CHAPTER 7

EPIDEMIOL GY OF SKIN CANCER

Ulrike Leitr, Thomas Eigentl r and Claus Garbe*

logy,fDivsnepartmc o Derma ,ygol tamreD UniverstyMdcal C, Eberhad ytisrevinU-slraK
of , n e g ni b u T .ynamreG
*Corespndig Author: Claus Garbe-Email: claus.garbe@m duni-tuebinge .d

Abstrac : Melanomd skinomela cr (NMSC) are now the most cntypes

of caner in white .snoitalupo Both tumor entis show an increasg incde
rate worldie but a stable or decrasing motly rate.
in caerNMSCsth mon den iks-etihw slaudiv dni witha ediwdlrow
increasg incde. NMSC is an increasg problem for healt care servic
worldiehc aus morbidty.gnfcThe risng incde rats ofNMSC
are probaly cused by a combinat f increasd xpou t ultravioe (UV) or
sun chagelit,odrnvs clthigsye, onvrad
ozne dplti,gcs an in some ca, imune .nois erp us An intesvUV
exposur in childo an adolescnw caustive for the devlopmntf basl
cel carinom (BC) wheras for the etiolgy of SC a chroni UV exposur in
the earli decas was acused.
is melanoth Cuscr apidlyneg wht ,snoitalupo
in the last 3 decas incde rates have risen up to 5-fold. In 208 melano
was on place 5 in women and on place 8 in men of the most comn solid tumor
entis in Germany. Th frequncy o its ocuren is closey asocited wh the
colrf thensiuv k,adthe lacihpargoe zone.iChags ctvudr
and exposur to sunlight during the past 50 years are an importan factor for the
ofincderasg .amonalem Mortaliyes f melanoshw stabilzon
in the USA, ustrali nd also in Europea cntis.I contras SC, melano
risk sem to be asocited with an interm exposur to sunlight. Prevntio
aim ndcpgsoerlahivu ,si ongaid whic resultd
in an ongi tred toward hin melano sic the last two decas. Howvr, th
impact of primay evnto masur on incde rats of melano is unlikey
to be sen in the near futre, rathe increasg incde rates to 40-5/1,
inhabts/yerould be expctd in Europe in the next decas.

Sunlight, Vitamn D and Skin Cancer, Second Edit on, edit by Jorg Reichrat.
14©20 Landes Bioscen ad Springe s eni uB+ecn i S Media.

120
 EPIDEMIOL GY OF SKIN CAN ER 12

NOITCUDORTNI
Melanoma and no melanoma skin can er (NMSC) are now the most com n types
of caner in hitew po ulations. Both tumor entis show na increasing inc de rate
world i e but a stable or decr asing mortali y rate.
NMSC is an increas g problem for health care servic s worldwi e whic cause
sign f ca t morbid ty. 1 NMSC consti u e more than one-third of al ancers in het US
with na estima ed inc de of over 60, case per year. Of thes, ap roximately
50, are basl elc car inoma (BC) nda 10 , 0-15 ,0 are squamo s cel
car inoma (SC). 2 heT inc de ofNMSC (BC and SC) is 18-20 times hig er than
tha of maligna t melano . Howevr, incde dat of hig epid m ol gical quality
on NMSC are spare becaus tradi onal can er regist e often exclude NMSC or are at
least incomplet . Weinstock estima ed the 194 NMSC inc de to be higer, betw en
90, and 1,20. 3
The ifetml risk erw estima ed to be 28% to 3% for BC
and 7% to 1% for SC (lifet m risk of dev loping NMSC for a child born in 194.)
Recntly, tudies repot no oc upation l risk factors for the dev lopment ofNMSC. Not
only oc upation l exposure to tar, mineral oils, infra ed radi t on have ben ident fied
as caustive agents for NMSC. Now, ther is consi ten epid m ol gical evid nce for a
positve as oci t n betw n oc upati n l ultravio e (UV) light exposur and an increas d
risk of SC and 5,4.C B In Germany, NMSC has ben defin d as an industrial disea
in outd or ?v.srekrow
The inc denc of melanoma is much lower compared with NMSC but has be n
risng in fair-sk n ed po ulations throughout the world for sev ral deca s. 8,9 The an ual
increas varies betw en po ulations but in gen ral has be n estimated to be betwe n 3
and 7%, with mortality rates increasing les quickly. Thes estimates sug est a doubling
o f atesr ev ry 10-20 years. Cutaneous melanoma is the most rapidly increasing cancer
in white po ulations. In Europe, hig est increas of inc denc rates wer found in
Scandi avi n and West rn European countries." As the age stand r ized rates dif er
sign f cantly betw en European countries, the frequ ncy o f higher age coh rts in w e s t r n
countries se ms to be under stima ed, ther fore rates of inc denc and mortality rates
could be m u c h hig er. Mortality rates of melanoma show a stabil zation, no furthe
increas could be reported.": This trend was found in dif er nt European countries. 41,3 1
The reason is ben fits of interv ntio stra egi s, early det c ion of su pect d lesion
whic eadl to a constan decr ase of tumor thicknes at the time of diagnosi and a
bet er prognosi ."

RECNA IKSAMONALif MNO

Incidence of Nonmelanoma Skin Cancer

Nonmelanom skin can er (NMSC) is by far the most frequnt can er in white
po ulations and numeros studie have shown tha incde rates ofNMSC are increasing
worldwi e.P?' NMSC gen ral y ocurs in person older than 50 years, nda in this gea
group, its inc de is increasing rapidly. heT hig est inc de rates ofNMSC wer
repo t d from Australi and New Zeal nd and vary vastly by geo raphic l are. In the
United Staes the estima ed inc de ofNMSC is more than 1,0 per year o f whic
roughly 20-30% are SC and 70-80% are 12.C B
 12 SUNLIGHT, VITAMIN D AND SKIN CANCER

In the white po ulation in the USA, Can da and Australi a mean increas ofNMSC
of 3-8% could be observ d since 960.1 22 Because the com on bas l cel nda squamous
cel can ers are not reportable to SER, ther are only few dat counti g for the inc denc
ofBC and SC.
Few studie found nearly 50-fold dif er nc s in the inc de of basl cel car inoma
(BC) and fold10- dif er nc s in SC betw en Cauc sian po ulations in northe n Europe
and Australi. 2 42,3 0 Withn Australi ther is a marked North to South gradient with het
most extrm inc de rates ofNMSC reco de in Que nsland.f-" A thre year study in
Que nsla d found age-stand r ized inc de rates ofBC of 145 for men and 943 for
women, and of SC wer 058 for men nda 42 for women.P-" This study also showed tha
withn the thre year study period 38.5% of the patien s suf er d from multip e NMSC.
In Europe, the inc denc rate ofNMSC was reported to be 129.3 in men und 90.8
in women (European stand r ), in Germany the raw inc denc rate was 19 .6/10 , 0
in men and 17 . /10 , 0 in women in 201. 1
The NMSC inc denc rates ni Germany
cor esponde wel with atd from Denmark (12 /10 , 0 in 7 2 . ) 7 0 2 In Wales anNMSC
inc denc rate o f 041 case for men and 83 case for women in 10 , 0 was observed."

Basal Cel Carcinoma

Bas l cel car inoma demonstra es to be the most com on maligna t skin cancer
worldwi e in fair skin ed peo le and ocurs 4 times more frequ ntly than SC. It is more
com nly found in men than in women. In Europe, Le., in Denmark betwe n 1978 and
207, the age-adjusted BC inc denc increas d from 27.1 to 96. asec per 10 ,
person-years for women and from 34.2 to 91.2 case for men" which is sim lar to the
inc denc rate found in Germany. Her, a crude inc denc rate for BC was given with
96.2 in men and 95.3 in women, stand r ized for the European Stand r po ulation with
80. for men and 63. for women (per 10, inhab t n s), T a b l e 1 . Compared with
northern European countries as Denmark or Germany, inc denc rates stand r ized for

Table 1. Incidenc rate ofNMSC in New Mexico, USA, in Que nsland, Australi and
Germany. Incidenc rates rea shown per 10, inhabit n s and year, age stand r ized
per the 20 United Staes po ulation, for the World Stand r Population and for the
European Stand r po ulation.":
Basl Cel Squamous Cel
Carcinoma Carcinoma
Australia 206
Men 145 72
Women 07 1 42
New Mexico, USA 198/
Men 920 356
Women 486 051
Germany 204
Men 80. 2.81
Women 3. 6 8.5
 EPIDEMIOL GY OF SKIN CAN ER 123

the United Sta es po ulation and the world stand r po ulation was found to be up to
10-fold higher in the USA and up to 20-fold higher in Australi . The inc denc rate of
BC ni the USA (New Mexico) have measurably increas d by 50% in males and 20% in
femals from 197/8 to 92, /89 1 se T a b l e 1 . In Que nsland, Australi hig est yearly
age stand r ized inc denc rates (per 10 , 0 inhabitan s) wer found for BC (2058
for men and 194 for women) in 197. 03

Squamous Cel Carcinoma

Squamous cel car inoma is mostly as ociated with an adv nci g age (mean age 70
years at diagnosi ), esp cial y in males, who are about twice frequ ntly af ect d. 80% of
case oc ur in peo le aged 60 years and above." In the USA an increas of age-adjusted
inc denc rates by 90% in males and by 109% in femal s could be o b s e r v d in New
Mexico 198/, (men 356, women 150 (per 10,» es T a b l e 1 . nI Que nsland,
Australi , inc denc rates in 197 ac ounted for 132 in men and 75 in women per
10 , inhabit n s and year, age stand r ized for the US po ulation and world stand r
po ulation, resp ctively, 03 se T a b l e 1 . In Germany, the inc denc rate for SC ac ounted
for 30 per 10 . inhabit n s and year. 13

Decrease of Mortality in Nonmelanoma Skin Cancer

Compared with the inc de , the mortali y ofNMSC is quite low. The age- djusted US
mortali y rate for NMSC aris ng on no genital skin from 961 to 20 was 0.69/10 , 0 /
year; the rate among men was twice higher than among women. Cor espondi g mortality
rates for maligna cies aris ng from genital skin wer higher in w o m e n (0.54) than in men
23.)03. ( Overal , no genital SC and BC death rates have declined, and mortality due to
genital car inoma was about half o f to al NMSC deaths." Ac ording to the Rhode Island
no genital SC mortality rate (adjusted to the US 1970 po ulation) a decr ase for men
and women was observ d when comparing two time periods (1979-87 and 198 -20 ).
Also, the BC mortality ater for the cur ent period was estimated at 0.5 compared with
0.1 for the earlier period. Henc , the BC and no genital SC mortality rates ap ear to
be declin g over ime.t 23 Sim lar fmdings have be n reported ni A u s t r a l i a . P ' r " In Europe,
sim lar y, a decr ase of mortality rates was found." In the Neth rlands SC mortality
rates decr ased o f -1.9% (95% CI: -3.1% to -0.7%) from 981 and 208 an ual y." In
Finland a decr asing mortality trend was shown for BC in 19 through 195 of 0.8
per 10, person-years in men and 0.5 in women.'? For NMSC, it was 0.38 in men
and 0.23 in women.'? Mortality rates from 1968-19 in western Germany rev aled a
conti uo s decr ase inces the 70s. In men the age stand r ized mortality rate decr ased
from 0.56 in 1968 to 0.24 in 19 (per 10 , inhabit n s and year), in w o m e n this rate
decr ased from 0.42 to .10 33

Clin cal Epidemiol gy of NMSC

Nonmelanoma skin can ers consti u e more than one-third of al can ers in the US,
and the stand r ized ratio ofBC to SC is roughly 4:1.2 53,
NMSC gen ral y ocurs in person older than 50 years, and in this age group, its
incde si increasing rapidly, patien s with CS wer gen ral y older at the time of
diagnosi .v-" The an tomic pat ern of increas in BC and SC inc de was consi ten
 124 SUNLIGHT, VITAMIN D AND SKIN CAN ER

with an efct o f higer sunlight exposur. Over 80% ofNMSC ocur on sun-expos d body
site. For NMSC the higest body site-pcf incde rates erw found for lip, orbit,
nasol bi and ear, nose, chek and the dorsum of the hands." The risng incde rates
ofNMSC is proba ly due to a combinat o of increas d sun exposur or exposur to UV
(UV) light, increasd outd r actives, hangesc in clothing style, increas d longevity,
and ozne depltion. Furthe tiolgcae factors wer gentics (Xerod ma pigmentosum,
Basl cel nevus syndrome (for BC), imune supreion, nda actin keratos, se
F i g u r e s 1 and 2 .A dose- p nde t increas in the risk of SC but not BC of the skin
asocited with exposur to PUV A therapy was repo t d by Stem et .1a 37 This observation
was con rda t to the result of a large Candi iskr actorf study, rev aling tha an
intesv UV exposur in child o and adolesc n was caus tive fort the dev lopment
o f BC wheras for the etiolgy o f SC a chroni UV exposur ni the arlie decas
was ac used.v-" In organ transpl t recipnts a higly increas d risk for NMSC was
found. 3 04,9 hisT caner risk asocited with transpl tion is higer for sun-expos d than
forn -sun expos d epithla tisue and depns on lifeong UV exposur, kind, dose and
duration o f im unos p re iv therapy. 04,93 Infectios with human pa il oma virus HPV 5
and HPV8 aditonly increas the risk for SC dev lopment in transpl t recipnts. The
mechanism by whic thes viruse may contribue to skin can er dev lopment stil remain
unclear. In 208 Brantsch et al. showed tha tumor thicknes is an indep nt progn stic
factor in SC, se F i g u r e 3 . Key progn stic factors for metasi wer increas d tumor
thicknes (HR 4,79) im unos p re ion (HR 4), loca iz t n at the ear HR( 3,61) and
increas d horizntal size (HR 2,). The risk of loca recu n e dep n d on increasd
tumor thicknes (HR 6,03) and desmopla i (HR 16,) F i g u r e 3 . 41

SUN EXPOSURE AND NO MELANOMA SKIN CANCER

Sun exposure has long ben regarde to be the major environme tal risk factor for
no melanoma skin can er.P'" Lifelong cum lative sun exposure has enb postulated
to eb a causl factor for 34C S while mixed efcts of intermit en and cum lative sun
exposure have be n discu ed as being causl for 24.C B A dose-r spon e curve for sun
exposure and basl cel car inoma could be reported by sev ral groups."
Incidenc rates ofNMSC vary vastly by geo raphical are nda lati ude with most
extr me rates reported from Australi and ewN Zealand." With n Australi ther si a
marked North to South gradient with the most extr me inc denc rates ofNMSC recorde
in Quenslad. 2 03,62 ,o It could be demonstra ed tha mortali y ofNMSC could be prev nted
by reducing exc s ive exposure to UV light nda prompt treatment ofNMSC. 42
Ther is strong evid nce to sug est tha the oler of UV (UV) radi t on in the
dev lopment of skin cancer is multi-fold:' it cause muta ions in cel u ar DNA tha
might ultima ely lead to unrest ained growth and tumor formation,' it induces a stae
o f relative cutaneous im une-sup res ion tha might prev nt tumor rej ction and'
might alow the persi ten infection with Human Papil oma Viruse (HPV) as shown in
im une-sup res d patien s. 63 Most UV - induced dam ge to the cel u ar DNA is repai d,
howev r, muta ions may oc ur as a result of base mispair ng of the cel u ar DNA. The
gens invol ed in the repair proces are also poten ial UV targe s. p53 is a nucleopr tein
encode by a tumor sup res or gen. Muta ions of the tumor sup res or gen p53 are
impl cated in the gen si of a wide variety of human neoplasi including 73CSMN Thes
muta ions wer reported to be pres nt in 50% to 90% o f 73C S and ap roximately 5%
YGOL IMED P OF SKI N CA CER 125

ctive i mu e ystem b locks

ma ligna nt t ransfo mt io n a( pot s i)

Figure 1. H yp oth esiz d pathw ys to th e de velopment of basl cel car inomas .

A ecvti imune ystem b locks

ma lignat transfo ion rmat ( a po t os i )s

Figure 2. Hypothesiz d pathwa ys to the dev lopment of squamo s cel car inomas.
 126 SUNLIGHT, VITAMIN D AND SKIN CANCER

Tumor thicknes m 0.2iS

Tumor thicknes 2.01-6m

Tumor thicknes >6.0m

P<O.01

60 12
Fol w-up time (months)

No desmoplasi and tumor thicknes m 0.6S:

desmoplasi or tumor thicknes >6.0m

P<O.01

Fal ow-up time (months)

Figure 3. Ten year recun fre survial rates ac ording to tumor thicknes lasec nda desmopla tic
growth ni squamo cel car inoma tread ta the departmen o f dermatol gy, Univers ty of Tuebing,
Germany, 19 0-2 1, acording to Brantsch et al. 208.
 EPIDEMIOL GY OF SKIN CANER 127

of BC includg very smal lesion," A second tumor supreo gen, the gen for
the patched (PTCH) protein ni the epidrmal gnitalum s-htworg Hedgho patwy, he
human gen homlg of the Drosphila segmnt polarity gen patched, has also ben
shown to be mutaed in more than 50% of sporadic BC, in patiens with Gorlin-tz
syndrome,a with Xerodma pigntsu.": Furthemo, i has ben repotd ha
the observd point mutaions both in the PTCH and the p53 gens wer predominatly
-specif UV transit ons.tv" hesT result provide the irstf gentic evidnc tha UV
raditon is the princal causl factor for NMSC. So far, mutaions in the PTCH gen
sem to be specif for BC ,noitamr fsna t aprt from SC in patiens with a history
of multipe BC. 9 4 nO the other hand, in BC, UV-specif mutaions of both p53 and
the PTCH gen sem to frequntly co-exist. 05,94 83
The routins of n sucre th skin by adults emo be toamenbl prvi
of cutaneos SC, but not 15.C B
,yltnec R omes studie repot on lanoitapuc o risk srotcaf for the tnempolev d of
NMSC. lanoitapuc O ot expsur ar,t havesbn rditofmeal, n
evitasu c Now,therfMSC.agnsi tne si noc lacigol imed p ecn dive for a positve
noita cos a betwn lanoitapuc o VU light erusopxe and an increasd risk of SC and
5,4.C B In , y n a m r e G NMSChas ben dfias n lairtsudni disean outdrwkes.v'

MELANOMA

Increase of Melanoma Incidenc in White Populations

The incde of cutaneos melano (CM) increasd most rapidly in the past
decas. From the mid 1980s onward, studie from Westrn Europe, Cand, the USA
and Australi revald th incde rats wer stabilzng or evn slowing down. l l,52-8

For 208 160, with 48,0 melano relatd deaths wer expctd worldwi e.P-"
In the United Sas n increasof melano ecn dicn was repotd in men from 7.5
to 0 ,0 1/6.13 and in women from 7.5 to 19./0, in the time period 5791morf to
206, se F i g u r e 4 0. 6 Loking at age specif secn dicn an increas ould be observd in
al age ,spuorg yl aiceps in old males. In women, ecn dicn rates wer genraly ow,
excptfor mals.yung 60 The igst ecn dicn rates w repotdin aAustrl New
withZealnd 30-6 per 0 ,0 1 .raey/stna ibahni 46-1 ,85 In thes ,seirtnuoc CM is one f the
most tneuq rf types.canr In the nor lairotauqe parts in dnals e uQ ecn dicn rates
up to 0 ,0 1/06 raey/stna ib hni wer .dnuof In theEurop, higest se a rcni of ecn dicn
rates wer found in naiv nid acS ?'.seirtnuoc ,hguohtlA in Central Europe and southern
Europe tnacif ngis se aercni ofmelan secn dicn wer 76-4 .detroper Thelowst ecn dicn
rates w found i nae r etid M and Ester ,seirtnuoc whic are les than lf o tha of
nrets W .eporuE 5 86-5 ,4 One reason f this htuoS-htroN declin s a darke sin type in the
nae r etideM on ehadpultin fr lanoitaerc seit v ca onthe ad. or
,dnoceS the most recnt setamitse of melano ecn dicn and mortaliy n Europe val
sharp secn ref id betwnEuropa ,seirtnuoc relatdposiby mised seit nutrop for
early si ongaid and et lpmocni of repting mla ndestr ouh .eporuE 41 sA
the age dezi radn ts rates difer yltnacif ngis betwn Europa ,seirtnuoc the ycneuq rf
of higer age cohrts in westrn seirtnuoc sem to be ,detami ser dnu erofer ht rates of
ecn dicn and mortaliy es could be much higer. This can be shown if raw rates wer
comparedwith age dezi radn ts rates, se F ig u re 5 .
 128 SUNLIGHT, VITAMIN D AND SKIN CANCER

40,

35,0

30,

25,0

20,
c
0
c
0 15 ,0
0
~
ia. 10, Incide USA 205 -209
tn Males per 10. 31.6
. ! oc 5,0
G:
selameF per 10. 19.
0, +-r- r- -r- r- ,- r- r- r-r- r- .,. . .-,- r-r- r-.,. . . ,r- r-r- r-.,. -r- r- r- r- r- r- r- r- r- ,- r- r- r-i

~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~

Years

Figure 4. Incide of melanom in the USA acording to SER Cancer Staisc Reviw 1975-20.

Figure 5. Incide rates of CM in Germany, raw rates and European age standrize rates Geslchaft
der epid m ol gischen Krebs gi ter in Deutschland e.V 96.)DIKEG(
 EPIDEMIOL GY OF SKIN CANCER 129

-both sex s
-males
«- s e la me f
Mortality USA 20 5-20 9

Males per 10. 4.6

perFmals 10. 2.0

Years

Figure 6. Mortali y of melanoma in the USA ac ording to SER Cancer Sta is c Reviw 1975-20 9

Stabil zation of Mortality Rates

Mortali y from CM has ben increas g until the late 1980s in young and mid le-ag d
po ulations from most European countries, 07,56 41 as wel as from North America, Australi
and New Zealand/" Mortality rates peaked in 198 -19 0. Ther after, trends have be n
les uniform, with mortality rates tils ris ng in sev ral European countries. In the US
and Australi an increas in mortality was stil reported in adults of more than 65 year
old, ithw a sign ficant trend toward a higher mortali y in males over 65 years.": More
favor ble trends wer observ d among women, and some lev ling of in rates orf
young adults, remain g roughly constan among men, se F i g u r e 6 . 1 The 11 7 0, 6 , favor ble
mortali y trends have be n related to changi pat erns o f sun hine exposure and sunb rn
in y o u n g e r gen rations as wel sa to a bet er and earlier diagnosi 47-n,75 6 ,45 3 , 1.M Cfo
A trend toward thin er and les invasi e melanomas ni both Central Europe, US and
Que nsland was observ d in the last two decades'S"

Impact o f Skin Cancer Scre ni g on Melanom Mortali y

In past decades signif cant ef orts wer made to reduce melanoma deaths through
scre ni g campaigns for the early det c ion o f skin can er. 97- ,51 Ther is s t r o n g evidence
tha a skin can er scre ni g prog am perfo med in N o r t h e r n Germany, Schleswig-Holstein
reduced melanoma mortality compared with sur ounding areas."

Clin cal Epidemiol gy

Age and Gendr

Analyse for the clin cal aspects of melanoma epidemiol gy are mainly based on
dat from the Central Maligna t Melanoma Registry 38-08,)RM C( which is p r e s n t l y
 130 SUNLIGHT, VITAMIN D AND SKIN CAN ER

one of the largest CM dat b se worldwide." In 1983 the German Dermatol gical
Society founde the Central Maligna t Melanoma Registry (CM R) a clin cal-b sed
melanoma registry in orde to overcome the shortage of basic information on M.C
Over the last two deca s the CM R dev loped into a large multi-cent r project
reco ding dat reto- and pros ectively from patien s diagnosed with CM in 80
dermatol gical cent rs located in Germany. Sevral dermatol gical cent rs provide
their CM dat b se dating back to the begin g sev nti s. Until 201, 106,438 case
with CM wer regist red.
Compared with the 70s wher almost 2/3 ofCM patien s wer women, equaliz t on
in othb exs was vis ble in the 90s ni Germany, and other European countries
ac ording to the raw rates and European ASR1 1 nI contras , ac ording to the World
ASR a pre onderance of women is stil vis ble. 68-4 ,06 41, Countries with a igh CM
inc denc as Australi show a more equivalenc pro rtion or evn a pre onderance
of men."
A recnt published study form the US rev aled in 20 2- 0 6 melanom rates in
no -Hispan c men wer 50% hig er than in no -Hispan c women for inc de and
more than double for mortali y in t12 SER areas/" Overal inc de rates increas d
for both men and women wheras death rates increas d in men but decr ased in women.
Incide rates increas d for al age groups in both men and women during 19 2- 0 6,
esp cial y in old males, in women inc de rates are lower excpt for younger males."
For both men and women death rates gen ral y decr ased among person younger
than 64 years wheras they increas d monga person how wer 65 earsy and older,
whic was sign f cant for men. Thes US findgs undersco e the ned for education l
prog ams targe in older peol, esp cial y older white men on sun cre n use or other
prev nti e ethodsm and scre ni g examinations.w"

Anatomic Site

The antomic site varies ac ording to gendr. In men most of the umorst rea
loca ized on the runk,t ni women the pref red site is lower extr mi y, se T a b l e 2 . In
men 53% o f MC are loca ized at the trunk, ther of 38% at the back he fol wed yb
the owerl leg in 15%. nI women 9.8%3 o f CM are loca ized at the lower extr mi y,
fol wed by the trunk (26%). CM loca ized at the head and neck region and the uper
extr mi y folw and are nearly equivalenc in both sex. 8 8,7 18,0
This site distr bu ion was found ni most industrial natio s with inhab t n s of
Cauc sian orign as Europe, the USA and Australi . 98,6 75,3 52
The site specif inc de o f melanoma ariesv ac ording to the age. The inc de
o f melanom loca ized no the trunk nda on the lower extr mi y decr as in hig er
ages, wheras a sign f cant increas o f melanoma loca ized in head and neck ares can
be found in older patien s.P'" Nearly 80% o f melanoma in age groups of 80 and more
years wer found in head and neck "?saera Melanom s dev loping at dif er nt body
site are as ociated ithw dist nc pat erns o f sun exposur. Melanom s of the head nda
neck are as ociated ithw chronic pat erns o f sun exposure wheras runkt melanom s
are as ociated with intermi ten pat erns o f sun exposure, sup orting the hypot esi
tha melanom s may arise through diverg nt auslc pathways."
 EPIDEMIOL GY OF SKIN CANCER 13

Table 2. Anatomic Sites ofCM in the CM R ac ording to gender 201. The median
age is given at the time point of diagnos .
Men Women
Anatomic Site % Median Age % Median Age
Face 7.9 65 9.7 68
Scalp 7. 64 2.8 67
Neck 2.6 58 1.8 53
Anterio trunk 15.0 54 7.8 41
Posterio trunk 1.83 57 1.8 47
Genital region 0.2 75 0.5 63
Uper extr mity 6.1 57 4.91 53
Lower extremity 16.9 53 39.8 50

Histol gical Subtype

Superfic al spreading melanoma is the most frequ nt histol gical subtype covering
nearly 56% of al CM fol wed by the nodular melanoma (20% of al CM) and the lentigo
malign a melanoma (9% ofCM) and the acrolentig nous melanoma (4% ofCM). A sim lar
distr bu ion is found in the an lyse o f inc de rates in the USA and Can d . 53,7

Dif er nt age distr bu ions are found for the resp ctive histol gical subtype. The peak:
for superfic al spreading melanomas is found in patien s of 5 to 59 ears,y for nodular
melanomas in patien s of 60 to 64 years, for acrolentig nous melanoma in patien s of 65
to 69 years and in lentigo maligna melanoma in patien s of70 to 74 years.

Tumor Thicknes

The tumor thicknes is the most important prognostic factor in p r i m a r y melanoma'?

and the most importan criterion for early diagnosi . In northern European countries as
Germany an ongoing trend toward thin melanoma can be found since the 1980s. 75 ,8 21

The median tumor thicknes in the CRM decreased from 1.8 m to 0.85 m in
the year 201 . The percentages of in itus and lev l I CM increased." This trend is
now al eviated and cur ently no dist nct trend to a further decrease of tumor thicknes
is vis ble, ( F i g . 6 ).
The tumor thicknes at the time point of primary diagnosi is lsoa age dep n t.
Gen ral y ther 's a sign ficant decr ase o f melanoma with a tumor thicknes of 1.0 m or
les in hig er ages and is les than 50% at het age of70. In contrast the fraction of thick
melanoma increas sign ficantly and reach s 20% at the age of 80 years in both gend rs.
An an lysi o f the progn si 9,52 patien s with primary CM o f the clin al registry of
the ni consideration o f tumor thicknes was perfo med at the departmen of dermatol gy
at the University o f Tuebing . In patien s with a tumor thicknes of 1.0 m ro les, 10
year survi al rates wer 95.3 % and decr ased to 83.4% in patien s with a tumor thicknes
 132 SUNLIGHT, VITAMIN D AND SKIN CANCER

Years of primay dgnos

Figure 7. Time trends of median tumor thicknes in the CRM betwn 1976 and 201.

of> .01 to 2.0 m and to 67.8% in patiens with a tumor thicknes of2.0 1-4.0 m. Ten
year urvials rates wer lowest (52.7%) ni patien s with a tumor thicknes of more than
4 m, F ig u re 7 . No changes could be observ d over the recnt decas.
In the US Melanoma inc denc rates increas d tumor for la thicknes among
no -Hispanic whites but
by sex and age. nI varied men < 93 young year inc denc
rates only increas d orf thin tumors < 1.0 m" In w o m e n inc denc rates increas d
for al tumor thicknes categories for al ages exc pt orf M > 2.0 m in women
betw en 40-64 years and M with 2.01-4.0 m in women younger than 04 years."
For older men and women rates for thick tumors increas d as nearly as much as for
thin tumors. The higher inc denc rates in women aged 15-39 years was confi ed to
thin lesion . The atesr of m < 4.0 m wer twice as hig in men as in women in
this age interval. 60

SUN EXPOSURE AND MELANOMA

To date, it is widely ac ept d tha toal risk of melanoma is det rmined through the
interplay betw n gentic factors and exposure to sunlight." 80% of melanoma devlop
in interm ntly sun expos d regions. Intermi ten sun exposure and sunb r history have
ben ident f as risk actorsf for melanoma in epid m ol gic studies.v-"
The pathogenic efcts of sun xposure could invole the genot xic, mitogen c, or
im unos p res iv respon es to the damge induce in het skin by UV. 49
Muta ion l
tesing showed tha the spectrum of drive muta ions provide uneq ivocal genomic
evid nce for a direct mutagenic role ofUV light in melanoma pathogen si ."
Ther is a solid evid nce ofUV light as an etiol g c factor in melanoma pathogen si :
1. UV exposure in the childho d se ms to be the main factor to induce
muta ions in the melanocytic sy tem as ociated with an increased induction
o f melanocytic nevi and an increased risk for the dev lopment of melanoma.
Melanocytic nevi have be n identif ed as het most important risk factor for
Clv, unS exposure, sunb rns, and light pigmenta ion have be n found to be
 EPIDEMIOL GY OF SKIN CAN ER 13

as ociated with their dev lopment in childho d. In adultho d, sunb rns and
sun exposure is as ociated with the dev lopment of actin c lentig nes.f-"
In a study of 182 German Kindergarten children high numbers of nevi in
children wer as ociated with the number o f we ks on sun y holidays, outdo r
activ ties at home, skin ype,t faci l freckling, ethnic ty and the number of
nevi on the arms of parents. A strong as ociation was found betwe n nevus
dev lopment in children and the number of parental moles, which most likely
points to an inherited factor." In Germany, moderate sun exposure such as
outdo r activ ties during a German sum er without sunb rns se med to be
suf ic ent for induction o f melanocytic nevi. 97-

2. Lati ude studies in no Hispanic whites showed a sign ficant cor elation with
lati ude and melanoma inc denc (r = - 0 . 8 5 , P = 0. 1) and rev aled a higher
mean UV index to be sign ficantly as ociated with na increas in melanoma
inc denc (r = 0.85, P = 0. 1) A sub tan ial portion of the vari nce in registry
inc denc in no Hispanic whites could be e x p l a i n e d by the UV index (R2 =
0.71, P = 0. 1) Melanoma inc denc was otn only shown to be as ociated
with increas d UV index and lower lati ude in n o - H i s p a n i c whites, but also in
Hispanics and blacks. 10 Althoug , melanoma are u n c o m o n in darke -skin ed
peo l ; in the United Sta es, the inc denc among blacks is o n l y l / l 0 that
among whites.'?
3. Epidem ol gical studie have confmned the hypothesi tha the majority
o f al melanoma case rea caused, at least in part, by exc s ive exposure to
sunlight. 9,603712 For exampl, the great s increas in incde o f melanom s
have ben sen in the regions o f the body subject d to intermi ten exposur , such
as the tors in men and the lower legs in women. Inde, it is likey tha abrupt
changes in sunlight exposur , is a causl factor in the increas in melanoma
inc de observ d in ecntr years. Epidem ol gical dat have also sug e t d
tha a history of exposure to large dose of sunlight suf ic ent to cause sunb r
in child o is a particular y importan melanoma risk factor'?
Contr ve sial is whet r the UVB or the UV A comp ne t of solar radi t on is more
importan in melanoma dev lopm nt. 104-7 To date it is not clear and furthe epid m ol gic
and basic scien tudies wil be nec s ary to unravel the contribu on tha UV A or UVB
might akem in het production of BRAF muta ions whic erw found to be pres nt in
about 60% of melanom s, 108 and in 20-80% of melanocyti nevi. 109- Among kindre s
predispo ed to multip e atypicl melanocyti nevi nda melanom s because of germ-line
muta ions in the CDKN2A gen encoding the tumor-sup res or proteins p 16 and p 19 or
pos ibly other gens, ret ospectiv anlyse sug est tha the inc de o f melanoma has
increas d in recnt gen rations, a phenom n ascribed to the indep nt risk factor
o f increas d sun exposur . 1
12

Ther are particular gentic changes in melanom s in dif er nt site, consi ten
dif er nc s relat d to UV exposure on site tha are chronical y exposed (head and neck)
or interm ntly exposed (chest and back) and in acrl and mucosal skin. For exampl ,
CND 1 amplif cat on ocurs predomina tly in acrl regions, wheras activng muta ions
in BRAF ocur most frequ ntly in skin site o f intermi ten sun exposure.l'"!
The epid m ol gic evid nce impl cating sun exposure in the caus tion o f melanoma is
sup orted by biol g c evid nce tha dam ge caused by UV radi t on, particular y damge
to DNA, plays a central part in the pathogen si of thes tumors. 64 9,2 6- 1 l l 9
 134 SUNLIGHT, VITAMIN D AND SKIN CAN ER

Gilchrest et al. described a poten ial explan tion for the epid m ol gy of melanoma
as compared with 021.CSMN After exposure to UV radi t on, the most sev r ly dam ged
keratinocytes undergo apo t si , leaving the esl dam ged keratinocytes to upregulate
their DNA -repair cap ity and to undergo nearly perf ct repai. The skin tans, provid ng
protec ive melani to the survi ng cels. Frequ nt sub equ nt exposure to UV radi t on
with n the SO -respon e period wil hent per tua e the increas in repair cap ity
and melani conte , min miz ng (but not elim nati g) cum lative muta ional damge.
Intermit en hig -dose exposure to UV radi t on would have lite ef ct on the
dev lopment ofBC and SC. Rep ated low-d se exposure would be exp cted to cause
multip e muta ions in the retained cels of the bas l compartment and henc to give rise
to keratinocyti can ers.
In m e l a n o c y t e s , in contrast, a high dose of UV radiation wil cause sub tan ial
dam ge but not apo t si ; the melanocytes wil survi e to muta e and dive. CM
exhib t markedly el vated base muta ion rates compared with al other solid tumors. 2 1, 2
This is at ributable to i n c r e a s e d abunda ce of cytid ne to thymid ne (C > T) transit ons
char cterist c for a UV induced muta ional signature. Sev ral models have linked UV
dep ndent tumorigenic ef cts to modulation of signaling pathways 321 and activation of
cJUN N -terminal kinase (JNK) pathway sup orting ano mutagenic role in melanom . 421
Conversely evidence for a direct UV mutagenic ef ect in melanoma pathogen si has
be n more equivocal. The recur ent base muta ions producing onc genic NRAS and
BRAF muta ions are not C > T transit ons which are ind cative for UV mutagen si .
Ther fore it is n e c s a r y to d e m o n s t r a e driver muta ions that are directly at ributable
to UV Dam ge in m e l a n o m a . To ad res the oler of UV mutagen si in het advent
o f melanoma driver gen muta ions Hodis et al. could show that 46% o f 62 driver
muta ions in 21 gen s wer caused by C > T or G muta ions char cterist c of UVB/ A
mutations." This percentage increased when driver muta ions in BRAF or NRAS
wer exclude . On the other hand sta ist cal y sign ficant hot spot muta ions in RAC 1,
STK19 nda P 6C could be shown to result from C > T transit ons at ributable to
direct UVB mediated dam ge provid ng defmit ve evidence for UV mutagen si in
melanoma pathogen si ." Some muta ions induced by UV radiation are thought to
enable melanocytes to c r o s the epidermal basem nt me brane into the dermis, wher
subsequent proliferation gives rise to junctional nevi.

CONCLUSION

Melanoma and no melanoma skin cancer (NMSC) are now the most com on
types of cancer in white po ulations. Both tumor enti es show an increasing inc denc
rate worldwi e. The ris ng inc denc rates proba ly caused yb a combination of
increased exposure to UV - (UV) or sun light, increased outdo r activ ties, changes in
clothing style, increased longevity, oz ne depl tion, gen tics and in few case , im une
sup res ion. An inte sive UV exposure in childho d and adolescence was caus tive
for the dev lopment of bas l cel carcinoma (BCe) wher as for the etiol gy of SC
a chronic UV exposure in the earlier decades was ac used. Melanoma risk se ms to
be as ociated with an intermit ent exposure to sunlight. So far, the impact of primary
prev ntion measures on inc denc rates of melanoma is u n l i k e l y to be se n in the near
fut re rather increasing inc denc rates to 40-50/10 ,0 inhabitan s/year should be
expected in Europe in the next decades.
 EPIDEMIOLOGY OF SKIN CANCER 135

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