BASAL CELL C A R C I N O M A

ABSTRACT.raThe c o m m o n o c c u r r e n c e o f basa l cell c a r c i n o m a , espe- cially in y o u n g e r popu la t ions , h a s m a d e it a m a j o r publ ic h e a l t h con- c e r n . It is t he c o m m o n e s t m a l i g n a n c y af fec t ing h u m a n s a n d is l a rge ly p r e v e n t a b l e . T h e s e facts h a v e m a d e it t h e f ocus of na t i ona l a t t e n t i o n a n d publ ic e d u c a t i o n c a m p a i g n s .

Conv inc ing ep idemio log i c da t a i n c r i m i n a t e u l t ravio le t B (UVB) as a m a j o r e t io logic fac to r , bu t t h e r e is a lso suf f ic ien t e v i d e n c e t h a t it is n o t t h e sole causa t ive agen t . O t h e r a g e n t s impl ica ted in t h e c a u s e o f basa l cell c a n c e r s i nc l ude l o n g - t e r m p s o r a l e n plus u l t raviole t A (PUVA) t h e r - apy, g r e n z rad ia t ion , X-radiat ion, c h r o n i c a r s e n i c i s m , p r e e x i s t i n g le- s ions s u c h as s e b a c e o u s n e v u s of J a d a s s o h n a n d l i nea r basa l cel l ne- vus, a n d gene t i c d i s e a s e s s u c h as x e r o d e r m a p i g m e n t o s u m a n d nevo id basa l cell c a r c i n o m a s y n d r o m e . Despi te t he fac t t ha t UVB h a s b e e n r e c o g n i z e d as a c a u s e fo r s e v e r a l yea r s , t he p a t h o p h y s i o l o g y of UVB- i n d u c e d basa l cell c a n c e r s h a s n o t b e e n c o m p l e t e l y d e f i n e d as yet. O t h e r f a c t o r s l ead to t he f o r m a t i o n of basa l cell c a n c e r s by d i f f e r en t m e c h a n i s m s , t he p a t h o p h y s i o l o g y of s o m e be ing p o o r l y u n d e r s t o o d .

R e c o g n i t i o n of t h e c a u s e s of basa l cell c a n c e r s h a s led to t h e devel- o p m e n t of p r e v e n t i v e m e a s u r e s s u c h as p h o t o p r o t e c t i o n by a v o i d a n c e of excess ive sun e x p o s u r e a n d u se of s u n s c r e e n s , l imited u se of g r e n z r a y a n d x - r ay t h e r a p y of t h e skin, m o n i t o r i n g of wel l w a t e r fo r its ar- sen ic c o n t e n t , a n d p r o p h y l a c t i c exc i s ion of n e v u s s e b a c e o u s w h e n s u c h a l e s ion is de t ec t ed . A w a r e n e s s of t h e i n c r e a s i n g i n c i d e n c e h a s led to t h e d e v e l o p m e n t of s c r e e n i n g p r o g r a m s fo r ea r ly d e t e c t i o n of l e s ions also.

U n d e r s t a n d i n g of t he b io logy of basa l cell c a n c e r s c o n t i n u e s to un- fold wi th c o n t i n u i n g inves t iga t ion . S tudies sugges t t ha t co l l agenase , de- r ived f r o m t u m o r s t r o m a l f ib rob las t s , plays a r o l e in c r e a t i n g a pa th fo r t u m o r invas ion by d iges t ing co l l agen in t he s u r r o u n d i n g de rmi s . F i b r o n e c t i n f o r m e d by t u m o r cells m a y be involved in t u m o r cell mi- g r a t i on as well. T r a n s p l a n t a t i o n s tudies in an ima l s have s h o w n tha t i m m u n o l o g i c p h e n o m e n a play a n i m p o r t a n t r o l e in t he b io logy of basa l cell c a n c e r s . H u m a n basa l cell c a r c i n o m a h a s b e e n r e c e n t l y t r a n s p l a n t e d success fu l ly to i m m u n o s u p p r e s s e d a thymic mice . T h e h u m a n h o s t a l lows g r o w t h of t h e c a n c e r due to u l t ravio le t r a d i a t i o n (UVR)- induced i m m u n o s u p p r e s s i o n . I m m u n o l o g i c a b n o r m a l i t i e s have b e e n d o c u m e n t e d in pa t i en t s ~vith basa l cell c a n c e r s . I m m u n o l o g i c de- t e r i o r a t i o n m a y be a f a c t o r in t h e r a r e i n s t a n c e of me ta s t a t i c basa l cell c a n c e r .

C o g n i z a n c e of t he v a r i o u s c o m m o n a n d u n c o m m o n cl inical a p p e a r - a n c e s of t h e s e n e o p l a s m s is i m p o r t a n t so tha t t h e y c a n be r e c o g n i z e d a n d t r e a t e d effectively. T h e m o s t c o m m o n p r e s e n t a t i o n is as a p e a r l y papu le o r n o d u l e wi th s u r f a c e t e l ang iec t a s i a s o n a s u n - e x p o s e d sur- face; o t h e r p r e s e n t a t i o n s i nc l ude t he p i g m e n t e d , m o r p h e a f o r m , supe r - ficial, a n d f i b r o e p i t h e l i o m a of P inkus types . Basal cell c a n c e r s m a y a lso be e n c o u n t e r e d o n s u n - p r o t e c t e d a r e a s . Famil iar i ty wi th t he bio-

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logic behavior of the various types a l lows se lec t ion of the appropriate therapeut ic modality. The histologic types of cl inical import are the nodular, superficial , m o r p h e a f o r m , adenoid , and metatypical l e s ions . The latter three types invade local t i s sues m o r e aggress ively and con- sequent ly are bes t treated wi th Mohs surgery to e n s u r e c o m p l e t e ex- tirpation.

Histologic conf i rmat ion of the d iagnos is and def ini t ion of tumor type should be obta ined prior to therapy. The six usual a p p r o a c h e s for treatment are curettage and e lec trodes iccat ion , exc is ion , cryosurgery, radiation therapy, topical chemotherapy , and Mohs micrograph ic sur- gery. The ret inoids , etretinate and isotret inoin, have b e e n useful in control l ing the rate of a p p e a r a n c e of basal cel l c a n c e r s in patients with multiple basal cell c a n c e r s due to extens ive sun exposure , xero- derma p igmentosum, and nevoid basal cel l c a r c i n o m a syndrome . However , m a i n t e n a n c e therapy is n e c e s s a r y for cont inued control . Systemic c h e m o t h e r a p y may be useful for reduc ing the s ize of inoper- able tumors so that may b e c o m e a m e n a b l e to surgical resec t ion , but this is s e ldmn required. Indefinite fo l low-up and patient educat ion are essent ia l e l e m e n t s of m a n a g e m e n t of basal cell c a r c i n o m a s .

IN B R I E F

Basal cell c a r c i n o m a is the c o m m o n e s t ma l i gnancy affecting h u m a n s , and its i nc idence c o n t i n u e s to inc rease in e p i d e m i c p ropor t ions . The i nc rea sed inc idence has b e e n especial ly a p p a r e n t in y o u n g e r age groups . The p r i m a r y cause of this has b e e n i nc rea sed p h o t o e x p o s u r e w i thou t p h o t o p r o t e c t i o n . Present ly a c c e p t e d es thet ic s t anda rds have m a d e s u n t a n n i n g a regular a n d a lmost universal activity. Only recen t ly has s u n s c r e e n use b e e n emphas i zed , and the haza rd s of p h o t o e x p o s u r e we re no t r e c o g n i z e d by the publ ic unt i l r e cen t na t i onwide e d u c a t i o n campaigns . The use of this knowledge by the p r e s e n t gene ra t i on of ch i ld ren will he lp to con t ro l a n d r e d u c e the occur - r ence of n o n m e l a n o m a skin c a n c e r in the future . However, this opt imis t ic ou t look m u s t be t e m p e r e d by the knowledge tha t es thet ica l ly mot iva ted habi ts are difficult to change.

Data c o n c e r n i n g the cause of basal cell c a r c i n o m a have a c c u m u l a t e d over the years , a n d the role of ul traviolet B (UVB) is genera l ly accep ted . Also ac- c e p t e d is the role of long- te rm pso ra l en plus ul traviolet A (PUVA) therapy, X irradiat ion, g renz ray therapy, ch ron ic arsenicism, preexis t ing nevus seba- ceous , i m m u n o s u p p r e s s i o n , a n d var ious genet ic diseases, inc lud ing xero- d e r m a p i g m e n t o s u m a n d nevo id basal cell c a r c i n o m a synd rome . The signif- i cance of ul t raviolet A (UVA) a lone has b e e n the subjec t of invest igat ion bu t has no t b e e n conclus ive ly es tabl ished.

Basal cell c ance r s arise f rom cells in the basal layer of the ep ide rmis and hair follicles. The s low growth rate of these t u m o r s is a ref lect ion of the bal- ance b e t w e e n cell rep l ica t ion on one h a n d a n d cell necros i s on the other . The t u m o r m a y take m o n t h s to years to doub le in size. As it g rows it invades local t issues; metas tas i s is very rare. T u m o r - s t r o m a - f i b r o b l a s t - d e r i v e d colla- genase, e l abora ted u n d e r the in f luence of t u m o r cell cytokines, m a y be re- sponsible for d iges t ion of s u r r o u n d i n g no rma l col lagen and the re fore for tu- m o r spread. F ib ronec t in m a y be p r o d u c e d by t u m o r ceils, a n d its role in tu- m o r cell migra t ion has b e e n specu la ted . Actin-like mic ro f i l aments in t u m o r cells m a y be respons ib le for cell moti l i ty and are p r e s e n t in g rea te r n u m b e r s in the invasive m o r p h e a f o r m and a d e n o i d types of basal cell ca rc inomas .

Host i m m u n e s ta tus is an i m p o r t a n t e l e m e n t in the biology of basal cell cancers . Growth of this i m m u n o g e n i c t u m o r in the skin occu r s because of local or sys temic i m m u n o s u p p r e s s i o n . UVB-induced i m m u n o s u p p r e s s i o n by i n d u c t i o n of specific s u p p r e s s o r cells is be l ieved to s u p p r e s s t u m o r re-

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j ec t ion by the host , p e r m i t t i n g its g rowth in the skin. I m m u n e defec ts in- volving T- ly3nphocytes have b e e n d e m o n s t r a t e d in p a t i e n t s w i th mu l t i p l e basa l cell c ance r s a n d in b lacks w i th basal cell cancers , b u t w h e t h e r th is is a c ause or effect is unc lea r . T h e dens i t y of the p e r i t u m o r a l d e r m a l i n f l a m m a - to ry infil trate is inverse ly re la ted to the size of the tumor , sugges t ing t ha t the p r e s e n c e of a d e n s e infi l trate l imits the size of the t u m o r .

Metas ta t ic s p r e a d of t u m o r o c c u r s very rarely, a n d its o c c u r r e n c e is t h o u g h t to be r e l a t ed to several factors: de t e r io ra t ion in hos t i m m u n i t y , ag- gressive m o r p h e a f o r m or m e t a t y p i c a l histology, a n d neg lec t or r e c u r r e n c e of large t u m o r s wi th vascu l a r or n e u r a l invas ion by the t u m o r . Once m e t a s t a s i s o c c u r s the p r o g n o s i s is poor : 50% of pa t i en t s die in 8 m o n t h s , a n d the 5- y e a r survival ra te is on ly 12%.

Clinically, the typica l p a t i e n t w i t h a basa l cell c a n c e r is elderly, white , w i th type 1 or 2 skin, a n d the t u m o r is l oca t ed on a s u n - e x p o s e d pa r t of the skin. Two th i rds of basa l cell c a n c e r s are l o c a t e d on p h o t o e x p o s e d skin, a n d m o s t of t hese are on the h e a d or neck. In p a t i e n t s w i th mu l t i p l e t u m o r s p re - v ious X rad ia t ion or" g renz rad ia t ion , or c h r o n i c a r s e n i c i s m s h o u l d be con- s idered. The p r e s e n c e of a t u m o r in a chi ld s h o u l d raise the s u s p i c i o n of an u n d e r l y i n g disorder" s u c h as x e r o d e r m a p i g m e n t o s u m , nevo id basa l cell car- c inoma, or" linear" basa l cell nevus . The clinical s u b t y p e s of basa l cell c ance r s inc lude n o d u l a r or nodu lou l ce ra t i ve , p i g m e n t e d , superf icial , m o r p h e a f o r m , a n d f i b roep i t he l i oma of Pinkus.

C o r r e s p o n d i n g h is to logic s u b t y p e s as well as s u b t y p e s de f ined by the i r h is tologic d i f ferent ia t ion have b e e n classified. T h o s e of clinical i m p o r t a n c e are the m a c r o n o d u l a r , superf icial , m o r p h e a f o r m , m i c r o n o d u l a r , me ta typ ica l , a n d a d e n o i d les ions. His tologic f ea tu res of one or m o r e his to logic s u b t y p e s m a y o c c u r in different pa r t s of the s a m e t u m o r . Recogni t ion of t he se his to- logic s u b t y p e s in f luences the t r e a t m e n t c h o s e n for the pa r t i cu l a r t u m o r . For example , m o r p h e a f o r m , me ta typ ica l , m i c r o n o d u l a r , a n d a d e n o i d t u m o r s , b e c a u s e of the i r invasive na ture , r equ i re a m e t h o d of t h e r a p y tha t d o e s no t rely on clinical def in i t ion of t u m o r extent , s u c h as cu re t t age a n d e lec t rode- s iccat ion. The i r locafly invasive g r o w t h also impl ies tha t a r e a s o n a b l e cure ra te can be o b t a i n e d on ly w i t h M o h s surgery. The h is to logic a p p e a r a n c e of me ta s t a t i c t u m o r n o d u l e s is u sua l ly s imi lar to tha t of the p r i m a r y t u m o r f r o m w h i c h they arise.

W h e n a les ion clinically s u s p i c i o u s for a basa l cell c a n c e r is e n c o u n t e r e d a p r e t r e a t m e n t b i o p s y m u s t be p e r f o r m e d , no t on ly to con f i rm the d iagnos i s bu t to def ine the h is to logic type so as to gu ide the a p p r o p r i a t e t r e a t m e n t . A shave b i o p s y is u sua l ly sufficient excep t for m o r p h e a f o r m or recurTent tu- mors .

The u sua l t h e r a p i e s inc lude cu re t t age a n d e lec t rodes icca t ion , excision, r ad ia t ion the rapy , c ryosurgery , M o b s m i c r o g r a p h i c surgery, a n d top ica l che- m o t h e r a p y . Cure t t age a n d e l ec t rodes i cca t i on is the m e t h o d m o s t c o m m o n l y u s e d b y de rmato log i s t s . It is an effective t echn ique , w i th cure ra tes of 95%, for n o d u l a r t u m o r s w i t h a sol id his tology, 1 c m or less in d iamete r , less t h a n 2 yea r s ' dura t ion , a n d l oca t ed on a flat sur face s u c h as the fo rehead , cheek, or back. It is no t a relible m e t h o d for t u m o r s l oca t ed on the tip or alae of the nose a n d naso lab ia l folds.

Excis ion a n d p r i m a r y r e p a i r is a n o t h e r op t i on for t u m o r s less t h a n 2 c m in d i a m e t e r tha t are no t in difficult to cu re si tes a n d do not b e l o n g to the aggressive his to logic sub types . Cure t t age can be u s e d as the first s t ep in ex- cis ional su rge ry to be t t e r def ine the t u m o r ex ten t a n d to avoid re l i ance on visual def in i t ion of t u m o r marg ins . T h e res idua l w o u n d m a y t h e n be exc i sed wi th a m a r g i n of 2 r am. Excis ional suI•ely p rov ides a s p e c i m e n for p a t h o - logic examina t ion , u sua l ly gives excel len t c o s m e t i c resul ts , a n d s h o r t e n s hea l ing t ime. However , it is m o r e t ime c o n s u m i n g a n d sacrif ices n o r m a l skin for w o u n d c losure (e.g., dog -ea r repair) .

Radia t ion t h e r a p y a n d c r y o t h e r a p y rely on visual def in i t ion of t u m o r m a r -

72, Curr Probl Dermatol, May/June 1990

gins. Clinical a s s e s s m e n t of t u m o r ex ten t is k n o w n to of ten be inaccura te , l ead ing to i n c o m p l e t e t r e a t m e n t un l e s s a m a r g i n of cl inically un invo lved skin is i nc luded . Both m e t h o d s requ i re spec ia l t ra in ing for the i r use, a n d w h e n p r o p e r l y se l ec t ed g o o d cure ra tes can be ob ta ined . The l o n g - t e r m se- que lae of r ad i a t ion the rapy , i nc lud ing late o c c u r r e n c e of ~kin cancers , radi- a t ion dermat i t i s , a n d on ly m o d e s t l o n g - t e r m c o s m e t i c resul ts , have l imi ted this m o d a l i t y to i n o p e r a b l e t u m o r s a n d the e lder ly pa t i en t w h o m a y no t be able to to lera te surgery. The advan tage of c r y o s u r g e r y is tha t it spa re s the lacr imal d u c t a n d car t i l ag inous s t r u c t u r e s f r o m d a m a g e w h e n t rea t ing tu- m o r s in the m e d i a l c a n t h u s or on the ear. G o o d cu re ra tes have b e e n re- p o r t e d for s e l ec t ed t umor s , bu t it is no t w ide ly used . Top ica l c h e m o t h e r a p y wi th 5-f luoruraci l (5-FU) is r e se rved for smal l superf ic ia l t u m o r s only.

M o h s m i c r o g r a p h i c su rge ry p rov ides the h ighes t cu re rates. Overall cu re ra tes are 95% to 99%. It d o e s no t d e p e n d o n clinical def in i t ion of t u m o r marg ins . It a l lows his tologic e x a m i n a t i o n of 100% of the m a r g i n s a n d is tis- sue spar ing. M o h s su rge ry is the m e t h o d of cho ice for t r e a t m e n t of basa l cell c ance r s tha t are i l l-defined, la rger t h a n 2 c m in d i a m e t e r on the face, r ecu r ren t , l o c a t e d in dif f icul t - to-cure si tes s u c h as the nasa l t ip a n d alae, na- solabial fold, eyel ids a n d canthi , ear a n d p r e a u r i c u l a r area, o r o t h e r es the t - ically critical a reas in y o u n g pa t ien ts , a n d his to logica l ly aggress ive t u m o r s .

O the r m e t h o d s s u c h as in t ra les iona l in te r fe ron in jec t ion are u n d e r inves- t igation. I so t r e t ino in a n d e t re t ina te have b e e n u s e d for the m a n a g e m e n t of mul t ip l e basa l cell c ance r s f rom p h o t o e x p o s u r e , x e r o d e r m a p i g m e n t o s u m , a n d nevo id basa l cell c a r c i n o m a s y n d r o m e . T h e s e re t ino ids have b e e n effec- tive in r e d u c i n g the ra te of t u m o r o c c u r r e n c e . D i s c o n t i n u a t i o n of t h e r a p y led to a p p e a r a n c e of t u m o r s at the p r e t r e a t m e n t rate, a n d indef in i te m a i n - t e n a n c e t r e a t m e n t at the m i n i m a l effective d o s e w o u l d be n e c e s s a r y for con- t i n u e d benefi t .

Sys temic c h e m o t h e r a p y wi th a w ide var ie ty of agen ts has b e e n a t t e m p t e d in m e t a s t a t i c basa l cell c a r c i n o m a . E n c o u r a g i n g resu l t s have b e e n r e p o r t e d w i th c ispla t in a n d doxorubic in , bu t da ta are l imi ted . P reopera t ive sys t emic c h e m o t h e r a p y h a s also b e e n u s e d as an a d j u n c t for r e d u c i n g the size of in- ope rab l e t u m o r s , w h i c h w e r e t h e n m a d e a m e n a b l e to surgical resec t ion .

Indef in i te fo l low-up is n e c e s s a r y for p a t i e n t s w h o have d e v e l o p e d a basa l cell c a r c inoma , b e c a u s e of the l ike l ihood of d e v e l o p i n g m o r e t u m o r s a n d for de t ec t i on of r e c u r r e n c e s . P reven t ion is the m o s t i m p o r t a n t a r m in the con- trol of the e p i d e m i c of n o n m e l a n o m a skin cancer . S u n s c r e e n s have b e e n the m a i n p reven t ive m e a s u r e , bu t a v o i d a n c e of t a n n i n g pa r lo r s a n d s u n expo- sure du r ing d a y t i m e p e r i o d s of m a x i m u m risk (10:00 AM to 3:00 PM) a n d self- e x a m i n a t i o n for ear ly de t ec t i on of n e w les ions are also i m p o r t a n t .

N,N

Curr Probl Dermatol , May/June 1990 73

Renuka Diwan, M.D., is an instructor at The Johns Hopkins School o f Medicine and a staff physician o f the Department o f Dermatology, Division o f Dermato- logic Surgery, at The Johns Hopkins Hospital. She graduated from Grant Medi- cal College, The University o f Bombay, India, in 1982, and completed a residency in dermatology and 2 years in internal medicine at Case Western Reserve Uni- versity, Cleveland, and Cleveland Metropolitan General Hospital. Her training also included a fellowship in dermatologic surgery at the University o f Califor- nia, San Francisco. She is board certified in dermatology. Her interests are cu- taneous oncology and Mohs micrographic surgery.

John W. Skouge, M.D., is assistant professor in the Departments o f Dermatology and Otolaryngology/Head and Neck Surgery at The Johns Hopkins School o f Medicine. He is Director o f the Division o f Dermatologic Surgery at The Johns Hopkins Hospital. He obtained his medical degree f rom the University o f Cali- fornia, lrvine School o f Medicine in 1980. He completed a residency in derma- tology at The Johns Hopkins University in Baltimore, and is board certified in dermatology. His residency was followed by a fellowship in dermatologic sur- gery at the University o f California, San Francisco. He is the author o f a number o f clinical and research articles covering different aspects o f dermatologic sur- gery.

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BASAL CELL C A R C I N O M A

D E F I N I T I O N A N D E P I D E M I O L O G Y

Basal cell c a r c i n o m a is a m a l i g n a n t t u m o r tha t ar ises f r o m p l u r i po t en t i a l cells, w h i c h are f o r m e d t h r o u g h o u t life, in the basa l cell l ayer of the epi- d e r m i s a n d the ou t e r roo t s h e a t h of ha i r follicles. T h u s it is a t u m o r f o r m e d f r o m i m m a t u r e cells r a t h e r t h a n anap la s t i c ce l l s )

It is the c o m m o n e s t m a l i g n a n t t u m o r o c c u r r i n g in h u m a n s a n d a c c o u n t s for 65% to 75% of all skin cancers . 2 T h e i n c i d e n c e of basa l cell c a r c i n o m a ex- c e e d s 500,000 p e r year . a T h e r ecen t r ap id i nc rea se in i n c i d e n c e is pa r t l y d u e to an inc rease in recre- a t ional s u n exposu re , a n d m a y be re la ted to the s low d e p l e t i o n of the p ro tec t ive o z o n e layer f r o m the s t r a t o s p h e r e . The o z o n e layer n o r m a l l y re- m o v e s a s ignif icant a m o u n t of ul t raviolet B (UVB) e n e r g y by op t i ca l filtration, t h e r e b y d e c r e a s i n g its h a r m f u l effects. 4 O z o n e d e p l e t i o n b y e n v i r o n m e n - tal c h l o r o f l u o r o c a r b o n s the re fo re cou ld p e r m i t g r ea t e r a m o u n t s of UVB to r e a c h the ea r th ' s sur - face, wi th a r e s u l t a n t i nc rea se in c u t a n e o u s car- c inogenes is .

Basal cell c a r c i n o m a s inc rease in f r e q u e n c y wi th dec rea s ing la t i tude. The a m o u n t of UVB rad i a t i on inc iden t on the ea r th ' s sur face inc reases c loser to the equa tor . W h e n p e o p l e of s imi lar p i g m e n t a t i o n are c o m p a r e d the i nc idence of skin c a n c e r d o u - bles for eve W 8- to 10-degree d e c r e a s e in la t i tude. 5 An inc rease in a l t i tude is also a c c o m p a n i e d b y an inc rease in i nc iden t UVB. Basal cell c ance r s are f o u n d m o r e c o m m o n l y in o u t d o o r w o r k e r s w h o have g rea te r c u t a n e o u s s u n exposu re . T h e y have b e e n f r equen t ly f o u n d on s u n - e x p o s e d si tes in g r ape pickers , f i she rmen , sailors, a n d c o n s t r u c t i o n workers . 5 O u t d o o r r ec r ea t i on s u c h as golfing, fish- ing, a n d sai l ing also p r e d i s p o s e s to basa l cell can- cers f rom photoexposure. T a n n i n g pa r lo r s have

b e c o m e p o p u l a r w i th c h a n g i n g es the t i c va lues a n d the des i re to spo r t a t a n n e d c o m p l e x i o n for a "hea l thy look." The w i d e s p r e a d p r o m o t i o n of s u c h facilities, u s ing b o t h UVB a n d UVA, has c o n t r i b u t e d to s ignif icant ly m o r e p h o t o d a m a g e t h a n w o u l d o the rwi se occur . P h o t o e x p o s u r e is no longe r sea- sonal, d u e to the c o n t i n u o u s u se of t a n n i n g facili- ties t h r o u g h o u t the year , m a k i n g it a y e a r - r o u n d haza rd .

T w o th i rds of all basa l cell c a r c i n o m a s o c c u r on s u n - e x p o s e d areas of the skin. T h e r e is also an age - re la t ed inc rease in the i n c i d e n c e of t hese neo- p l a sms , w i th a p e a k i n c i d e n c e at 60 to 65 yea r s of age. Older s tud ies have f o u n d tha t m e n w e r e af- fec ted twice as of ten as w o m e n , d u e to d i f ferences in o c c u p a t i o n a l a n d rec rea t iona l hab i t s a n d conse - quen t s u n exposu re . However , m o r e r e c e n t da ta s h o w tha t the re is an equa l i n c i d e n c e of basa l cell c a r c i n o m a s in b o t h sexes. 5

Basal cell c a r c i n o m a s are ra re in chi ldren , u sua l ly o c c u r r i n g in these age g r o u p s in u n u s u a l c i r c u m - s tances , s u c h as x e r o d e r m a p i g m e n t o s u m , nevo id basa l cell c a r c i n o m a s y n d r o m e , a n d a lbinism, ge- ne t ic d i seases p r e d i s p o s i n g to d e v e l o p m e n t of cu ta - n e o u s ma l ignanc ie s . 6 Fac tors involved in the c a u s e of basa l cell c ance r s are c o n s i d e r e d below.

E T I O L O G Y A N D P A T H O G E N E S I S

M a n y fac tors have b e e n s h o w n to be of signifi- c ance in the c a u s e of basa l cell c a r c i n o m a s (Table 1).

ULTRAVIOLET RADIATION

Ultraviolet r ad ia t ion (UVR) has b e e n w id e ly ac- c e p t e d as a c a u s e of n o n m e l a n o m a skin cancer , on

Curr Probl Dermatol, May/June 1990 75

TABLE 1. Causes of Basal Cell Carcinomas

Etiologic Factor

UVB

UVA

Genetic susceptibility

X-ray and grenz ray irradiation

Arsenicism

Trauma

Immunosuppression

Nevus sebaceous of Jadassohn

Source

Natural sunlight, from occupational or recreational exposure

Tanning salons, UVB therapy for various dermatoses

As above; not established as a cause

PUVA, >200 treatments Celtics (fair skin, poor tanning

ability) Nevoid basal cell carcinoma

syndrome, xeroderma pigmentosum

Used for treatment of cancers, and in the past for recalcitrant benign dermatoses

Medicinal, as Fowler's solution Dietary, from well water

contaminated with pesticides containing arsenicals

Vaccination, chickenpox, burn scars

Immunodeficiency diseases such as AIDS

Immunosuppressive drugs (e.g., in renal transplant patients)

Usually on scalp; also on other parts of the head

the basis of conv inc ing ep idemio log ic data. The s t rong associa t ion be tween s u n exposure and the d e v e l o p m e n t of basal cell c a n c e r is d e m o n s t r a t e d by the following observationsS:

1. Occur rence of basal cell cancers p r e d o m i - nan t ly on s u n - e x p o s e d areas. Approx imate ly two thi rds of basal cell cance r s are f o u n d on sun-ex- p o s e d areas.

2. Inc reased inc idence of basal cell cancers a m o n g those involved in o u t d o o r work or recre- at ional activities, as c o m p a r e d wi th those engaged pr imari ly in i ndoo r activities.

3. Increase in the inc idence of basal cell cancers wi th decreas ing la t i tude a n d increas ing altitude, c o r r e s p o n d i n g to the increase in sun exposure in these geograph ic areas.

4. Inverse corre la t ion b e t w e e n the degree of skin p igmen ta t i on a n d t ann ing ability a n d t h e inci- dence of n o n m e l a n o m a skin cancer . Light-skinned popu la t i ons are main ly affected by basal cell can- cers, as o p p o s e d to da rk-sk inned people , w h o sel-

dora develop these neop lasms . W h e n dark- sk inned peop le do develop basal cell cancers , they t e n d to o c c u r on n o n - s u n - e x p o s e d sites.

5. Genetically p r e d i s p o s e d pa t ien ts (e.g., those wi th x e r o d e r m a p i g m e n t o s u m ) are at high risk for skin cancers in s u n - e x p o s e d sites only. 5

While there was wide a c c e p t a n c e that UVR was carcinogenic , the ac t ion s p e c t r u m that was re- sponsible for this effect was no t def ined unti l the 1950s. Present knowledge abou t p h o t o c a r c i n o g e n - esis is der ived f rom animal exper iments , because it is imposs ible to define in h u m a n s . The animal m o d e l u s e d m o s t extensively for these s tudies is the mouse , for e c o n o m i c a l a n d efficacy reasons . 4 Blum 7 s h o w e d that the wavelengths that c a u s e d skin cancers in mice were pr imar i ly in the 290 to 320 n m range (i.e., UVB). F r e e m a n s n o t e d that 300 n m was m o r e effective t h a n 310 n m in p r o d u c i n g skin cancers in mice and that 320 n m was ineffec- tive even at m u c h larger doses. The cancers in- d u c e d in mice were s q u a m o u s cell ca rc inomas . UVB-induced basal cell cancers have no t been pro- d u c e d in mice or any o the r animals, resul t ing in a lack of an animal m o d e l for UVB-induced basal cell cancers .

However, UVB, w h i c h is k n o w n to cause el]ythema in h u m a n skin, has been s h o w n to be re- sponsible for the e r y t h e m a r e sponse in m u r i n e skin as well. It has therefore been a s s u m e d that the s p e c t r u m respons ib le for c u t a n e o u s p h o t o c a r - c inogenes is in h u m a n s will also be the same as that for mice. T h u s UVB has been impl ica ted indi- rect ly in c u t a n e o u s carc inogenes is in h u m a n s , ior bo th basal a n d s q u a m o u s cell cancers . The role of ultraviolet A (UVA; 320 to 400 n m wavelengths) in p h o t o c a r c i n o g e n e s i s is no t clearly established.

The exact m e c h a n i s m by w h i c h UVR-induced carc inogenes i s occu r s has no t b e e n comple te ly e lucidated. Pho toca rc inogenes i s appea r s to be one mani fes ta t ion of a larger pho tob io log ic p rocess in- volving bo th local a n d sys temic r e sponses to UVR. Animal s tudies have s h o w n that UVR has b o t h di- rect and indirect effects. The direct effects involve the t r ans fo rma t ion of n o r m a l cells to mal ignan t cells by the ac t ion of UVB, and poss ib ly UVA, on cellular DNA. The indirect effects are the e n h a n c - ing effects of UVB and UVA via their effects on the i m m u n e system, bo th locally a n d systemically.

D i r e c t E f f e c t s UVB is h ighly effective as b o t h an i n d u c e r a n d

p r o m o t e r of skin cance r in mice. s UVB is k n o w n to p r o d u c e s t ruc tura l changes in DNA b o t h , i n vitro and in vivo in h u m a n skin. The ma jo r al terat ion is the fo rmat ion of t hymine dimers, w h i c h m a y re- sult in m u t a g e n i c changes and the fo rmat ion of tu-

76 Curr Probl Dermatol, May/June 1990

mors . 5 However , several p ro tec t ive m e c h a n i s m s exist in m a m m a l i a n cells tha t r epa i r UVR-induced DNA damage . The different DNA repa i r m e c h a - n i s m s inc lude excis ion repair , p o s t r e p l i c a t i o n re- pair , a n d pho to reac t i va t i on . 5'~ Fai lure or defi- c i ency of these r epa i r m e c h a n i s m s leads to an in- c r e a s e d risk for cancer . 9 E x p e r i m e n t s in h a M e s s m i c e have s h o w n tha t the effect iveness of UVR ra- d ia t ion in t u m o r f o r m a t i o n i nc rea se s w h e n the UVR doses are de l ivered in f ract ions, a n d t u m o r f o r m a t i o n i nc rea se s p r o p o r t i o n a t e l y wi th the cu- mula t ive UVR exposu re . ~°

Studies have c o n f i r m e d DNA al te ra t ions i n d u c e d by UVA i r rad ia t ion in the e p i d e r m i s of skin in g u i n e a pigs, in tac t skin in h u m a n s , a n d in cells in cul ture . T h e s e a l te ra t ions inc lude p y r i m i d i n e d i m e r f o r m a t i o n (the m a j o r DNA lesion), s ingle- s t r a n d breaks , a n d DNA-pro te in crossl inks. 11 The m e c h a n i s m s of t he se c h a n g e s r e m a i n u n k n o w n . In addi t ion , o t h e r da t a s u p p o r t a c o c a r c i n o g e n i c role for UVA in ha i r less mice . ~2 W h e t h e r these exper i - m e n t a l resu l t s in an ima l s are re levant in h u m a n s is u n k n o w n . O t h e r effects of UVA via spec t r a l in ter- activity r e m a i n to be de f ined fur ther . The q u e s t i o n of the role of UVA in ca rc inogenes i s r e m a i n s im- p o r t a n t b e c a u s e signif icant UVA e x p o s u r e c a n re- sul t f rom UVA t a n n i n g pa r lo r s a n d the u se of effec- tive UVB s u n s c r e e n s .

I nd i r ec t E f f ec t s The i m m u n o l o g i c effects of UVR have an i m p o r -

t an t in f luence on UVR-induced t u m o r fo rmat ion . UVR-induced t u m o r s are h ighly ant igenic , a n d w h e n t r a n s p l a n t e d f rom the hos t m o u s e to a syn- gene ic m o u s e t h e y are r e j ec t ed by the r ec ip i en t m o u s e a n d fail to grow. However , the hos t m o u s e is u n a b l e to re jec t the t u m o r . This is be l ieved to re- sult f rom the i m m u n o s u p p r e s s i v e effects of UVR on the hos t an imal . These i m m u n o l o g i c a l t e ra t ions o c c u r b o t h locally, w i th in the skin, as wel l as sys- temical ly . 13 At a c u t a n e o u s level, L a n g e r h a n s cells are r e d u c e d in n u m b e r , a n d those that are p r e s e n t are inac t iva ted so tha t the i r an t igen p r e s e n t i n g func t ion is impa i r ed , t h e r e b y b lock ing ac t iva t ion of the effector cell p a t h w a y a n d the g e n e r a t i o n of an i m m u n o l o g i c r e s p o n s e . Systemical ly, t u m o r - s p e - cific s u p p r e s s o r cells are i n d u c e d . The ne t resu l t of t hese i m m u n o l o g i c a l te ra t ions is to p r e v e n t hos t re jec t ion of t u m o r , a l lowing its g r o w t h in the skin.

O t h e r In f l uences

P U V A . - - L o n g - t e r m PUVA t h e r a p y for pso r i a s i s (more t h a n 200 PUVA t r ea tmen t s ) has b e e n s h o w n to inc rease the risk for deve lop ing s q u a m o u s a n d basa l cell c a nce r s of the skin. 14 The d o s e - d e p e n - d e n t i nc rease in the risk for basa l cell c a n c e r s is

m o d e s t , bu t still significant, w h e n c o m p a r e d w i th the i nc rea se in risk for deve lop ing s q u a m o u s cell cancers . Pat ients receiving PUVA wi th skin types 1 a n d 2 have a h ighe r abso lu te risk for basa l cell can- cers t h a n pa t i en t s w i th skin types 3 a n d 4.

The i n c r e a s e d risk for c u t a n e o u s ca rc inogenes i s f rom the c u m u l a t i v e effect of h i g h - d o s e PUVA is due to its k n o w n m u t a g e n i c effect a n d p r o b a b l y • also d u e to its i m m u n o s u p p r e s s i v e effect. T u m o r s deve lop ing in assoc ia t ion w i th PUVA t h e r a p y ap- p e a r to have the s a m e biologic behav io r as t hose c a u s e d by s u n exposu re .

Ant iox idan t s a n d O ther C h e m i c a l s . - - C e r t a i n di- e tary an t iox idan t agen ts have b e e n s h o w n to p ro - tect aga ins t UVR-induced ca r c inogenes i s in vivo in m o u s e skin, a n d in cell cu l tu re UVR cyto toxic i ty was reversed , is Ant iox idan t s m a y act by p r ev en t - ing the effects of s inglet oxygen a n d free radicals . Other agen ts s h o w n to inhibi t UV ca rc inogenes i s are caffeine a n d theophy l l ine , pos s ib ly by inhibi t - ing e r r o r - p r o n e p o s t r e p l i c a t i o n DNA repair .

Ret inoic acid, in c o n c e n t r a t i o n s tha t are no t toxic or irritating, can b o t h s t imu la t e a n d inhibi t UV-induced ca rc inogenes i s in different c i r c u m - s t ances in an ima l s tudies . T h u s it c a n be s e e n tha t a var ie ty of in f luences can m o d i f y p h o t o c a r c i n o - genesis , at least in an ima l s tudies .

M u s t a r g e n a n d the n i t ro soureas , e spec ia l ly car- m u s t i n e (BCNU), in s u b c a r c i n o g e n i c dose s acce le r - ate LrVR-induced ca rc inogenes i s . 15 Since these agen ts are of ten u s e d for the t r e a t m e n t of d i seases s u c h as psor ias i s a n d m y c o s i s fungoides , w h i c h are also t r e a t ed wi th UVB a n d PUVA, this in te rac- t ion is i m p o r t a n t to recognize .

P h o t o c a r c i n o g e n e s i s is a c o m p l e x p rocess , a n d the role of UVR in the p a t h o g e n e s i s of basa l cell c a r c i n o m a s is poo r ly u n d e r s t o o d . Desp i te the fact tha t t he re is s t rong e p i d e m i o l o g i c ev idence in- c r imina t ing UVR in the c a u s e of t he se n e o p l a s m s , the re is p o o r cor re la t ion b e t w e e n UVR e x p o s u r e dose a n d the i n c i d e n c e of basa l cell c a n c e r s at c o r r e s p o n d i n g sites on the face. TM This ra ises ques - t ions a b o u t the role of o t h e r factors , local or sys- temic, tha t m a y be opera t ive in the cause of these t umor s .

GENETIC SUSCEPTIBILITY

Ind iv idua ls of Celtic d e s c e n t w h o have type 1 p h e n o t y p e , b u r n i n g r a t h e r t h a n t a n n i n g on UVR exposure , are espec ia l ly s u s c e p t i b l e to the ca rc ino- genic effects of UVR. People of Scand inav ian de- scent , w h o are as light c o m p l e x i o n e d as Celtics, have a be t t e r t a n n i n g ability in r e s p o n s e to UVR ex- p o s u r e a n d a l ower i n c i d e n c e of n o n m e l a n o m a sMn cancer . Thus , apa r t f r o m be ing pa le c o m p l e x -

Curr Probl Dermatol, May/June 1990 77

ioned, the ability to t an is an i n d e p e n d e n t r isk fac- toE" foE" basal cell c ance r s a n d a c c o u n t s for the in- he r en t p r o p e n s i t y of Celtics for basa l a n d s q u a m o u s cell c a n c e r s ) 7

Genet ic d i seases s u c h as x e r o d e r m a p i g m e n t o - s u m (XP), nevo id basa l cell c a r c i n o m a s y n d r o m e (NBCCS), a n d a lb in i sm p r e d i s p o s e to d e v e l o p m e n t of basa l cell c a r c i n o m a s b y dif ferent m e c h a n i s m s .

Xeroderma Pigmentosum X e r o d e r m a p i g m e n t o s u m is a ra re a u t o s o m a l re-

cessive d i s o r d e r in w h i c h the re is cel lu lar h y p e r - sensi t ivi ty to UVR a n d ce r ta in chemica l s , associ- a ted wi th defect ive DNA repa i r m e c h a n i s m s . The man i f e s t a t i ons of the d i sease involve the skin, eyes, a n d n e r v o u s sys tem. Skin s igns inc lude freckling, exquis i te UVR sensi t ivi ty w i th s u n b u r n on m i n i m a l UVR exposu re , mu l t i p l e ac t in ic kera toses , basal a n d s q u a m o u s cell cancers , a n d mul t ip l e p r i m a r y m e l a n o m a s . C u t a n e o u s c h a n g e s a p p e a r by age 1 y e a r in 50%, a n d the m e d i a n age for d e v e l o p m e n t of skin cance r s is 8 years . T h e r e is a g rea t e r t h a n 1,000-Ibld inc rease in the risk of basa l or s q u a n l o u s cell c ance r s of the skin. Ocu la r m an i f e s t a t i ons of pho tosens i t i v i ty i nc l ude p h o t o p h o b i a , en t rop ion , ec t rop ion , keratit is, a n d c a r c i n o m a s on the UV-ex- p o s e d pa r t s of the eye. The def ic ient DNA repa i r can be d e t e c t e d in skin f ibroblasts . 18' 19

Nevoid Basal Cell Carcinoma Syndrome Also k n o w n as Gorl in 's s y n d r o m e , NBCCS is a

Pare a u t o s o m a l d o m i n a n t d i sease c h a r a c t e r i z e d by early onse t of basa l cell cancers , p a l m a r a n d p lan- tar pits, m a n d i b u l a r kera tocys ts , a n d o the r skeletal a n d cen t ra l ne rvous s y s t e m abnorma l i t i e s .1.20 Basal cell c ance r s o c c u r on s u n - e x p o s e d as well as n o n - s u n - e x p o s e d skin. Clinically the re is a strik- ing a p p e a r a n c e of basal cell c ance r s in a reas t r ea t ed w i th r ad ia t ion the rapy , b u t a s imi lar cellu- lar hypersens i t iv i ty h a s no t b e e n d e m o n s t r a t e d wi th c u l t u r e d d e r m a l f ibroblasts . Pe r iphera l lym- p h o c y t e s f rom pa t i en t s w i th NBCCS s h o w an im- pa i r ed r epa i r r e s p o n s e to x - P a y - i n d u c e d DNA d a m a g e as c o m p a r e d wi th l y n l p h o c y t e s f rom pa- t ients w i th mul t ip l e basa l cell c ance r s d u e to sun - light. 21 Basal cell c ance r s have b e e n f o u n d to de- ve lop in the p a l m a r pits. 1 Pa t ien ts are also at in- c r ea sed risk for in te rna l n e o p l a s m s , s u c h as m e d u l l o b l a s t o m a a n d ovar ian f ibromas . O t h e r be- n ign c u t a n e o u s t u m o r s , m e n t a l r e ta rda t ion , a n d calcif icat ion of the falx cerebr i are a few of the var- ious man i fes t a t ions . C h r o m o s o m a l abnorma l i t i e s have b e e n f o u n d in s o m e pa t ien t s , bu t the preva- lence or p a t t e r n of t he se has not b e e n es tab l i shed .

Bazex Syndrome Bazex s y n d r o m e is an a u t o s o m a l d o m i n a n t dis-

o rde r tha t cons is t s of fol l icular a t r o p h o d e r m a on

the l imbs a n d mul t ip l e facial basal cell c a r c i n o m a s first a p p e a r i n g as ear ly as ch i ldhood . D i so rde r s of swea t ing a n d ha i r m a y also exist. 1

IONIZING RADIA'IION

I r rad ia t ion of the skin wi th x-rays was c o m - m o n l y p e r f o r m e d in the p a s t for t r e a t m e n t of re- f rac to ry ben ign d e r m a t o s e s , s u c h as t inea capit is , a c h e vulgaris, a n d psor ias is , as wel l as m a l i g n a n t cond i t ions . Twenty-f ive yea r s af ter i r rad ia t ion 5% of the t r e a t ed p o p u l a t i o n h a d d e v e l o p e d basa l cell c a r c i n o m a s . Mul t ip le basa l cell c ance r s are ch a r ac - teristic of r ad i a t ion effect. 2z The ca rc inogen ic effect of ioniz ing rad ia t ion is p r o m o t e d by UVR a n d PUVA. As n o t e d above, pa t i en t s wi th basa l nevus s y n d r o m e are espec ia l ly suscep t ib l e to the carci- nogen ic effect of ioniz ing radia t ion .

Grenz rays have b e e n also r e c o g n i z e d as carci- nogenic . 23 A smal l p r o p o r t i o n of pa t i en t s e x p o s e d to g renz rays for t h e r a p y of var ious skin d i seases deve lop basa l a n d s q u a m o u s cell c ance r s in the ir- r ad i a t ed areas, w h e n the re has b e e n no e x p o s u r e to o the r ca rc inogens . The re is no t h r e s h o l d d o s e of r ad ia t ion above w h i c h it c ause s n o n m e l a n o n l a skin cancer . T u m o r s t e n d to be mu l t i p l e a n d are p r e d o m i n a n t l y s q u a m o u s cell cancers . Only t hose wi th a gene t i c suscep t ib i l i ty to skin c a n c e r in- d u c e d by g r enz rays deve lop n o n m e l a n o m a sMn c a n c e r af ter e x p o s u r e to s u c h radia t ion.

ARSENICISM

Chron ic a r sen ic exposure , via dietary, med ic ina l , or o c c u p a t i o n a l sources , resu l t s in the deve lop- m e n t of hyperpigmentation, kera toses , a n d cUta- n e o u s ma l ignanc ie s . The c u t a n e o u s c a n c e r s aPe mu l t i p l e a n d p r e d o m i n a n t l y l oca t ed in n o n - s u n - e x p o s e d a reas s u c h as the t r unk a n d bu t tocks . The m o s t f r equen t is Bowen ' s disease, fo l lowed in de- c reas ing o r d e r of f r e q u e n c y by s q u a m o u s cell car- c i n o m a s a n d basa l cell cancers . Basal cell ca rc ino- m a s m a y be of the n o d u l a r or supeE~icial m u l t i c e n - t r i c type. 24 The biologic b e h a v i o r of basa l cell can- cers developing f r o m c h r o n i c a r s e n i c i s m h a s no t b e e n s h o w n to be different f rom those tha t de- ve lop f rom c h r o n i c UVR exposu re .

TRAUMA

Pat ients of ten re la te a h i s to ry of p r e c e d i n g t r a u m a at the site of d e v e l o p m e n t of a basa l cell cancer . T h e y have b e e n n o t e d to o c c u r in vacc ina - t ion s c a r s j 2~ c h i c k e n p o x s c a r s , 26 b u r n s e a r s , 27 a n d s tasis u lcers .

78 Curr Probl Derrnatol, May/June 1990

N E V U S S E B A C E O U S OF J A D A S S O H N

Nevus s e b a c e o u s of J a d a s s o h n is a h a m a r t o m a tha t occu r s m o s t f r equen t ly on the sca lp a n d face as a congen i ta l a lopec ic p laque . Basal cell c a n c e r s are k n o w n to deve lop wi th in these lesions, as are o t h e r n e o p l a s m s , du r ing a d u l t h o o d . The i n c i d e n c e of a clinically a p p a r e n t basa l cell c a n c e r ar is ing w i th in this les ion is 5% to 7% .1 Therefore , w h e n - ever poss ib le the nevus s h o u l d be p rophy l ac t i c a l l y exc ised before a d u l t h o o d .

LINEAR BASAL CELL NEVUS

Linear basa l cell nevus is a very rare congen i t a l cond i t i on w i th the clinical a p p e a r a n c e of a l inear or zos t e r i fo rm d i s t r ibu t ion of n o d u l e s of basa l cell c a r c i n o m a i n t e r s p e r s e d wi th c o m e d o n e s a n d ar- eas of a t r o p h y J The les ions are p r e s e n t at b i r th or a p p e a r in c h i l d h o o d .

I M M U N OS UPPRESSI ON

Systemic i m m u n o s u p p r e s s i o n f r o m diseases , s u c h as a c q u i r e d i m m u n e def ic iency d i sease (AIDS), or f r o m i m m u n o s u p p r e s s i v e drugs, s u c h as those u s e d in rena l t r a n s p l a n t pa t ien ts , is k n o w n to p r e d i s p o s e to the d e v e l o p m e n t of ma l ignanc ies . Skin cance r s c o m p r i s e the ma jo r i ty of c ance r s in rena l t r a n s p l a n t pa t ien ts . S q u a m o u s cell c a n c e r s are m o r e f r equen t ly f o u n d t h a n basa l cell cancers , a n d m a i n l y o c c u r on s u n - e x p o s e d areas . The rat io of basa l cell to s q u a m o u s cell c a n c e r in t r a n s p l a n t r ec ip ien t s is 1:1.7, c o m p a r e d wi th 4 :1 in the gen- eral p o p u l a t i o n , zS' z~

OTHER FACTORS

H u m a n p a p i l l o m a vi ruses (HPV) have b e e n in- c reas ing ly a s s o c i a t e d wi th h u m a n ma l ignanc ies . The p r e s e n c e of HPV-2 g e n o m e has b e e n d o c u - m e n t e d w i th in basa l cell c ance r s in two i m m u n o - s u p p r e s s e d pa t i en t s . The et iologic s ignif icance of this f inding is no t known . 3°

B I O L O G Y O F BASAL CELL C A N C E R S

Basal cell c a n c e r s en large s lowly a n d p rog re s - sively, taking m o n t h s to yea r s to d o u b l e in size. 31 T h e y are local ly invasive, infi l trat ing ad j acen t tis- sues a n d caus ing signif icant d e s t r u c t i o n a n d de- formity. It is this s lowly p rogress ive d e s t r u c t i o n tha t has l e d to the des igna t ion r o d e n t u l ce r (lik- e n e d to the g n a w i n g of a rat; Fig 1). Subcl inical ex- t ens ion of the t u m o r b e y o n d clinically visible m a r - gins of the tumor" occu r s f r equen t ly a n d m a y be a s y m m e t r i c , e x t e n d i n g m o r e in one d i rec t ion t h a n in o thersf f z Desp i t e the i r m a l i g n a n t na ture , t he i r

Curr Probl Dermatol , May/June 1990

FIG 1. Large ulcerated basal cell cancer, also known as "rodent ulcer," involving the ear.

biologic b e h a v i o r is relat ively b e n i g n a n d they m e - tas tas ize on ly very ra re ly to reg iona l l y m p h nodes , lungs, a n d bone .

The g r o w t h kinet ics of t he se n e o p l a s m s have b e e n s t u d i e d a u t o r a d i o g r a p h i c a l l y us ing t r i t ia ted t h y m i d i n e . 31 The average cell in a basa l cell c a n c e r r e p r o d u c e s every 9 days. This w o u l d sugges t a fas te r g r o w t h ra te t h a n tha t cl inically observed . The o b s e r v e d s low rate of g r o w t h can be e x p l a i n e d by the fol lowing f indings: on ly 10% to 40% of the total cell p o p u l a t i o n is dividing at a n y given p o i n t in t ime; 5% to 40% of the cell p o p u l a t i o n is ar- r e s t ed in G2 or GO phases3~; a n d c o n c u r r e n t w i th cell g r o w t h the re are foci of cell d e a t h wi th in the t u m o r . The obser-ved g r o w t h ra te is t hus a reflec- t ion of the b a l a n c e b e t w e e n these two i n d e p e n - den t p h e n o m e n a of cell p ro l i fe ra t ion a n d cell ne- crosis. Cell nec ros i s is r e s p o n s i b l e for the p h e - n o m e n o n of t u m o r r eg res s ion occas iona l ly s een clinically. 34 Histologically, t u m o r nec ros i s is evi- d e n c e d by cells s h o w i n g au to ly t ic changes , cyst ic space s wi th in the t umor , cyst ic s p a c e s s epa ra t i ng t u m o r i s lands f rom the i r s u r r o u n d i n g s t roma, 35 a n d the p r e s e n c e of a m y l o i d depos i t s at the m a r - gins of t u m o r lobules a n d in the s t roma . 36 Amylo id depos i t s are f o r m e d f rom a p o p t o t i c t u m o r cells a n d u l t r a s t ruc tu ra l ly s h o w the p r e s e n c e of kera t in f i l aments tha t are f o u n d in the cells of basa l cell c ance r s if6

7 9

The f inding of a relat ively smal l cycl ing cell p o p - u la t ion at any given t ime is one r e a s o n for the rel- ative r e s i s t ance of large sol id t u m o r s to t r e a t m e n t wi th c h e m o t h e r a p e u t i c agen ts t ha t are cell-cycle or iented , s u c h as m e t h o t r e x a t e . TM as

Local invas ion of t i s sues o c c u r s by c o n t i g u o u s s p r e a d of t u m o r cells. The m e c h a n i s m of t u m o r invas ion is no t en t i re ly clear. T u m o r cells p r o b a b l y e x t e n d into s u r r o u n d i n g t i s sues b y d iges t ion of d e r m a l co l lagen via the ac t ion of col lagenase . Studies have s h o w n e n h a n c e d co l l agenase syn the - sis by d e r m a l f ibroblas ts in the s t r o m a s u r r o u n d - ing t u m o r lobules . U n d e r the in f luence of a cytok- ine de r ived f rom t u m o r cells, s t r om a l f ibroblas ts are s t i m u l a t e d to i nc rea se the i r syn thes i s of colla- genase , a7 Col lagenase digests co l lagen fibers creat - ing a p a t h for t u m o r sp read . T h e t u m o r - d e r i v e d cytokine a p p e a r s to be an in te r l euk in l - l i k e fac tor tha t acts at a p r e t r a n s l a t i o n a l level to s t imu la t e co l l agenase syn thes i s . 37' 38 T h u s basa l cell c ance r s a p p e a r to be at leas t pa r t l y c a p a b l e of m o d u l a t i n g the i r o w n invas iveness . T h e y also a p p e a r to be de- p e n d e n t on the i r s t r o m a for the i r abili ty to invade n e i g h b o r i n g t issues, s t r e n g t h e n i n g the h y p o t h e s i s of e p i d e r m a l - d e r m a l in te rac t ion , a9

A n o t h e r fac tor tha t m a y be of s ignif icance in lo- cal invas ion is f ibronect in . S tudies have s u g g e s t e d tha t f ibronect in , a g lycopro te in , m a y be e l a b o r a t e d by t u m o r cells. 4° It is k n o w n to p l ay a role in n o r m a l cel lular a t t a c h m e n t to the basa l l a m i n a a n d adja- cen t cells .41 it is t h o u g h t to p l a y an i m p o r t a n t role in cell migra t ion , e spec ia l ly in w o u n d heal ing. 42 It is poss ib le the re fo re t ha t the p r e s e n c e of f ib ronec t in a long the m a r g i n s of t u m o r lobules 4° m a y be re- l a ted to t u m o r cell m ig ra t i on a n d local invasive- hess .

Ul t ras t ruc tura l s tud ies of basa l cell c a r c i n o m a s have s h o w n the p r e s e n c e of act inl ike microf i la- m e n t s in t u m o r cells. 43 T h e s e f i l aments are espe- cially n u m e r o u s in cells at the p e r i p h e r y of the tu- m o r lobules . T h e y are also f o u n d in g rea te r n u m - bers in the cells of the aggress ive m o r p h e a f o r m a n d a d e n o i d t u m o r s . T h e s e m i c r o f i l a m e n t s m a y be e l e m e n t s r e s p o n s i b l e for cell motil i ty, a n d the i r p r e s e n c e in t u m o r cells sugges ts tha t t hey m a y be involved in t u m o r invas iveness . 4a

The biologic b e h a v i o r of a basa l cell c a n c e r m a y also be r e l a t ed to the hos t i m m u n e s ta tus a n d re- s p o n s e to t h e n e o p l a s m . Del lon et al. 44 f o u n d tha t a d e n s e d e r m a l i n f l a m m a t o r y infi l trate a n d n o r m a l or t r ans i en t ly d e p r e s s e d c i rcu la t ing T lymi3hocyte levels w e r e a s s o c i a t e d wi th smal l t u m o r s . The in- f l a m m a t o r y infi l trate w a s be l ieved to be a l imi t ing in f luence o n t u m o r g rowth . The c i rcu la t ing T lym- p h o c y t e level r e t u r n s to n o r m a l af ter the t u m o r is e rad ica ted . The ce l lu lar i n f l t r a t e is also a s s o c i a t e d wi th t u m o r regress ion . On the o t h e r hand , large or d e e p l y invasive t u m o r s u sua l ly do no t have a der-

real i m m u n o l o g i c r e s p o n s e a n d c i rcu la t ing T lym- p h o c y t e levels are s ignif icant ly l ow before as wel l as after exc is ion of the t u m o r . This sugges ts tha t the i m m u n e s t a tus p lays a role in d e t e r m i n i n g tu- m o r growth . Studies of c a r c i n o m a s of o t h e r o rg an s have also d e m o n s t r a t e d a posi t ive co r re la t ion be- t w e e n the dens i t y of the l y m p h o c y t i c inf i l t ra t ion of the t u m o r a n d the p r o g n o s i s for survival. The der - ma l cel lular infiltrate, w h e n p resen t , is c o m p o s e d m o s t l y of T l y m p h o c y t e s . A p p r o x i m a t e l y 50% to 60% of the T cells are h e l p e r T cells, a n d 30% are of the s u p p r e s s o r - c y t o t o x i c type. An a l te ra t ion in h e l p e r T cell n u m b e r s a c c o u n t s for the d i f fe rence b e t w e e n d e n s e a n d mi ld infiltrates. O t h e r cells p r e s e n t in the infil trate are L a n g e r h a n s cells, m a c - rophages , m a s t cells, a n d p l a s m a cells. A d e c r e a s e in the e x p r e s s i o n of [3z-mieroglobulin, HLA-I, a n d HLA-DR an t igens on t u m o r cells ha s b e e n d e m o n - s t ra ted. 4s E x p r e s s i o n of t he se an t igens is i m p o r - t an t for the associa t ive r ecogn i t ion of t u m o r ant i - gens by cy to toxie T cells a n d for the specif ic acti- va t ion of T h e l p e r cells. The re fo re it is d e b a t e d w h e t h e r the T cells are specif ical ly or nonspec i f i - cally ac t iva ted aga ins t t u m o r cells.

A def ic ient c e l l - m e d i a t e d i m m u n i t y has also b e e n d e m o n s t r a t e d in b lack pa t i en t s w h o deve lop basa l cell cancer . 46 A d e c r e a s e d b l a s togen ic re- s p o n s e of the p e r i p h e r a l b l o o d l y m p h o c y t e s of pa - t ients w i th mu l t i p l e basa l cell c ance r s has b e e n d o c u m e n t e d , 47 b u t w h e t h e r this is a c a u s e or a n effect of the mu l t i p l e t u m o r s is no t clear. All of t he se f indings c o n s i d e r e d t oge the r s e e m to indi- ca te an i m p o r t a n t role of the hos t i m m u n e s t a tus in the b io logy of basa l cell cancers .

A n o t h e r i m m u n o l o g i c m e c h a n i s m tha t influ- e n c e s t u m o r g r o w t h has b e e n d e m o n s t r a t e d b y an ima l e x p e r i m e n t s c o n d u c t e d by Kripke. 13 Basal cell c ance r s are s t rongly i m m u n o g e n i c . Basal cell c ance r s t r a n s p l a n t e d to m o u s e skin g r o w on ly in i m m u n o s u p p r e s s e d an imals . However , basa l cell c ance r s are able to g r o w in the skin of the hos t w i t h o u t be ing re jec ted . The hos t skin p e r m i t s g r o w t h of the t u m o r due to UVR-induced i m m u n o - s u p p r e s s i o n . UVR e x p o s u r e is k n o w n to s u p p r e s s con t ac t hype r sens i t i v i ty b y i n d u c t i o n of h a p t e n - specif ic s u p p r e s s o r cells, a n d the s a m e m e c h a - n i s m is be l ieved to be r e s p o n s i b l e for s u p p r e s s i o n of t u m o r r e j ec t ion a n d a l lowing t u m o r p e r s i s t e n c e a n d g rowth . 13

Metas ta t ic s p r e a d of basa l cell c a n c e r is an ex- t r e m e l y rare event , c o n s i s t e n t wi th i t , re lat ively nonaggre s s ive na tu re . The r e p o r t e d i n c i d e n c e of me ta s t a t i c d i sease var ies f r o m 0.55% to 0.028%, de- p e n d i n g on the p o p u l a t i o n surveyed . 4s The aver- age interval b e t w e e n the a p p e a r a n c e of the pr i - m a r y t u m o r a n d the first sign of m e t a s t a s i s is 10 years . However , o n c e m e t a s t a s i s occu r s it fol lows a very m a l i g n a n t course , wi th 50% of pa t i en t s dy ing

80 Curr Probl Dermatol, May/June 1990

of the disease in on ly 8 m on ths . 49 One review esti- m a t e d a 5-year survival rate of 12°7o .48

A p p e a r a n c e of metas tases has been t h o u g h t to result f rom ei ther an al terat ion in hos t res is tance or the biologic behavior of the tumor . A deter iora- t ion in the i m m u n o l o g i c ba lance b e t w e e n the hos t and the t u m o r has been sugges ted as a cause 4s'5° for metastasis , bu t s u c h factors are no t always ap- pa r en t in pa t ien ts w h o develop d i s semina ted dis- easeff I The p r e s e n c e of s q u a m o u s features is con- s idered to be an i m p o r t a n t factor in metas ta t ic tu- mors by s o m e . 4 s ' 5 1 S q u a m o u s his tologic features p r e s u m a b l y alter the biologic o u t c o m e by making a t u m o r behave m o r e like a s q u a m o u s cell carci- noma , w h i c h is m o r e p r o n e to metastas is . The rea- son for the rare o c c u r r e n c e of metas ta t ic basal cell c a r c i n o m a despi te the c o m m o n o c c u r r e n c e of this t u m o r is obscure . One hypo thes i s is tha t the "stro- mal d e p e n d e n c e " of the t u m o r (see later) is an im- po r t an t factor a n d that basal cell cancers can me- tastasize on ly w h e n a c c o m p a n i e d by their native connect ive tissue, w h i c h is essential for their sur- vival,S2, 53 or w h e n they develop "stromal i n d e p e n - dence." Thus a c o m b i n a t i o n of factors m a y be nec- essary before a basal cell c a r c i n o m a metas tas izes .

The c o n c e p t tha t basal cell cancers are s t romal d e p e n d e n t for their g rowth has received a g o o d deal of a t ten t ion a n d is general ly accepted . "~4 This c o n c e p t p r o p o s e s that basal cell c a rc inomas are inextr icably d e p e n d e n t on u n d e f i n e d e lements wi th in the s t roma (i.e., the connect ive tissue) of the t u m o r for their survival. This idea arose f rom the f inding that basal cell cancers t r ansp lan t ed to m u - rine skin d id no t survive, a n d the r eason for this was t h o u g h t to be that the t r ansp l an t ed c a n c e r cou ld not survive unless unde r ly ing dermis was t r an s p l an t ed wi th it. However, recen t a t t empts at t u m o r t r ansp lan ta t ion to a thymic mice have been m o r e successful , chal lenging this hypothes i s . 55' 26 The ability to t r ansp lan t basal cell cancers , in fact, appea r s to d e p e n d on i m m u n o l o g i c to le rance of the t r ansp l an t ed t u m o r by the hos t animal. How- ever, o ther m o r e com plex de rma l -ep ide rma l inter- ac t ions m a y o c c u r . 5 7

CLINICAL F E A T U R E S

The typical pa t i en t wi th a basal cell c ance r is el- derly, white, wi th type 1 of" 2 skin, a n d with signif- icant p h o t o d a m a g e . The t u m o r is likely to be lo- ca ted on a s u n - e x p o s e d par t of the skin. One th i rd of all basal cell cancers are loca ted on non - sun -ex - p o s e d skin. The clinical a p p e a r a n c e of the t u m o r itself m a y be one of five types: noduloulcera t ive , p igmented , m o r p h e a f o r m , superficial, and fibroep- i the l ioma of Pinkus. The nodulou lcera t ive type is the m o s t c o m m o n (Fig 2). The t u m o r appea r s as a

FIG 2. Nodular basal cell carcinoma with typical pearly appearance and surface telangiectasia.

small papu l e or n o d u l e wi th an e~Nthematous or pear ly appea rance . The pear ly or opa lescen t qual- ity is some t imes a p p a r e n t on ly on b l a n c h i n g the surface by apply ing pressure . Telangiectasias, a character is t ic feature, are often seen over the sur- face of the tumor . The surface of the t u m o r is s m o o t h and does no t typical ly exhibit scaling. W h e n a t u m o r is large or has b e e n p resen t for a long t ime the surface m a y be u lce ra ted a n d crusted. The clinical marg ins are usual ly well de- fined, bu t on occas ion can be difficult to apprec i - ate. An area of i ndu ra t ion m a y be palpable a r o u n d the tumor , indicative of infiltration of the sur- r o u n d i n g skin. Palpat ion of the skin a r o u n d the tu- m o r is therefore impor t an t to de tec t s u c h exten- sion a n d to define the limits of the t u m o r m o r e ac- curately. Occasionally, clinical regress ion of the tu- m o r m a y be evident as an area of clearing wi th in the tumor .

The p i g m e n t e d type is similar to the n o d u l a r type except that the nodu le is b r o w n or black (Fig 3), w h i c h m a y make it indis t inguishable f rom a me lanocy t i c lesion. The p i g m e n t a t i o n is of no o ther significance.

Mor,pheaform t u m o r s clinically resemble a le- s ion of m o r p h e a (localized sc leroderma) or a scar. The lesion is a whit ish, i n d u r a t e d scarlike de- p re s sed dermal p laque that lacks the typical ele- vated rol led b o r d e r and is usua l ly i l l-defined (Fig 4). This m o r p h o l o g y is less f requent ly e n c o u n t e r e d than the nodulou lcera t ive type. M o r p h e a l o r m tu-

Curr Probl Dermatol, May/June 1990 81

FIG 3. Pigmented basal cell cancer mimicking a melanocytic lesion.

m o r s are m a i n l y f o u n d on the h e a d a n d n e c k (97% in one study). 58 T h e y are m o r e of ten loca t ed on the n o s e 59 or cheeks , bu t m a y be e n c o u n t e r e d in o the r loca t ions as well.

Supel t fc ia l mu l t i c en t r i c basa l cell c a r c i n o m a s a p p e a r as d i sc re te e r y t h e m a t o u s , scaly p l a q u e s (Fig 5) a n d m a y be m i s t a k e n for les ions of e c z e m a - tous de rma t i t i s o r Bowen ' s d isease . T h e y are f o u n d wi th equa l f r e q u e n c y in s u n - e x p o s e d as well as s u n - p r o t e c t e d areas of the skin.

F ib roep i t he l i oma of P inkus p r e s e n t s as a soft, f lesh-colored, sessi le papu le , r e s e m b l i n g an acro- cho rdon , loca ted on the t runk.

Mul t ip le basal cell c ance r s m a y be f o u n d in pa- t ients wi th ch ron ic a r sen ic i sm, those w h o have re- ceived g r enz ray or x- ray t r e a t m e n t several yea r s previously , or in t h o s e w i th extensive so la r d a m - age. The total r ad i a t ion field s h o u l d be e x a m i n e d for add i t iona l ear ly t u m o r s w h e n a pa t i en t has a

FIG 5. Superficial basal cell cancer, which may be mistaken clinically for Bowen disease or eczematous dermatitis.

basal cell c a n c e r in an a rea p rev ious ly i rradiated wi th g r enz rays or x-rays.

In add i t ion to the typica l clinical p r e s e n t a t i o n s d e s c r i b e d above, basa l cell c ance r s m a y also o c c u r in o the r u n u s u a l s i tuat ions . T h e y rare ly o c c u r in chi ldren, a n d w h e n e n c o u n t e r e d in this age g r o u p s h o u l d ra ise the poss ib i l i ty of i nhe r i t ed d i so rde r s s u c h as x e r o d e r m a p i g m e n t o s u m . 6 T h e y have b e e n r e p o r t e d in b lack pa t i en t s 6° in s u n - e x p o s e d as well as s u n - p r o t e c t e d areas , a n d p r e s e n t as pig- m e n t e d les ions tha t are of ten clinically mi sd i ag - nosed .

Metas ta t ic basa l cell c a r c i n o m a is rare. M e n are twice as likely to have m e t a s t a t i c d i sease as w o m e n , a n d the m e d i a n age of the pa t i en t at the t ime of d e v e l o p i n g the p r i m a r y t u m o r is 45 y e a r s ( c o m p a r e d w i th the p e a k i n c i d e n c e of basa l cell c ance r s at 65 years) . Eighty-five p e r c e n t of les ions tha t m e t a s t a s i z e are l oca t ed on the h e a d a n d neck, 48 a n d are very large, neg l ec t ed or r e c u r r e n t t u m o r s . Metas ta t i c s p r e a d has b e e n t h o u g h t b y s o m e to be m o r e likely w i th the m e t a t y p i c a l t ype of basal cell c ance r s 4s' .~1 a n d p r i m a r y or r e c u r r e n t t u m o r s w i th p e r i n e u r a l a n d pe r iva scu l a r involve- m e n t Y The m a j o r rou te s of m e t a s t a s i s are lym- pha t i c a n d h e m a t o g e n o u s Y The m o s t f r equen t si tes for t u m o r s p r e a d are regional l y m p h nodes , fo l lowed by the lungs a n d bones . L y m p h n o d e s are involved in 70% of cases . Less f r equen t ly in- volved o rgans are the liver, kidney, sp leen, a n d brain. S u b c u t a n e o u s me ta s t a se s , 49 usua l ly d i s t an t f r o m the site of the p r imary , also occ t ~r.

FIG 4. Morpheaform basal cell cancer presenting as an indurated scar- like plaque rather than as a nodule. The presence of telangiecta- sias is helpful in raising the possibility of basal cell cancer.

HISTOLOGY

There are several d is t inc t h is tologic sub types . Sonle of t hese are i m p o r t a n t to r ecogn ize b e c a u s e the h is to logic p a t t e r n is indicat ive of the biologic behav io r a n d the t r ea tmen t . The types of clinical

82 Curr Probl Dermatol, May/June 1990

s ignif icance are the m a c r o n o d u l a r , m i c r o n o d u l a r , m o r p h e a f o r m , me ta typ ica l , adeno id , a n d superf i - cial. T h e s e are d e s c r i b e d hereaf ter .

The m o s t c o m m o n var ie ty of basa l cell c a n c e r is the n o d u l a r type. Mic roscop ica l ly it d e m o n s t r a t e s a sol id or m a c r o n o d u l a r p a t t e r n (Fig 6). Histologi- cally, t u m o r lobu les arise f r o m the overlying epi- dermis , or less c o m m o n l y f rom a ha i r follicle, a n d invade the a d j a c e n t dermis . T h e y are c o m p o s e d of large basoph i l i c cells wi th a large, oval nuc l eus . The cells have a h igh n u c l e o c y t o p l a s m i c ratio. The t u m o r cells are s o m e t i m e s re fe r red to as "basal- i o m a cells." At the p e r i p h e r y of the t u m o r lobules the cells have a p a l l i s a d e d a r r a n g e m e n t , a n d cen- tral to the p e r i p h e r a l r im of cells they are h a p h a z - a rd ly a r r a n g e d w i t h lack of polar i ty . In the dermis , para l le l co l lagen b u n d l e s are a r r a n g e d a r o u n d the t u m o r lobules a n d m a y s h o w s o m e m u c i n o u s changes . Cystic s p a c e s are of ten s een b e t w e e n the t u m o r lobules a n d the s u r r o u n d i n g s t r o m a a n d are charac te r i s t ic . T h e s e s p a c e s are genera l ly be- l ieved to be ar t i factual , 1 having b e e n c a u s e d b y shr inkage of the s t r o m a away f r o m the t u m o r dur - ing fixation, b u t are also t h o u g h t b y s o m e to be c r ea t ed b y nec ros i s of t u m o r cells in the p e r i p h - eral cell layer of the t u m o r . 3s Ind iv idua l nec ro t i c t u m o r cells are ev iden t as dyskera to t i c cells s h o w - ing cel lular degene ra t ion . Anlyloid bod i e s are f o r m e d f rom apo to t i c dyskera to t i c cells a n d are s een wi th in a n d b e n e a t h the t umor . 36 Growth of the t u m o r m a y resu l t in d e e p e r d e r m a l invas ion as well as u l ce ra t ion of the surface.

W h e n the t u m o r m a s s e s arise f r o m mu l t i p l e po in t s off the e p i d e r m i s a n d r e m a i n c o n f i n e d to the pap i l l a ry de rmis , the t u m o r is a superf ic ia l mu l t i cen t r i c t ype of basa l cell c a n c e r (Fig 7).

Focal d i f ferent ia t ion of the t u m o r cells t o w a r d

FIG 7. Superficial multicentric basal cell cancer, with tumor Iobules aris- ing from separate foci off the epidermis and lying within the papil- lary dermis (original magnification x90).

a p p e n d a g e a l s t r u c t u r e s m a y be seen, c o n s i s t e n t wi th the p lu r ipo t en t i a l na tu r e of the cell of origin of basa l cell cancers . D e p e n d i n g on the pa r t i cu l a r d i rec t ion of differentiat ion, basa l cell c ance r s can be classif ied into sub types . T h u s the kera to t ic type of basa l cell c a r c i n o m a s h o w s di f ferent ia t ion to- w a r d ha i r follicles, a n d the a d e n o i d type t o w a r d apoc r ine or eccr ine g l ands (Fig 8). T h e cyst ic type of basa l cell c a r c i n o m a is t h o u g h t to have seba- ceous different iat ion, 1 bu t u l t r a s t r uc tu r a l s tud ies 61 of the cells of s u c h t u m o r s have no t r evea led a_ny s e b a c e o u s charac ter i s t ics . T h e t u m o r cells d id s h o w degenera t ive changes , a n d there fore cyst ic space s in t u m o r s ewe t h o u g h t to be a sign of t u m o r d e g e n e r a t i o n r a t h e r t h a n s e b a c e o u s differentia- t ion. Some t u m o r s reveal focal s q u a m o u s differen-

FIG 6. Macronodular or solid histologic type of basal cell cancer. Note the epidermal origin of the tumor, which is composed of a large, solid Iobule in the dermis; pallisading of the peripheral layer of cells; and the presence of characteristic cystic spaces between the tu- mor and the surrounding dermis (original magnification x30).

Curr Probl Dermatol, May/June 1990

FIG 8. Adenoid type of basal cell cancer in which the tumor Iobules sim- ulate the appearance of glandular structures (original magnifica- tion x 130).

83

FIG 9. Metatypical basal cell carcinoma. A tumor Iobule that shows the typical appearance of a solid BCCA on the left, with transition to typical squamous features, including pearl formation and keratini- zation, on the right (original magnification x65).

tiation, wi th typical pear l format ion, and are clas- sified as the meta typ ica l type (Fig 9). Of signifi- cance is the fact that a d e n o i d t u m o r s are k n o w n to invade deeply, a n d meta typ ica l t u m o r s are asso- ciated wi th significant t issue invasion as well.

M o r p h e a l o r m t u m o r s (Fig 10) are def ined as those wi th a sclerotic s t roma infiltrated by small irregular t u m o r is lands that m a y be only two or three cells thick. This is some t imes no t differenti- a ted from the infiltrative type, w h i c h shows infil- t rat ing t u m o r s t rands a n d is lands bu t is no t neces- sarily assoc ia ted wi th a sclerotic s t roma. Other his- tologic sub types of basal ceil cance r s m a y have ar- eas with an infiltrative pat tern .

The m i c r o n o d u l a r type (Fig 11) of basal cell can- cer is c o m p o s e d of several small t u m o r lobules, in

FIG 10. Morpheaform basal cell cancer with small infiltrating tumor islands within a sclerotic stroma containing dense collagen bundles (orig- inal magnification x90).

84

FIG 11. Micronodular BCCA showing small tumor Iobules. Compare with the macronodular type (see Fig 6), which has larger Iobules (origi- nal magnification x 130).

cont ras t to the larger t u m o r lobules assoc ia ted wi th a m a c r o n o d u l a r or solid type, and is associ- a ted wi th an aggressive g rowth pat tern . Other vari- at ions in the shape of the t u m o r lobules m a y be seen. An angu la r or spiky conf igura t ion of the is- lands (Fig 12) is assoc ia ted wi th a m o r e aggressive biologic behavior. Absence of a wel l - formed pe-

FIG 12. Infiltrative basal cell cancer with small "spiky" tumor islands invad- ing the dermis, distinguished from the morpheaform type by lack of a sclerotic stroma (original magnification x130).

Curr Probl Dermatol, May/June 1990

r iphera l pa l i s ade a p p e a r s to cor re la te wi th m o r e aggressive biologic behavior . 62 Meta typ ica l a n d m o r p h e a f o r m t u m o r s are a s soc i a t ed w i th an ag- gressive a n d infiltrative g rowt h pa t t e rn , of ten ex- t e n d i n g s ignif icant ly b e y o n d the clinical marg ins , 5~ a n d call for m o r e c o m p l e t e t h e r a p e u t i c m e a s u r e s , tha t is, M o h s su rge ry (see later) to e n s u r e total ex- t i rpat ion. Often one or m o r e of the aforementioned his tologic p a t t e r n s o c c u r t o g e t h e r in the s a m e tu- mor , a n d the biologic behavior" of the t u m o r s h o u l d t h e n be r e g a r d e d as tha t r ep re sen t a t i ve of the m o r e aggress ive type.

A mi ld i n f l a m m a t o r y r e s p o n s e in the s t r o m a is c o m m o n , bu t var ies in extent . The i n f l a m m a t o r y infil trate is p r i m a r i l y l ymphocy t i c . The p r e d o m i - n a n t cell type is the h e l p e r T cell, c o m p r i s i n g 50% to 60% of the l y m p h o c y t e s . S u p p r e s s o r - c y t o t o x i c l y m p h o c y t e s a c c o u n t for a p p r o x i m a t e l y 30% of the l y m p h o c y t e s . 35 Also p r e s e n t are m a c r o p h a g e s , p l a s m a cells, a n d m a s t cells. The la rger the t u m o r the less p r o n o u n c e d the ce l lu lar infi l trate a r o u n d the t u m o r . 44

In the rare c i r c u m s t a n c e of me ta s t a se s , m e t a - static t u m o r n o d u l e s are s imi lar in h is to logic ap- p e a r a n c e to the p r i m a r y t u m o r 4a f rom w h i c h t hey arise.

Ul t ras t ructura l ly , in an und i f f e r en t i a t ed basa l cell c a n c e r two dis t inc t p o p u l a t i o n s of t m n o r cells can be di f ferent ia ted. 61 The p r e d o m i n a n t cell t ype has a large r o u n d nuc leus . T h e second , less c o m - m o n type of cell h a s a dark, g r anu l a r c y t o p l a s m a n d an iN'egular nuc leus . Both types of t u m o r cells exhibi t d e s m o s o m e s a n d h e m i d e s m o s o m e s , b u t differ f rom n o r m a l e p i d e r m a l basa l cells by hav ing a m a r k e d l y d e c r e a s e d n u m b e r of d e s m o s o m e s 6~ a n d h e m i d e s m o s o m e s . The re is an i n c r e a s e d n u m b e r of act inl ike mic ro f i l amen t s , w h i c h are ra re ly f o u n d in n o r m a l basa l kera t inocy tes . 43 T h e m o r e infiltrative types of basa l cell c a n c e r have m o r e act inl ike m i c ro f i l am en t s t h a n the less infil- trative types . T u m o r cells are s u r r o u n d e d in m o s t a reas by an u l t r a s t ruc tu ra l ly in tac t b a s a l l amina . Adjacen t to a reas w h e r e a basa l l a m i n a is a b s e n t focal col lagen d e g r a d a t i o n is seen. In a reas of d e e p d e r m a l inf i l t rat ion extensive col lagen d i s r u p t i o n is seen, wi th loss of large col lagen fibers. 43

I m m u n o f l u o r e s c e n c e s tud ies have s h o w n a spe- cific defect in the bu l lous p e m p h i g o i d an t igen in the basa l l a m i n a of these t u m o r s . O the r c o m p o - n e n t s of the b a s e m e n t m e m b r a n e are p r e sen t , as in n o r m a l b a s e m e n t m e m b r a n e . The a b s e n c e of the bu l lous p e m p h i g o i d an t igen has b e e n t h o u g h t to be re la ted to the lack of d i f ferent ia t ion of the tu- m o r cells. 63 (The an t igen m a y be n e c e s s a r y for m a t u r a t i o n of basa l cells, or its a b s e n c e m a y be re- l a ted to the inabi l i ty of the t u m o r cells to syn the - size it.)

DIAGNOSIS

Histologic con f i rma t ion s h o u l d be o b t a i n e d be- fore ins t i tu t ing definit ive t he rapy . Shave b i o p s y usua l ly p rov ides an a d e q u a t e s p e c i m e n a n d of ten heals w i th a cosmet i ca l ly a c c e p t a b l e scar. D e e p e r biopsy, w h i c h c rea tes a m o r e s ignif icant scar, c an be avoided, espec ia l ly if the les ion p roves to be his tological ly benign . Not iceab le scars f rom b i o p s y or t h e r a p y of b e n i g n les ions are m o r e difficult for pa t i en t s to justify a n d a c c e p t t h a n are scars resul t - ing f r o m the m a n a g e m e n t of m a l i g n a n t les ions. However , p u n c h b i o p s y is n e c e s s a r y for d iagnos i s of m o r p h e a f o r m a n d r e c u r r e n t t u m o r s , b e c a u s e the deeper" p a t h o l o g y in these m a y be m i s s e d wi th a shave b iopsy . Bes ides con f i rming the diagnosis , b i o p s y also ident if ies the h is to logic type of basa l cell cancer , a l lowing a p p r o p r i a t e se lec t ion of ther - a p y for t u m o r s w i th aggress ive m o r p h o l o g y . O the r ent i t ies tha t en t e r the differential d iagnos is in- c lude d e s m o p l a s t i c t r i c h o e p i t h e l i o m a a n d occa- s ional ly s q u a m o u s cell c a r c i n o m a z or m ic rocys t i c adnexa l c a r c i n o m a .

THERAPY

The goal of t rea t ing basa l cell c a n c e r s is c o m - p le te e r ad i ca t ion of t u m o r . Six m e t h o d s of t reat- m e n t are c o m m o n l y used: cu re t t age a n d elec- t rodes icca t ion , excis ional surgery, r ad io the rapy , c ryosurgery , top ica l c h e m o t h e r a p y ( a n d M o h s mi- c rog raph i c surgery . In addi t ion , the u se of o t h e r less e s t ab l i shed m e t h o d s s u c h as i m m u n o t h e r - a p y w i th in te r fe ron 64' 65 a n d d i n i t r o c h l o r o b e n z e n e ( D N C B ) 66 has also b e e n r epo r t ed . The re t ino ids 67 have b e e n u s e d for the t r e a t m e n t of mu l t i p l e basa l cell c a n c e r s resu l t ing f rom s u n exposure , 6s basa l cell nevus s y n d r o m e , 6s' 69 a n d x e r o d e r m a p i g m e n - t o s u m . TM Of these op t ions , the t r e a t m e n t se lec ted d e p e n d s on the pa r t i cu l a r cha rac te r i s t i c s of the t u m o r .

Curettage and electrodesiccation (C&E) is the m e t h o d m o s t c o m m o n l y u s e d b y de rmato log i s t s . The t e c h n i q u e relies on the d i f fe rence in cons is - t ency b e t w e e n the t u m o r a n d the s u r r o u n d i n g n o r m a l skin. Because t u m o r t i s sue is sof ter t h a n n o r m a l skin w h e n s c r a p e d wi th a curet te , t u m o r ex tens ions b e y o n d the clinically visible m a r g i n s can of ten be def ined. The p r o c e d u r e does n o t de- p e n d o n visual def in i t ion of t u m o r marg ins . Curet - tage is fo l lowed by e l ec t rodes i cca t i on to a s su re de- s t ruc t i on of any res idua l t u m o r cells, a n d this se- q u e n c e is r e p e a t e d th ree t imes to a s su re c o m p l e t e t u m o r e rad ica t ion . 71 C&E is a n effective t e c h n i q u e for n o d u l a r t u m o r s w i th a sol id h is to logic p a t t e r n tha t are I c m or less in d iamete r , of less t h a n 2 yea r s ' dura t ion , a n d are l oca t ed o n flat sur faces

Curr Probl Dermatol, May/June 1990 85

s u c h as the fo rehead , cheek, o r back. W h e n p r o p - er ly p e r f o r m e d fox- t he se s i tua t ions C&E yie lds cu re ra tes of a p p r o x i m a t e l y 95%.7t It is no t a reli- able m e t h o d for t u m o r s l oca t ed o n the t ip of the nose , the nasa l alae, the lower pa r t of the d o r s u m of the nose , the naso lab ia l folds, a n d the m e d i a l c an thus , rl Because it rel ies on the differential be- t w e e n the c o n s i s t e n c y of the t u m o r a n d n o r m a l skin, it is no t useful for m o r p h e a f o r m or r e c u r r e n t t u m o r s tha t are sc lerot ic a n d firm.

The t e c h n i q u e is s imple , e a sy to lemln, a n d quick. Pos topera t ive ca3-e is s imple , a n d w o u n d s usua l ly hea l wi th g o o d cosn le t i c resul ts .

E x c i s i o n a l s u r g e r y , r ad i o t he r apy , a n d c ryosu r - gery rely on visual def in i t ion of t u m o r marg ins . The i n a c c u r a c y of de l inea t ion of t u m o r m a r g i n s by clinical e x a m i n a t i o n has b e e n d o c u m e n t e d . 32'7z Therefore , to achieve c o m p l e t e e r ad i ca t i on of the t u m o r a m a r g i n of cl inically n o r m a l skin m u s t be i n c l u d e d b e y o n d the visible m a r g i n s of the t u m o r .

Wolf a n d Zitelli a2 r e c o m m e n d excis ion of a 4 m m marg in a r o u n d the a p p r e c i a b l e t u m o r l imits to assure c o m p l e t e surgical r e m o v a l in m o r e t h a n 95% of all p r i m a r y basa l cell c a n c e r s (not h is to log- ically subdivided) w i th cl inically we l l -de f ined bor- ders m e a s u r i n g less t h a n 2 cm. In fol lowing these r e c o m m e n d a t i o n s , however , a s ignif icant a m o u n t of n o r m a l skin will be sacrif iced. This is no t a lways feasible n o r des i rab le in es the t ica l ly i m p o r - t an t a reas for w h i c h a n a l ternat ive a p p r o a c h , for example , M o h s s u rge ry (see later), is se lec ted . Likewise, t u m o r s w i th aggressive h i s to logy s h o u l d be s e p a r a t e d a n d t r e a t e d w i t h M o h s su rge ry for the benef i t of t i s sue spar ing . However , if the facil- ities for M o h s su rge ry are no t available the above gu ide l ines for surgical m a r g i n s are useful . R e c o m - m e n d a t i o n s for surgica l m a r g i n s for larger t u m o r s , i l l -def ined t um or s , a n d t u m o r s w i th aggressive h i s to logy c a n n o t be rel iably m a d e , a n d conse - quen t l y t he se t u m o r s car ry a h i ghe r r e c u r r e n c e ra te fol lowing excis ional surgery. Such t u m o r s are the re fo re be s t m a n a g e d by M o h s m i c r o g r a p h i c surgery.

T u m o r s tha t can benef i t f r o m C&E can also be excised. T h e advan t ages of exc is ion a n d p r i m a r y r epa i r are a s h o r t e n e d hea l ing t ime, usua l ly excel- len t c o s m e t i c resul ts , a n d the abil i ty to ob ta in a s p e c i m e n for eva lua t ion of its m a r g i n s to e n s u r e tha t excis ion was c o m p l e t e . T h e d i s advan t ages are tha t it is m o r e t ime c o n s u m i n g to pe r fo rm, sacri- fices n o r m a l t i s sue in achiev ing w o u n d closure , a n d wi th conven t iona l sec t ion ing m e t h o d s u s e d b y m o s t p a t h o l o g y l abora to r i e s on ly a f rac t ion of the cut m a r g i n s are e x a m i n e d Y 3 If the m a r g i n s of the exc ised s p e c i m e n are "positive" for t u m o r the les ion s h o u l d be reexc ised . A 5-year p r o s p e c t i v e s t u d y of i n c o m p l e t e l y exc i sed basa l cell c ance r s

r evea led r e c u r r e n c e in 93% of cases tha t his tologi- cally s h o w e d p o o r p e r i p h e r a l pa l i sad ing in m o r e t h a n 75% of the t u m o r 9 Repor t s of a l ow recur - r e n c e ra te of i n c o m p l e t e l y exc i sed basa l cell can- cers m u s t be i n t e r p r e t e d caut ious ly . The re is con- s iderab le var ia t ion a m o n g pa tho log i s t s of the defi- n i t ion of pos i t ive a n d negat ive t u m o r marg ins . 74 Consequen t ly , it is imposs ib l e to k n o w w h e t h e r the so-ca l led i n c o m p l e t e l y exc i sed t u m o r s w e r e in real i ty c o m p l e t e l y or i n c o m p l e t e l y excised. An- o t h e r fac tor likely to con t r i bu t e to a falsely l ow re- c u r r e n c e ra te is the fact tha t t hese i n c o m p l e t e l y exc i sed t u m o r s are no t fo l lowed long e n o u g h to de t ec t all r e c u r r e n c e s , w h i c h m a y o c c u r as late as 10 yea r s af ter the initial excis ion. 75 W h e t h e r a le- s ion is t r e a t e d by C&E or excis ion is d e t e r m i n e d by c o n s i d e r a t i o n of the advan t ages a n d d i sadvan- tages of e a c h m e t h o d a n d the n e e d s of the par t ic - u la r pa t ien t .

Cure ra tes fox" t u m o r s t r e a t e d wi th excis ion are d e t e r m i n e d b y w h e t h e r a t u m o r is p r i m a r y or re- cur ren t , the loca t ion of the t umor , its size, a n d his- tology. 7z W h e n p r o p e r l y se lec ted , cu re ra tes of 95% can be achieved. T u m o r s tha t have r ecu r red , have an aggressive his to logic m o r p h o l o g y , are la rger t h a n 2 c m in d iamete r , are i l l-defined, have b e e n p r e s e n t for a long t ime, or are l oca t ed in h igh- r i sk a reas (see later) c a n be e x p e c t e d to have h ig h e r re- c u r r e n c e ra tes fol lowing excis ion a n d are bes t t r e a t ed wi th M o h s m i c r o g r a p h i c surgery.

Radia t ion t h e r a p y is genera l ly r e se rved for i nop- erable t umor s , t u m o r s in pa t i en t s w h o will no t tol- e ra te a l ternat ive t h e r a p y s u c h as excis ional sur - gery, or e lder ly pa t ien t s . The l imi ted use of th is m e t h o d reflects the c o n c e r n rega rd ing the late de- v e l o p m e n t of r a d i a t i o n - i n d u c e d skin c a n c e r as well as r ad ia t ion dermat i t i s . Younge r pa t i en t s w h o are e x p e c t e d to live long e n o u g h to deve lop t he se c o m p l i c a t i o n s are the re fo re t r e a t ed wi th a l t e rna- tive m e t h o d s . R e p o r t e d 5-year cu re ra tes are 93% to 95%,76' 77 a n d 10-year cu re ra tes are in the r ange of 88% to 90% .76

Cryosu rge ry is p e r f o r m e d u n d e r local a n e s t h e - sia, a n d requ i res spec ia l e q u i p m e n t a n d t r a in ing for its rel iable u se in the t r e a t m e n t of basa l cell cancers . 77 It is t h o u g h t to be espec ia l ly useful for t u m o r s of the ea r b e c a u s e it spa re s the u n d e r l y i n g cart i lage f rom damage , a n d for m e d i a l c an th a l tu- m o r s b e c a u s e it spa re s the lacr imal d u c t as it de s t roys t u m o r in its vicinity. 77 A 5-year cu re ra te of 96% to 97% h a s b e e n r e p o r t e d for s e l ec t ed t u m o r s . 77 Nodu lou lee ra t ive t u m o r s la rger t h a n 3 c m in d iamete r , t u m o r s tha t have r e c u r r e d af ter excision, m o r p h e a f o r m t u m o r s , t hose l o ca t ed o n the nasa l alae, naso lab ia l folds, a n d p o s t a u r i c u l a r sulcus , a n d t u m o r s f ixed to u n d e r l y i n g cart i lage or b o n e are c o n s i d e r e d con t r a ind i ca t i ons to c ryosu r -

86 Curr Probl Dermatol, May/June 1990

because of the m u c h h igher r e c u r r e n c e rate asso- c ia ted wi th t r e a tmen t of s u c h tumors . 77

Topical c h e m o t h e r a p y wi th 5-FU has b e e n re- p o r t e d to be effective for b iopsy -p roven superficial basal cell cancers . It requires appl ica t ion of a 5% o i n t m e n t of 5-FU to the lesion for 4 to 6 weeks to achieve an in f l ammato ry response , w h i c h is fol- l owed by hea l ing over the next 2 to 3 weeks. Topi- cal 5-FU s h o u l d be u s e d wi th cau t ion and on ly for small superficial basal cell cancers . 75 There is no role for topical c h e m o t h e r a p y for any o the r basal cell cancers .

Mohs mic rog raph i c surgery, first desc r ibed in 1936 by F rede r i ck Mohs, TM does not rely on defini- t ion of t u m o r marg ins pr ior to t rea tment . The t e chn ique involves excision of a disk of skin that inc ludes the definable t u m o r a n d a 2 m m marg in of s u r r o u n d i n g skin. The edges of the s p e c i m e n are color c o d e d wi th dyes. The s p e c i m e n is t h e n laid flat so tha t its lateral edges are in the same p lane as its deep margin, a n d hor izon ta l f rozen sect ions are ob t a ined f rom the unde r su r f ace of the spec imen. A single hor izon ta l sec t ion thus allows examina t ion of all lateral and deep marg ins of the spec imen. Any res idual loci of t u m o r that are de- t ec ted by m i c r o s c o p i c examina t ion are local ized in the spec imen, a n d co r r e spond ing ly in the w o u n d , wi th respec t to the co lo r - coded marg ins and then selectively reexcised. The who le p roces s is re- p e a t e d unti l m i c r o s c o p i c examina t ion fails to re- veal the p r e s e n c e of tur ror . This m e t h o d thus al- lows selective a n d comple te excision of tumor - in - volved skin u n d e r m ic ro scop i c gu idance , wi th a marg in of no m o r e than 2 m m. The resul tant de- fect is t h e n repa i red wi th the usua l recons t ruc t ive t echn iques w i t h o u t the fear of any res idual tumor . The overall 5-year cure rates are 95% to 99% and are the best obta inable wi th any t echn ique . The key difference b e t w e e n Mohs surgery and rou t ine excisional surgery is the m e t h o d of p roces s ing the spec imen, wi th hor izon ta l sec t ioning for Mohs surgery. Mohs surgery pe rmi t s examina t ion of 100% of the marg ins of the spec imen, whe rea s wi th rou t ine p roces s ing d o n e in m o s t p a t h o l o g y laborator ies on ly a fract ion of the s p e c i m e n mar- gins are evaluated. TM Mohs surgery is p e r f o r m e d on an ou tpa t i en t basis wi th local anes thes ia a n d requires a t echn ic i an special ly t ra ined in ob ta in ing hor izon ta l f rozen sections. T h r o u g h a collaborative a r r angemen t wi th dermatologis t s t r a ined to per- form Mohs surgery, otola1~lgologis ts and plast ic su rgeons have been able to offer their pa t ien ts wi th c u t a n e o u s cancers the h ighes t cure rates. The in terdisc ip l inary a p p r o a c h has led to bet ter cure rates for t u m o r s t reated by any of the afore- m e n t i o n e d specialties.

Mohs surgel~y is reserved, wi th s o m e except ions ,

for basal cell cance r s that m e e t one ' of the follow- ing criteria:

1. Locat ion: Lesions loca ted in aesthet ical ly im- po r t an t areas w h e r e comple t e t u m o r excision m u s t be ach ieved wi th min ima l t issue loss. Such areas inc lude the eyelids a n d the canthi , the nasal tip a n d alae, and naso]abial folds. Other areas of the face, s u c h as the lips, cheek, or forehead, in y o u n g cosmet ica l ly c o n s c i o u s pa t ien ts s h o u l d re- ceive the same cons ide ra t ion a n d m a y also be t rea ted wi th this t echnique . T u m o r s in cer tain o ther locations, s u c h as the scalp, temple, a n d pos t au r i cu la r sulcus, are k n o w n to have significant subclinical ex tens ion along fascial p lanes and are c o n s i d e r e d by s o m e author i t ies to be ind ica t ions for Mohs surgery.

2. Indis t inc t margins : T u m o r s wi th indis t inct marg ins are not amenab le to t r ea tment wi th tech- n iques that require adequa t e defini t ion of t u m o r edges. They are best t rea ted wi th Mohs surgery to ensure curative t rea tment , because Mobs surgery does not rely on visible margins .

3. Recur rence : Recur ren t t u m o r s are difficult to define in extent and therefore are difficult to cure with o the r m e t h o d s .

4. Size: T u m o r s larger t han 2 cm in diameter" lo- ca ted on the face or l a rge r t h a n 4 cm loca ted on o ther par ts of the body.

5. Aggressive histology: Morphea fo rm, meta typi - cal, m ic ronodu la r , adenoid , a n d infiltrative types of basal cell cancers are biologically m o r e aggres- sive a n d often have cons iderab le extens ions be- y o n d visible margins .

In conc lus ion , there are no universal ly a c c e p t e d criteria or any r e c o m m e n d e d guidel ines fl 'om the Amer ican College of Mohs Micrograph ic Surgery and C u t a n e o u s Oncolos~y. The a f o r e m e n t i o n e d categories are those m o s t c o m m o n l y used, but are not exclusive of o the r criteria that m a y be in- c luded by others.

Large invasive or r ecu r ren t t u m o r s m a y d e m o n - strate per ineura l invasion, w h i c h s h o u l d be recog- n ized in order" to achieve c o m p l e t e resec t ion of tu- mor. Neglected t u m o r s that invade cranial or facial bones or the orbit require co l labora t ion wi th neu- rosurgeons , otola~yngologists, or oph tha lmolog i s t s .

Other special s i tuat ions have cal led for treat- m e n t by still other" m e t h o d s . The ret inoids, i sot re t inoin and etretinate, have been used for their sys temic effect in pa t ien ts wi th mul t ip le basal cell cancers f rom extensive solar exposure , NBCCS, or XP. Patients wi th NBCCS or XP m a y have a h u n d r e d or m o r e skin cancers at a time.

Curr Probl Dermatol, May/June 1990 87

Surgery or a n y of the o t h e r c o n v e n t i o n a l m e t h o d s for the m u l t i t u d e of t u m o r s is mu t i l a t i ng a n d of ten imprac t ica l . Ret inoids are k n o w n to p r o m o t e nor - m a l m a t u r a t i o n a n d d i f fe rent ia t ion of epi thel ia l tis- sues, a n d the i r u s e for the t r e a t m e n t a n d p r even - t ion of c a n c e r is the m o s t s ignif icant po ten t i a l ap- p l i ca t ion for t hese agents .

N u m e r o u s r epo r t s 6r-7°' 79 have n o w s h o w n tha t i so t re t ino in a n d e t re t ina te i n d u c e the clinical re- g ress ion of s o m e basa l cell c a n c e r s in p a t i e n t s wi th NBCCS or XP. T h e clinical r eg re s s ion h a s b e e n his to logical ly c o n f i r m e d in s o m e cases, b u t in o thers r e s idua l c a n c e r was found . The m o s t sig- n i f icant effect of t hese agents , however , ha s b e e n a d r a m a t i c d e c r e a s e in the ra te of d e v e l o p m e n t of n e w t u m o r s whi le t h e y were be ing a d m i n i s t e r e d . The p reven t ive effect was a p p a r e n t w i th in 3 m o n t h s of ini t ia t ing t r e a t m e n t . Once t r e a t m e n t w a s s t o p p e d the p reven t ive effect d i s a p p e a r e d , a n d wi th in 3 m o n t h s m u l t i p l e t u m o r s deve loped , ca t ch ing u p w i th or even e x c e e d i n g the p re t r ea t - m e n t t u m o r i n c i d e n c e rate. T h e p reven t ive effect h a s b e e n ach i eved b y a dose of i so t re t ino in as low as 0.4 mg/kg/day. 69 However , t a p e r i n g the d o s e to 0.2 mg/kg /day r e s u l t e d in loss of efficacy. T h u s l o n g - t e r m m a i n t e n a n c e t h e r a p y w i t h low dosage s e e m s to b e n e c e s s a r y for c o n t i n u e d effect iveness of the drug. In one r e p o r t 69 i so t r e t ino in has b e e n m a i n t a i n e d at a dose of 0.4 m g / k g / d a y for 3 y e a r s w i t h o u t u n u s u a l s ide effects. A l though re t ino ids do not a p p e a r to be of u se in cu r ing basa l cell cancers , t h e y are an i m p o r t a n t a d j u n c t in the m a n a g e m e n t of m u l t i p l e basa l cell cancers . T h e m e c h a n i s m of the i r p reven t ive effect ha s no t b e e n def ined, b u t the i r effect s e e m s to o c c u r at a la te s tage in the p r o c e s s of ca rc inogenes i s . T h e y ap- p e a r to m-rest the p r o g r e s s i o n of ear ly basa l cell cancers , p r e v e n t i n g the i r cl inical man i fe s t a t ion . T h e s e a r r e s t e d cancers , however , g r o w rap id ly o n c e the r e t ino id is w i t h d r a w n , as e v i d e n c e d by the i nc rea se in the i r i n c i d e n c e w i t h i n 3 m o n t h s . Genet ic counse l l ing s h o u l d be an i m p o r t a n t c o m - p o n e n t of the m a n a g e m e n t of XP or NBCC syn- d r o m e .

Metas ta t ic basa l cell c a r c i n o m a carr ies a very p o o r p rognos i s . Data o n the t r e a t m e n t of m e t a - s tat ic d i sease are scant . If m e t a s t a s e s are c o n f i n e d to regional l y m p h nodes , cu re c a n still be a ch i eved wi th surgical r e sec t ion a lone or c o m b i n e d wi th ra- d ia t ion the rapy . For m o r e w i d e s p r e a d d i sease t r e a t m e n t has b e e n a t t e m p t e d w i th a var ie ty of c h e m o t h e r a p e u t i c agents , i n c l u d i n g c y c l o p h o s - p h a m i d e , d o x o r u b i c i n m e c h l o r e t h a m i n e , 5-FU, m e t h o t r e x a t e , b l eomyc in , d a c t i n o m y c i n , v incr is- fine, a n d cisplat in . Cispla t in h a s b e e n r e p o r t e d to have p r o v i d e d two c o m p l e t e r e s p o n s e s a n d o t h e r par t ia l r e s p o n s e s s° in pa t i en t s wi th d i s tan t m e - tas tases . A n o t h e r r e p o r t sl d o c u m e n t s the succe s s

of a c o m b i n a t i o n of c i sp la t in a n d d o x o r u b i c i n in achieving c o m p l e t e r e m i s s i o n in 5 of 11 p a t i en t s w i th a c o m b i n a t i o n of c i sp la t in a n d doxorub ic in . The pa t i en t s in th is r epo r t h a d large or r e c u r r e n t t u m o r s , a n d one w h o d id no t r e s p o n d h a d p u h n o - n a r y m e t a s t a s e s . T h e pa t i en t s have b e e n t u m o r free w i t h o u t a n y m a i n t e n a n c e c h e m o t h e r a p y for p e r i o d s r ang ing f r o m 2 to 31 m o n t h s . C o m b i n a t i o n c h e m o t h e r a p y h a s b e e n u s e d as an a d j u n c t for the t r e a t m e n t of n o n r e s e c t a b l e basa l cell c a n c e r s as well. 82 C h e m o t h e r a p y wi th c isplat in , doxorub ic in , a n d c y c l o p h o s p h a m i d e w a s u s e d to r e d u c e the size of the t u m o r s so tha t t h e y w e r e a m e n a b l e to surgica l resec t ion .

P O S T T R E A T M E N T F O L L O W - U P

Adequa t e care of the p a t i e n t w h o has d e v e l o p e d a basa l cell c a n c e r ex t ends b e y o n d the t r e a t m e n t of the t u m o r itself. An integral c o m p o n e n t of c o m - p le te care i nc ludes a p p r o p r i a t e fo l low-up a n d p re - vent ive educa t ion . Fo l low-up is i m p o r t a n t no t on ly for d e t e c t i o n of r e c u r r e n c e s fol lowing i n c o m p l e t e t r e a t m e n t b u t also for the ear ly d e t e c t i o n a n d t imely t r e a t m e n t of a n y add i t iona l basa l cell carci- n o m a s tha t m a y develop . 8a' s4 A 5-year p r o s p e c t i v e s t u d y of p a t i e n t s t r e a t ed for basa l cell c a n c e r f o u n d tha t 22% of the p o p u l a t i o n s t u d i e d devel- o p e d a s e c o n d basa l cell c a n c e r by the e n d of the first year , 33% h a d d e v e l o p e d a s e c o n d basa l cell c a n c e r by the e n d of the s e c o n d year , a n d a total of 36% by the e n d of 5 years , s5 Of these s e c o n d basa l cell c ance r s on ly 27% h a d b e e n d e t e c t e d b y the pa t i en t a n d b r o u g h t to the p h y s i c i a n ' s a t t en - tion. Similar da t a w a s f o u n d in a s t u d y b y Berg- s t r e s se r a n d Halpr in . s6 A l though m o s t r e c u r r e n c e s f rom i n c o m p l e t e l y t r e a t ed basa l cell c a n c e r s are man i f e s t in the first 2 yea r s af ter t r e a t m e n t , t h e y m a y a p p e a r as late as 10 y e a r s af ter t r e a t m e n t d u e to the s low-growing na tu r e of the n e o p l a s m . This e m p h a s i z e s the n e e d for c o n t i n u e d regu la r follow- u p of pa t i en t s t r e a t ed for basa l cell cancer .

Fo l low-up at 6 - m o n t h intervals is r e c o m m e n d e d for the first 2 years , a n d a n n u a l fo l low-up is rec- o m m e n d e d indef in i te ly for pa t i en t s w h o have h a d two or m o r e basa l cell cancers , 83 given the c u r r e n t h igh i n c i d e n c e of skin cancers . Indef in i te follow- u p is just i f ied for pa t i en t s w h o have h a d any basa l cell c a n c e r as well.

P R E V E N T I O N

Public e d u c a t i o n is the on ly m e c h a n i s m of alert- ing the p o p u l a t i o n at risk of the h a z a r d s of expo- sure to ul t raviolet light. I m p o r t a n t a spec t s of e d u - ca t ion inc lude the u s e of s u n s c r e e n s a n d p r o t e c - tive clothing, avo idance of t a n n i n g pa r lo r s a n d

8 8 Curr Probl Dermatol, M a y / J u n e 1990

dayt ime p e r i o d s o f m a x i m u m risk, a n d early de tec - t ion of skin c a n c e r s by se l f - examinat ion .

S u n s c r e e n s are available in a variety of formula- t ions of different p h o t o p r o t e c t i v e efficacy. M o s t s u n s c r e e n s are effective against UVB; s o m e also prov ide s o m e p r o t e c t i o n f rom UVA. I n a s m u c h as c u t a n e o u s c a r c i n o g e n e s i s o c c u r s f rom c u m u l a t i v e s u n e x p o s u r e , s u n p r o t e c t i o n s h o u l d be in i t iated in c h i l d h o o d , e spec ia l l y in l ight c o m p l e x i o n e d pa- t ients w h o do n o t tan wel l . S u n s c r e e n s are effec- tive for b lock ing direct ly i n c i d e n t l ight as we l l as ref lected light. S u n s c r e e n s w i t h an SPF of 15 b lock 97% of i n c i d e n t UVB a n d are u s u a l l y r e c o m - m e n d e d u n l e s s t i lrther p r o t e c t i o n is n e c e s s a r y be- c a u s e of u n u s u a l photosens i t i v i ty . Protect ive c lo th- ing is an effective barrier a n d d e c r e a s e s the surface that n e e d s to be c o v e r e d w i t h a s u n s c r e e n , m a k i n g s u n s c r e e n u s e eas ier to c o m p l y wi th . Pat ients s h o u l d be e d u c a t e d regarding a v o i d a n c e of out - d o o r activit ies b e t w e e n 10:00 aM a n d 3:00 PM, the p e r i o d of m o s t i n t e n s e UVB e x p o s u r e .

T h e f inding of a n y s u s p e c t l e s i o n s o n se l f -exam- ina t ion by the pat i ent s h o u l d be c o n f i r m e d by a p h y s i c i a n tra ined in the early r e c o g n i t i o n a n d t r e a t m e n t of sk in c a n c e r s to m i n i m i z e the m o r b i d - ity resu l t ing f rom the ir t reatment . Prevent ion is ul- t imate ly the m o s t i m p o r t a n t too l in contro l l ing the increas ing i n c i d e n c e of skin cancers , i n c l u d i n g basal cell cancers , a n d m i n i m i z i n g the m o r b i d i t y f rom this c o m m o n mal ignancy .

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