QJM Advance Access published November 10, 2014

Q J Med
doi:10.1093/qjmed/hcu206

Pulsed dye laser therapy for infantile hemangiomas:

a systemic review and meta-analysis
L. SHEN1,2*, G. ZHOU1,2*, J. ZHAO1, P. LI3, Q. XU1, Y. DONG1 and Z. ZHANG1,4
From the 1Department of Oral Maxillofacial-Head Neck Oncology, 2Laser&Cosmetic Center, Ninth
Peoples Hospital, Shanghai Jiao Tong University, Shanghai, China, 3VIP Department, Stomatology
Hospital of Shandong University, Jinan, China, 4Shanghai Key Laboratory of Stomatology, Shanghai
Jiao Tong University, Shanghai, China

Address correspondence to Dr Zhiyuan Zhang Shanghai Key Laboratory of Stomatology, Department of Oral
Maxillofacial-Head Neck Oncology, Ninth Peoples Hospital, Shanghai Jiao Tong University, Shanghai, China.
email: zhzhy@omschina.org.cn

Downloaded from http://qjmed.oxfordjournals.org/ by guest on June 7, 2016

*These authors contributed equally to this work.

Received 8 August 2014 and in revised form 7 September 2014

Summary
Background: Infantile hemangiomas (IH) are common
pediatric tumors. This meta-analysis was performed to
review the therapeutic efficacy and safety of pulsed
dye laser (PDL) in the treatment of IH.
Methods: Seven databases were searched, including
PubMed, OvidSP, Karger, Elsevier, EMBASE, Web of
Science and Wiley Online Library. The review col-
lected the characteristics of year of publication,
hemangiomas cases, prior treatment, laser param-
eters, adverse side, pretreatment symptom, and
number of response from all articles.
Results: A total of 1580 studies were identified, the
first round search retrieved 39 articles met inclusion
criteria. Of those, only 13 articles with 1529 hem-
angiomas were included in the meta-analysis. This
meta-analysis demonstrated an overall resolution
rate of 89.1% with 6.28% incidence of adverse
effect.
Conclusion: PDL may be the effective modality to
decrease the proliferative phase and accelerate rates
of involution and resolution with few adverse
events.

Introduction intervention appear such as bleeding, obstruction of

Infantile hemangiomas (IH) (Strawberry nevi) are
pediatric benign tumors of vascular characterized
by an initial phase of rapid proliferation, followed
by slow spontaneous involution.1,2 They are the
most common tumors of infancy, affecting 23% of
newborns and up to 10% of infants within the first
year of life.35 The head and neck are the most
common lesion locations with 60% of hemangi-
omas.6 Most hemangioma lesions regress completely
over time, but 1012% of hemangioma lesions
will develop complications that can be life threaten-
ing or permanent.79 Complications requiring the
a vital structure, hemorrhage, and ulceration with
secondary infection or pain.8,10
Various treatment options have been used for
complications of the hemangioma. These include
propranolol, corticosteroids, surgical excision, and
laser therapy.11 The pulsed dye laser (PDL) may be
effective in the treatment of IH to reduce the prolif-
erative phase and hasten the process of involution. It
has become the treatment for cutaneous vascular
anomalies since the late 1980s.12 A number of stu-
dies have assessed the efficacy and safety of the PDL
treatment. Many of them report that the hemangi-
omas of patients were completely clearance or

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 L. Shen et al.
excellent improvement in the treatment of the
PDL.1319 However, the conclusions from published
studies were inconsistent.20 Therefore, we per-
formed a meta-analysis to systematically review
the current published data on the efficacy of PDL
in the treatment of IH.
Materials and methods
Literature search
Published literatures assessing the PDL treatment for
IH from A to B were searched through seven
databases, including PubMed, OvidSP, Karger,
Elsevier, EMBASE, Web of Science and Wiley
Online Library. The key words used for search
were as follows: Hemangioma, Infantile
Hemangiomas, Childhood Hemangioma, cutane-
ous vascular lesions, cutaneous capillary
haemangiomata, tunable dye laser and pulsed
dye laser. Publication language was restricted to
English language only. Meanwhile, reference lists
were examined manually to further identify poten-
tially relevant studies. Unpublished reports were not
considered.
Inclusion and exclusion criteria
Abstracts of all citations and retrieved studies were
reviewed. Published reports meeting the following
criteria were included: (i) the study has a clear
report of effect in the treatment of hemangiomas in
pediatric population with the PDL. Studies were
excluded if one of the following existed: (i) the
study used the PDL for the treatment of non-cutane-
ous hemangiomas; (ii) there was no clear report of
outcomes for extraction of data.
Data extraction
All data were extracted independently by two re-
viewers (L. Shen and G. Zhou) according to the in-
clusion criteria listed earlier. The results were
compared and disagreements were discussed and
resolved with consensus. Evaluation was based on
title and abstract whenever available. Full-text art-
icles of potentially relevant studies were obtained
and re-evaluated for inclusion. The following char-
acteristics were collected from each study using an
Excel data extraction form: first author, year of pub-
lication, hemangiomas cases, prior treatment, laser
parameters, adverse side, pretreatment symptom,
and number of response were collected from all art-
icles (Table 1).
Statistical analysis
The statistical analysis was conducted using R stat-
istical software (Version 3.1.1), package META. Q
testing and I2 statistics were used to examine hetero-
geneity among studies.21 A value of P < 0.1 was
considered significant for the Q testing and I2 was
interpreted as the proportion of total variation con-
tributed by between-study variation. If there was a
significant heterogeneity (P-value < 0.1), we se-
lected a random effects model to pool the data. If
not, we selected a fixed-effects model to pool the
data. Heterogeneity was also quantified using the I2
metric (I2 < 25%, no heterogeneity; I2 = 2550%,
moderate heterogeneity; I2 > 50%, large or extreme
heterogeneity).22 We graphed the forest plot that
contains individual studies representing the horizon-
tal solid line with their confidence intervals.
Publication bias was examined with Eggers
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tests.23,24 If the P value of Eggers tests was <0.05,
there is evidence of publication bias.
Results
Study characteristics
One thousand five hundred eighty studies were
identified (Figure 1). A total of 39 studies were
retrieved after the first search, and 26 of
these were excluded from the analysis for reasons
detailed in Figure 1. Only 13 studies met the
inclusion criteria in this meta-analysis, which
included 1529 hemangiomas. Characteristics of
studies included in the meta-analysis were pre-
sented in Table 1. The flow chart of collection of
studies and reasons for exclusion was presented in
Figure 1.
Efficacy and complication profile of PDL
therapy
One thousand two hundred forty-seven patients
were enrolled in this study. The study patient popu-
lation consisted of 909 girls (73%) and 338 boys
(27%). A total of 1529 hemangiomas were treated
with PDL. Of these, 764 lesions (50%) were located
on head and neck, 413 lesions (27%) on trunk, 298
lesions (19%) on extremity, 40 lesions (3%) on geni-
tal area, and 14 lesions (1%) on perineal. Six hun-
dred sixty-seven hemangiomas of pretreatment
(44%) were classified as superficial, 371 lesions
(24%) as mixed hemangiomas, and 435 lesions
(28%) as cutaneous nodular. The wavelength 585
and 595 nm, spot size 5 and 7 mm and pulse dur-
ation 0.45 ms were the most commonly used laser
parameters. Each hemangioma underwent a mean
Page 2 of 8
 Table 1 Characteristics of studies of hemangiomas treated with PDL in our meta-analysis

Study Prior treatment No. of Pretreatment Laser/parameters No. of treatments Response of Evidence Adverse effects (no.
hemangiomas symptom (mean) improvement level of cases)
with PDL
treatment

Batta et al.20 NR 60 Superficial early 585 nm PDL, 3 NR 25 patients (com- IV Required steroid
hemangiomas 5 mm spot size, plete clearance or treatment (n = 1,
0.45 ms pulse dur- minimum residual 2%); ulceration
ation, 6.07.5 J/ signs) (n = 4, 7%); pain-
cm2 energy ful ulceration
fluence (n = 3, 5%); bleed-
ing (n = 2, 3%);
infection (n = 2,
3%)
Hunzeker and NR 22 Superficial IH 595-nm PDL, 0.45 214 treatments 22 patients III Hyperpigmentation
Geronemus13 1.5 ms pd, 7 mm (5, 6) (76100% im- (n = 2, 9.1%)
spot size, 11.0 to provement or
11.5 J/cm2 energy 5175%
fluence improvement)
Chang et al.25 NR 164 Cutaneous 585 nm PDL,7 mm 16 treatments 164 hemangiomas III NR
hemangiomas spot size, 0.45 ms (1, 8) (76100% im-
pulse duration, provement or
5.58 J/cm2 for 5175%
NC-LT, 910 J/cm2 improvement)
for CSC-LT
Haywood et al.27 NR 39 Early superficial 585 nm PDL, 7.1 J/ Average 2.4 24 patients (com- II NR
hemangiomas cm2 energy plete clearance or
fluence minimum residual
signs)
PDL therapy for infantile hemangiomas

Rizzo et al.26 NR 105 Superficial (65) or 595-nm LP-PDL, 7 117 treatments 91 hemangiomas III Hyperpigmentation
mixed superficial 10 mm spot size, (6.7) (100% improve- (n = 4, 4%); hypo-
and deep hem- average energy ment or 76100% pigmentation
angiomas (40) fluence of 11.5 J/ improvement or (n = 15, 14%); ul-
cm2 (range 7.5 5175% ceration (n = 1,
14.0 J/cm2) or improvement) 1%)
8.6 J/cm2 (range
6.211.5 J/cm2)
Tay and Tan14 NR 23 Superficial hemangi- 595 nm PDL, 1.5 Short pulse duration: 23 patients (re- IV Hyperpigmentation
oma (10); mixed 3 ms or 10 ms 314 treatments gressed or almost (n = 3, 13%);
hemangioma (13); Pulse duration, (8); long pulse regressed) hypopigmentation
proliferative phase 7 mm spot size, duration: 414 (n = 4, 17%); mild
(21); stable phase Fluence 1013.5 J/ treatments (9) textural changes
superficial cm2 or 10.5 (n = 3, 13%)
14.5 J/cm2

Page 3 of 8
(continued)

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 Table 1 Continued

Study Prior treatment No. of Pretreatment Laser/parameters No. of treatments Response of Evidence Adverse effects (no.
hemangiomas symptom (mean) improvement level of cases)
with PDL
treatment

Admani et al.15 NR 5 hemangioma (3); 585 or 595 nm PDL, 28 treatments (5.2) Five patients II NR
mixed hemangi- 712 mm spot
oma (2) size, 5.010 J/cm2,
0.451.5 ms pulse
duration
David et al.8 NR 147 Ulcerated 585 nm PDL, 5 Average two 71 patients II NR
hemangiomas 6.8 J/cm2, 5 or treatments
7 mm spot size
Reddy et al.16 Propranolol (n = 5) 17 Superficial 595 nm PDL, 7 28 (4.2) 17 patients IV NR
hemangioma 10 mm spot size,
8.512 J/cm2,
0.451.5 ms pulse
duration
Alcantara-Gonz Propranolol (n = 8), 22 Involuting (20); 595 nm PDL, 10 mm 15 treatments (2) 16 patients (over III Mild atrophy (n = 2,
alez et al.17 systemic corticosteroids Proliferative (2) spot size, 10 ms five scores) 9.1%); ulceration
(n = 3), surgery (n = 4) pulse, fluence of (n = 1, 4.6%);
610 J/cm2 hyperpigmentation
(n = 1, 4.6%)
Raulin and Greve18 NR 29 Superficial 585 nm FPDL, 5 mm Average of 3.0 24 hemangiomas II Hypopigmentation
L. Shen et al.

hemangiomas spot size, 0.3 treatments (83%) (n = 3, 10%);

0.45 ms impulse hyperpigmentation
duration (n = 6, 20%); atro-
phic scars (n = 1,
3.4%)
Poetke et al.19 NR 225 Superficial hemangi- 585 nm FPDL, 5 mm Average of two 171 hemangiomas III Hyperpigmentation
omas (153); Mixed spot size, 57 J/ treatments (76%) (n = 2, 1%); hypo-
hemangioma (54); cm2, 0.3 ms pulse pigmentation
Small superficial duration (n = 9, 4 %)
Hohenleutner et al.28 NR 671 Hemangioma 585 nm FPDL; 5 112 treatments 177 hemangiomas III Small atrophic scar
(68);Superficial 7 mm spot size, (mean, 2 (28.7% total reso- (n = 27, 4%)
hemangioma (40); 0.45 ms pulse dur- lution or marked
cutaneous nodular ation, 510 J/cm2 regression)
(435); mixed (128)

NR = not Report
NC-LT = non-cooled laser treatment
CSC-LT = cryogen spray cooling and laser treatment
LP-PDL = long pulse-pulsed dye laser

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 PDL therapy for infantile hemangiomas
Potentially relevant articles (n=1580)
Articles specifically targeted at the
treatment of hemangiomas with PDL
(n=39)
Useable articles (n=13)
Figure 1. Flow chart of inclusion of studies and specific reasons for exclusion from the meta-analysis.
Figure 2. Forest plots of all included studies for the meta-analysis.
of 2.77 laser treatments before remarkable response.
The treatments were usually repeated every 28
weeks. The mean follow-up period was 6.61
months.
Remarkable lesion improvement was observed in
all the 13 studies. Of these, seven studies (54%)
reported that all of their patients have remarkable
response, three studies (23%) reported 6090% of
their patients responded, and the remaining three
studies (23%) reported 2550% of their patients
responded. Meta-analysis demonstrated an overall
response rate of 89.1% of patients regressed their
lesions markedly following treatment with PDL
(I2 = 99%, P < 0.0001) (Figure 2).
There were 96 out of 1529 hemangiomas (6.28%)
occurred adverse effects in the review of 13 studies.
The complications identified in their study included
steroid (1, 1.04%), atrophic scarring (30, 31.25%),
ulceration (9, 9.38%), bleeding (2, 2.08%), infection
(2, 2.08%), mild textural changes (3, 3.13%), hyper-
pigmentation (18, 18.75%), and hypopigmentation
(31, 32.29%).
Not a report of effect in the treatment
of hemangiomas with PDL (n=1541)
Exclusion: the study used the PDL
for the treatment of non-cutaneous
hemangiomas or no clear report of
outcomes for data extraction (n=26)
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Sensitivity analysis and publication bias
The influence of a single study on the overall meta-
analysis was investigated by omitting one study at a
time, and the omission of any study made no signifi-
cant difference, indicating that our results were stat-
istically reliable. Publication bias of the literature
was assessed using Eggers test. P-value of Eggers
test is 0.09575, so no publication bias was observed
in this meta-analysis.
Discussion
IH, especially facial hemangiomas with slow regres-
sion, have the negative effect on a childs confi-
dence and create considerable emotional stress in
parents.29,30 In addition, hemangiomas may also de-
velop painful ulcerations, respiratory compromise,
impaired vision, or inability to feed.2 Accelerated
regression of hemangiomas have both psychological
and physiological benefits. Laser therapy is one of
the effective modalities of treatment for IH.14
Page 5 of 8
 L. Shen et al.
Some studies reported that the PDL has the low rate
of complications in treatment of IH.19,3132 The PDL
has also been advocated to intervene hemangiomas
early in other studies.19,28 Our meta-analysis
demonstrated an overall resolution rate of 89.1%
with 6.28% incidence of adverse effect. This treat-
ment modality seems to show the effect and safety in
the treatment of IH.
The PDL uses the mechanism of selective photo-
thermolysis. Specifically, it affects blood vessels by
heat transfer.46 The clinical objective of laser ther-
apy of hemangiomas is to maximize thermal
damage to vascular while minimizing injury to the
surrounding epidermis and dermal tissue.14 To
decrease this risk of damage to the epidermis and
papillary dermis, clinicians have used the flash
lamp-pumped PDL (LP-PDL) (575600 nm wave-
length), which emits light absorbed preferentially
by hemoglobin in the cutaneous vessels.3234 In
our systematic review, 585 and 595 nm are two
commonly used wavelengths. Previous studies
have shown unfavorable outcomes when the
585-nm PDL with a pulse width of 0.45 ms was
used in the treatment of hemangiomas with a
subcutaneous component.19,28,34,35 Recently, the
595-nm LP-PDL with dynamic cooling and pulse
widths of up to 1.5 ms have enabled the better tar-
geting of the deeper component of hemangiomas.26
Because the suitable laser energy from PDL is select-
ively absorbed by oxyhemoglobin, the target
chromophore,8,46,47 there is minimal heat radiation
to the surrounding epidermis and dermal tissue.
A variety of treatment modalities have been used
in the treatment of IH, including propranolol hydro-
chloride, systemic corticosteroids, PDL or other vas-
cular-selective lasers, imiquimod, and topical
timolol.16 PDL generally effectively affects the
most superficial aspect of hemangiomas.2 Because
the efficacy of the PDL is limited by its depth of
vascular injury (12 mm) and the mixed hemangi-
omas might be far beyond this depth, subcutaneous
or mixed hemangiomas do not benefit from PDL
treatment.19 In our study, 1123 cases (73.45%) of
hemangiomas are in initial, small, superficial hem-
angiomas, where 79% of the lesions showed a com-
plete or marked clearance after mean follow up of
6.61 months. The success of laser treatment in sub-
cutaneous or mixed hemangiomas is observed in
35.77% lesions. Because PDL treatment may be in-
adequate for some lesions consisting of large or
deep vessels, the propranolol are often used in the
treatment of deep or large facial hemangiomas.3740
Some studies proved propranolol to be a consistent
and rapid therapeutic effect for IH with fewer side
effects and good clinical tolerance.4144 However,
the experience of propranolol for treatment of IH is
limited and the mechanism of action is currently
unknown.39,44 In addition, propranolol has some
potentially side effects, including hypoglycemia,
bronchospasm, and hypotension, so hemangiomas
are preferably treated in a multidisciplinary setting
by physicians knowledgeable about the effects and
side effects of propranolol.45
There are some limitations in this study. Most of
individual studies included in this review are non-
randomized trials and lack of the control group.
Some of them have the relatively small number of
patients. The other limitation is that the criteria of
marked regression among all included studies are
inconsistent. Randomized trials with adequate pa-
tients and similar criterion should be included to
determine the effectiveness and safety of the PDL
treatment.
In conclusion, PDL is an effectiveness and safety
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therapy in the treatment of hemangiomas, especially
for superficial hemangiomas. Our study suggests
that this treatment modality to be considered as
one option to intervene IH. However, further rando-
mized controlled studies are suggested to evaluate
PDL therapy for IH.
Funding
This study was supported by the Research Fund of
Science and Technology Commission of Shanghai
Municipality (grant no. 12nm0501800).
Conflict of interest: None declared.
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