CHAPTER 13 - Skin and Subcutaneous Tissue

David M. Young Stephen J. Mathes INTRODUCTION The skin is the largest and one of the ost !o ple" organs of the #od$. Its unifor appearan!e #elies its great variation fro region to region of the #od$ and the !o ple" organi%ation and intera!tion of the an$ different !ells and atri!es of the skin. &lthough the skin fun!tions si pl$ as a prote!tive #arrier and interfa!e 'ith our environ ent( its stru!ture and ph$siolog$ are !o ple". The skin is an e"tre el$ good interfa!e 'ith our environ ent. It is prote!tive against ost of the no"ious agents( su!h as !he i!als )#$ the i per ea#ilit$ of the epider is*( solar radiation )#$ eans of pig entation*( infe!tious agents )through effi!ient i unosurveillan!e*( and ph$si!all$ defor ing for!es )#$ the dura#ilit$ of the der is*. The skin is the a+or organ responsi#le for ther oregulation( having an effi!ient a#ilit$ to !onserve or disperse heat. To dire!t all these fun!tions( the skin has a highl$ spe!iali%ed nervous stru!ture. These various fun!tions are #etter served #$ different !o ponents of skin( so teleologi!all$ there developed regional variation. The pal s and soles are parti!ularl$ thi!k( to #ear 'eight. The fingertips have the highest densit$ of sensor$ innervation and allo' for intri!ate tasks. ,ven the lines of the skin( first des!ri#ed #$ -anger( are oriented perpendi!ularl$ to the long a"is of us!les to allo' the greatest degree of stret!hing and !ontra!tion 'ithout defor it$. The relative ease of o#serving and o#taining skin spe!i ens for e"a ination and e"peri ents has ade skin one of the #est.studied tissues of the hu an #od$. Thus skin is not +ust the su#+e!t of the field of der atolog$( #ut also the stud$ of the skin laun!hed the fields of i unolog$( transplantation( and 'ound healing. &lthough this !hapter e phasi%es surgi!all$ treated diseases of the skin( it is i portant for students of surger$ to #e fa iliar 'ith the #asi! ph$siolog$ and stru!ture of skin sin!e an$ of the future advan!es in edi!ine 'ill !o e fro these studies. &N&TOMY &ND /0YSIO-O1Y The skin has #een traditionall$ divided into three la$ers2 the epider is( the #ase ent e #rane( and the der is )3ig. 45.4*. The epider is is !o posed ainl$ of !ells( 'ith ver$ little e"tra!ellular atri". ,a!h !ell t$pe serves a spe!ifi! #arrier fun!tion. 6eratino!$tes provide a e!hani!al #arrier( elano!$tes a radiation #arrier( and -angerhans7 !ells an i unologi! #arrier. The der is !ontains ostl$ e"tra!ellular atri"( providing support for nerves( vas!ulature( and adne"al stru!tures. The der is allo's skin to resist defor ing for!es and return to its resting state( thus providing dura#ilit$. The #ase ent e #rane is a spe!iali%ed stru!ture that an!hors the epider is to the der is. The ain !ell t$pe in the epider is is the keratino!$te. The deep( itoti!all$ a!tive( #asal !ells are a single !ell la$er of the least.differentiated keratino!$tes. So e ultipl$ing !ells leave the #asal la$er and #egin to travel up'ard. In the spinous la$er the$ lose the a#ilit$ to undergo itosis. These differentiated !ells start to a!!u ulate

keratoh$alin granules in the granular la$er. 3inall$( in the horn$ la$er( the keratino!$tes age( the on!e. nu erous inter!ellular !onne!tions disappear( and the dead !ells are shed. Using radioa!tive and fluores!en!e la#eling( e"peri ents have sho'n the keratino!$te transit ti e to #e fro 89 to :; da$s. The !ontrol of keratino!$te ultipli!ation and su#se<uent aturation is an area of a!tive stud$ and a$ !larif$ the !o ple" e!hanis of !ellular differentiation. Melano!$tes igrate to the epider is fro pre!ursor !ells in the neural !rest. The$ lie s!attered #eneath #asal !ells and have dendriti! pro!esses that rea!h out to surrounding keratino!$tes. The$ nu #er appro"i atel$ one for ever$ 5: keratino!$tes. The elano!$tes produ!e a pig ent( elanin( fro t$rosine and !$steine. The pig ent is pa!kaged in elanoso es and transported to the tips of the dendriti! pro!esses. The tips are sheared off )apo!opation* and then phago!$ti%ed #$ the keratino!$te( thus transferring the pig ent to the keratino!$te. On!e in the keratino!$te the$ aggregate on the superfi!ial side of the nu!leus in an u #rella shape. The densit$ of elano!$tes is !onstant #et'een individuals of different skin !olor. The rate of elanin produ!tion( transfer to keratino!$tes( and elanoso e degradation deter ine the degree of skin pig entation. These a!tivities are influen!ed #$ geneti!all$ a!tivated fa!tors as 'ell as ultraviolet radiation and hor ones su!h as estrogen( adreno!orti!otropi! hor one( and elano!$te.sti ulating hor one. The -angerhans7 !ells igrate fro the #one arro' and fun!tion as the skin7s a!rophages. The -angerhans7 !ells !onstitutivel$ e"press !lass II a+or histo!o pati#ilit$ antigens and have antigen.presenting !apa#ilities. These !ells pla$ a !ru!ial role in i unosurveillan!e against viral infe!tions and neoplas s of the skin( and a$ initiate skin allograft re+e!tion. The der is !onsists ostl$ of several stru!tural proteins. Collagen !onstitutes =9 per!ent of the dr$ 'eight of der is and is responsi#le for its re arka#le tensile strength. Tropo!ollagen !onsists of three pol$peptide !hains )for ed ainl$ of h$dro"$proline( h$dro"$l$sine( and gl$!ine* 'rapped in a heli". These long ole!ules are then !ross.linked to one another to for !ollagen fi#ers. Of the seven stru!turall$ distin!t !ollagens( the skin !ontains ostl$ t$pe I. ,arl$ fetal der is !ontains ostl$ t$pe III )reti!ulin fi#ers* !ollagen( #ut this re ains onl$ in the #ase ent e #rane %one and the perivas!ular regions in postnatal skin. ,lasti! fi#ers are highl$ #ran!hing proteins that are !apa#le of #eing reversi#l$ stret!hed to t'i!e their resting length. This allo's skin to return to its original for after stret!hing. 1round su#stan!e is an a orphous aterial that fills the re aining spa!es. It !onsists of various pol$sa!!haride.pol$peptide )gl$!osa inogl$!ans* !o ple"es. The nonsulfated for is ostl$ h$aluroni! a!id( and the sulfated for s are heparin sulfate( der atan sulfate( and !hondroitin.;.sulfate. 1l$!osa inogl$!ans( 'hi!h !an hold up to 4999 ti es their o'n volu e in 'ater( !onstitute ost of the volu e of der is. 3i#ro#lasts are s!attered throughout the der is and are responsi#le for produ!tion and aintenan!e of the protein atri". Re!entl$ proteins that !ontrol the proliferation and igration of fi#ro#lasts have #een isolated. The stud$ of fi#ro#last a!tivit$ #$ these gro'th fa!tor intera!tions is !ru!ial to our understanding of 'ound healing and organogenesis.

The #ase ent e #rane %one of the der oepider al +un!tion is a highl$ organi%ed stru!ture of proteins that an!hors the epider is to the der is. Me!hani!al disruption or a geneti! defe!t in the s$nthesis of this stru!ture )epider ol$sis #ullosa* results in separation of the epider is fro the der is. In the der is are situated the re aining stru!tures of the skin. &n intri!ate net'ork of #lood vessels regulates #od$ te perature. T'o hori%ontal ple"uses( one at the der al>su#!utaneous +un!tion and one in the papillar$ der is( are inter!onne!ted #$ verti!al vas!ular !hannels. 1lo us #odies are tortuous arteriovenous shunts that allo' a tre endous in!rease in #lood flo' to the skin 'hen open. This large a ount of #lood flo' in e"!ess of its nutritional needs allo's skin to dissipate a vast a ount of #od$ heat 'hen needed. Ther oregulation is !arried out #$ autono i! fi#ers that s$napse to s'eat glands( the hair ere!tor us!les( and !ontrol points in the vas!ulature. Sensor$ innervation follo's a der ato al distri#ution fro seg ents of the spinal !ord. These fi#ers !onne!t to !orpus!ular re!eptors )pa!inian( Meissner7s( and Ruffini7s* that respond to pressure( vi#ration( and tou!h( to ?unspe!iali%ed@ free nerve endings asso!iated 'ith Merkel !ells of the #asal epider is( or to hair folli!les. These nerves are sti ulated #$ te perature( tou!h( pain( and it!h. The skin has three ain adne"al stru!tures. The e!!rine glands( 'hi!h produ!e s'eat( are lo!ated all over the #od$ #ut are !on!entrated on the pal s( soles( a"illae( and forehead. The hair folli!les !onsist of a itoti!all$ a!tive ger inal !enter that produ!es a !$linder of tightl$ pa!ked !ornified epithelial !ells. Control of the gro'th !$!le of the hair is little understood. The se#a!eous glands produ!e an oil$ su#stan!e that !oats the skin. Together these t'o stru!tures for a pilose#a!eous unit. The apo!rine glands are found pri aril$ in the a"illae and the anogenital region. In lo'er a als these glands produ!e s!ent hor ones )phero ones*.

TRAUMA
Penetrating Injuries Disruption of the !ontinuit$ of the skin allo's the entr$ of organis s that !an lead to 'ound infe!tion. Sharp la!erations( #ullet 'ounds( ?road rash@ )in+ur$ fro s!raping against road pave ent*( and degloving in+uries should #e treated #$ gentle !leansing( de#ride ent of all foreign de#ris and ne!roti! tissue( and appli!ation of a proper dressing. Dirt$ or infe!ted 'ounds should #e left open to heal #$ se!ondar$ intention or dela$ed pri ar$ !losure. Clean la!erations a$ #e !losed pri aril$. Road rash in+uries are treated as se!ond.degree #urns and degloving in+uries as third.degree #urns. The degloved skin !an #e pla!ed #a!k on the 'ound like a skin graft and assessed for survival prospe!ts. If the skin #e!o es ne!roti! it is re oved and the 'ound is !overed 'ith split.thi!kness skin grafts. Pressure Ulcers !ecubitus Ulcers" /ressure ul!ers( as the na e i plies( are !aused #$ e"!essive( unrelieved pressure. In ani al studies( ;9 0g pressure applied to the skin for 4 h produ!es histologi!all$ identifia#le in+uries su!h as venous thro #osis( us!le degeneration( and tissue ne!rosis. The average hu an #eing e"erts ;9 to =9 0g pressure on su!h #od$ areas as the sa!ru ( o!!iput( and heels 'hile l$ing in #ed or on the is!hia 'hile sitting

in a !hair. 0ealth$ people( ho'ever( regularl$ shift their #od$ 'eight( even 'hile asleep. Sitting in one position !auses pain in areas of in!reased pressure( thus sti ulating ove ent. /atients una#le to sense pain or to shift their #od$ 'eight( su!h as paraplegi!s or #edridden individuals( develop prolonged elevated tissue pressures and( eventuall$( ne!rosis. Mus!le tissue is ore sensitive to is!he ia than the overl$ing skin. That is 'h$ the ne!roti! area is al'a$s 'ider and deeper than it appears on first inspe!tion )3ig. 45.A*. Treat ent of pressure sores re<uires relief of pressure 'ith spe!ial !ushions and #eds and nutritional support to pro ote healing. The ne!roti! tissue should #e re oved( often along 'ith the underl$ing #on$ pro inen!e. Shallo' ul!ers a$ !lose #$ se!ondar$ intention( #ut deeper 'ounds 'ith involve ent of the underl$ing #one re<uire surgi!al de#ride ent and soft tissue and skin !overage. To prevent future #reakdo'n of the area( sta#le !overage should #e o#tained 'ith lo!al $o!utaneous or fas!io!utaneous flaps. /revention of ul!ers is #est a!hieved #$ !lose attention to sus!epti#le areas and fre<uent repositioning of paral$%ed patients. &ir flotation attresses and gel seat !ushions redistri#ute pressure( de!rease the in!iden!e of pressure ul!ers( and are !ost effe!tive in the !are of patients at high risk. The addition of gro'th fa!tors to these 'ounds has #een found to in!rease healing and offers pro ising therap$ in the future. #eloids and H$%ertro%&ic Scars &ll 'ounds heal #$ s!ar for ation. 0$pertrophi! s!ars are raised( red( and nodular( #ut re ain 'ithin the li its of the original in!ision or trau a. 6eloids are u!h #ulkier( and their nodularit$ and fir ness e"tend #e$ond the 'ound )3ig. 45.5*. &lthough there are distin!t histologi! and #io!he i!al differen!es #et'een keloids and h$pertrophi! s!ars( the distin!tion is largel$ !lini!al. Dark.skinned individuals are ore likel$ to develop keloids and h$pertrophi! s!ars( and a geneti! !o ponent has #een found. The lo!ation of a 'ound( su!h as a!ross a +oint and on the sternu ( is an i portant fa!tor in develop ent of these lesions. 3i#ro#lasts isolated fro patients 'ith keloids s$nthesi%e in!reased a ounts of e"tra!ellular atri" proteins and gro'th fa!tors. Medi!al treat ent in!ludes intrader al in+e!tions of !orti!osteroids )tria !inolone a!etonide* to redu!e the it!hing and flatten the s!ar. Me!hani!al pressure )as 'ith pressure gar ents* also !an soften and flatten raised s!ars. ,"!ision of keloids and h$pertrophi! s!ars re ains the ost effe!tive treat ent. These lesions are prone to re!ur unless steroid in+e!tions or pressure therap$ 'ith sili!one gel sheeting is #egun soon after surger$. -aser treat ent and radiation therap$ of these lesions have #een found to #e effe!tive. Bith a #etter understanding of the pathogenesis of these a#nor al states of 'ound repair( ore effe!tive therap$ 'ith lo!al gro'th fa!tors or their #lo!kers is #eing developed. I'(ECTI)'S *acterial In+ections 3olli!ulitis( 3urun!les( and Car#un!les

(olliculitis is infe!tion and infla ation of a hair folli!le. The !ausative organis is usuall$ Staph$lo!o!!us and o!!asionall$ a gra .negative organis . +uruncle boil* #egins as folli!ulitis #ut progresses to for a nodule that eventuall$ #e!o es flu!tuant. The a#s!ess eventuall$ ruptures and usuall$ resolves. Deep.seated infe!tions that result in ultiple draining !utaneous sinuses are !alled !ar#un!les. 3olli!ulitis usuall$ resolves 'ith ti e and ade<uate h$giene. Bar soaks to a furun!le a$ hasten li<uefa!tion( speed drainage( and en!ourage healing. O!!asionall$ anti#ioti!s are used to anage surrounding !ellulitis. Carbuncles are ore diffi!ult to treat and re<uire in!ision and drainage or 'ide e"!ision of the infe!ted tissue and sinuses. Hidradenitis Su%%urati,a Ca!terial infe!tion of a plugged apo!rine gland o!!urs ost !o onl$ in the a"illae and inguinal and perianal regions. &n a#s!ess for s 'ith su#se<uent drainage and sinus for ation. Repeated infe!tions !reate a 'ide area of infla ed and s!arred tissue that is foul.s elling and painful )3ig. 45.8*. Treat ent of a!ute infe!tions in!ludes appli!ation of 'ar !o presses( anti#ioti!s( and open drainage. /roper h$giene and dis!ontinuation of deodorants a$ prevent re!urren!e. Chroni! hidradenitis re<uires e"!ision of the entire area of infe!tion and !losure 'ith skin grafts. Pilonidal !isease Infe!ted pilonidal !$sts of the sa!ro!o!!$geal region o!!ur pri aril$ in $oung adults and are four ti es ore !o on in ales. The pathogenesis of the disease is u!h de#ated( #ut s'eat$ a!tivit$ and #utto!k fri!tion( su!h as o!!urred in +eep drivers in Borld Bar II )+eep driver7s disease*( is asso!iated 'ith a high in!iden!e of pilonidal disease. The infe!tion pro#a#l$ #egins in a pilose#a!eous unit in the natal !left. Re!urrent trau a !auses o#stru!tion of a hair folli!le and leads to infe!tion. The lo!ali%ed folli!ulitis spreads into the surrounding soft tissue and produ!es an a#s!ess. This eventuall$ drains to the surfa!e and produ!es a sinus that is usuall$ lo!ated lateral to the idline. The sinus is lined 'ith granulation tissue #ut over ti e !an epitheliali%e. Constant ove ent and fri!tion of the #utto!ks !auses hair and loose de#ris to enter the tra!t( in!iting a foreign.#od$ rea!tion. &!ute pilonidal a#s!esses should #e drained. Bithout further therap$( an$ 'ill re!ur. Use of perioperative anti#ioti!s does not affe!t the out!o e of the disease. There are an$ different 'a$s of treating the !hroni! sinus tra!t( in!luding tra!t !urettage( lo!al e"!ision and !losure( 'ide e"!ision and arsupiali%ation( and 'ide e"!ision and flap !losure. &nother ethod !urrentl$ gaining favor is fistuloto $ and arsupiali%ation. ,a!h ethod has its dra'#a!ks. /atients undergoing pri ar$ !losure sta$ in the hospital longer #ut return to 'ork sooner than patients 'ith the 'ound left open after e"!ision. Nonsurgi!al treat ent of a pilonidal lesion #$ natal. !left shaving and perineal h$giene re<uires the least a ount of hospitali%ation #ut a$ have a higher re!urren!e rate. The ost !ost. effe!tive ethod re ains to #e deter ined. To"i! ,pider al Ne!rol$sis and Staph$lo!o!!al S!alded Skin S$ndro e These t'o diseases !reate a si ilar !lini!al pi!ture( 'hi!h in!ludes er$the a of the skin( #ullae for ation( and( eventuall$( 'ide areas of skin loss. Staph$lo!o!!al s!alded skin s$ndro e )SSSS* is !aused #$ an e"oto"in produ!ed during a

staph$lo!o!!al infe!tion of the nasophar$n" or iddle ear in the pediatri! population. To"i! epider al ne!rol$sis )T,N* is thought to #e an i unologi! rea!tion to !ertain drugs( su!h as sulfona ides( phen$toin( #ar#iturates( and tetra!$!line. Diagnosis !an #e ade 'ith a skin #iops$ e"a ination #e!ause SSSS produ!es a !leavage plane in the granular la$er of the epider is( 'hereas T,N o!!urs at the der oepider al +un!tion. The in+ur$ is si ilar to a se!ond.degree #urn. Treat ent involves fluid and ele!trol$te repla!e ent and 'ound !are as in a #urn in+ur$. In Stevens.Johnson s$ndro e epithelial sloughing of the respirator$ and ali entar$ tra!ts o!!urs( 'ith resultant respirator$ failure and intestinal ala#sorption. /atients 'ith T,N should #e treated in #urn units to de!rease the or#idit$ fro the 'ounds. The skin slough has #een su!!essfull$ treated 'ith !adaveri! or por!ine skin or se is$ntheti! #iologi! dressings )Cio#rane*. Te porar$ !overage 'ith a #iologi! dressing allo's the underl$ing epider is to regenerate spontaneousl$. Corti!osteroid therap$ has not #een effi!a!ious. Actino-$cosis &!tino $!osis is a lo!ali%ed infla ator$ ass( usuall$ of the +a' area( that spreads #$ ultiple fistulas and a#s!esses into the ne!k and fa!e. The underl$ing #one also !an #e!o e infe!ted( as !an the ape" of the lung. The !ausative agent is &!tino $!es( an organis of the &!tino $!eta!eae fa il$( in the &!tino $!etales order. Other a!tino $!etes( in!luding No!ardia( &!tino adura( and Strepto $!es( !ause $!eto as( 'hi!h are deep !utaneous infe!tions that present as nodules and spread to for draining tra!ts to the skin and surrounding soft tissue. Chroni! disease !auses fi#rosis and !ontra!tures. The ost !o on site for infe!tion is the foot )Madura foot*. The gra .negative #a!teria that !ause these infe!tions 'ere on!e #elieved to #e fungi #e!ause the$ gro' slo'l$ as #ran!hed fila ents and !hains. Diagnosis depends on the presen!e of !hara!teristi! sulfur granules on i!ros!opi! e"a ination. Spe!ial stains should #e used to e"!lude fungal infe!tion. /eni!illin and sulfona ides are effe!tive against these infe!tions. &#s!esses and areas of !hroni! s!arring a$ re<uire surgi!al therap$. .$-%&ogranulo-a /enereuChla $dia tra!ho atis is a se"uall$ trans itted( intra!ellular( gra . negative #a!teriu . &fter infe!tion and a A.'eek in!u#ation period( an in!onspi!uous ul!er appears on the penis or la#ia( although in ore than half the !ases this lesion is not noti!ed or does not appear. & fe' 'eeks later( inguinal l$ phadenopath$ erupts. The nodes #e!o e ver$ large and painful )#u#oes* and are o!!asionall$ !onfused 'ith an in!ar!erated inguinal hernia. &denopath$ !an o!!ur a#ove and #elo' the inguinal liga ent( for ing a !hara!teristi! groove. The atted nodes a$ suppurate( and o!!asionall$ the$ rupture. Surgi!al drainage of unruptured a#s!esses is not re!o ended #e!ause a !hroni! draining sinus often develops. &!tive infe!tion is treated 'ith do"$!$!line for 4 'eek or a%ithro $!in in one dose. Infla ation fro infe!tion !an lead to l$ phati! o#stru!tion and !hroni! lo'er e"tre it$ ede a. Re!tal stri!tures also !an o!!ur.

/iral In+ections
Barts are epider al gro'ths asso!iated 'ith hu an papillo avirus infe!tion. 0istologi!all$ the$ are !hara!teri%ed #$ h$perkeratosis )h$pertroph$ of the horn$ la$er*( a!anthosis )h$pertroph$ of the spinous la$er*( and papillo atosis. 6oilo!$tes( large keratino!$tes 'ith e!!entri! nu!lei( are present. Different orphologi! t$pes have a propensit$ to o!!ur on different parts of the #od$. The !o on 'art )verru!a vulgaris* is found on the fingers and toes( and has a rough( gra$.#ro'n surfa!e. /lantar 'arts )verru!a plantaris* o!!ur on the soles and pal s( and a$ look like a !allus. 3lat 'arts )verru!a plana*( 'hi!h are flat #ut slightl$ raised( appear on the fa!e( legs( and hands. Denereal 'arts )!ond$lo ata a!u inata* gro' in the oist areas around the vulva( anus( and s!rotu . Barts !an #e re oved #$ a nu #er of !he i!als( in!luding for alin( podoph$llu ( and phenol.nitri! a!id. Curettage 'ith ele!trodesi!!ation also !an #e used for s!attered lesions. Treat ent of e"tensive areas of skin re<uires surgi!al e"!ision under general anesthesia. Ce!ause of the infe!tious etiolog$( re!urren!es are !o on( and repeated e"!isions often are ne!essar$ to eli inate lesions. So e 'arts )espe!iall$ hu an papillo avirus t$pes :( E( and 49* are asso!iated 'ith s<ua ous !ell !an!ers( and therefore lesions that gro' rapidl$ or ul!erate should #e #iopsied. Cond$lo ata a!u inata are se"uall$ trans itted and !an #e parti!ularl$ #otherso e. /atients 'ith hu an i unodefi!ien!$ virus )0ID* infe!tion are ore likel$ to develop !lini!all$ signifi!ant venereal 'arts. The lesions often are ultiple and !an gro' to large si%e )Cus!hke.-o'enstein tu or*. S all lesions !an #e treated 'ith podoph$lloto"in !rea . -arger lesions have a signifi!ant risk of alignant transfor ation and should #e e"!ised. The lesions often re!ur. &d+uvant therap$ 'ith interferon( isotretinoin( or autologous tu or va!!ine de!reases re!urren!e rates. C,NI1N TUMORS C$sts E%ider-al0 !er-oid0 Tric&ile--al* ,pider al !$sts are the ost !o on t$pe of !utaneous !$st. The$ o!!ur an$'here on the #od$( as a single fir nodule. On the s!rotu the$ are often ultiple and !an !al!if$. Tri!hile al )pilar* !$sts( the ne"t ost !o on( o!!ur ore often in fe ales and usuall$ on the s!alp. Bhen ruptured these !$sts have a !hara!teristi! strong odor. Der oid !$sts are present at #irth and a$ result fro epitheliu trapped during idline !losure in fetal develop ent. Der oids are ost often found in the idline of the fa!e )e.g.( on the nose or forehead* and are also !o on on the e$e#ro' )3ig. 45.:*. On gross e"a ination( it is diffi!ult to distinguish one t$pe of !$st fro another. The$ are all su#!utaneous( thin.'alled nodules !ontaining a 'hite( !rea $ !enter. 0istologi! e"a ination is needed to differentiate the . The 'alls of all these !$sts !onsist of a la$er of epider is oriented 'ith the #asal la$er superfi!ial and the ore ature la$ers deep )i.e.( 'ith the epider is gro'ing into the !enter of the !$st*. The des<ua ated !ells )keratin* !olle!t in the !enter and for the !rea $ su#stan!e of the !$st. ,pider al !$sts have a !o pletel$ ature epider is !ontaining a granular la$er. Tri!hile al !$st 'alls do not !ontain a granular la$er #ut do have a distin!tive outer la$er rese #ling the outer root sheath of the hair folli!le )tri!hile o a*. Der oids have a s<ua ous epitheliu ( e!!rine glands( pilose#a!eous units( and( o!!asionall$( #one( tooth( or nerve tissue. Surgeons often refer to !utaneous !$sts as se#a!eous

!$sts #e!ause the$ appear to !ontain se#u F this is a is a!tuall$ keratin.

isno er #e!ause the su#stan!e

C$sts usuall$ are as$ pto ati! and ignored until the$ rupture and !ause lo!al infla ation. The area #e!o es infe!ted and an a#s!ess for s. In!ision and drainage is re!o ended for an a!utel$ infe!ted !$st. &fter resolution of the a#s!ess the !$st 'all ust #e e"!ised or the !$st 'ill re!ur. Si ilarl$( 'hen e"!ising an unruptured !$st( !are ust #e taken to re ove all of the 'all in order to prevent re!urren!e. #eratoses Seborr&eic0 Solar" Se#orrhei! keratoses !o onl$ o!!ur on the !hest( #a!k( and a#do en of older individuals. The lesions are light #ro'n or $ello' and have a velvet$( greas$ te"ture. The$ are rarel$ istaken for other lesions( so #iops$ and treat ent are seldo needed. Sudden eruptions of ultiple lesions in elderl$ patients a$ #e asso!iated 'ith internal alignan!ies. Solar )or a!tini!* keratoses are also found in the older age group. The$ arise in sun. e"posed areas of the #od$( su!h as the fa!e( the forear s( and the #a!k of the hands. 0istologi!all$ the$ !ontain at$pi!al.appearing keratino!$tes and eviden!e of solar da age in the der is. These are thought to #e pre alignant lesions( and s<ua ous !ell !ar!ino a a$ develop over ti e. Treat ent is #$ lo!al re oval or appli!ation of topi!al :. fluoroura!il. Malignan!ies that do develop rarel$ etastasi%e. 'e,i Ac1uired0 Congenital" &!<uired elano!$ti! nevi are !lassified as +un!tional( !o pound( or der al( depending on the lo!ation of the nevus !ells. This !lassifi!ation does not represent different t$pes of nevi #ut rather different stages in the aturation of nevi. Initiall$( nevus !ells a!!u ulate in the epider is )+un!tional*( igrate partiall$ into the der is )!o pound*( and finall$ rest !o pletel$ in the der is )der al*. ,ventuall$ ost lesions undergo involution. Congenital nevi are u!h ore rare( o!!urring in onl$ 4 per!ent of neonates. These lesions are larger and a$ !ontain hair. 0istologi!all$ the$ appear si ilar to a!<uired nevi. Congenital giant lesions )giant hair$ nevus* ost often o!!ur in a #athing trunk distri#ution or on the !hest and #a!k )3ig. 45.;*. These lesions are a a+or !os eti! pro#le . In addition( the$ develop alignant elano a in : per!ent of the !ases. ,"!ision of the nevus is the treat ent of !hoi!e( #ut often the lesion is so large that !losure of the 'ound 'ith autologous skin grafts is not possi#le #e!ause of the la!k of ade<uate donor sites. Serial e"!isions over several $ears 'ith either pri ar$ !losure or skin grafting is the present ode of therap$. Tissue e"pansion of nor al surrounding skin is no' also used to a!!elerate the rate of nevus e"!ision and avoid the use of skin grafts. /ascular Tu-ors 0e angio as )Capillar$( Cavernous* 0e angio as are #enign vas!ular neoplas s that arise soon after #irth. The$ undergo rapid !ellular proliferation initiall$ and slo'l$ involute through earl$ !hildhood. Capillar$ )stra'#err$* he angio as are soft( !o pressi#le papular lesions 'ith sharp #orders lo!ated ostl$ on the shoulders( fa!e( and s!alp. Cavernous he angio as are #right red or purple and have a spong$ !onsisten!$. 0istologi!all$ !apillar$

he angio as are !o posed of endothelial !ells seen pri aril$ in fetal veins. Cavernous lesions !ontain large( #lood.filled spa!es lined #$ nor al.appearing endothelial !ells. 0e angio as !an enlarge during the first $ear of life( and ore than G9 per!ent of the involute over ti e. &llo'ing lesions to regress spontaneousl$ usuall$ gives opti al !os eti! results )3ig. 45.=*. &!ute treat ent is li ited to lesions that interfere 'ith #odil$ fun!tions( su!h as vision( feeding( and urination( or lead to s$ste i! pro#le s( su!h as thro #o!$topenia and high.output !ardia! failure. The gro'th of these rapidl$ enlarging lesions !an #e stopped 'ith a !ourse of prednisone or interferon.alpha.Aa. 0e angio as that re ain after earl$ adoles!en!e 'ill pro#a#l$ not involute further. Surgi!al e"!ision is re!o ended. /ascular Mal+or-ations Port 2ine Stains0 Arterio,enous Mal+or-ations0 3lo-us Tu-ors" Das!ular alfor ations are a result of stru!tural a#nor alities for ed during fetal develop ent and hen!e are not neoplas s. Unlike he angio as( vas!ular alfor ations do not undergo rapid gro'th and involution #ut rather gro' in proportion to the #od$. 0istologi!all$ the$ !ontain enlarged vas!ular spa!es lined #$ nonproliferating endotheliu ( and not the itoti!all$ a!tive endothelial !ells of a he angio a. The port 'ine stain )nevus fla eus* is a flat( dull red !apillar$ alfor ation that !an #e lo!ated on the trunk( e"tre ities( and( ost !o onl$( along a trige inal distri#ution on the fa!e. 0istologi!all$ these nevi are !o posed of e!tati! !apillaries lined #$ ature endotheliu . The$ a$ #e part of the Sturge.Be#er s$ndro e )lepto eningeal angio atosis( epileps$( and glau!o a*. Unsightl$ lesions !an #e !overed 'ith !os eti!s( treated 'ith pulsed d$e laser( or surgi!all$ e"!ised. &rteriovenous alfor ations are high.flo' lesions. The$ appear as a ass under the skin 'ith lo!all$ elevated te perature( a der al stain( and a thrill and #ruit. Overl$ing is!he i! ul!ers( ad+a!ent #one destru!tion( or lo!al h$pertroph$ a$ o!!ur. -arge alfor ations !an !ause !ardia! enlarge ent and !ongestive heart failure. Co pli!ations of arteriovenous alfor ations( su!h as pain( he orrhage( ul!eration( !ardia! effe!ts( and destru!tion of surrounding stru!tures( should #e treated #$ eli ination of the lesion. Therap$ !onsists of angiograph$ 'ith sele!tive e #oli%ation or !o plete surgi!al rese!tion. , #oli%ation is parti!ularl$ useful for lesions not a!!essi#le to surger$ or in !ases in 'hi!h rese!tion 'ould !ause too u!h utilation. , #oli%ation also !an #e used preoperativel$ to redu!e #lood loss during surger$. O!!asionall$ h$pother ia and !ardia! #$pass are re<uired in order to ini i%e #lood loss during surgi!al e"!ision of large lesions. 1lo us tu ors are #lue.gra$ nodules that are e"tre el$ tender. The$ !an o!!ur an$'here on the #od$( #ut the ost !o on lo!ation is su#ungual. The tu or arises fro a glo us #od$ and histologi!all$ rese #les the arterial portion of the glo us. ,"!ision of the tu or relieves the pain. So+t Tissue Tu-ors Acroc&ordons0 !er-ato+ibro-as0 .i%o-as*

&!ro!hordons )skin tags* are flesh$( pedun!ulated asses lo!ated on the a"illae( trunk( and e$elids. The$ are !o posed of h$perplasti! epider is over a fi#rous !onne!tive tissue stalk. These lesions usuall$ are s all and are al'a$s #enign. Der atofi#ro as are usuall$ solitar$ nodules easuring appro"i atel$ 4 to A ! in dia eter. The$ are found pri aril$ on the legs and sides of the trunk. The lesions are !o posed of 'horls of !onne!tive tissue !ontaining fi#ro#lasts. The ass is not en!apsulated( and vas!ulari%ation is varia#le. Der atofi#ro as !an #e diagnosed #$ !lini!al e"a ination. Bhen lesions enlarge to A to 5 ! ( e"!isional #iops$ is re!o ended to assess for alignan!$. -ipo as are the ost !o on su#!utaneous neoplas . The$ are found ostl$ on the trunk #ut a$ appear an$'here. The$ a$ so eti es gro' to a large si%e. Mi!ros!opi! e"a ination reveals a lo#ulated tu or !ontaining nor al fat !ells. ,"!ision is perfor ed for diagnosis and to restore nor al skin !ontour. Neural Tu ors )Neurofi#ro as( Neurile o as( 1ranular Cell Tu ors* Cenign !utaneous neural tu ors arise pri aril$ fro the nerve sheath. Neurofi#ro as !an #e sporadi! and solitar$( #ut the$ are ore !o onl$ noted in ultiple for ations asso!iated 'ith !afH.au.lait spots and an autoso al do inant inheritan!e )von Re!klinghausen7s disease*. The lesions are fir ( dis!rete nodules atta!hed to a nerve. 0istologi!all$ there is proliferation of perineurial and endoneurial fi#ro#lasts and S!h'ann !ells e #edded in !ollagen. Neurile o as are solitar$ tu ors found along peripheral nerves of the head and e"tre ities. The$ are dis!rete nodules that a$ #e lo!all$ painful or radiate along the distri#ution of the nerve. Mi!ros!opi!all$ the tu or !ontains S!h'ann !ells 'ith nu!lei pa!ked in palisading ro's. 1ranular !ell tu ors usuall$ are solitar$ lesions of the skin or( ore !o onl$( the tongue. The$ !onsist of granular !ells derived fro S!h'ann !ells that often infiltrate the surrounding striated us!le. MA.I3'A'T TUM)RS The ost !o on !an!ers of the skin arise fro the !ells of the epider isF the$ are( in order of fre<uen!$( #asal !ell !ar!ino a( s<ua ous !ell !ar!ino a( and elano a. Malignan!ies arising fro !ells of the der is or adne"al stru!tures are u!h less !o on. ,nviron ental influen!es and !on!o itant diseases are asso!iated 'ith an in!reased in!iden!e of epider al alignan!ies. These fa!tors have #een e"tensivel$ studied and for so e of our #est understanding a#out the !auses of !an!er. ,pide iolog$ In!reased e"posure to ultraviolet radiation is asso!iated 'ith an in!reased develop ent of all three of the !o on skin alignan!ies. ,pide iologi! studies have sho'n that people 'ith outdoor o!!upations have skin alignan!ies ore often than people 'ho 'ork indoors. S<ua ous !ell !an!er is u!h ore !o on on the lo'er lip than the upper. /eople 'ith fair !o ple"ions are ore prone to skin !an!er. These sa e people also are ore likel$ to develop alignan!ies if the$ live in areas of the 'orld that re!eive ore sunlight( su!h as Ne' Iealand( as !o pared to 1reat Critain. &l#ino individuals of dark.skinned ra!es are prone to develop !utaneous

neoplas s that usuall$ are rare in the nonal#ino e #ers( suggesting that has a large role in prote!tion fro !ar!inogenesis.

elanin

Other fa!tors asso!iated 'ith skin alignan!ies also have #een identified. Che i!al !ar!inogens have long #een kno'n. In the eighteenth !entur$ Sir /er!ival /ott noted the asso!iation of soot and s!rotal !an!er in !hi ne$ s'eeps. Tar( arseni!( and nitrogen ustard are kno'n !ar!inogens. 0u an papillo avirus has #een found in !ertain s<ua ous !ell !an!ers and a$ #e linked 'ith on!ogenesis. Radiation therap$ in the past for skin lesions su!h as a!ne vulgaris( 'hen it resulted in radiation der atitis( is asso!iated 'ith an in!reased in!iden!e of #asal and s<ua ous !ell !an!ers in the treated areas. &n$ area of skin su#+e!ted to !hroni! irritation( su!h as #urn s!ars )Mar+olin7s ul!ers*( repeated sloughing of skin fro #ullous diseases( and de!u#itus ul!ers( all have an in!reased !han!e of developing s<ua ous !ell !an!er. & variant of this t$pe of lesion develops on skin that has suffered repeated #urns. S$ste i! i unologi! d$sfun!tion is related to an in!rease in !utaneous alignan!ies. I unosuppressed patients re!eiving !he otherap$ for other alignan!ies or i unosuppressants for organ transplants have an in!reased in!iden!e of #asal !ell and s<ua ous !ell !an!ers and alignant elano a. The a!<uired i unodefi!ien!$ s$ndro e )&IDS* is asso!iated 'ith an in!reased risk of developing skin neoplas s. /atients 'ith 0ID infe!tion should #e onitored vigilantl$ for earl$ diagnosis of skin !an!er. *asal Cell Carcino-a Casal !ell !ar!ino as !ontain !ells that rese #le the #asal !ells of the epider is. It is the ost !o on skin !an!er and is su#divided into several t$pes #$ gross and histologi! orpholog$. The nodulo!$sti! or noduloul!erative t$pe a!!ounts for =9 per!ent of #asal !ell !ar!ino as. It is a 'a"$( !rea .!olored lesion 'ith rolled( pearl$ #orders )3ig. 45.E*. It often !ontains a !entral ul!er. Bhen these lesions are large the$ are !alled ?rodent ul!ers.@ /ig ented #asal !ell !ar!ino as are tan to #la!k in !olor and should #e distinguished #$ #iops$ e"a ination fro elano a. Superfi!ial #asal !ell !an!ers o!!ur ore !o onl$ on the trunk and for a red( s!aling lesion so eti es diffi!ult to distinguish grossl$ fro Co'en7s disease. & rare for of #asal !ell !ar!ino a is the #asos<ua ous t$pe( 'hi!h !ontains ele ents of #asal !ell and s<ua ous !ell !an!er. These lesions !an etastasi%e ore like a s<ua ous !ell !ar!ino a and should #e treated aggressivel$. Other t$pes in!lude orpheafor ( adenoid( and infiltrative !ar!ino as. Casal !ell !ar!ino as usuall$ are slo' gro'ing( and patients often negle!t these lesions for $ears. Metastasis and death fro this disease is e"tre el$ rare( #ut the lesions !an !ause e"tensive lo!al destru!tion. The a+orit$ of s all )less than A *( nodular lesions a$ #e treated #$ der atologists 'ith !urettage and ele!trodesi!!ation or laser vapori%ation. & a+or dra'#a!k to these pro!edures is that no pathologi! spe!i en !an #e o#tained to !onfir the diagnosis. -arger tu ors( lesions that invade #one or surrounding stru!tures( and ore aggressive histologi! t$pes ) orpheafor ( infiltrative( and #asos<ua ous* are #est treated #$ surgi!al e"!ision 'ith a A. to 8. argin of nor al tissue. 0istologi! !onfir ation that the argins of rese!tion do not !ontain tu or is re<uired. Ce!ause nodular lesions are less likel$ to re!ur( the s aller argin a$ #e used( 'hereas the other t$pes need a

'ider argin of rese!tion. &lternative ethods of treat ent( su!h as radiation therap$ and Mohs7 surger$( are dis!ussed later. S1ua-ous Cell Carcino-a S<ua ous !ell !ar!ino as arise fro keratino!$tes of the epider is. It is less !o on than #asal !ell !ar!ino a #ut is ore devastating #e!ause it !an invade surrounding tissue and etastasi%e ore readil$. In situ lesions have the epon$ of Co'en7s disease( and in situ s<ua ous !ell !ar!ino as of the penis are referred to as er$throplasia of Jue$rat. Contrar$ to previous reports( Co'en7s disease is not a arker for other s$ste i! alignan!ies. Tu or thi!kness !orrelates 'ell 'ith its #iologi! #ehavior. -esions that re!ur lo!all$ are ore than 8 thi!k and lesions that etastasi%e are 49 or ore. The lo!ation of the lesion also is i portant. Tu ors arising in #urn s!ars )Mar+olin7s ul!er*( areas of !hroni! osteo $elitis( and areas of previous in+ur$ etastasi%e earl$. -esions on the e"ternal ear fre<uentl$ re!ur and involve regional l$ ph node #asins earl$. S<ua ous !ell !an!ers in areas 'ith solar da age #ehave less aggressivel$ and usuall$ re<uire onl$ lo!al e"!ision. &lthough s all lesions !an #e treated 'ith !urettage and ele!trodesi!!ation( ost surgeons re!o end e"!ision of the tu or. -esions should #e e"!ised 'ith a 4.! argin( if possi#le( and histologi! !onfir ation that the argins are tu or.free is andator$. Tu or invading #one should #e e"!ised if re!urren!e is to #e avoided. Regional l$ ph node e"!ision is indi!ated for !lini!all$ palpa#le nodes )therapeuti! l$ ph node disse!tion*. -esions arising in !hroni! 'ounds #ehave aggressivel$ and are ore likel$ to spread to regional l$ ph nodes. 3or these lesions l$ phadene!to $ #efore the develop ent of palpa#le nodes is indi!ated )proph$la!ti! l$ ph node disse!tion*. Metastati! disease is a poor prognosti! sign( 'ith onl$ 45 per!ent of patients alive after 49 $ears. &lternative Therap$ &lternatives to surgi!al therap$ for s<ua ous and #asal !ell !an!ers !onsist of radiation therap$ or topi!al :.fluoroura!il for patients una#le or un'illing to undergo surger$. Radiation therap$ for s all and superfi!ial lesions o#tains !ure rates !o para#le to surgi!al e"!ision. Radiation da age to surrounding nor al skin 'ith infla ation and s!arring !an #e a pro#le . &lso the develop ent of !utaneous alignan!ies in irradiated skin is a serious long.ter risk 'ith this ethod. 3or lesions on the fa!e near the nose or e$e( rese!tion of a 'ide ri of nor al tissue to re ove all the tu or !an !ause signifi!ant fun!tional and !os eti! pro#le s. These lesions !an #e re oved #$ Mohs7 i!rographi! surger$. Mohs7 te!hni<ue( developed in 4G5A( is a ethod to seriall$ e"!ise a tu or #$ taking s all in!re ents of tissue until the entire tu or is re oved. ,a!h pie!e of tissue re oved is fro%en and i ediatel$ e"a ined i!ros!opi!all$ to deter ine 'hether tu orous tissue has #een rese!ted. The advantage of this ethod over that of standard histologi! e"a ination after 'ide surgi!al rese!tion is that the entire argin of rese!tion is evaluated. The a+or #enefit is the a#ilit$ to re ove a tu or 'ith the least sa!rifi!e of uninvolved tissue. This te!hni<ue is effe!tive for treating !ar!ino as around the e$elids and nose( 'here tissue loss is ost !onspi!uous. The pro!edure is e"tre el$

length$ )up to several da$s* sin!e !o plete e"!ision a$ re<uire ultiple atte ptsF this re ains its a+or dra'#a!k. Cure rates are !o para#le to those of 'ide e"!ision. /atients 'ith #asal !ell !ar!ino as have #een treated 'ith intralesional in+e!tion of interferon. The a+orit$ of the lesions 'ere eli inated or !ontrolled #$ the in+e!tions. The lesions that did not respond re<uired surgi!al e"!ision. Bhen lesions respond to in+e!tions( operation is avoided and no re!onstru!tion of the defe!t is re<uired. The a+or disadvantages of this treat ent are the need for ultiple offi!e visits over several 'eeks for in+e!tions( the s$ste i! side effe!ts of interferon( and a potential need for surger$ if the lesions do not respond to in+e!tions. Clini!al trials 'ith !o #inations of retinoids )vita in & derivatives* and interferon have de onstrated good response rates in patients 'ith advan!ed( inopera#le s<ua ous !ell !ar!ino as. These results suggest that interferon is likel$ to have a greater role in therap$ of !utaneous neoplas s in the future. Malignant Melano-a Bhat 'as a relativel$ rare disease :9 $ears ago has no' #e!o e alar ingl$ ore !o on. The rise in the rate of elano a is the highest of an$ !an!er in the United States. In 4G5: the annual in!iden!e of the disease 'as 4 per 499(999 people. C$ 4GG4 the in!iden!e had risen to 4A.G per 499(999. There 'ere 5A(999 ne' !ases of elano a in 4GG4. The !ase fatalit$ rate has fallen over the $ears( pro#a#l$ as the result of earlier dete!tion and treat ent. Ce!ause elano a is #e!o ing so !o on( it is i portant for all ph$si!ians to #e fa iliar 'ith this disease. The i portant !lini!al features of a elano a in!lude a pig ented lesion 'ith an irregular( raised surfa!e and irregular #orders. &#out : to 49 per!ent of elano as are not pig ented. -esions that !hange in !olor and si%e and ul!erate over a fe' onths7 ti e are suspi!ious and should #e #iopsied. Surger$ is still the ainsta$ of therap$ for elano a( so it is i perative that surgeons #e a'are of the latest ethods of diagnosis( staging( and therap$. /athogenesis Melano a arises fro transfor ed elano!$tes and !an arise an$'here that elano!$tes have igrated during e #r$ogenesis. The e$e( !entral nervous s$ste ( gastrointestinal tra!t( and even the gall#ladder have #een reported as pri ar$ sites of the disease. Over G9 per!ent are found on the skinF ho'ever( 8 per!ent of elano as are dis!overed as etastases 'ithout an identifia#le pri ar$ site. Man$ elano as( espe!iall$ in the earl$ phases of gro'th( are found to !ontain areas of tu or regression on histologi! e"a ination. Regression represents a host i une response to the tu or. Metastati! elano as 'ith unkno'n pri ar$ sites pro#a#l$ arise fro !o pletel$ regressed lesions that are diffi!ult to lo!ate. Nevi are #enign elano!$ti! neoplas s found on the skin of ost people. D$splasti! nevi are u!h rarer and !ontain a histologi!all$ identifia#le fo!us of at$pi!al elano!$tes. This t$pe of nevus a$ represent an inter ediate #et'een a #enign nevus and a true alignant elano a. It is 'ell do!u ented that patients 'ith elano a have signifi!antl$ ore nevi and d$splasti! nevi than at!hed !ontrols. The relative risk of developing elano a in!reases 'ith the nu #er of d$splasti! nevi that a patient develops. The relationship is si ilar to that #et'een the nu #er of !oloni! pol$ps and the develop ent of !olon !an!er. /atients 'ith d$splasti! nevi and

fa il$ e #ers 'ith d$splasti! nevi and elano a are at in!reased risk for developing elano a( suggesting that in these patients there is a geneti! !o ponent to the risk of developing the alignan!$. On!e the elano!$te has transfor ed into the alignant phenot$pe( the gro'th of the lesion is radial in the plane of the epider is. ,ven though i!roinvasion of the der is !an #e o#served during this radial gro'th phase( etastases do not o!!ur. Onl$ 'hen the elano a !ells for nests in the der is are etastases o#served. The transfor ed !ells in the verti!al gro'th phase are orphologi!all$ different and e"press different !ell.surfa!e antigens than those in the radial phase or !ells of the d$splasti! nevus. In addition( these !ells #ehave differentl$ in !ell !ulture. The$ !an gro' in a less enri!hed edia and have a longer life span. T$pes There are four !o on distin!t t$pes of elano a. These are( in order of de!reasing fre<uen!$( superfi!ial spreading( nodular( lentigo aligna( and a!ral lentiginous. ,a!h has distin!t !hara!teristi!s and #ehaviors. The ost !o on t$pe( representing =9 per!ent of elano as( is the superfi!ial spreading t$pe. These lesions o!!ur an$'here on the skin e"!ept the hands and feet. The$ are flat( !o onl$ !ontain areas of regression( and easure 4 to A ! in dia eter at the ti e of diagnosis )3ig. 45.G*. There is a relativel$ long radial gro'th phase #efore verti!al gro'th #egins. The nodular t$pe a!!ounts for 4: to A9 per!ent of elano as. These lesions are darker and raised. The histologi! !riterion for a nodular elano a is the la!k of radial gro'th peripheral to the area of verti!al gro'thF hen!e all nodular elano as are in the verti!al gro'th phase at the ti e of diagnosis. &lthough it is an aggressive lesion( the prognosis for a patient 'ith a nodular.t$pe lesion is the sa e as that for a patient 'ith a superfi!ial spreading lesion of the sa e depth of invasion. The lentigo aligna t$pe( a!!ounting for : to 49 per!ent of elano as( o!!urs ostl$ on the ne!k( the fa!e( and the #a!k of the hands of elderl$ people. These lesions are al'a$s surrounded #$ der is 'ith heav$ solar degeneration. The$ tend to #e!o e <uite large #efore a diagnosis is ade #ut also have the #est prognosis #e!ause invasive gro'th o!!urs late. The rarer a!ral lentiginous t$pe is distin!tl$ different. It o!!urs on the pal s and soles and in the su#ungual regions. &lthough elano a a ong dark.skinned people is relativel$ rare( the a!ral lentiginous t$pe a!!ounts for a higher per!entage in dark. skinned people than in people 'ith less pig ented skin. The su#ungual lesions appear as #lue.#la!k dis!olorations of the posterior nail fold and are ost !o on on the great toe or thu #. /rognosti! 3a!tors The original staging s$ste !lassified elano a into lo!al )Stage I*( regional l$ ph node )Stage II*( and etastati! )Stage III* disease. This staging s$ste had the disadvantage of lu ping ost patients into Stage I disease( therefore li iting its usefulness in prognosti! studies. The ost !urrent staging s$ste ( fro the & eri!an

Joint Co ittee on Can!er )&JCC*( !ontains the #est ethod of interpreting !lini!al infor ation in regard to prognosis of this disease )Ta#le 45.4*. The T !lassifi!ation of the lesion !o es fro the original o#servation #$ Clark that prognosis is dire!tl$ related to the level of invasion of the skin #$ the elano a. Bhereas Clark used the histologi! level )I( superfi!ial to #ase ent e #rane Kin situLF II( papillar$ der isF III( papillar$Mreti!ular der al +un!tionF ID( reti!ular der isF and D( su#!utaneous fat*( Creslo' odified the approa!h to o#tain a ore reprodu!i#le easure of invasion #$ the use of an o!ular i!ro eter. The lesions 'ere easured fro the granular la$er of the epider is or the #ase of the ul!er to the greatest depth of the tu or )I( 9.=: or lessF II( 9.=; to 4.: F III( 4.:4 to 5.9 F ID( 5.9 or ore*. These levels of invasion have #een su#se<uentl$ odified and in!orporated in the &JCC staging s$ste )3ig. 45.49*. ,viden!e of tu or in regional l$ ph nodes is a poor prognosti! sign. This is a!!ounted for in the staging s$ste #$ advan!ing an$ T !lassifi!ation fro Stage I or II to Stage III. The 49.$ear survival rate drops pre!ipitousl$ 'ith the presen!e of l$ ph node etastasis. The nu #er of positive l$ ph nodes also is !orrelated 'ith survival rates. The presen!e of distant etastasis is a grave prognosti! sign )Stage ID*. The edian survival ranges fro A to = onths( depending on the nu #er and site of etastases( #ut survival up to a fe' $ears has #een reported )3ig. 45.44*. Other independent prognosti! fa!tors have #een identified2 )4* &nato i! lo!ation. Independent of histologi! t$pe and depth of invasion( people 'ith lesions of the e"tre ities do #etter than people 'ith elano as of the trunk or fa!e )EA per!ent 49.$ear survival rate for lo!ali%ed disease of the e"tre it$( !o pared to ;E per!ent survival 'ith a lesion of the fa!e*. )A* Ul!eration. /resen!e of ul!eration in a lesion !arries a 'orse prognosis. 3or unkno'n reasons these elano as a!t ore aggressivel$ than nonul!erated ones. The 49.$ear survival rate for patients 'ith lo!al disease )Stage I* and an ul!erated elano a 'as :9 per!ent( !o pared to =E per!ent for the sa e stage lesion 'ithout ul!eration. )5* Se". Bo en have elano as in ore favora#le anato i! sites( and these lesions are less likel$ to !ontain ul!eration. Despite !orre!tion for these fa!tors( fe ales have a higher survival rate than en )E9 per!ent 49.$ear survival for 'o en versus ;4 per!ent for en 'ith Stage I disease*. )8* 0istologi! t$pe. Nodular elano as have the sa e prognosis as superfi!ial spreading t$pes 'hen lesions are at!hed for depth of invasion. -entigo aligna t$pes( ho'ever( have a #etter prognosis even after !orre!ting for thi!kness( and a!ral lentiginous lesions have a 'orse prognosis. Treat ent The treat ent of elano a is pri aril$ surgi!al. The indi!ation for pro!edures su!h as l$ ph node disse!tion( superfi!ial parotide!to $( and rese!tion of distant

etastases have !hanged so e'hat over ti e( #ut the onl$ hope for !ure and the #est treat ent for regional !ontrol and palliation re ains surger$ )3ig. 45.4A*. Radiation therap$( regional and s$ste i! !he otherap$( and i unotherap$ are effe!tive in a li ited set of !ir!u stan!es( #ut none is a first.line option. &ll suspi!ious lesions should undergo e"!isional #iops$. & 4. argin of nor al skin is taken if the 'ound !an #e !losed pri aril$. If re oval of the entire lesion !reates too large a defe!t( then an in!isional #iops$ of a representative part is re!o ended. Ciops$ in!isions should #e ade 'ith the e"pe!tation that a su#se<uent 'ide e"!ision of the #iops$ site a$ #e done. On!e a diagnosis of elano a is ade( the #iops$ s!ar and an$ re ains of the lesion need to #e re oved to eradi!ate an$ re aining tu or. 3or in situ lesions a 9.:. to 4.! argin of nor al skin is ade<uate for !ure. & T4 elano a )less than 9.=; deep* re<uires a 4.! argin to prevent lo!al re!urren!e. 3or thi!ker lesions a A. to 5.! argin is re!o ended. &n$ 'ider argin of rese!tion does not de!rease lo!al re!urren!e rates. The surrounding tissue should #e re oved do'n to the fas!ia to re ove all l$ phati! !hannels. If the deep fas!ia is not involved #$ the tu or( re oving it does not affe!t re!urren!e or survival rates( so the fas!ia is left inta!t. If the defe!t !annot #e !losed pri aril$( a skin graft or flap is used. &ll !lini!all$ positive l$ ph nodes should #e re oved #$ regional nodal disse!tion. If possi#le( the l$ phati!s #et'een the lesion and the regional nodes are re oved in !ontinuit$. -eaving tu or #ehind results in re!urren!e of lesions that !ause great or#idit$. Bhen groin l$ ph nodes are re oved( the deep )ilia!* nodes ust #e re oved along 'ith the superfi!ial )inguinal* nodes( or disease 'ill re!ur in that region. 3or a"illar$ disse!tions the nodes edial to the pe!toralis inor us!le ust also #e rese!ted. 3or lesions on the fa!e( anterior s!alp( and ear( a superfi!ial parotide!to $ to re ove parotid nodes and a odified ne!k disse!tion is re!o ended. Disruption of the l$ phati! outflo' does !ause signifi!ant pro#le s 'ith !hroni! ede a( espe!iall$ of the lo'er e"tre it$. Treat ent of regional l$ ph nodes that do not o#viousl$ !ontain tu or in patients 'ithout eviden!e of etastasis )Stage I and II* is deter ined #$ !onsidering the possi#le #enefits of the pro!edure as 'eighed against the risks. In patients 'ith thin lesions )less than 9.=: * the tu or !ells are still lo!ali%ed in the surrounding tissue( and the !ure rate is e"!ellent 'ith 'ide e"!ision of the pri ar$ lesionF for these patients treat ent of regional l$ ph nodes is not #enefi!ial. Bith ver$ thi!k lesions ) ore than 8 *( it is highl$ likel$ that the tu or !ells have alread$ spread to the regional l$ ph nodes and distant sites. Re oval of the l$ ph nodes has no effe!t on survival. Most of these patients die of etastati! disease #efore developing pro#le s in regional nodes. Ce!ause there are signifi!ant or#id effe!ts of l$ phadene!to $( ost surgeons defer the pro!edure until !lini!all$ evident disease appears. &ppro"i atel$ 89 per!ent of these patients eventuall$ develop disease in the l$ ph nodes and re<uire a se!ond palliative operation. ,le!tive l$ phadene!to $ is so eti es perfor ed in these patients as a staging pro!edure #efore entr$ into !lini!al trials. In patients 'ith inter ediate.thi!kness tu ors )TA and T5( 9.=; to 8.9 * and no !lini!al eviden!e of nodal or etastati! disease( the use of proph$la!ti! disse!tion )ele!tive l$ ph node disse!tion on !lini!all$ negative nodes* is !ontroversial. To

date( prospe!tive( rando i%ed studies have not definitivel$ de onstrated that ele!tive l$ ph node disse!tion i proves survival in patients 'ith inter ediate.thi!kness elano as. Careful e"a ination of spe!i ens in patients undergoing ele!tive l$ ph node disse!tion have found that in A: to :9 per!ent of the !ases( spe!i ens !ontain i!ro etastases. & ong patients 'ho do not have an ele!tive l$ ph node disse!tion( A9 to A: per!ent eventuall$ develop !lini!all$ evident disease and re<uire l$ phadene!to $. More eviden!e suggests that there a$ #e i proved survival 'ith ele!tive l$ ph node disse!tion in patients 'ith higher risk of developing etastasis )i.e.( lesions 'ith ul!eration or on the trunk( head( and ne!k*. The ost !o pelling argu ent for the potential #enefits of ele!tive l$ ph node disse!tion !o es fro eviden!e in large !lini!al trialsF patients 'ith inter ediate.thi!kness elano as 'ithout ele!tive node disse!tion( !ontinue to die of the disease 49 $ears later( 'hereas patients 'ho had an ele!tive l$ ph node disse!tion do not. &lthough not $et statisti!all$ signifi!ant( these differen!es a$ #e!o e signifi!ant in the future. One surgi!al odalit$ gaining a!!eptan!e is the use of intraoperative ethods to lo!ate the pattern of l$ phati! drainage fro the pri ar$ lesion. Dital #lue d$e or a radioisotope is in+e!ted at the site of the elano a. This per its identifi!ation of the first )sentinel* l$ ph node draining the tu or. The node is re oved( and if i!ro etastases are identified in fro%en.se!tion e"a ination( a !o plete l$ ph node disse!tion is perfor ed. Bhen the sentinel node !an #e identified( it serves as an a!!urate indi!ation of the status of the rest of the nodes in the region. This ethod a$ #e used to identif$ patients 'ho 'ould #enefit fro l$ ph node disse!tion 'hile sparing others an unne!essar$ operation. Bhether this pro!edure a!tuall$ i proves survival in these patients a'aits the results of !lini!al trials. Bhen patients develop distant etastases surgi!al therap$ a$ #e indi!ated. Solitar$ lesions in the #rain( gut( or skin that are s$ pto ati! should #e e"!ised 'hen possi#le. &lthough !ure is e"tre el$ rare( the degree of palliation !an #e high and as$ pto ati! survival prolonged. & de!ision to operate on etastati! lesions ust #e ade after !areful deli#eration 'ith the patient. The ost pro ising area of elano a treat ent is in the use of i unologi! anipulation. The onl$ ad+uvant therap$ kno'n to influen!e survival so far is the use of intravenous interferon alpha.A# )IN3 alpha.A#* in patients 'ith lesions of 8 or ore )T8* or nodal etastasis )N4*. In these patients #oth the relapse.free interval and overall survival are i proved 'ith use of IN3 alpha.A#. To"i!it$ 'hile under therap$ 'as a pro#le F the a+orit$ of the patients re<uired odifi!ation of the initial dosage( and A8 per!ent dis!ontinued treat ent. These re!ent findings are en!ouraging #e!ause trials of ad+uvant therap$ in the past have never de onstrated a #enefi!ial effe!t. Da!!ines have #een developed 'ith the hope of sti ulating the #od$7s o'n i une s$ste against the tu or. Melano a !ells !ontain a nu #er of distin!tl$ different !ell.surfa!e antigens. Mono!lonal anti#odies have #een raised against these antigens. These anti#odies have #een used alone or linked to a radioisotope or !$toto"i! agent in an effort to sele!tivel$ kill tu or !ells. &ll treat ents are !urrentl$ investigational.

&lthough initiall$ thought to #e ineffe!tive in the treat ent of elano a( radiation therap$ has #een sho'n to #e useful. 0igh.dose.per.fra!tion radiation produ!es a #etter response rate than lo'.dose( large.fra!tion therap$. Radiation therap$ is the treat ent of !hoi!e for patients 'ith s$ pto ati! ultiple #rain etastases. 0$perther i! regional perfusion of the li # 'ith a !he otherapeuti! agent )e.g.( elphalan* is the treat ent of !hoi!e for patients 'ith lo!al re!urren!e or in.transit lesions )lo!al disease in l$ phati!s* on an e"tre it$ and not a ena#le to e"!ision. The goal of regional perfusion therap$ is to in!rease the dosage of the !he otherapeuti! agent to a"i i%e tu or response 'hile li iting s$ste i! to"i! effe!ts. Bhile diffi!ult to perfor and asso!iated 'ith !o pli!ations( it does produ!e a high response rate )greater than :9 per!ent*. The introdu!tion of tu or ne!rosis fa!tor alpha and interferon.g to the li # perfusate a$ in!rease the tu or response rate 'ithout in!reasing to"i!it$. /rospe!tive !lini!al trials are under 'a$ to evaluate the use of regional perfusion for elano a of the li #s as ad+uvant therap$ for patients 'ith Stage I disease. In addition( regional perfusion therap$ for etastati! disease to the liver is under investigation. /athologi! Conditions &sso!iated 'ith Skin Malignan!ies There are several 'ell.re!ogni%ed diseases asso!iated 'ith an in!reased in!iden!e of skin alignan!ies. So e are asso!iated 'ith a spe!ifi! neoplas ( 'hereas others appear to have the less spe!ifi! effe!t of leaving the patient sus!epti#le to a variet$ of neoplas s. Diseases linked 'ith #asal !ell !ar!ino a in!lude the #asal !ell nevus s$ndro e and nevus se#a!eus of Jadassohn. Casal !ell nevus s$ndro e is an autoso al do inant disorder !hara!teri%ed #$ the gro'th of hundreds of #asal !ell !ar!ino as during $oung adulthood. /al ar and plantar pits are a !o on ph$si!al finding and represent fo!i of neoplas s. Treat ent is li ited to e"!ision of onl$ aggressive and s$ pto ati! lesions. Nevus se#a!eus of Jadassohn is a lesion !ontaining several !utaneous tissue ele ents that develops during !hildhood. This lesion is asso!iated 'ith a variet$ of neoplas s of the epider is( #ut ost !o onl$ #asal !ell !ar!ino a. !iseases associated 4it& s1ua-ous cell carcino-a a$ have a !ausative role in the develop ent of !ar!ino a. Skin diseases that !ause !hroni! 'ounds( su!h as epider ol$sis #ullosus and lupus er$the atosus( are asso!iated 'ith a high in!iden!e of s<ua ous !ell !ar!ino a. ,pider od$splasia verru!ifor is is a rare autoso al re!essive disease asso!iated 'ith infe!tion 'ith hu an papillo avirus. -arge verru!ous lesions develop earl$ in life and often progress to invasive s<ua ous !ell !ar!ino a in iddle age. Neroder a pig entosu is an autoso al re!essive disease asso!iated 'ith a defe!t in !ellular repair of DN& da age. The ina#ilit$ of the skin to !orre!t DN& da age fro ultraviolet radiation leaves these patients prone to !utaneous alignan!ies. S<ua ous !ell !ar!ino as are ost fre<uent( #ut #asal !ell !ar!ino as( elano as( and even a!ute leuke ias are seen. D$splasti! nevi a$ represent a pre!ursor to elano a. 3a ilial d$splasti! nevus s$ndro e is an autoso al do inant disorder. /atients develop ultiple d$splasti!

nevi( and longitudinal studies have de onstrated an al ost 499 per!ent in!iden!e of elano a. 3a ilial d$splasti! nevus s$ndro e is si ilar to fa ilial pol$posis !oli and the asso!iation 'ith !olon !an!er. Bhile the develop ent of !olon !an!er !an #e arrested 'ith total pro!to!ole!to $( a si ilar solution is not possi#le 'ith fa ilial d$splasti! nevi. Close surveillan!e and fre<uent #iops$ of all suspi!ious lesions !onstitutes the #est therap$. )t&er Malignancies Merkel Cell Carcino-a Pri-ar$ 'euroendocrine Carcino-a o+ t&e Skin* Originall$ thought to #e a variant of s<ua ous !ell !ar!ino a( it has onl$ re!entl$ #een de onstrated #$ i unohisto!he i!al arkers that Merkel !ell !ar!ino as are of neuroepithelial differentiation. These tu ors are asso!iated 'ith a s$n!hronous or etas$n!hronous s<ua ous !ell !ar!ino a A: per!ent of the ti e. These tu ors are ver$ aggressive( and 'ide lo!al rese!tion 'ith 5.! argins is re!o ended. -o!al re!urren!e rates are high( and distant etastases o!!ur in one.third of patients. /roph$la!ti! regional l$ ph node disse!tion and ad+uvant radiation therap$ are re!o ended. Overall( the prognosis is 'orse than for alignant elano a. E5tra-a--ar$ Paget6s !isease This tu or is histologi!all$ si ilar to the a ar$ t$pe. It is a !utaneous lesion that appears as a pruriti! red pat!h that does not resolve. Ciops$ de onstrates !lassi! /aget7s !ells. /aget7s disease is thought to #e a !utaneous e"tension of an underl$ing adeno!ar!ino a( although an asso!iated tu or !annot al'a$s #e de onstrated. Adne5al Carcino-as This group in!ludes apo!rine( e!!rine( and se#a!eous !ar!ino as( all rare tu ors. The$ are lo!all$ destru!tive and !an !ause death #$ distant etastasis. Angiosarco-as &ngiosar!o as a$ arise spontaneousl$( ostl$ on the s!alp( fa!e( and ne!k. The$ usuall$ appear as a #ruise that spontaneousl$ #leeds or enlarges 'ithout trau a. Tu ors also a$ arise in areas of prior radiation therap$ or in the setting of !hroni! l$ phede a of the ar ( su!h as after aste!to $ )Ste'art.Treves s$ndro e*. The angiosar!o as that arise in these areas of !hroni! !hange o!!ur de!ades later. The tu ors !onsist of anaplasti! endothelial !ells surrounding vas!ular !hannels. Bhile total e"!ision of earl$ lesions !an provide o!!asional !ure( the prognosis usuall$ is poor( 'ith :.$ear survival rates under A9per!ent. Che otherap$ and radiation therap$ are used for palliation. #a%osi6s Sarco-a 6aposi7s sar!o a )6S* appears as ru##er$ #luish nodules that o!!ur pri aril$ on the e"tre ities #ut a$ appear an$'here on the skin and vis!era. These lesions are usuall$ ultifo!al rather than etastati!. 0istologi!all$ the lesions are !o posed of !apillaries lined #$ at$pi!al endothelial !ells. ,arl$ lesions a$ rese #le he angio as( 'hile older lesions !ontain ore spindle !ells and rese #le sar!o as. Classic #S is seen in people of ,astern ,urope or su#.Saharan &fri!a. The lesions are lo!all$ aggressive #ut undergo periods of re ission. Dis!eral spread of the lesions is rare( #ut a su#t$pe of the &fri!an variet$ has a predile!tion for spreading to l$ ph nodes. & different variet$ of 6S has #een des!ri#ed for people 'ith &IDS or 'ith

i unosuppression fro !he otherap$. 3or reasons not $et understood( &IDS. related 6S o!!urs pri aril$ in ale ho ose"uals and not in intravenous drug a#users or he ophilia!s. In this for of the disease( the lesions spread rapidl$ to the nodes( and the gastrointestinal and respirator$ tra!t often are involved. Develop ent of &IDS.related 6S a$ #e asso!iated 'ith !on!urrent infe!tion 'ith a herpes.like virus. Treat ent for all t$pes of 6S !onsists of radiation to the lesions. Co #ination !he otherap$ is effe!tive in !ontrolling the disease( although ost patients develop an opportunisti! infe!tion during or shortl$ after treat ent. Surgi!al treat ent is reserved for lesions that interfere 'ith vital fun!tions( su!h as #o'el o#stru!tion or air'a$ !o pro ise. !er-ato+ibrosarco-a Protuberans Der atofi#rosar!o a protu#erans !onsists of large nodular lesions lo!ated ainl$ on the trunk. The$ often ul!erate and #e!o e infe!ted. Bith enlarge ent the lesions #e!o e painful. 0istologi!all$ the lesions !ontain at$pi!al spindle !ells( pro#a#l$ of fi#ro#last origin( lo!ated around a !ore of !ollagen tissue. So eti es the$ are istaken for an infe!ted keloid. Metastases are rare( and surgi!al e"!ision !an #e !urative. ,"!ision ust #e !o plete #e!ause lo!al re!urren!es are !o on. (ibrosarco-a 3i#rosar!o as are hard( irregular asses found in the su#!utaneous fat. The fi#ro#lasts appear arkedl$ anaplasti! 'ith disorgani%ed gro'th. If the$ are not e"!ised !o pletel$( etastases usuall$ develop. The :.$ear survival rate after e"!ision is a#out ;9 per!ent. .i%osarco-a -iposar!o as arise in the deep us!le planes and( rarel$( fro the su#!utaneous tissue. The$ o!!ur ost !o onl$ on the thigh. &n enlarging lipo a should #e e"!ised and inspe!ted to distinguish it fro a liposar!o a. Bide e"!ision is the treat ent of !hoi!e( 'ith radiation therap$ reserved for etastati! disease.

(UTURE !E/E.)PME'TS I' S#I' SUR3ER7

The a+or !hallenge in surgi!al therap$ for diseases of the skin is in the la!k of repla!e ent for diseased or da aged tissue. The develop ent of autologous skin grafting for treat ent of skin defe!ts 'as a tre endous advan!e ent. 0o'ever( te!hni!al li itations( su!h as graft !ontra!tion and donor site pro#le s( and #iologi! li itations( su!h as the li ited a ount of autologous skin availa#le( ake autografts less than a universal solution. The future of surgi!al therap$ for diseases of the skin lies in the develop ent of skin repla!e ent. Current resear!h is dire!ted at tissue e"pansion( !ell !ulture e"pansion( and neogenesis of skin. Te!hni<ues for tissue e"pansion have #een reported sin!e 4GEA. During skin e"pansion 'ith su#!utaneous #alloon i plants )3ig. 45.45*( ne' epider is and so e !ollagen is produ!ed. Mu!h of this ne' tissue( ho'ever( is rearrange ent of the old tissue. ,"pansion of skin produ!es a li ited a ount of tissue for use. The e"pansion of epider is #$ the gro'th and aturation of keratino!$tes in !ulture !an #e perfor ed. The use of a postage.sta p.si%ed #iops$ spe!i en to produ!e

enough autologous epitheliu to !over a #urn area of ore than G9 per!ent of total #od$ surfa!e area has #een reported )3ig. 45. 48*. &lthough this 'as a a+or advan!e ent in !overing large 'ounds( the final results are less than opti al. The !ultured epider is often #listers and sloughs( and 'ound !ontra!tures are !o on. Skin )!o prising der is( vas!ulature( adne"al stru!tures( and pig entation* is u!h ore !o ple" than +ust epider is( and repla!e ent of these other stru!tures is under investigation. Der al repla!e ents fro s$ntheti! aterials or !adaveri! sour!es are in !lini!al use. & #ila inar !ollagen and proteogl$!an der is )Integra* has #een approved #$ the 3ood and Drug &d inistration for !lini!al use. This prostheti! der is( availa#le in read$.to.use for ( !an #e used to !over large surfa!e areas( de!reasing fluid losses through the 'ound( 'hi!h is !ru!ial in #urn patients. Das!ulari%ation of this der is takes A 'eeks( and final epider al !overage of the 'ound re<uires a thin skin graft. The final result is fun!tionall$ and aestheti!all$ <uite good. Despite its li itations( it is the first pro ising der al repla!e ent to #e 'idel$ used. &utologous skin grafts revas!ulari%e in A to 8 da$s #e!ause the$ alread$ !ontain a net'ork of !apillaries in the der is. 3or s$ntheti! der is to survive as 'ell as an autologous graft( the pro#le of dela$ed vas!ular ingro'th ust #e solved. /ig entation pro#le s also a$ #e addressed #$ repopulating skin repla!e ents 'ith !ultured elano!$tesF ho'ever( elano!$te #iolog$ is ver$ !o ple"( and pig entation !ontrol is still rudi entar$. Bith ore sophisti!ated ethods of tissue !ulture( a ore !o ple" skin repla!e ent 'ill #e!o e availa#le. &s investigators learn ore a#out the protein fa!tors that !ontrol 'ound healing and tissue gro'th( the repla!e ent for da aged skin 'ill eventuall$ !o e fro !o plete neoorganogenesis of tissue. Chara!teri%ation of these gro'th fa!tors on a stru!tural and fun!tional level is +ust #eginning( #ut the infor ation o#tained to date has #een su#stantial. 3a!tors have #een isolated that !ause spe!ifi! esen!h$ al !ells to proliferate )fi#ro#last gro'th fa!tor*( igrate )epider al gro'th fa!tor*( and organi%e into stru!tures su!h as !apillaries )transfor ing gro'th fa!tor.#eta* or even rudi entar$ organoid tissue. This a$ allo' generation of ne' tissue in situ for skin repla!e ent. )Ci#liograph$ o itted in /al Ca!k to Contents version*