Nd:YAG Laser Treatment of Keloids and Hypertrophic Scars.

1.3 MB·English

by  Akaishi, Satoshi

Nd:YAG Laser Treatment of Keloids and
Hypertrophic Scars
SatoshiAkaishi,MD,PhD,SachikoKoike,MD,TeruyukiDohi,MD,KyokoKobe,MD,
HikoHyakusoku,MD,PhD,andReiOgawa,MD,PhD
DepartmentofPlastic,ReconstructiveandAestheticSurgery,NipponMedicalSchool,Tokyo,Japan
Correspondence:[email protected]
PublishedJanuary11,2012
Pathologicalcutaneousscarssuchaskeloidsandhypertrophicscars(HSs)arecharac-
terized by a diffuse redness that is caused by the overgrowth of capillary vessels due
to chronic inflammation. Our group has been using long-pulsed, 1064-nm Nd:YAG
laserinnoncontactmodewithlowfluenceandasubmillisecondpulsedurationtotreat
keloids and hypertrophic scars since 2006 with satisfactory results. The present study
examined the efficacy of this approach in 22 Japanese patients with keloids (n = 16)
orhypertrophicscars(n=6)whoweretreatedevery3to4weeks.Treatmentsettings
were as follows: 5 mm spot size diameter; 14 J/cm2 energy density; 300 μs exposure
timeperpulse;and10Hzrepetitionrate.Theresponsesofthepathologicalscarstothe
treatment were assessed by measuring their erythema, hypertrophy, hardness, itching,
andpainortenderness.Moreover,skinsamplesfrom3volunteerpatientsweresubjected
to histological evaluation and 5 patients underwent thermography during therapy. The
averagetotalscarassessmentscoredroppedfrom9.86to6.34.Hematoxylinandeosin
stainingandElasticaMasson-Goldnerstainingshowedthatlasertreatmentstructurally
changed the tissue collagen. This influence reached a depth of 0.5 to 1 mm. Electron
microscopyrevealedplasmaproteinleakage,proteoglycanparticles,andachangeinthe
collagenfiberfascicles.FurtheranalysesrevealedthatnoncontactmodeNd:YAGlaser
treatmentishighlyeffectiveforkeloidsandhypertrophicscarsregardlessofpatientage,
theoriginandmultiplicityofscarring,thelocationofthescar(s),orthetensiononthe
scar.
Pathologicalcutaneousscarssuchaskeloidsandhypertrophicscars(HSs)arecharac-
terizedbyadiffuserednessthatiscausedbytheovergrowthofcapillaryvesselsbecauseof
chronicinflammation.1Thepulseddyelaser(PDL)treatmentofscarswasfirstdescribedby
Alsteretal2in1993,afterwhichitrapidlybecameamainstreamformoflasertreatmentof
scars.Pulseddyelaserhasahighabsorptioncoefficientforhemoglobinandisusedtoreduce
therednessandthicknessofcutaneousscars.3 AlthoughPDLismoreeffectivethanargon
and carbon dioxide lasers, which target the water in the skin,4-7 a single PDL irradiation
procedureisnotsufficienttocompletelyimprovethescarsurfaceconditions.Consequently,
toobtainbetterclinicaloutcomes,PDLshouldbecombinedwithcorticosteroidinjections
and/or5-fluorouraciltreatment.8,9
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Ourgrouphasbeenusingalong-pulsed,1064nmNd:YAGlaserinnoncontactmode
withlowfluenceandsubmillisecondpulsedurationtotreatkeloidsandHSssince200610-12
withsatisfactoryresults.Thispaperexaminestheefficacy,adaptability,andlimitationsof
this treatment. Moreover, to elucidate the mechanism by which this treatment modality
acts, biopsies of irradiated and nonirradiated keloids were subjected to histopathological
andmicroscopicanalysis.
STUDYDESIGNANDMETHOD
Intotal,22Japanesepatients(4menand18women)withameanageof34.95yearswere
enrolled.Ofthesepatients,16hadkeloidsand6hadHSs(Table1).Inthisstudy,akeloid
wasdefinedasascarthatextendedbeyondtheconfinesoftheoriginalwound.Thepatients
were treated every 3 to 4 weeks with the long-pulsed, 1064 nm Nd:YAG laser (Genesis,
CuteraInc,Brisbane,California),whichwasappliedinnoncontactmode.
The laser irradiation was applied in a zigzag fashion by a hand piece held 2 to 3 cm
above the skin surface. The treatment settings were as follows: a spot-size diameter of 5
mm, an energy densityof 14 J/cm2, an exposure time per pulse of 300 μs (0.3 ms), and a
repetitionrateof10Hz(500to1000pulses/cm2).Thecoppercoolingtipofthehandpiece
was not used to cool the skin before or after treatment. To prevent the overheating of the
epidermis,thetreatmentareawascooledbyanicedgelpackbefore,during,andafterlaser
irradiation.Astrong(betamethasonebutyratepropionate)orverystrongsteroid(clobetasol
propionate) ointment was administered at 0.1 g/cm2 for 2 to 3 days after the treatment to
reduce the chance of a bulla developing after irradiation. The total number of treatments
rangedfrom5to49exposures.Onaverage,thepatientsreceived14.05exposures.
CLINICALEVALUATION
Theresponsivenessofthepathologicalscarstothetreatmentwasassessedbymeasuringthe
following5parameters:erythema,hypertrophy,hardness,itching,andpainortenderness.
Theassessmentswereperformedby3independentexperiencedplasticsurgeonsbeforethe
treatmentsstartedandaftertheywerecompleted.Scoringwasbasedona4-pointscalethat
rangedfrom0to3(0=absent,1=mild,2=moderate,3=severe).Thus,themaximum
possiblescoreforapatientwas15points.Thedatawereanalyzedstatisticallybyusingthe
Mann-WhitneyUtest.
HISTOLOGICALEVALUATION
Three volunteer patients who had multiple keloids on their chest and were scheduled for
keloidexcisionsprovidedskinsamplesfor histologicalevaluation.Thus,for eachpatient,
half of the scar was irradiated by laser 3 days before the excision. In total, 500 to 1000
pulses were delivered per cm2. After excision, the histopathology of the specimens was
examined by hematoxylin and eosin staining and Elastica Masson-Goldner staining. The
tissuespecimenswerethenexaminedunderanelectronmicroscope.These3patientswere
notamongthe22patientswhowereenrolledinthetrial.
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AverageTotal)Scores(Post) 117 6103633 3 108612106009211103 uencyranged
q
e
TotalPre) onfr
AverageScores( 1515 121512966 5 12108131313669410108 irradiati
e
on Th
educti SlightClear ClearSlightClearNoClearClear Slight SlightSlightSlightSlightSlightClearClearClearNoSlightNoNoClear =6).
R n
(
Treatments 749 597141413 17 35899107235285131012 ophicscars
mplications NonNon NonNonNonNonNonNon Non NonNonNonNonNonNonNonNonNonNonNonNonNon 6)orhypertr
o 1
C =
TheNumberofTumors 11 132113 1 Multiple11111Multiple2Multiple1MultipleMultiple1 adkeloids(n
Size(BiggestRegionTumor),mm ×Pubic5641×Rightshoulder7565 ×Anteriorchest1065×Leftshoulder18050×Anteriorchest308×Pubic7024×Leftupperarm268×Leftshoulder3025 ×Anteriorchest407 ×Leftshoulder2720×Anteriorchest5620×Thigh110175×Anteriorchest3226×Rightupperarm7060×Anteriorchest7336×Lowerjaw55×Upperlip1010×Bilshoulder1020×Neck245×Anteriorchest310×Lowerjaw310×Leftforearm2250 meanageof34.95yearswhohntsideeffectswereobserved.
e
am
Table1.Patientdata Keloid/HypertrophicNoAgeSexPretreatmentCausescar 168FNonOperationKeloid226FDyelaser,steroidOperationKeloidinjection,excision,electron-beamirradiation323FNonAcneKeloid448FNonBCCKeloid564FDyelaserInsectbiteKeloid652FNonOperationKeloid733FSteroidODTOperationHS843FExcision,OperationKeloidelectron-beamirradiation,steroidODT931MExcision,OperationKeloidelectron-beamirradiation1030FNonAcneKeloid1124FNonAcneKeloid1239MSiliconegelsheetBurnHS1344FNonTraumaKeloid1422MSiliconegelsheetBurnHS1563FNonTraumaKeloid1618MNonAcneKeloid1733FNonBurnHS1819FNonAcneKeloid1927FNonOperationHS2021FNonAcneKeloid2120FNonAcneKeloid2221FNonOperationHS Thesubjectswere22Japanesepatients(4menand18women)withfrom5to49exposures.Theaveragewas14.05exposures.NotreatHSindicateshypertrophicscar;ODT,occlusivedressingtherapy.
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THERMOGRAPHICEVALUATION
Five patients with keloids agreed to assessments of the temperature of their treated skin
surface.Thus,athermograph(TVS-700,NipponAvionicsCo,Ltd,Tokyo,Japan)wasused
to measure the skin temperature 5 timesduring the procedure. Of the 5 patients,2, 1, and
2hadlesionsontheirchest,lowerabdomen,andshoulder,respectively.Furthermore,fresh
ex vivo pigskins were irradiated and analyzed with a thermograph to determine the depth
to which the laser heat-inducing influence penetrated. The results were analyzed by using
AVIOPEProfessionalsoftware(version3.12,NipponAvionicsCo,Ltd,Tokyo,Japan).
RESULTS
The average total scar assessment score fell from 9.86 to 6.34 after irradiation. Of the 22
patients,8exhibitedaclearreductioninthesizeoftheirlesions(<90%oftheoriginalarea),
10hadaslightreduction(90%95%),and4showednochange(>95%).Theaveragescores
ofthe5scarparameters(erythema,hypertrophy,hardness,itching,andpainortenderness)
beforeandafterthetreatmentsareshowninFigure1.Inparticular,therewasaremarkable
improvement in itchiness scores. Mann-Whitney U tests revealed that all the parameters
had improved significantly after treatment was completed (P < .01 for all comparisons)
(Fig1).
Figure 1. Averageassessmentscoresforallkeloidandhypertrophicscarsbeforeand
afterlasertreatment.Mann-WhitneyUtestsrevealedsignificantimprovementsinscar
erythema,thickness,hardness,itchiness,andpain(P<.01forall)afteranaverageof
14.05exposures(range,5-49).Inparticular,thesubjectivesymptomsimprovedafter
irradiation.
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Figure 2. Average total scores of the keloids and hypertrophic scars before and
aftertreatment.Thelasertreatmenteffectivelyimprovedthekeloids,asindicatedby
Mann-Whitney U testing (P < .01). In contrast, the treatment was not as effective
withhypertrophicscars(P=.058).Thismayreflecttherelativelysmallnumberof
hypertrophicscarsthatwereexamined.
The scars were then divided into 2 groups depending on whether they were keloids
orHSsandthechangeintheiraveragetotalscoresaftertreatmentwasassessed.Thelaser
treatment effectively improved the keloids, as indicated by the Mann-Whitney U tests (P
< .01). While the HSs also showed some improvement, this did not achieve statistical
significance.(P=.058)(Fig2).
The keloids were then divided into subgroups according to patient age (less or
more than 31 years of age), cause (acne, insect bites, BCG vaccinations, trauma, or
surgery), location (high tension sites such as the anterior chest wall versus low ten-
sion sites such as the face), and number (multiple or single). The average total scores
of the subgroups before and after laser treatment were then compared by using Mann-
Whitney U tests. All subgroups apart from the low-tension site scar subgroup showed
significantimprovementsintheiraveragetotalscoreafterlasertreatment(Patleast<.05;
Fig3).
Hematoxylin and eosin staining and Elastica Masson-Goldner staining of treated
and untreated keloids revealed that laser treatment induced a structural change in the
collagen of the tissue (Fig 4). This influence reached a depth of 0.5 to 1 mm. Electron
microscopy revealed plasma protein leakage, proteoglycan particles, and a change in the
collagen fiber fascicles (Fig 5). This is significant because there is considerable evidence
thatproteoglycansareboundtocollagenfibrilsandthatanythingthatseriouslydisruptsthe
collagen meshwork entrapping proteoglycan aggregates will inevitably lead to the release
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of proteoglycans from the matrix. Changes in vascular endothelial cells and fibroblasts
werenotobserved.Thus,thisusageoftheNd:YAGlaserdoesnotappeartoinduceblood
vesselcoagulation.Rather,itseemstoactviadifferentmechanismstoreduceseveralscar
symptoms.
Figure 3. Averagetotalscoresofkeloidsbeforeandafterlaserirradiation,afterthey
had been divided into subgroups on the basis of patient age, cause, location, and
numberperpatient.Thekeloidsweredividedonthebasisofpatientage(lessormore
than 31 years of age), cause (acne, bites, BCG vaccinations, trauma, or surgery),
region(hightensionsitessuchastheanteriorchestwallvslowtensionsitessuchas
theface),andthenumberperpatient(multipleorsingle).Theaveragetotalscoresof
thesesubgroupsbeforeandafterlasertreatmentwerethencomparedbypairedttest.
Apartfromthelow-tensionsitescars,thekeloidsinallgroupsimprovedsignificantly
afterlasertreatment(Patleast<.05).∗P<.05,†P<.01.y/oindicatesyearsofage.
Thermography of several scars during their laser treatment revealed that the skin
◦ ◦ ◦
surfacetemperatureswerebetween43 Cto46 C(anaveragetemperatureof44.5 C)when
thepatientscomplainedofheatsensationduringalasertherapysession(Fig6).Irradiation
ofrawporcineskinsfollowedbythermographyshowedthetemperatureriseoccurredata
skindepthofabout0.5to1mm.Thisindicatesthatthelaserwillnotreachthedeeplayer
ofscarsifthescarhasathickcollagenlayer.Notably,itisknownthattemperaturesabove
54◦C are required to thermally denature collagen fibers.13 Thus, the data obtained from
this investigation suggests that noncontact mode Nd:YAG laser therapy does not appear
to induce the thermal denaturation of collagen; rather, it induces collagen fiber fascicle
decomposition.
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Figure 4. Changes in keloid tissue after laser irradiation, as observed by light microscopy. Half
of the precordial keloid of a 26-year-old woman was irradiated with laser. Three days later, the
unirradiated(left)andirradiatedkeloidhalves(right)wereexcisedandexaminedbyhematoxylin
andeosinstaining(topimages)andElasticaMasson-Goldner(middleandbottomimages)staining.
Structural changes were observed in the collagen of the irradiated tissues. Intense inflammatory
cellinfiltrationwasobservedbyhematoxylinandeosinstaining.
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Figure 5. Changes in keloid tissue after laser irradiation, observed by electron mi-
croscopy.Achangeinthecollagenfiberfascicles(solidarrow)wasseenat×2000
magnification, but changes in the vascular structure were not observed (broken ar-
row)(above).Lymphocyteaggregateswereobserved(above).Plasmaproteinleakage
(solid arrow) and proteoglycan particles (broken arrow and inset) were observed
(below).
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Figure 6. Heat-inducedchangesinakeloidscarandarawpigskin,asdeterminedbythermography.
Thekeloidwasirradiatedwiththelaseranditstemperaturewasmeasuredwhenpainwasinduced.
Theaveragetemperaturethatinducedpainwas44.5◦C(left).Inrawpigskins,ariseoftemperature
wasobservedatadepthofabout1mmundertheepidermis(right).
DISCUSSION
Oneofthemostimportanteffectsoflasersintreatingscarsisthattheygenerateheat,which
initiatesinflammationandinturnelevatesvascularpermeability,matrixmetalloproteinase
(MMP)production,andcollagenfiberfascicledecomposition.Paquetetal14havesuggested
that the increased vascular permeability and collagen fiber fascicle decomposition that is
observedafterlaserirradiationisduetothereleaseofMMPs.Thisnotionissupportedby
Kuo et al,34 who found that PDL therapy of keloids stimulated the production of MMPs
such as collagenase. This effect is considered to be more pronounced with the Nd:YAG
laser because it reaches greater depths than a PDL. Clinical findings from 2 cases (cases
1and2)supportthistheorysinceneithercaseexhibitedscarringinthekeloidalareaafter
it had been restored by Nd:YAG laser therapy. Because other short wavelength lasers do
not appear to significantly induce MMP production, it may be that different lasers have
differenteffectsonscars.
Supporting this is that electron microscopic analysis of keloid scars after one half of
eachscarhadbeentreatedwiththenoncontactmodeNd:YAGlasershowedthattherewas
no immediate change in the vascular endothelial cells after therapy. Clear intravascular
bloodcoagulationorvascularobstructionwasalsonotobserved.Incontrast,Paquetetal16
havesuggestedthatPDLimproveskeloidsorHSsbyinducingcapillarydestruction,which
generateshypoxemiaandinturnaltersthelocalcollagenproduction.Dierickxetal17 have
also attributed the therapeutic effect of PDLs to hypoxemia resulting from laser-induced
heatandvascularinjury.
Electron microscopy also revealed the disruption of collagen bundles and proteogly-
canparticlesintheinterstice.Aproteoglycanisdefinedasaproteinthatbearsoneormore
glycosaminoglycan chains. There is considerable evidence that proteoglycans are bound
tocollagenfibrilsandthatanythingthatseriouslydisruptsthecollagenmeshworkentrap-
pingproteoglycanaggregateswillinevitablyleadtothereleaseof proteoglycansfrom the
matrix.18,19 Thus,itappearsthattherewereproteoglycanparticlesintheintersticebecause
thetherapyhaddisruptedthecollagenbundles.
Electron microscopy also detected extravascular leakage of plasma protein, which
suggeststhatNd:YAGlasertreatmentmayhaveincreasedvascularpermeability.Histology
showed that noncontact mode Nd:YAG laser therapy induced structural changes in the
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collagen-bearingtissueatadepthof500to1000μm.Incontrast,585nmPDLisknownto
changetheheatoftargetvesselsthatare71.6to100.3μmdeep.13Inaddition,theirradiation
of raw pigskins followed by thermography revealed that noncontact mode Nd:YAG also
induced heat at a depth of about 500 to 1000 μm. The papillary and reticular dermis is
locatedapproximately100to500μmbelowtheskinsurface.Theseobservationssuggest
thatthethermalheatofthenoncontactmodeNd:YAGlaserreachesthemiddlelayerofthe
dermis, where keloids develop. Nd:YAG laser energy is weakly absorbed by melanin and
wateraswellaslongerwavelength,laserbeampenetratesdeepintotheskin.Thisfinding
accountsforthehistologicalchangeinthecollagenfiberfascicles.
Inapreviousstudy,histologyofaportwinestainthathadbeentreatedwithcontact-
modeNd:YAGlaserat130J/cm2,6ms,5mmspotrevealedthatthedeepestvesseldamage
was2mmfromthedermoepidermaljunction.20 Togetherwithourownobservationshere,
this suggests that the thermal effects and vascular damage induced by noncontact mode
Nd:YAGlaseroccurmuchdeeperthanthosegeneratedbyPDLbutlessdeeplythanNd:YAG
incontactmode.Inthisstudy,weusedNd:YAGinthenoncontactmodetotreatscarswithout
inducing pain. However, should we be able to treat scars painlessly by using the Nd:YAG
laser,ourresultssuggestthatthecontactmodewillhavebetterclinicaloutcomesthanthe
noncontactmodeinthetreatmentofkeloidsandHSs.
CONCLUSIONS
This clinical evaluation found that noncontact mode Nd:YAG laser treatment is highly
effective for both keloids and HSs, regardless of patient age, the origin and multiplicity
of scarring, the location of the scar(s), or the tension on the scar. However, the ability of
noncontactmodeNd:YAGlasertherapytotreatmultipleactivebigscarsislimitedbecause
its efficacy decreaseswith the thicknessof the scar. Moreover, such scars would require a
largenumberoflaserirradiations,whichwouldbetootime-consumingandcostlyformost
patients.Thus,thislasertreatmentmodalityisparticularlyhelpfulforkeloidsandHSsthat
havejustappearedand/orhaveremainedsmallandthin.
Inthepresentstudy,theonlykeloidsubgroupthatdidnotexhibitsignificantchanges
in average total scores after treatment was the low-tension site scar group. However, the
samplesizeofthisgroupwassmall.Thus,theeffectivenessofnoncontactmodeNd:YAG
lasertreatmentforlowtensionsitesremainsunknown.Thisquestionshouldbeaddressed
with a greater number of subjects. In addition, a randomized split scar study is needed to
showwhetherthenoncontactandcontactmodesofNd:YAGlaseraloneorincombination
differinefficacy.Asimilarstudyexaminingtheefficacyofcombinationtherapywithadye
laserandNd:YAGwouldalsobeofinterest.
[Case1,No.2]
Thepatientwasa26-year-oldwomenwithakeloidontherightshoulderthatwastheresult
of acne. Although the lesion had been excised and treated with electron-beam irradiation
4 years previously, it subsequently returned. The patient was then treated 5 times with a
pulsed dye-laser and 3 times by local steroid injection at a different clinic. However, the
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