Therapeutic strategies for untreated capillary malformations of the head and neck region: a systematic review and meta-analyses

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Therapeutic strategies for untreated capillary malformations of the head and neck region: a systematic review and meta-analyses

Journal name: American Journal of Clinical Dermatology

Gonca Cinkara ¹ , Ginger Beau Langbroek ² , Chantal M.A.M. van der Horst ³ , Albert Wolkerstorfer ⁴ , Sophie E.R. Horbach ³ , Dirk T. Ubbink ²

1. Faculty of Medicine, University of Amsterdam, Amsterdam, The Netherlands

2. Department of Surgery, Amsterdam University Medical Centers - location AMC, Amsterdam, The Netherlands

3. Department of Plastic-, Reconstructive- and Hand Surgery, Amsterdam University Medical Centers - location AMC, Amsterdam, The Netherlands

4. Department of Dermatology, Amsterdam University Medical Centers - location AMC, Amsterdam, The Netherlands

*Both authors contributed equally to this review

Corresponding author:

Ginger Beau Langbroek, Department of Surgery, Amsterdam University Medical Center (UMC) location AMC, Amsterdam, P.O. Box 22660, 1100 DD Amsterdam, The Netherlands. Telephone: 0031(0)20562974.

E-mail: g.b.langbroek@amsterdamumc.nl Funding sources: none.

Conflict of interest: all authors declare that they have no conflict of interest.

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Electronic supplementary information

Supplementary Table 1. Search strategy PubMed, EMBASE and Cochrane, last searched 16 December 2020

PubMed (MEDLINE) EMBASE Classic + Embase Cochrane

("Port-Wine Stain"[Mesh] OR port-wine[tiab] OR

portwine[tiab] OR capillary malformation*[tiab] OR nevus flameus[tiab] OR naevus flammeus[tiab] OR flame nevus[tiab] OR flame naevus[tiab] OR nevus vinosus[tiab] OR naevus vinosus[tiab]) AND

("Lasers"[Mesh] OR "Laser Therapy"[Mesh] OR "Surgical Procedures,

Operative"[Mesh] OR

"surgery" [Subheading] OR

"Photochemotherapy"[Mesh]

OR "therapy" [Subheading]

OR "Tattooing"[Mesh] OR laser[tiab] OR surger[tiab]

OR surgical[tiab] OR operati[tiab] OR reconstruct[tiab] OR tattoo[tiab] OR camouflage[tiab] OR photodynamic therap[tiab])

nevus flammeus/ or (port-wine or portwine or capillary malformation* or nevus flameus or naevus flammeus or flame nevus or flame naevus or nevus vinosus or naevus vinosus).ti,ab,kw AND

exp laser/ or low level laser therapy/ or exp surgery/ or photochemotherapy/ or tattooing/ or (surgery or therapy).fs.

OR

(laser* or surger* or surgical* or operati* or reconstruct* or tattoo* or camouflage* or photodynamic therap*).ti,ab,kw.

“Port wine stain” or

“Capillary

Malformation”

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Supplementary Table 2. Study characteristics of the included studies per treatment modality

Pulsed Dye Laser (PDL)

Treatment characteristics

Author (year) Country Translated Type studof

y

Total no of patients

Age (mean or

range in years)

Fitzpatrick

Skin-type Reported CM Characteristics

Pre- treatm

ent Wave- length

(nm) Spot

size (mm)

Pulse duration

(ms)

Fluence

(J/cm2) Cooling Mean No. of treatm ent session

s

Treatment interval (weeks)

Follow- up

Primary Outcome (quantitative improvement)

Secondary Outcomes (adverse

events)

Ackermann (2002) [27] German

y No RS (674 CM

lesions)^A 23.0 II-III Colour: pale pink

to red and purple - 585 7 0.45 6.8 - 6.3 ⁃ 6-8

weeks Degree of

blanching ⁃

Anolik (2012)

[31] USA No RS 24 0.08 I-III ⁃ - 595 10 1.5 8.5-9.5 Yes 5 2-4 ⁃ Improvement

in %

Hyperpigmentation Hypopigmentation

Scarring Asahina

(2006) [26] Japan No PC 35^A 39.0 II-IV

Colour: mixed Hypertrophic:

mixed Size: <20 -

>200 cm2

- 595 7 10 12 Yes 4 8 4 weeks Mean

clearance score Hyperpigmentation Hypopigmentation Baghad (2016)

[32] Morocc

o Yes RS 68^A (18)^C II-IV ⁃ - 595 10 1.5-3 8-12 - 6-10 8 ⁃ Improvement

in % ⁃

Chang (2002)

[33] Taiwan No RS 64 24.4-26.3 ⁃ Hypertrophic:

mixed - 585-

595 7 1.5 7-10 Yes 3.3 - 12

months Blanching in quartiles of %

Scarring Chapas (2007)

[34] USA No RS 49 < 0.6 ⁃ Surface area 5-

100 cm2 No 595 10 1.5 7.75-9.5 Yes 9.3 4-6 12

months Clearance in % Scarring Fallahi (2020)

[38] Iran No RCT 15 21.76 I-IV Structure: patchy

or nodules No 595 7 1.5 12 Yes 4 8 8

months Mean

improvement Pain

Geronemus

(2000) [39] USA No PC 16 0.3 ⁃ ⁃ - 595 7 1.5 11-12 Yes 3.2 3-6 ⁃ Clearance in %

ranges

Scarring Greve (2001)

[41] German

y No PC 7^A 31.7^D I-III Size: 10 cm2-

>100cm2 No 585 7 0.45 6 Yes 1 ⁃ ⁃ Mean

clearance in % ⁃

Huerta-Rivera

(2019) [42] Mexico Yes RS 8 39.5 III-IV ⁃ No 595 7 0.45 9-12 - 7.75 5 ⁃ Clearance in % ⁃

Huikeshoven (2007) [43]

The Netherl

ands No PC 51 23.0 ⁃ ⁃ No 585 5-7 45 6-8 Yes 6-39 ⁃ 9.5 years

Clearance in L*a*b* colour

coordinate system

⁃

Jeon (2019)

[44] USA No RS 149^A 0.3 I-VI Size: 0.49-600

cm2 - 595 10 1.5 8-9 - 9.8 2-3 ⁃ Clearance in

VAS grade

Scarring Kelly (2002)

[45] USA No PC 14^A 28.0 I-IV ⁃ No 585-

595 7 1.5 7-15 Yes 3.3 8-12 18

months Blanching in

quartiles of % Scarring Koster (2001)

[46]

The Netherl

ands No PC 70 13.3 ⁃

Colour: pale pink to dark red Hypertrophic:

mixed

No 585 5 0.45 ⁃ - 6 ⁃ ⁃

Clearance in L*a*b* colour

coordinate system

⁃

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Leaute- Labreze (2002)

[49] France No RS 8 9.4 ⁃

Neurological involvement (all)

(Sturge Weber Syndrome)

- 585 3-7 0.45 5-7 - 4.1 16-24 ⁃ Decrease of

colour in % ⁃

Li (2020) [50] China No RS 261 0-60 II-III

Colour: red to purple Hypertrophic:

mixed

No 595 7 0.45-10 8-14 Yes 2-13 4-6 ⁃ Blanching score

in % ranges

Hyperpigmentation Scarring

Pain Passeron

(2014)[55] France No RCT 10^A 0.9 ⁃ Size: max 100

cm2 No 595 7 1.5 8 Yes 3 4 1 month Clearance in

IGA score ⁃

Pham Cao

(2019) [58] Italy No RS 42 ⁃ ⁃

Colour: pink, red, or purple.

Hypertrophic:

mixed Size: <20 cm2 or >20 cm2.

- 595 7 1.5 11-12.5 - ⁃ ⁃ ⁃ Clearance in %

ranges ⁃

Ren (2013)

[60] China No PC 11 24.8 III-IV Colour: pink,

purple or red No 595 7 1.5 9-12 Yes 3-5 8 2

months Clearance in %

ranges ⁃

Sadeghinia

(2019) [61] Iran No PC 27 5.7 III-IV

Colour: pink to deep red Size: <20 - >40

cm2 Hypertrophy: no

No 595 7 1.5-3 9-13 Yes 6.2 4-6 ⁃ Clearance in %

ranges Hyperpigmentation Scarring

Sharma (2007)

[62] India No PC 27 21.6 IV-V

Colour: Pink, red, violet Size: <50 cm2 or

>50 cm2

- 585 7 0.45 5-7.5 Yes 6.29 4-6 ⁃ Clearance in %

ranges

Scarring Sommer

(2000) [63] UK No RS 10^A 18.8 V ⁃ No 585 5-10 0.45 4.5-7.25 - 7.7 16 49

months Clearance in % ranges

Scarring Wang (2018)

[67] China No CCT 61^B 19.9 III-IV Flat lesions. Size:

>9 cm2 No 595 10 0.5 8-8.5 Yes 2 4-6 2

months

Mean improvement

score

Scarring Wimmershoff

(2001) [69] German

y Yes RS 217^A ⁃ ⁃

Colour: red to dark red

Size: <100 cm2 - 585 5-7 0.45 4-10 - ⁃ 5 ⁃ Improvement

in % ranges ⁃

Yang (2005)

[71] USA No CCT 11 (PDL)

A,B 33.7 I-IV (mixed)

Colour: pink, red and purple Hypertrophic:

mixed Size: >5 cm2

- 595 7 1.5 8 Yes 3 4 ⁃ Lightening in %

ranges -

Yu (2016) [73] China No PC 13 18.5 ⁃ ⁃ No 595 7 1.5 12 Yes 3 8 2

months

Blanching in l*a*b* colour

coordinate system

⁃

Yu (2019) [74] China No PC 26 ⁃ ⁃ ⁃ No - 7 1.5 12 Yes 2-3 ⁃ 2

months

Blanching in l*a*b* colour

coordinate system

⁃

Yuan (2008)

[72] China No RAC 275

(PDL)^B 3-30 ⁃

Colour: pink and purple

Size: 5-78 cm2 No 585 5 0.30-0.45 4.8-6.5 - 3.5 -

4.1 8 5 - 30

months

Cosmetic improvement

grades

Scarring

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Zhang (2014)

[75] China No RS 128

(PDL)^B 6.9 ⁃

Colour: red and purple Hyertrophy: no Size: 4-127 cm2

No 585 5-7 - 4.8-6.5 Yes (after

treatmen

t) 1 ⁃ 2

months Blanching in % ranges

Scarring Neodymium-doped yttrium aluminium garnet (Nd:YAG laser)

Author (year) Country Translated Type studof

y

Total no.

of patients

Age (mean or

range in years)

Fitzpatrick

Pre- treatm

(nm) Spot

size (mm)

Pulse duration

(ms)

Fluence

(J/cm2) Cooling Mean No. of treatm ent session

s

Treatment intervals

(weeks)

Follow- up

Secondary Outcomes (adverse

events)

Al-Dhalimi

(2016) [29] Irak No RCT 14 22.1 III-IV

Colour: pink-red, dark-red, dark-

purple Hypertrophy: no

No 532 or

1,064 3 20-25 30-300 Yes 6 4 3

months

Improvement in quartiles of

%

Hyperpigmentation Scarring

Al-Janabi

(2017) [30] Irak No PC 16 20.8 III-IV

Colour: pink-red, dark-red, dark-

purple Hypertrophy: no

- 532 3 25 30 Yes 12 4 3

months

%

⁃

Farid-ur- Rehman (2007) [37]

Pakista

n No PC 20 23.5 ⁃

Colour: pink, pink-red, red,

red-purple, purple.

Structure: patch or plaques.

No 532 2 0.0016 7.25-9.67 - 7.55 4-6 ⁃

% Hyperpigmentation

Kono (2009)

[47] Japan No PC 10 14-16 III-IV Hypertrophy: all - 1,064 3 10 - 20 80-100 Yes 4 4-8 ⁃ Clearance in

quartiles of %

Scarring Kwiek (2017)

[48] Poland No RS 44 31.0 I-III ⁃ No 532 5 - 10 5 - 9 8-11.5 Yes 7.8 4 ⁃

Global clearance

effect (GCE) Scarring Pence (2006)

[56] Turkey No PC 88^A 21.2 II-IV

Colour: pink-red, red-purple,

purple- cavernous

- 532 2 - 6 2 - 50 Max 38 Yes 5.03 8 2

months Improvement in % ranges

Scarring

Yang (2005)

[71] USA No CCT 11 (Nd:

YAG)^A,B 33.7 I-IV

Colour: pink, red, purple, dark

purple Size: > 5 cm2 Hypertrophic:

mixed

- 1,064 7 3 - 15 40-250 Yes 3 4 ⁃ Lightening in %

ranges Scarring

Zhong (2014)

[76] China No RS 101^A 16.0^D III-IV Colour: pink, red,

purple, dark

purple No 1,064 3 - 10 0.1 - 300 3 - 300 Yes ⁃ 8 3

months Lightening in %

ranges ⁃

Intense pulsed light (IPL)

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Author (year) Country Translated Type

of study

Total no.

of patients

Age (mean or

range in years)

Fitzpatrick

Pre- treatm

(nm) Spot

size (mm)

Pulse duration

(ms)

Fluence

(J/cm2) Cooling Mean No. of treatm sessionent s

(weeks)

Follow- up

Secondary Outcome (adverse events)

Dong (2010)

[36] China No PC 30 22.2 IV

Colour: purple, red, pink Hypertrophy:

mixed

No 560-

590 ⁃ 6-10.5 17-25 Yes 5 4-5 6 - 12

Scarring Ozdemir

(2008) [54] Turkey No PC 12 26.3 II-IV Colour: pink-dark

reddish purple

Size: 5 - 15 cm2 No 585 ⁃ 2-10 18-28 Yes (after

treatmen

t) 4.75 4-6 6 - 13

Scarring Wang (2013)

[66] China No PC 29 19.4 III-IV Colour: pink, red,

purple No 550 ⁃ 4.5-5 18-25 Yes 5 4-5 3

Scarring Pain Photodynamic therapy (PDT)

Author

(year) Country Translated Type study of

Total no.

patients of (mean Age

or range

in years)

Fitzpatrick Skin-type

Reported CM Characteri

stics Pre- treatm

ent

Type of drug

Drug dose (mg/kg)

Light source

Wave- length (nm)

Energy density (mJ/cm2)

Drug to light interval

(min)

Mean No.

of treatmen t sessions

(weeks) Follow-

up

Secondary Outcomes (adverse

events)

Li-Qiang

(2018) [51] China No PC 77^A 1-14 ⁃

Colour:

pink, purple Hypertrop

hy: no

No HMME 5 LED

green

light 532 96-115 20 2 8 ⁃ Improvement

in % Pain

Ma (2019)

[52] China No RS

Group 1 (PsD-007):

n=21 Group 2 (HMME):

n=17 24.33

24.06 III or IV

Colour:

pink- bright red Hyertroph y: mixed

No PsD-007

HMME 5 KTP laser 532 80-90 20-30 1 ⁃ 2

Hyperpigment ation Hypopigmenta

tion Scarring

Pain

Ren (2014)

[59] China No PC 8^A 24.0 - Colour:

purple No PsD-007 4-5 Nd:YAG

laser 532 96-180 20-30 ⁃ ⁃ 3 - 6

months Lightening in

% ⁃

Wen (2019)

[68] China No PC 22 3-39 -

Colour:

pink, purple Hypertrop hy: mixed

- HMME 5 LED light 532 80-100 20-30 1 ⁃ 8 weeks Blanching in % ranges ⁃

Xiao (2011)

[70] China No RS 282^A 11.5 –

26.3^D III-IV

Nodules papules: and some

No HMME 3.5-5 Copper

vapour laser

510.6 or

578.2 80-100 20-40 2.6-8.2 8 1 - 5

years Improvement

in % ranges ⁃

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Yuan (2008)

[72] China No RAC 306

(PDT)^B 3-30 ⁃

Colour:

pink and purple Hypertrop

hy: no Size: 5 - 78 cm2

No HMME 3.5-5 Copper

vapour laser

510.6

578.2 or 140-240 20-40 1.2-3.7 8 5 - 30 months

Cosmetic improvement

grades

tion Scarring

Zhang

(2014) [75] China No RS 132

(PDT)^B 6.9 ⁃

Colour:

red, purple Size: 12 - 150 cm2 Hypertrop hy: no

No HMME 3.5 Copper

vapour

laser - 80-100 20-25 1 ⁃ 2

tion Scarring

Other laser and light modalities

Author

(year) Country Translated Type of study

Total no.

of patients

Age (mean

or range

in years)

Fitzpatrick

Pre- treatm

ent

Type of treatmen

t

Wave- length

(nm)

Spot size (mm)

Pulse duration

(ms)

Fluence (J/cm2) Cooli

ng

Mean No.

of treatmen t sessions

(weeks) Follow-

up

events)

Ahcan

(2004) [28] Slovenia No CS 10 16.2 II- III

Colour: pale pink to red and

purple.

Homogenous texture.

No KTP+/KTP

laser 532-1,064 3 25 6- 14 Yes 1 ⁃ 8 weeks (Mean)

blanching score

Hyperpigment ation Scarring

Del Pozo

(2001) [35] Spain No PC 19^A 51.5 ⁃

Hypertrophy:

yes Nodules: yes Size: 0- > 40

cm2

No CO2-laser - 10 90 10 - 2.8 ⁃ 6 weeks Improvement

in quartiles of

%

Hyperpigment ation Scarring

Mohamed

(2019) [53] Egypt No PC 37^A 19.3 II-IV ⁃ No Pro-

yellow

laser 577 ⁃ 20 - 32 17 - 22

(afteYes r treat men t)

7.76 4 1

month

%

⁃

Periyasamy

(2019) [57] India No RS 11 27.5 ⁃

Colour: red Hypertrophy:

mixed Nodular: mixed

- DSWL 595-1,064 7 - 10 0.5 - 40 4 - 50 Yes 5 4 ⁃ Improvement

in % ⁃

Wang (2018)

[67] China No CCT 61

(DSWL)^B 19.9 III-IV Flat lesions.

Size: >9 cm2 No DSWL 595/

1,064 10 2/

15 7.5-11/

25-35 Yes 2 4-6 2

months

Mean improvement

score

tion Scarring Medical tattooing

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Author

(year) Country Translated Type of study

Total no.

of patients

Age (mean or range in years)

Fitzpatrick

treatmPre- ent

Device measuring

colour Tattoo instrument Needle depth (mm)

Mean No. of treatment

sessions

(weeks) Follow-up

events) Grabb

(1977)

[40] USA No RS 19 (4-20) ⁃

colour: mildly red, moderately

red, very purplish-red.

- Densichron densitometer

Air-driven Styker dermatattoo

handpiece

⁃ 3.05 12-24 3.1 years Improvement

in % ⁃

Thomson (1971)

[64] Canada No RS 41 ⁃ ⁃ ⁃ - Densichron

densitometer High-speed

turbine 1.5 7.5 ⁃ 12 months

Loss of colour in qualitative

grading system

⁃

van der Velden (1993) [65]

The

Netherlands No CS 5 34.4 ⁃

Colour: light pink to purple Size: <20 cm to 1

> 100 cm2.

No ⁃ Derma injector 1.1-1.3 10.2 4-8 19.8

months Degree of

coverage ⁃

CCT, Controlled clinical trial; CM, Capillary malformation; cm2, square centimeter; CO2, carbon dioxide; CR, Case report; CS, Case series; DSWL, Dual sequential wave length; HMME, Hematoporphyrin monomethyl ether; IGA, Investigator Global Assessment;

IPL, Intense pulsed light; J/cm2, joule per square centimeter; KTP, potassium titanyl phosphate; LED light, Light emitting diode; mJ/cm2, millijoule per square centimeter; Mg/kg, milligrams per kilogram; min, minute; mm, millimeter; ms, millisecond; Nm, nanometer; Nd:YAG, neodymium-doped yttrium aluminum garnet; PC, Prospective cohort; PDL, Pulsed dye laser; PDT, Photodynamic Therapy; PsD-007, second-generation photosensitizer developed in China; PWS, Port wine stain; RAC, Retrospective analytic cohort; RCT, Randomized controlled trial; RS, Retrospective study; USA, United States of America; VAS, Visual Analogue Scale; ^A only patients extracted who met the inclusion criteria; ^B this article is described twice due to the evaluation of two therapies; ^C, median age; ^D, mean age or age range all patients; -, not reported.

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Supplementary Table 3. Predefined outcomes per treatment modality

Pulsed Dye Laser (PDL) Author (year) Type of

study Total no of

patients Any quantitative improvement No of patients with

≥75% improvement Patient satisfaction Hyperpigmentation Hypopigmentation Scarring Pain Other adverse events

Ackermann

(2002)[27] RS (674 CM lesions)

674 CM lesions >50%. Mean grade of fading of CM on the neck was 2.32+/-0.87 (50%-75%), whereas on the face it ranged from 2.47+/-0.83 (50%-75%) (periorbital) and 2.69+/-1.10 (50%-75%) (perioral) to 2.73+/-0.96 (50%-75%)

(forehead/

temple).

- - - -

Anolik (2012) [31] RS 24 All patients showed 50-100% improvement. 16 - 3 0 0 - Purpura: n=24

Erythema: n=24 Edema: n=24 Asahina (2006)

[26] PC 35^A 35 patients had 50% clearance. Mean clearance score: 2.80 - - 5 3 - - -

Baghad (2016)

[32] RS 68^A >50% n=47 - - - -

Chang (2002) [33] RS 64

<25%: n= 12 26%-50%: n= 18 51%-75%: n= 18

>76%: n= 16

16 - 26 0 0 - -

Chapas (2007) [34] RS 49 Mean clearance: 88.6% after 12 months of treatment 44 - - - 0 - Atrophy: n=0

Fallahi (2020) [38] RCT 15

Outcomes extracted only for PDL Mean colorimetric improvement:

Medial side of the face: 3.80±2.96 Lateral side of the face: 3.80±2.96 Mean IGA score: 64.33±23.67%.

Mean PGA score: 65±20.44%.

(correlation coefficient: 0.85, P-value < 0.001)

- - - 15 Purpura: n=15

Erythema: n=15 Edema: n=15

Geronemus (2000)

[39] PC 16 n=10 (63%) had >75% clearing after approximately 4

treatment sessions. 2 infants <25% clearance 10 - 0 0 0 - Dermatitis: n=3

Greve (2001) [41] PC 7^A Mean clearance with cooling = 38.6% - - - -

Huerta-Rivera

(2019) [42] RS 8 8 patients had >90% clearance after 7.75 sessions average. 8 - - - No long-term

adverse events

Huikeshoven

(2007) [43] PC 51 The median ΔE was significantly lower at follow-up (12.4;

interquartile range, 8.7 to 14.8) than before laser treatment

(15.2; interquartile range, 12.3 to 19.5; P<0.001). -

30/51 patients (59%) was satisfied with treatment outcome:

3/51 patients (6%) reported that the CM became lighter, 30/51 patients (59%) reported no change in color since

last treatment.

- - - - -

Jeon (2019) [44] RS 149^A Mean VAS grade: 3.93 (median score, 4) - - 1 0 0 - -

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Kelly (2002) [45] PC 14^A

Blanching score:

<25%: n= 3 25-49%: n=3 50-74%: n=5

>75%: n= 3

3 - - - 0 - -

Koster (2001) [46] PC 70 ΔE reduced by 12% with each treatment, on average. - - - -

Leaute-Labreze

(2002) [49] RS 8

Results per segment of the face:

V1 50%-70% clearance: n=5 and 30%-50%: n=3 V2 30%-50% clearance: n=8

V3 <30% clearance: n=8

0 - - - -

Li (2020) [50] RS 261

Blanching score:

Complete (>90%): n=21 Significant (60-90%): n=113 Moderate (30-60%): n=100

Poor (<30%): n=27

- - 24 - 6 - Pain most patients

Topical edema (<

few hours) Passeron (2014)

[55] RCT 10^A Marked improvement or complete clearance: 1/10 patients - Median VAS score was

7.0 (range 4.1–7.6) - - - - -

Pham Cao (2019)

[58] PC 42

76%-100% lightening: n=18 51%-75% lightening: n=8 26%-50% lightening: n=8 0%-25% lightening: n=8

18 - - - -

Ren (2013) [60] PC 11

Poor (< 25%), n=1 Fair (26–50%), n=3 Good (51–75%), n=2 Excellent (76–100%), n=5

5 - - - -

Sadeghinia (2019)

[61] PC 27

Mean improvement 70.74 ± 18.5%

Improvement score:

<50%: n=4 50-74%: n=9

>75%: n= 14

14 - 1 - 1 -

All patients:

purpura, erythema and edema Post-laser skin erosion, blister, or

crust: n=6 Sharma (2007)

[62] PC 27

Up to 25% lightening; n=6 26% to 50%; n=8 51% to 75%; n=8 76% to 99%; n=5 100% lightening; n=0

5 - 7 1 0 - -

Sommer (2000)

[63] RS 10^A

<25%; n=2 25%-50%; n=0 51%-74%; n=4 75%-90%; n=2 >90%; n=2

4 - 4 1 2 - Blistering: n=4

Crusting: n=3

Wang (2018) [67] CCT 61 (PDL)^B Mean colour improvement score: 2.5 - - 11 (<3 months) 2 0 -

Purpura and edema: n=61 Blistering and crusting: n=2 No infection, atrophy, keloid

formation.

Wimmershoff

(2001) [69] RS 217^A

> 95% brightening (excellent), n=2 75–95%Brightening (very good), n=3

50–75% brightening (good), n=26 25–50% brightening (moderate), n=85

<25% brightening (poor), n=87 0% no brightening (no effect). N=14

5 - - - -

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Yang (2005) [71] CCT 11 (PDL)^{A, B}

0%; n=0 1% to25%; n=0 26%to50%; n=5 51%to75%; n=3 76% to 100%. n=3

3 - - - Pyogenic

granuloma: n=1

Yu (2016) [73] PC 13

The average ΔE for the central and lateral facial PWS sites was 3.33 (SD 1.24) and 7.40 (SD 3.54), respectively (P = .002). The

blanching rate of the PWS skin for the central and lateral facial sites was 8.68% (SD 5.19) and 34.01% (SD 16.75),

respectively (P = .003)

- - - -

Yu (2019) [74] PC 26 Mean ΔE= 10.97 (face), 7,45(neck)

Mean blanching rate: 59,9% (face) and 37,5% (neck) - - - -

Yuan (2008) [72] RAC 275 (PDL)^B

(I) excellent-colour was close to normal skin colour; n=23 (II) good-marked blanching, thicker lesion become flat, no

scar formation; n=113

(III) fair-partial blanching, thicker lesion become flat moderately; n=115

(IV) poor-slight blanching, thicker lesion become flat slightly;

n=21 (V) no change; n=3

23 - 16 11 6 - Skin phototoxity:

n=0 Mild fibrosis n=35

Zhang (2014) [75] RS 128 (PDL)^B

>75%; n=14 51—75%; n=58 25—50%; n=42 <25%; n=11

0%; n=3

14 - 14 7 6 - Skin phototoxity:

n=0

Total 1,697^C N.a. 188 N.a. 112 25 21 15 N.a.

Neodymium-doped yttrium aluminum garnet (Nd:YAG laser) Author (year) Type of

patients Any quantitative

improvement No of patients with

≥75% improvement Patient satisfaction Hyperpigmentation Hypopigmentation Scarring Pain Other adverse events

Al-Dhalimi (2016)

[29] RCT 14

532 nm vs 1,064 nm 0%; n=0 vs n=1 1–25%; n=2 vs n=12 26–50%; n=4 vs n=1 51–75%; n=4 vs n=0

>75%; n=4 vs n=0

4 vs 0 Mean VAS score: 7.6 +/-

2.3 vs 3.3 +/- 0.8 1 (532nm) - 0 - All patients: transient erythema,

scaliness, and burning sensation (lasting not more than 4 days)

Al-Janabi (2017)

[30] PC 16

0%; n=0 1–25%; n=1 26–50%; n=2 51–75%; n=5

>75%; n=8

8 Mean VAS score: 8.9 ±

1.1. - - - - All patients: transient erythema,

scaliness, and burning sensation (lasting not more than 5 days)

Farid-ur-Rehman

(2007) [37] PC 20

0%; n=0 1–25%; n=0 26–50%; n=2 51–75%; n=3

>75%; n=15

15 - 13 - - -

Textural changes; n=6 Eczematization; n=4 intraoperative hemorrhage ; n=2

pyogenic granuloma; n=2

Kono (2009) [47] PC 10

0%; n=0 1–25%; n=0 26–50%; n=2 51–75%; n=5

>75%; n=3

3 - 0 0 0 - No adverse events

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Kwiek (2017) [48] RS 44

GCE 25; n= 44 GCE 50; n=34 GCE 75; n=17 GCE 90; n=6

17 - - - 1 - Edema: n=44 (<7 days) Bruising: n=44 (7-

14 days)

Minority of patients: Crusting/blistering

Pence (2006) [56] PC 88^A

< 25%; n=0 25–49%; n=4 50–74%; n=39 75–94%; n=34 > 95%; n=11

45 - 2 (transient) 1 1 - -

Yang (2005) [71] CCT 11 (Nd:YAG)^A,B 0 - 50%; n= 5 51 -75%; n=5

>75%; n=1 1 - - - 1 - -

Zhong (2014) [76] RS 101^A

<25%; n=2 25–49%; n=9 50–75%; n=68

>75%; n=22

22 - - - -

Total 304^C N.a. 115 N.a. 16 1 3 - N.a.

Intense Pulsed Light (IPL) Author (year) Type of

patients Any quantitative improvement No of patients with

≥75% improvement Patient satisfaction Hyperpigmentation Hypopigmentation Scarrin

g Pain Other adverse events

Dong (2010)

[36] PC 30

No change (0%); n=0 Mild (>0 to ≤ 25%); n=0 Some (> 25%, ≤ 50%); n= 5 Moderate (> 50%, ≤ 75%); n=16 Significant (>75% to <100%); n=9

Complete (100%); n=0

9 - 0 1 0 -

Edema (<5 days) Blisters; n=2 Swelling; n=9 (resolved within a week)

Ozdemir

(2008) [54] PC 12

No change (0%); n=0 Mild (>0 to ≤ 25%); n=1 Some (> 25%, ≤ 50%); n= 3 Moderate (> 50%, ≤ 75%); n=6 Significant (>75% to <100%); n=1

Complete (100%); n=1

2 - 2 (<9 months) 1 2 - Blisters; n=4

Swelling; n=5 (<10 days)

Wang (2013)

[66] PC 29

0–25%; n=2 26–50%; n=8 51–75%; n=15 76–100%; n=4

4

5/29 patients (17.24%) moderately to extremely satisfied after

1 session. 17/29 patients (55.17%)

moderately to extremely satisfied at

follow up.

3 (<3 months) 0 0 29 Edema: n=29 (< 2-6 h)

Purpura: n=25 (< 10 days)

Total 71 N.a. 15 N.a. 5 2 2 29 N.a.

Photodynamic therapy (PDT) Author

(year) Type of study Total no of

improvement No of patients with ≥75%

improvement Patient satisfaction Hyperpigmentation Hypopigmentation Scarring Pain Other adverse events Li-Qiang

(2018)

[51] PC 77^A

≥ 90%; n= 24

≥ 60%, < 90%; n=34 ≥ 20%, < 60%; n=14

< 20%; n=5

- - - 77 Varying degrees of burning

sensation: n=70

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Ma (2019)

[52] RS

Group 1 (PsD- 007): n=21

0%; n=2

<25%; n=3 25–49%; n=7 50–75%; n=6

>75%; n=3

3 All patients: burning

sensation, edema, crusting, temporary hyperpigmentation (<2

months). Drug extravasation: n=1 in each

group. No systemic side effects in either group.

- 0 0 0 38

Group 2 (HMME):

n=17

0%; n=1

<25%; n=1 25–49%; n=10

50–75%; n=4

>75%; n=1

1

Ren (2014)

[59] PC 8^A

Mean clearance rate = 56.25% in 8 patients with 20

CM lesions

>75% clearance: n=6 (7 lesions)

7 - - - No blistering, erythema, or

scabbing

Wen (2019)

[68] PC 22 patients (with

31 lesions of PWS)

≥ 90%; n= 2/31

≥ 60%, < 90%; n=6/31 ≥ 20%, < 60%; n=19/31

< 20%; n=4/31

- - - -

Xiao (2011)

[70] RS 282^A >50%; n=85

<25%; n=33 - - - -

Yuan (2008)

[72] RAC 306 (PDT)^B

(I) excellent-colour was close to normal skin colour; n=100 (II) good-marked blanching, thicker lesion become flat, no

scar formation; n=126 (III) fair-partial blanching, thicker lesion become flat

moderately; n=57 (IV) poor-slight blanching, thicker lesion become flat

slightly; n=23 (V) no change; n=0

100 - 22 3 13 - Skin phototoxicity; n=0

Mild fibrosis; n=0

Zhang (2014)

[75] RS 132 (PDT)^B

>75%; n=33 51—75%; n=60 25—50%; n=26

<25%; n=10 no blanching; n=3

33 - 5 2 4 - Skin phototoxicity; n=0

Total 865 N.a. 144 N.a. 27 5 17 115 N.a.

Other laser and light modalities Author (year) Type of

improvement No of patients with ≥75%

improvement Patient satisfaction Hyperpigmentation Hypopigmentation Scarring Pain Other adverse events Ahcan (2004)

[28] CS 10 Mean blanching score

KTP+/KTP: 2.6 +/- 0.7 (26- 75%).

1 - 10 (KTP+) - 2 (KTP) - -

Del Pozo (2001)

[35] PC 19^A Mean improvement = 58.4%

for all patients. 5 - 1 - 2 - -

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Mohamed (2019)

[53] PC 37^A

75%-100%; n=10, 50%-74%; n=14,

25%-49%; n=7,

<25%; n=6

10 - - - Transient erythema and

irritation (<2 days): n=37

Periyasamy

(2019) [57] RS 11

< 20%; n=0 21 to 40%; n=2 41 to 60%; n=4 61 to 80%; n=4 > 80%; n=1

- - - No adverse events

Wang (2018) [67] CCT 61 (DSWL)^B Mean colour improvement

score: 2.7 - - 11 (<3 months) 2 3 -

Purpura and edema: n=61 Blistering and crusting:

n=19 No infection, atrophy,

keloid formation.

Total 138^C N.a. 16 N.a. 21 2 7 - N.a.

Medical tattooing Author (year) Type of study Total no of

patients Any quantitative improvement No of patients with ≥75%

improvement Patient

satisfaction Hyperpigmentation Hypopigmentation Scarring Pain Other adverse events

Grabb (1977)

[40] RS 19

Expert panel vs Patient panel Worse; n=2 vs Worse; n=0 The same; n=7 vs The same; n=2 25% better; n=8 vs 25% better; n=12

50% better; n=2 vs 50% better; n=3 75% better; n=0 vs 75% better; n=2 100% better; n=0 vs 100% better; n=0

2 - - - -

van der Velden

(1993) [65] CS 5

Patient 1: good result, no loss of color Patient 2: good result, no loss of color Patient 3: good coloration, no loss of color

Patient 4: good result, no loss of color Patient 5: good result, 95% coverage. No loss

of color

- - - -

Thomson (1971)

[64] RS 41

Mild lesion: 18.8% a bit better,81.3% quite a bit better

Medium lesions: 2.2% worse, 10.3% no better, 23.5% a bit better, 64% quite a bit

better

Severe lesions: 3.1% worse, 10.6% no better, 33.8% a bit better, 52.5% quite a bit better.

- - - -

Total score 65 N.a. 2 N.a. - - - - N.a.

CCT, Controlled clinical trial; CM, Capillary malformation; cm², square centimeter; CS, Case series; ΔE, color difference according to L*a*b coordinate system values; GCE, Global clearance effect; HMME, Hematoporphyrin monomethyl ether; IGA, Investigator Global Assessment; IPL, Intense pulsed light; LED light, Light emitting diode; N.a., Not applicable; nm, nanometer; Nd:YAG, neodymium-doped yttrium aluminum garnet; PC, Prospective cohort; PDL, Pulsed dye laser; PDT, Photodynamic Therapy; PGA, Patient global assessment;

PsD-007, second-generation photosensitizer developed in China; PWS, Port wine stain; RAC, Retrospective analytic cohort; RCT, Randomized controlled trial; RS, Retrospective study; SD, Standard deviation; USA, United States of America; V1, ophthalmic division of the trigeminal nerve; V2, maxillary division of the trigeminal nerve; V3, mandibular division of the trigeminal nerve; VAS, Visual Analogue Scale; ^A, only patients extracted from the study who met the inclusion criteria; ^B, this article is used twice due to the evaluation of two therapies; ^C, total number includes double counted patients due to the inclusion of studies testing two therapies within the same patient; -, not reported.

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Supplementary Table 4. GRADE summary

Treatment; Outcome Impact No of participants

(studies) Quality of the evidence (GRADE) PDL; improvement

result 2-grade scale: excellent (≥ 75%) or poor to good (<75%) Follow up: range 2 – 18 months

Excellent 43% (31/71), Poor to good 57% (40/71) 71

(5 observational studies) ⨁◯◯◯

VERY LOW

^{a - e}

a. No objective outcome measurement (risk of bias); b. No confidence interval (imprecision) c. Results varied largely between studies

due to heterogeneity (inconsistency); d. Small sample size (imprecision); e. Large publication bias; PDL, Pulsed dye laser.

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Supplementary Fig. 1 Flow chart for study inclusion, according to the PRISMA guidelines. n, number

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Therapeutic strategies for untreated capillary malformations of the head and neck region: a systematic review and meta-analyses