the use of a non-
contact vacuum with a 595-nm PDL against a 595-nm PDL
alone in 11 patients with resistant PWS. Based on the subjec-
tive evaluation of lesion blanching assessed by unblinded
investigators, the authors reported enhanced efficacy in 63%
of patients, favouring the noncontact vacuum plus PDL.75
Importantly, however, the PSF technique interferes with
effective skin cooling during laser treatment and may prove
to be a limitation. PSF or vacuum-induced vasodilation, is an
important development in PWS therapy, as it may allow for
improved efficacy of photocoagulation, particularly in recalci-
trant PWS lesions.
Site-specific pharmaco-laser therapy
Site-specific pharmaco-laser therapy (SSPLT) is an experimental
treatment modality that combines traditional laser therapy
with the antecedent administration of prothrombotic and ⁄or
antifibrinolytic compounds.72 Incompletely photocoagulated
vessels have been implicated in treatment-resistant PWS and
serve as the target of SSPLT. The endovascular response to
laser-induced thermal injury consists of both a static photo-
thermal component and a fluid haemodynamic component.
The haemodynamic response is characterized by thrombosis
followed by fibrinolysis and, unlike the photothermal
response, can be altered pharmacologically.76–79 By promoting
further thrombosis in a partially coagulated vessel and ⁄or in-
hibiting the breakdown of laser-induced blood coagulation,
 2013 The Authors
BJD  2013 British Association of Dermatologists

total occlusion of the target vessel may be possible and trans-
late clinically to enhanced lesional clearance.76
As a safety measure and for more specific drug delivery, a
thermosensitive liposomal drug delivery system that selectively
targets active thrombus formation in PDL-treated PWS vascula-
ture is used to avoid any untoward systemic effects associated
with pharmaceutical use.80 While in vitro studies and other in-
vestigations have been promising thus far, SSPLT is still in the
early developmental stages and it has yet to be determined if
this modality will become a safe, effective and practical treat-
ment for resistant PWS.
Conclusions
The variable and sometimes disappointing outcomes seen in
PDL treatment of PWS is largely influenced by both the inher-
ent heterogeneity of the lesions themselves and the therapeutic
limitations of the PDL system. While much is known about
the possible mechanisms of resistance of PWS to PDL treat-
ment, an agreed upon definition or set of criteria that classify
a PWS as ‘PDL-resistant’ must be developed and subsequently
validated in order then to demonstrate accurately the compara-
ble efficacy of alternative modalities. Furthermore, there exists
a lack of evidence comparing lesion response with continued
PDL treatment vs. the newer lasers and light sources. Regard-
less of the stated limitations, review of the evidence has
shown that treatment of these resistant and refractory lesions
requires special consideration of the mechanisms of treatment
resistance, as well as the use of novel laser systems and tech-
niques.
What’s already known about this topic?
• Port-wine stains (PWS) are common congenital vascular
malformations for which patients often seek treatment.
• Although pulsed dye laser (PDL) is considered first-line
for the treatment of PWS, a substantial number of le-
sions reach a treatment plateau and some fail to lighten
at all.
• These PDL-resistant PWS require special consideration.
What does this study add?
• This is a comprehensive review of alternative treatments
and novel approaches for PDL-resistant PWS.
• Evidence-based knowledge is provided to help guide
management decisions made by physicians faced with
recalcitrant PWS.
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