1. One thingwe do not like tosee ona histopathologyreportof abasal or squamouscell carcinomaisthe
presence of perineural invasion(PNI).Althoughbynomeansrare approachestoPNIvary and there isno
clearcut consensus.
An australi9angrouphas beentryingtobringorderto thisissue.Publishedinthe February2016 issue of
the AustralasianJournal of Dermatology(Volume 57,Issue 1 February2016 Pages3–13) isan excellent
overviewof theirworktodate.Thisarticle is mandatoryreadingforanyone treatingskinmalignancy.
The authors state that perineural invasion referstotumourgrowthinor arounda nerve. Itoccurs bythe
contiguousspreadof malignantcellsalongthe potential space betweenanerve anditssurrounding
sheath. PNIoccurs inlessthan5% of all cutaneousmalignancies. Itismore commonamongsquamous
cell carcinomas(SCC),involving3–14%of cases,comparedwith0.18% to 10% of basal cell carcinomas
(BCC).
Why isPNIimportant? itconfersan increasedriskof recurrence inbothBCCand SCC and of the
developmentof metastasisinSCC,anda poorerprognosisdue tomore aggressive tumourbehaviour.
Howeverthe riskof deathfromPNIin BCC isfar less.InSCC it’spresence issoimportant that in the
updated7th editionof the AmericanJointCommittee onCancerstagingsystemforcutaneousSCC, the
presence of PNIisone of the high-riskfeaturesthatcontribute tothe upstagingof aT1 SCC to a T2 SCC.
So froma clinicianspointof viewwhatdowe dowithPNI?The authorsstate that the managementof
PNIrequires;
1. diagnosisthroughclinical assessment,imagingandhistopathological review.
2. evaluationof its neural distributionandextent.
3. considerationof otherhigh-risktumourfeaturespresent.
4. Decisiononmanagementwhichincludesexcision(preferablywithmargincontrol) andadjuvant
radiotherapy.
The authors make the followingpoint“The evidence base forthe managementof PNIconsistsmainlyof
institutional observational cohortstudies,withthe inherentassociatedbiasesof suchstudies.
Therefore,ourrecommendationsare basedonthislevel of evidenceincombinationwithexpert
opinion.”
DIAGNOSIS
2. As statedabove the mostaccurate diagnosisof PNUisbasedo0n clinical,radiological and
histopathological assessment.
CLINICAL
The classicsymptomwe were all taughtin medschool of PNIisformicationora sensationof ants
crawlingonthe skin. Sadly 60–70% of patientswithhistologicallyconfirmedPNIare asymptomatic.
Thus we needtomaintaina highindex of suspiciontodetectPNI,especially fortumoursoverlyingmajor
nerve trunksandtheirbranches.
In those whoare symptomaticissuesreportedmayinclude;
Sensorysymptomsincludevariousformsof dysaesthesia,particularlyformication –the
sensationof antscrawlingunderneaththe skin,tingling,painandhypoaesthesiaornumbness.
These mostoftenare seeninthe distributionof the trigeminal nerve.
Muscle weaknessandfasciculationmaybe describedbythe patientordetectedoncranial nerve
(CN) examination,mostcommonlyinvolvingthe facial nerveandit’sbranches.A misdiagnosisof
Bell’spalsymaybe made inthese patients.
In some patientswithcranial nerve palsiesandsensorydeficitsthere maywell be no
documentedhistoryof nonmelanomaskincancerwithPNI.Insuchcircumstances,imaging
followedbya biopsyconfirmationof suspiciouslyenlargednervesmaybe warranted. Inother
words symptomatic PNI maybe the firstpresentationof thesemalignancies. Imagingfollowed
by a biopsyconfirmationof suspiciouslyenlargednervesmaybe warranted.
Imaging
The authors state that magneticresonance imaging(MRI) neurographicprotocol isthe preferred
imagingmodalitytodetectandassessthe extent of macroscopicPNI,demonstratingsuperiorsoft-tissue
contrast andgreatersensitivityandspecificityinthe evaluationof large nerve PNIthancomputed
tomography(CT) andother imagingmodalities.
Radiographicfeaturessupportiveof perineural spread include enlargementorabnormal enhancement
of the nerve,orobliterationof the normal fatplane surroundingthe nerve.There isevidence that
spatial resolutionisimprovedbyusing3-Telsascanners,whichhave high-fieldmagnetsinsteadof
traditional magneticfieldstrengths.Gadolinium-contrastMRIwithfatsuppressionfurtherincreasesthe
radiographicabilitytodetectearlyPNI,thusimprovingpresurgical staging.
3. A negative MRIdoesnot,however,excludePNI,asfalse negativesmayoccur.Accordingtoone study,
the sensitivityof MRIfor detectionof macroscopicPNIwas95% but fell to63% fordemonstratingthe
entire extentof disease. CTismore useful foridentifyingbone invasionthanchangesinthe nerve itself,
and can detectthe erosionorenlargementof the foraminaassociatedwiththe involvedCN. Itisa better
imagingmodalitytoassessforthe involvementof regional lymphnodes,andMRI andCT complement
each other.
Histopathology
The commonestwaythatPNIis identifiedisasan incidental findingona histopathologyreporti.e.with
no clinical suspicion.
HistopathologicallyPNIisdefinedas“the findingof tumourcellswithinanyof the three layersof the
nerve sheath(epineurium, perineuriumandendoneurium),ortumourcellsinvolvingatleast33% of the
circumference of the nerve.” The 33% rule isto differentiate PNIfromtumourfocallyabuttinganerve.
Rememberapathologistonlyseesatinypercentage of anexcisedspecimen.Featuresthatsuggest
nearbyPNIinclude perineural inflammationandnerve-fibre degeneration.If these are seenfurther
sectionsshouldbe cutintothe blocklookingfordefinitiePNI. Inflammationinvolvingbothneural and
non-neural structurescanindicate non-specificinflammation,whereasisolatedperineural inflammation
may be more suggestive of nerve involvementbythe tumour.
As everusingaspecialistdermatopathologististhe ideal withskinmalignancy. Thisisespeciallysoas
PNIcan be mimickedhistopathologically.Overdiagnosisof PNI leadstoextratreatmentmorbidity.The
commonestmimicis peritumoural fibrosis, where concentricringsof fibroustissueare foundadjacent
to tumourcell nests andpresentinapproximately5% of SCC and6% of BCC may be mistakenfornerve
tissue withoutthe use of additionalstainssuchasS100.
Epithelial sheathneuroma,re-excisionPNIandreparativeperineuralproliferation will all mimicPNIalso.
Epithelial sheathneuromasappearmicroscopicallyasdiscrete nervecomplexesinthe reticulardermis,
consistingof central nerve trunksenvelopedbymature squamousepithelium.Thereisnoassociated
carcinomaor scarringfromprevioussurgery.Re-excisionPNIreferstothe presence of benignsquamous
epitheliuminthe perineuralspacesof previouslybiopsiedsites.Thisislikelytoreflectaberrantreactive
proliferationof traumatisedeccrinesweatglandsintoaplane of lowerresistance.Reparative perineural
proliferationconsistsof the appearance of concentricringsof spindle-shapedcellsenvelopinganerve
adjacentto scarringand reparationfromprevioussurgery.Immunohistochemistrycandistinguishthis
processfromPNI.Spindle cellsdemonstrate negative stainingforS100 andcytokeratinsbutpositive
stainingforepithelialmembraneantigen.
4. Whenfoundthe pathologistshouldreportthe followingdescriptorsof PNI;
whetherthe PNIisintratumoural orextratumoural,
belowdermisormultifocal,
the distance to the nearestmargin
and the size of the nervesinvolved.
If your labreport mentionsPNIbutnotthe presence/absence of these otherfeaturesyouwillhave to
requestit.Thisinformationinfluencesmanagement.
Classification.
The broad catergoriesof PNIare incidental orclinical.
Incidental PNIisidentifiedonlyathistopathologyinclinicallyasymptomaticpatientswithnegative
imaging. Thisisalsotermedminimal ormicroscopic PNI.
Clinical PNIis whenthe patientexhibitssensoryormotorchanges,or there isradiographicevidence of
PNI. It may alsobe referredtoas extensive ormacroscopicPNI.Itisuncommonto observe imaging-
positive PNIin anasymptomaticindividual.
Doesthismatter?Yes as itis of great prognosticandhence managementsignificance. One studyfounda
5-yearlocal control rate of 80% for cutaneousmalignancieswithincidental PNI,comparedwith54%for
clinical PNIdespiteaggressive treatmentwithradiotherapywithorwithoutsurgeryorchemotherapy,or
both. The studypopulationincludedpatientswithSCC,BCCandbasosquamouscarcinomas.
TREATMENT
Incidental PNI.
5. For incidental PNI,MohsMicrographicSurgery(MMS) has consistentlydemonstratedsuperiorlocal
control rates comparedtostandard excisionforNMSCwithPNI.Thisisdue to significantdifferencesin
the technique usedtoexamineexcisionspecimens.Standardassessmentwithvertical sectioning
examines<1%of the margins.By usingenface sections,MMS enablesexaminationof close to100% of
the peripheral anddeepmargins,allowingthe betterdetectionof PNIandmore complete excision.
In a recentstudy MMS plus adjuvantradiotherapy improvedcause-specificsurvival andlocal control
ratesin patientswithincidental PNI,comparedwithconventional surgicalexcisionplusART.The 5-year
cause-specificsurvival forMMS patientswas84% comparedwith68% for non-MMS patients,andthe
local control rates were 86% and 76%, respectively. While thisstudyincludedpatientswithbothSCC
and BCC,resultswere notstratifiedbyhistologicalsubtype andmost(89%) caseswere SCC.Thislimits
the applicationof these findingstootherNMSC.
RememberanSCCwithincidental PNIismore likelytobe larger,more poorlydifferentiated,have
greatersubclinical extension i.e.biggerthantheylook andlargerpostoperativedefectsthantumours
withoutPNI. Asincidental PNIisassociatedwiththeseotherpoorprognosticantstreatmentneedstobe
more aggressive andcurrentlyall the evidence pointstoMMS beingthe treatmentof choice.
Evenso recurrence ratesafterMMS of tumourswithincidentalPNIare significantlyhigherthanthose
withoutPNI.Thiswasonce felt tobe due to ‘skiplesions’i.e.areasof uninvolvednervebetween
depositsof PNI.This hasbeendisprovedandPNIis contiguous.Skiplesionsare processingartefactmost
likely whereasymmetrical tumourgrowtharoundanerve andtissue manipulationduringsectioning
may resultina false negative margin. Otherexplanationsforskipareashave includedaninflammatory
reactionwithimmune-mediatedtumourregression,ortrue skippingof regionsof nervesassingle
malignantcellsalongthe perineurium.
AfterachievinghistologicallyclearmarginsintumourswithPNI,some Mohssurgeonsexcise anextra
tissue levelandeitherexamineitonce againwithfrozensectionsorsenditforstandardparaffin
sectionsbecause of the possibility of undetectedPNI.Thisapproach,however,isnonspecificanddoes
not conferassurance of complete tumourremoval.Furthermore,the additional removal of tissue with
clearhistological marginsdoesnotallow formaximaltissueconservation,whichisparticularly
significantinareasof functional andcosmeticimportance.
So if we want toimprove local control ratesand maximise tissue conservationwe needtoconsiderpost-
operative adjuvantradiotherapytoawide local field. This canbe effective insterilisingmicroscopic
6. depositsof cancercellsthatmay be presentaftersurgical excisionand,inselectcases,electively
treatingregional nodeswithoutthe needforregional surgery.
One of the problemswiththe publisheddataof PNIinNMSC is thatthe publishedstudiesoftenlump
BCC and SCCwithPNItogether.Itis feltthatcontrol ratesfor BCC withPNIare betterthanwithSCC.
The authors have triedtocome upwithguidelinesforBCCandSCC.
Treatmentof SCC withIncidental PNI
The authors pointoutthat ina large seriesof patientswith SCCwithincidental PNI manywere curedby
MMS alone i.e.withoutadjuvantradiotherapy.The mere presence of incidental PNIinaSCCdoersnot
mandate radiotherapy.Thustheyoutline featuresotherthanPNIthatare importantindeterminingthe
needforadjuvantradiotherapy.Inotherwordswhatotherprognosticfeaturesinfluence the decisionto
add radiotherapytothe treatment?
Theylistthe followingfeatures;
extratumoural PNI,thatis,invasionoutsidethe maintumourmass,isassociatedwithmore
aggressive tumourbehaviourthanintratumoural PNI.
PNIlimitedtosmall calibre nerves(<0.1mm) likelycarriesabetterprognosiswithsignificantly
lowerrisksof recurrence andmetastasisandincreased disease-specificandoverall survival
comparedto PNIof nerves> 0.1 mm indiameter.Atthe momentfurtherresearchisneededto
determine if 0.1mm isthe ideal cutoff.
the extentof intratumoural perineuralinvolvementinSCC isalsolikelyanimportant
prognosticant.There are betteroutcomeswhenPNIwaslimitedtoafew small dermal nerves
and minimal focal disease,thanwithmore diffuseperineuralspreadwithinthe tumourmass.
MMS doesnot examine the intratumoral massandso preoperative biopsy specimensor
examiningthe central debulkingtissue,eitherwithfrozensectionsatthe time of Mohs surgery
or subsequentstandardparaffinsectionsmaybe needed.
Depthof invasionisalsoimportantwithlesionslimitedtothe dermisdoingbetterthanthose
invadingsubcutis/muscle.
PNIina recurrentlesioncarriesaworse prognosisthanthatfoundat initial presentation.
Thenthere the adverse prognosticantsunconnectedtoPNIi.e.
7. poor differentiation,
tumourdiameter≥ 2 cm
invasionbeyond subcutaneousfat.
All of these are more likelyincasesof PNIinvolvinglargernerves.
Otherfactors include;
Immunosupressionespeciallyintransplantpatients.SCCsinthe immunosuppressedare more
biologicallyaggressivewith poordifferentiation,rapidgrowth,increasedperineural and
lymphaticinvasion,andhigherriskof developingregional anddistantmetastases. Thus
incidental PNIinanimmunosuppressedpatientmayleadone touse adjuvantradiotherapy.This
isalso an indicationof whythe levelof immunosuppressionneedstobe keptunderreview.
Treatment
Belowisthe algorithmformanagementof PNIinSCC.
A lowrisklesionwhere surgeryalone mightbe all thatisneeded includesincidentalPNIthatis
intratumoural,focal,involvessmall nerves,islimitedtodermis,andoccursinprimarytumours.MMS is
the preferredprimaryexcisionstrategywhere PNIisdiagnosedonbiopsy.
Adjuvantradiotherapy shouldbe consideredif patientsare immunosuppressed,oradditional high-risk
tumour-relatedfeaturesare presentsuchastumoursize ≥ 2 cm, or poor differentiation.
The medium-riskgroupincludesincidental PNIwithanyof the high-riskfeaturesidentified above.These
patientswouldpossiblybenefitmostfromARTregardlessof the primary surgical approachused.
High-riskpatientsare those withclinical PNIinwhommanagementmayinvolve nerveresection,usually
by a skull base surgeon,withthe additionof ARTor alternativelydefinitiveRT. These shouldgotoa
headand neckclinic.
8.
9. The authors addressthe role of sentinel lymphnode biopsyinhighriskSCC.Asexpecteditis
controversial. Itwouldneedtobe addressedonacase by case basis.
BCC with incidental PNI.
The authors state that cure ratesfor MMS andstandard surgeryplusadjuvantradiotherapyare similar
for these muchlowerrisklesions(comparedtoSCC). Around90% 5 yeardisease free survivalisseen
witheither. There are nodata specificallyevaluatingthe outcomesof incidentalPNIinBCCmanaged
withstandardsurgical excisionalone.
BCC withPNIstill hasa higherrecurrence rate thanBCC withoutPNI.PNIismore frequentlyassociated
withaggressive BCCsubtypes,includinginfiltrative,morphoeic,sclerosingandmicronodularvariants.
The locallyinvasive nature of these BCCsubtypesmaywarrantconsiderationof local ART,especiallyin
the settingof incidental PNI.
The algorithmbelownicelysummarisesthe authorsapproachtoBCC withPNI.
10. What aboutjust radiationtherapyasdefinitivetreatmenti.e.withoutanyinitial surgerybeyondbiopsy?
As expectedthereisdebate.Itiscertainlyauseful modalityinnonsurgical candidates.The authors
pointoutthat althoughtraditionallyrestrictedtothose over60 due to concernsre longtermsequelae it
has beenusedinyoungerpatients.Itiscontraindicatedinnaevoidbasal cell carcinoma(Gorlins) and
xerodermapigmentosum. These patientsneedsurgical treatmentandclose followup.
11. Thenwe come to clinical PNIi.e.the patientswithsymptoms/signsof PNIorPNIdetectable onMRI.You
will notcome across toomany of these butequallyyoudonow want to missthemwhentheydo
present.
These patientsreceive treatmenttailoredtotheircase basedonthe extent andresectabilityof the PNI,
and alsothe patientprofile.A multidisciplinaryapproach,oftenincludingstagingandplanningwithMRI,
surgical excisionundergeneral anaesthetic,preferablywithfrozensectioncontrol,andRT is often
required.MMS of the primarytumour maybe a valuable supplement;howeverpatientswithclinical PNI
oftenhave involvementof structuresthatprecludesthisapproach.Obviouslyfactorssuchaspatient
age,performance statusandpreference,together withthe presence of comorbidities,alsoneedtobe
consideredwhendeterminingappropriatemanagement.
While the natural historyof PNIusuallyinvolvescentral progression,thiscanbe an unpredictable,long
and indolentprocess.Manyyearsmay elapse fromdiagnosisof aheadand neckprimarycutaneous
tumourwithPNIbefore invasionintothe central nervoussystem. Furthermore,the patientgroupthat
appearsto be most at riskof PNIare olderCaucasianmen,manywithcomorbiddisease andahistoryof
multiple previousskincancers. These becomeparticularlysignificantconsiderationswhen
contemplatingaggressivetreatmentandweighingthe potential survival benefitagainstthe side-effect
profile inthissubsetof patients.
SCC portendsamore unfavourableprognosisthanBCCas for incidental PNI.A recentstudyreporteda
5-yearrelapse-free survival of 39%for patientswithclinical PNIandSCCversus80% for BCC whenboth
patientgroupswere treatedwithradiotherapyorsurgery,orboth.Thus managementvariesfromSCC
to BCC withclinical PNI.
SCC with clinical PNI
Resection withmargincontrol plus adjuvantradiotherapyoffersthe bestchance of cure.What is
resectable nowisadifferentkettle of fishtopreviously.ForexampleSCC withextensive intracranial PNI
involvingcranial nerves uptothe Gasserianganglion(zone 2) maybe operable,andthistreatment
potentiallyoffersimprovedsurvival rateswithacceptablemorbidity.Thisisof course verymajorsurgery
and islimitedtoselectedpatientsinspecialisedunits.
Extensionbeyondthe GasserianorGeniculate ganglion(zone3) generallydeemsapatienttobe
inoperable due tothe risksof exposingcerebrospinalfluidtotumourcells,andsubsequentseedingin
12. the brainstemandspinal cord.PatientswithsuchextensivePNI,aswell asthose whoare medicallyunfit
for surgery,maybe managed withRT alone (definitive orpalliative),oralternatively,bestsupportive
care. RT is ofteneffectiveinpalliatingdebilitatingneuropathicpainandpreventing,ordelaying,the
progressionof intracranial disease anditsassociatedconsequences.High-dose definitiveRTalone can
alsoofferthe chance of cure in ∼50–60% of suitable patients,butwithassociated acute andlate side-
effects.
For radiotherapytogetbestresultsinthese patientsitisadvisedthatthe targetvolume include the
portionsof the nerve proximal anddistal tothe tumoursite,skininnervatedbythe diseasednerve,
majorcommunicatingbranchesandthe compartmentinwhichthe nerve isembedded,suchasthe
parotidglandfor CN VII.Thisis to treatboth antegrade andretrograde PNI,aswell ascrossoverspread
fromone major nerve orbranch to another. Regional nodesmayalsobe included.
As youwouldexpectwithsuchdangerouslesionsthere are alsotreatmentsasyetconsidered
experimental.These incude adjuvantordefinitivechemoradiotherapy,withplatin-basedchemotherapy
(as a radiosensitiser),inthe managementof clinical PNIincutaneousSCCinselectpatients.
Where the tumouris consideredinoperable,cetuximab (epidermalgrowthfactorreceptorinhibitor)
may provide palliative relief.
BCC withclinical PNI
The principlesare similarasforSCC withtreatmentcomingdowntosurgeryplusadjuvantradiotherapy
or definitive radiotherapyforinoperable lesions.Interestingthere isadearthof literature definingthe
role of radiationtreatmentforBCC accordingto thisarticle.
Experimentalapproaches
For advancedBCCwithPNI,the use of Hedgehog(Hh) pathwayinhibitorssuchasvismodegibrepresents
an as yetunexploredtreatmentoption.VismodegibhasrecentlybeenTherapeuticGoods
Administrationapprovedforthe treatmentof adultpatientswithmetastaticBCCor withlocally
advancedBCC where surgeryandradiotherapyare notappropriate.A phase IItrial founda response
rate of 43% inpatientswithlocallyadvancedBCC,withacomplete response reportedin21%.
Remainingchallengeswiththistherapyinclude asignificantadverseeffectprofile,developmentof
resistance anddisease reboundafterthe drugisdiscontinued.Toovercome this,considerationisbeing
giventothe possible role forHhinhibitorsasadjuvanttherapytosurgical excisionorMMS. The rapid
effectof Hh inhibitorsinshrinkingtumoursize mayenable definitivemanagementinanatomically
difficultorhigh-risksitessuchasthe headand neck.New Hhinhibitorsare alsobeingdeveloped,
13. includingsaridegibandsonidegib,withthe aimof reducingadverse effectswhile maintainingclinical
efficacy.
I thinkthisisa mustreadarticle for all of us involvedinskincancermanagement.The presenceof PNI
on a histopathologyreportshouldtriggeryoutoconsidermore aggressivemanagement.Thisis
definitelyasituationwhere itisgoodto‘phone a friend’orreferon.Inmy practice I tend to eithercall a
radiationoncologistwithextensive skincancerexperienceorone of the specialisedheadandneckclinic
specialists.
