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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2821_Библиотеки_им_академика_М_И_Перельмана
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FIGURE15-2.BrownmaculesoftheoralmucosaassociatedwithPeutz–Jegherssyndrome(borrowedfromthe
MountSinaiCollectionphotographs).
KaposiSarcoma
Althoughmorefullydiscussedinotherchaptersofthistext,Kaposisarcoma(KS)isincluded
becauseitmaypresentwithviolaceousmaculesandpapulesthatcoalesce (Fig.15-3). Four
types of KS are generally recognized: classic, African, allograft associated, and epidemic
(AIDS related). It is imperative that AIDS-associated KS be treated with highly active
antiretroviral therapy.14 Other treatments include intralesional chemotherapy or radiation
therapy, with systemic chemotherapyreserved foradvancedcases ofthedisease andAIDS-
associatedKS.
14
PatientswithKSsecondarytotheclassictypemaydowellusinglaserandphotodynamic
therapy.13Ithasalsobeenshownthattheclassictypeaswellaspatientswhoareelderlyand
immunocompromisedhaverespondedwelltotheuseoftopicalimmuneresponsemodifiers.
15
Theuseofintralesional3%sodiumtetradecylsulfatehasalso beenproposed,especiallyin
cases where KS presents as nodular lesions, ultimately resulting is sclerotization of the
vessels.
15
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FIGURE15-3.ClassicKaposisarcomaaffectingthedorsumofthefoot(borrowedfromtheMountSinaiCollection
photographs).
KERATOTICLESIONSOFTHEFOOT
Foot care practitioners and their patients readily admit to the prevalence of keratotic skin
disorders.Over-the-counterremediesabound,eachattemptingtothinand/oraccommodatethe
area(s) ofchiefcomplaint.Whatgoes unrecognized,however,is therelationofkeratosisto
truly neoplastic or systemic disease. The most useful algorithmic approach to this
commonplaceidentitywouldallowrapidcategorizationofdiseaseentities,witheachcategory
representing nonoverlapping diagnostic and therapeutic interventions. The algorithm should
alsoarrangethesecategoriesintermsoftheirclinicalurgency.
Thealgorithmpresentedhere,therefore,attemptstoanswerthefollowingquestions:(1)is
thepresentingkeratosisorkeratosesasignofamorewidespreadsystemicillness,or(2)isthe
keratoticchangeassociatedwitha cutaneousneoplasm?Thereader isremindedthatdiffuse
keratoses arethose thatextendovermostorall oftheplantarsurface.Guttatekeratosesare
drop-likelesions such as heloma miliare,andgeographic keratoseshave a morphology that
falls somewhereinbetween,suchas inatyloma. Thecategoriesofsystemicandneoplastic
disease will be discussed without subclassifying keratotic lesions into diffuse, guttate, or
geographicgroups.
This sectionismeantonlytoaugmentpreexistingcomprehensiveworksthatdescribe,in
detail, each of the entities mentioned later. Because the palms share the same ontogenic
developmentofthesoles, anexaminationof thehandsis alwaysin order.Abnormalitiesof
dentition,thecornea,andotherectodermallyderivedtissuesmayalsooccur.
KeratoticDiseasesAssociatedwithSystemicIllness
In this category,clinicians shouldexcludeHowel–Evanssyndrome, hypothyroidism, chronic
arsenic intoxication, secondary syphilis, Bazex syndrome, and the basal cell nevus (BCN)
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syndrome.
Howel–EvansSyndrome
Patientspresentwithdiffusekeratosesoftheirpalmsandsolesbilaterally,inassociationwith
a past or present history ofesophageal carcinoma. Attimes,suspecting clinicians mayfirst
make the diagnosis solely on the basis of diffuse palmoplantar keratoses in a patient with
symptomsofdysphagiaand/orhematemesis.
Hypothyroidism
Diffuseplantarkeratoses,thickandbrittlenails,andeasybruisabilityofthelegs(manifested
aspurpuraorecchymoses)suggestthediagnosis.Confirmationisaidedbyfindingthecardinal
symptoms and signs of weight gain, constipation, cold intolerance, and mental or physical
sluggishness.Thehypothyroidfootcancloselyresembleonewiththedry,scalyformoftinea
pedis. This diagnosis might therefore be considered in patients who are unresponsive to
standardantifungaltherapy.
ChronicArsenicIntoxication
Acuteintoxicationdoes not fall intothiscategorybecauseitpresentswithnausea,vomiting,
and other signs of gastrointestinal upset rather than skin change. Ingestion of contaminated
groundwater is considered to be the most common cause of chronic arsenic poisoning,
especiallyendemicinregionssuchasBangladesh,InnerMongolia,China,andtheWestBengal
province of India.
16–18
Inorganic arsenic sulfide was also found in Chinese proprietary
medicines as well as in American tobacco in the 1950s.19 There appears to be a dose–
response relationship or rather a dose and frequency relationship, with skin manifestations
being the most common adverse effect; furthermore, chronic exposure has been known to
increasetheriskofcanceraffectingmultipleorgansandnotlimitedtotheskin.
16–18
Themost
common initial skin manifestations are melanosis, keratosis, leukomelanosis, and
hyperkeratosis
16–18
(Fig. 15-4). There are a number of treatment options for the skin
manifestations secondary to chronic arsenic exposure; however, the effects may be
irreversible,thoughworthexploring,andmayinvolvephototherapy,topicalkeratolytics,and
chemotherapeuticagentsalongwithsurgicalexcisionandcryotherapy.
17
SecondarySyphilis
Guttatekeratoses ofthepalms andsoles arealso foundinpatientswithsecondary syphilis.
Concomitantly,theyalsoexhibitageneralized,ham-colored,maculopapularrash(Fig.15-5).
Questionsshouldbeposedregardingsexualhistory,andthespontaneousresolutionofagenital
“sore”(theprimarychancre).
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FIGURE15-4.Arsenicalkeratosespredilectingfortheskincreases(borrowedfromtheMountSinaiCollection
photographs).
FIGURE15-5.Theham-coloredmaculopapulardermatosisofsecondarysyphilis(borrowedfromtheMountSinai
Collectionphotographs).
BazexSyndrome
Bazexsyndrome(acrokeratosisparaneoplastica)occursinassociationwithcarcinomaofthe
upper respiratory and gastrointestinal tracts. Symmetrical, well-defined psoriasiform nails,
palmoplantar hyperkeratoses, and keratosis of the ears, nose, and cheeks comprise the
syndrome’smajorclinicalfeatures.
20–22
Thisconditionmaymanifestwithrecentonsetofnail
dystrophy,nailatrophy,localizederythema,andedemaofthedigitwithoutimprovementwith
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usualtopicalantifungalsorkeratolytics.
20
Thekeratosesgenerallyprecedetumorsymptomsordiagnosisbyalmost1year,withthe
eruptionbeingresistanttotopicaltherapy.Clearingofthetumorusuallyresultsinaclearingof
allcutaneouschangesexceptfornailinvolvement,withexacerbationofdermatologicdisease
heraldingrecurrenceormetastasis.Animmunereactiontothepresenceofanantigencommon
toboththetumorandnormalskin,ortumorproductionofakeratinocytegrowthfactorhasbeen
proposed as a potential etiology. Thediagnosis is basedon establishing a thoroughhistory,
physicalfindings,andhistologicfindings.
BasalCellNevusSyndrome
BCNsyndromeisanautosomaldominantdisordercausedbyamutationinthePatched1gene
or G protein–coupled receptor Smoothened (SMO).
23,24
It involves a triad of cerebral
calcifications, basal cell carcinomas, and keratocysts.23 Multiple basal cell tumors and
mandibular cysts typify this disorder. In contrast to the conditions previously described,
keratotic pits or depressionsare found on the palms and soles. Keratotic pits may also be
found in patients with other diseases unrelated to BCN syndrome. For example, pitted
keratolysis,causedbyacorynebacterialinfection,ismanifestedbypitsontheplantaraspectof
the foot.These pitstrapdirtand debristhatcausethepitstobecomehyperpigmented.Inthe
case of BCN syndrome, the pigment is easily removed with an alcohol sponge. In pitted
keratolysis, the pigmentation cannot be removed, because it is a genuine discoloration
producedbybacterialdiphtheroidsbelievedtocausethedisease.Althoughpittedkeratolysis
isoftenasymptomatic,painfulvariantsinadultmalesduringmilitaryserviceandinchildren
canoccur.In pediatric cases, topical erythromycin cancure thedisorder.BCNsyndromeis
associatedwithanumber ofneurologic findings.Medulloblastomas andcalcificationofthe
falxcerebriandduraoccur.
DiagnosisisbasedonmajorandminorcriteriaestablishedbyEvansetal.,andmodified
byKimonisetal.andBreeetal.23EarlyclinicalfeaturesalongwithafamilyhistoryofBCN
syndromeshouldwarranttheneedforstandardimagingtestssuchaspanorexofthejaw,MRI
ofthebrain,CT,PETscan,alongwithbiopsiesoflesionsandgenetictesting.
24,25
Definitive
therapyinvolvessurgicalexcisionortheuseofMohs,andradiationtherapy.Palliativetherapy
includes the use of retinoids, photodynamic therapy, vitamin D supplements, topical
chemotherapeutic agents, cryotherapy, and laser therapy.
23–25
Emerging therapy has been
developedtargetingthegeneticdeficiencies,suchasSMOinhibitorswhichhaveshowngreat
promise in inhibiting the Hedgehog signaling pathway known to drive the development of
BCC.
23–26
KeratoticChangeAssociatedwithCutaneousNeoplasm
A discussionofcutaneous neoplastic disease is certainly beyondthescope of this chapter;
however, there are a number of clinical clues to suggest that a keratotic lesion is in fact
neoplastic. First, it is safe to assume that many cutaneous neoplasms lose their classic
morphologicappearancewhenaffectingthesole,somebecomingasnondescriptasalocalized
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areaofhyperkeratosis.
Second, clinicians have come to expect that isolated keratoses form around sites of
pressure, friction, or invasive events. Keratoses that form de novo in foot areas that are
typicallynonweight-bearingandrelativelyfreefromtrauma(i.e.,themidsole,thephalangeal
ormetatarsalshafts,etc.),orthosethatdonotrespondtoaccommodativemeasuresare,asa
result,alsosuggestiveofneoplasm.
Last,keratosesthatharborneoplasticchangeoftenexhibitanerythematousrim,probably
anindicator ofthemetabolicand inflammatoryeventsoccurringatthe marginofthe lesion.
This erythematous rim has also been described in heritable keratotic diseases, known
collectively as the genokeratoses. The family history, however, should readily distinguish
neoplasmfromgenokeratosis.
TreatmentoftheKeratoticDiseases
The standard treatments for keratotic diseases have always included paring, abrasive tools
(e.g.,pumicestones,loofahpads,etc.),accommodativeinsoles,pads,and/orshoes,emollients
(includingurea),keratolytics,andantiproliferationagents.Attimes,surgicalresectionofbony
prominencesand localskinflapshavebeenadvocated.Retinoids arealsoused,andwillbe
discussedseparately.
Emollients
These drugsfunction byadding moisture andlubricationtothe skinwhen applied topically.
Majorcategoriesincludeureapreparations,topicalvitaminsA,D,andE,andafinalgrouping
thatcontainsvariousmixturesoftheaboveingredientswithmineraloil,glycerin,petrolatum,
andanyoneofalargenumberofvehicles.Ofspecialnoteisthewidespreaduseofparabens
inthesemixtures,becauseparabensareknownskinsensitizerscapableofinitiatingamarked
dermatitis.Patientswhoareparabensensitive should beware,because44ofthe 93(almost
50%!)prescriptionandover-the-counteremollientsrecentlylistedcontainedparabens.
Keratolytics,AntiproliferativeandDesmolyticAgents
Anthralin, salicylic acid (SA), podophyllin, and cantharidin have been the best known
keratolyticandantiproliferative preparations. However,researchhasshownthatvitaminD
3
helpstoregulategrowthanddifferentiationofmanycelltypesincludingepidermalcells27;it
alsoenhancesthecornifiedenvelopformationaswellasexhibitsanti-inflammatoryeffectsby
inhibitingneutrophilfunction.6VitaminD3and itsanalogshavebeencommerciallyavailable
sincethemid-1990sintheUnitedStatesasatopicaltreatmentforpsoriasisandhasprovento
havemoderateefficacy.Additionally,vitaminD3(calcipotriol, calcitriol,andtacalcitol) has
definite potential in treating ichthyoses and other diseases resulting in excessive epidermal
proliferation.28Calcipotriolhasbeenusedintreatingchronicplaquepsoriasis,andfoundtobe
aspotentascorticosteroidsandmoreeffectivethanusingcoaltar,short-termdithranol,aswell
astacalcitol.
29
Most importantly, patienteducationof thebasics inskinhygiene andin preventivecare
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Table15-1.
including maintaining a certain level of humidity in the home, using mild and unscented
soaps/detergents,andavoidinglonghotshowersorbathsiscrucial.4Iftheareasshowsignsof
localizedinflammation,one may includeamild topical steroid, whichmay be discontinued
after7to14days.
30
SA was once categorized as a keratolytic agent; however, it is now considered as a
desmolytic agent, due to its mechanism of action, which involves disrupting intercellular
junctions.12SAhastheabilitytoaltertheunderlyingdermaltissuewithoutdirectlywounding
theskin.12Ineffect,SAresultsinexfoliationduetoitsabilitytoextractdesmosomalproteins
causingalossofcohesionbetweenepidermalcells.Ithasantihyperplasticeffects,whichhave
beenstudiedintheguineapigepidermis,andareductioninhyperplasiaofviableepidermal
cells. Loden et al.31 studied SA on human skin and concluded that it does not affect the
thicknessoftheepidermis,ratherresultinginthinningofthecorneallayer.
12
Contraindicationstousing SAinclude contactallergies, activeinfection,pregnancy,skin
malignancy, andconcurrentuseoftopicalretinoids.Retinoidsshouldbe discontinued1to2
weeks prior to use, in order to avoid complications such as postinflammatory
hyperpigmentation,excessiveerythema,anddesquamation.
12
VariousUsesofSABasedonItsConcentration
SAConcentration(30)(%) Uses
0.5–10 Acne
3–6 Hyperkeratosis,psoriasis,ichthyoses,keratosispilaris
5–40 Warts,corns
50 Actinicdamageandpigmentedlesions
20–30 Superficialchemicalpeelingoftheface
SA,salicylicacid.
Salicylism,secondarytocutaneousabsorption,isararephenomenon.SAisalipid-soluble
agent that is readily absorbed by the skin; its rate of absorption can be enhanced when
combined with a hydrophilic base or under occlusion.30 SA toxicity has been reported by
dermatologistswhen20%ofSAisappliedto50%ofthebodysurfaceandat40%and50%
SApastepreparations(Table15-1).
12
Anthralin is a naturally occurring substance known as Goa powder derived from the
ararobatree;itinhibitsDNAsynthesisandcellmitosis,whichinturninhibitsepidermalcell
proliferation.
32,33
Common side effects include staining and pigmentation of the skin and
clothingand contactdermatitis.Extremecautionmustbeusedwithchildrenandpregnantor
lactatingfemales.
Coaltarworksalongthesamemechanismasanthralin,anditsactionsareenhancedwith
theuseofultravioletlight;whencombined,itresultsinaphototoxicreactionresultinginthe
inhibitionofepidermalDNAsynthesis.
33
Cantharidinis a keratolyticagentandtopical vesicant resultinginselectiveacantholysis
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that occurs intraepidermally.
16,34
A progressive degeneration ofdesmosomal dense plaques
results from the activation of neutral serine proteases when absorbed by the lipids in the
keratinocyte.
35,36
Whenapplied,cantharidincausesblisterformationin24to48hours.Primary
indicationshavebeenforverrucavulgarisandmolluscumcontagiosum.36The off-label uses
forcantharidininclude callusremoval, perforating collagenosis, postherpetic neuralgia,and
leishmaniasis lesions.36 The most common adverse reactions are blistering, localized
erythema,andpain.
Podophyllin is locally cytotoxic, causing mitotic arrest. Unfortunately, it can lead to
ulcerationof the skin or severe neuropathy, especiallywhen applied to largeareas ofskin.
Although the total cross-sectional area of the soles is relatively small, patients should be
warnedofandmonitoredforthesechanges.
Whenthesemedicamentsareusedsinglyorincombination,noninvolvedareasofskinmust
be protected. Application under occlusion will enhance penetration and, therefore, effect.
Couplingthesetherapieswithmechanicaldebridement(paring)istime-consumingbutoffersa
speedyrewardforthesufferingpatient.
Retinoids
Retinoids,bothtopicalandsystemic,caninhibitkeratinformationandfunctionasmorphogens
capable of altering growth and differentiation of the epidermis.29 Retinoids, vitamin A
derivatives,itsanalogsandsynthetics,exertanantiproliferativeeffectactingatthemolecular
level, with some inhibiting the expression of keratinocyte enzyme transglutaminase.29 By
inhibiting theexpressionofthisenzyme,itdirectlyresultsinadecreaseinproliferationand
cohesion of cornified cells,29 ultimately normalizing keratinization and decelerating the
processofdesquamation.Tretinoin,thefirsttopicalretinoidonthemarket,continuestohave
secondary antimicrobial and anti-inflammatory activity.29 Newer synthetics (adapalene,
tazarotene)havemoreselectivereceptorbindingandanti-inflammatoryactivity.37Currently,in
theUnitedStates,thetopicalretinoidsavailableincludetretinoin,second-generationtretinoin,
andthird-generationretinoids(adapaleneandtazarotene).
34,37
Accutane (isotretinoin) was taken off the market in the summer of 2009, due to the
expiration of its patents and also because of thousands of litigation issues. Roche, its
manufacturer,hasstoodbytheirproduct’ssafety;however,ithasbeenlinkedtoseriousbirth
defects, bowel disorders, depression, and suicidal ideation. Accutane’s generic equivalent
continues to be available. According to Davis et al.,38 in its generic form, isotretinoin
continues to be theleading medication usedby dermatologistsinteenswith acne. Although
therehasbeenadeclineintrendduetothesafetyconcernsandstrictrequirementsoffederal
monitoringprograms,acitretin,asecond-generationretinoid,continuestobeavailableonthe
market.However,etretinate,alsoasecond-generationretinoid,hasbeen discontinueddueto
itsnarrowtherapeuticindexaswellasitslongeliminationhalf-life,makingdosingdifficult.
FDA-approvedindicationsforretinoidshavebeenacnevulgaris,mitigationoffinewrinkles,
mottledhyperpigmentation,andtactileroughnessoffacialskinandplaquepsoriasis.Off-label
usesincludephotoaging,intrinsicaging,actinickeratosis,andactiniclentigines.
34
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Isotretinoin and acitretin are administered orally and share similar adverse effects:
hypertriglyceridemia, hair loss and skin fragility, hyperostoses, tendinous and ligamentous
calcifications (especially in patients on long-term therapy, i.e., five or more years), and
markedteratogenicity.Forthe latterreason,pregnancyisanabsolutecontraindicationtothe
useofthesedrugs.
VESICULOBULLOUSDISEASES
Vesiclesarepalpable,fluid-filledskinlesionslessthan1cmindiameter.Bullaearesimilarly
definedexceptthattheydemonstratelargerdimensions.
Vesiculobullous lesions can be localized as to whether they are intraepidermal or
subepidermal.Erythemamultiformeisoneexampleofasubepidermalreaction.Thiscondition
is characterized by large bullae which dissect and extend along the epidermal–dermal
interface.
Diseases of the skin demonstrating intraepidermal vesicle or bulla formation include
disordersasvariedasherpessimplexorherpeszoster.
MechanobullousDiseases
As a group, each of these diseases is inherited with traumatically induced vesiculobullae
appearing in characteristic pressure areas, that is, feet, knees, hands, and elbows.
Epidermolysisbullosaisoftenconsideredtheprototypeforthemechanobullousdisorders.
Thedermatosesaresubdividedintoscarringandnonscarringtypes,withtheformerusually
having their onset in infancyand resulting in mutilating pseudosyndactyly and contractures,
withgeneralizeddiseaseresultinginearlymortality(Fig.15-6).
Weber–Cockaynedisease,alsoreferredtoasrecurrentbullousdermatosisofthefeet,isan
exampleofthenonscarringvariety.Prolongedmarchingduringsummermonthsexacerbatesthe
condition.Althoughthispresentationisreminiscentofskinchangesinhealthyindividuals,the
familyhistorypointstotheultimatediagnosis.
ParaneoplasticPemphigus
Vesiculobullous eruptionsassociated with internal carcinoma havebeenreportedinpatterns
resembling dermatitis herpetiformis, bullous pemphigoid, erythema multiforme, and in
leukemiasandlymphomas.Inonereport,thedevelopmentofpalmoplantarblistersheraldeda
leukemic crisis. Recently, a bullous disorder resembling pemphigus has been described in
patientswithunderlyingneoplasms.
AcrodermatitisEnteropathica
Onsetusuallyoccursbefore2 yearsofage, with vesiculobullae onerythematousbases that
collapse to form papulosquamous plaques. The dorsal toes (resembling candidiasis at the
proximalnailfold)andperiorificialareasaretypicallyaffected.
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FIGURE15-6.Trivialinjurytothefragileskinofpatientswithepidermolysisbullosasimplexleadstoblisterformation
(borrowedfromtheMountSinaiCollectionphotographs).
Hemodialysis
Simple vesiculobullae on the dorsum of a foot can develop spontaneously in patients
undergoingthistherapy.
Hand,Foot,andMouthDisease
Football-shapedvesiclesandbullaeonanerythematousbaseaffectthesiteslistedinthisselflimiting disorder (Fig. 15-7). The Coxsackie A16 virus is the causative agent, resulting in
epidemicsamongschool-agedchildren.
HerpesGestationis
Blisters developing during pregnancy or shortly after parturition may result from herpes
gestationis,whichhasbeenassociatedwithahigher-than-normalincidenceofmaternaland/or
fetalcomplications(Fig.15-8).
GlucagonomaSyndrome
Repeatedforthe sakeofcompleteness,the readerisreferred tothesectionon erythematous
macules.
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