Melanoma epidemiology, etiopathogenesis and prevention - Professor Torello Lotti, MD - University G.Marconi, Rome, Italy - and Linda Tognetti, MD - Department of Dermatologic Sciences University of Florence, Italy

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Melanoma incidence has continued to increase significantly during the last half of 20th century wherever available data exist. …

Melanoma incidence has continued to increase significantly during the last half of 20th century wherever available data exist.
The incidence of malignant melanoma appears to be lower and stable in dark-skin individuals (Africans, Native Americans, Asians, and Hispanics).
Decreased incidence reported from some countries is probably partly due to an influx of low risk immigrants.

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  • 1. The International School of Vitiligo & Pigmentary Disorders Barcelona, 2-5 November 2011 Edizioni Fernando Folini, Alessandria 2008 Torello Lotti Department of Dermatologic Sciences University of Florence, Italy Melanoma epidemiology, etiopathogenesis and prevention
  • 2. Melanoma EPIDEMIOLOGY
  • 3. Epidemiologic data
    • Although malignant melanoma comprises less than 5% of malignant skin tumors, it is responsible for almost 60% of lethal skin neoplasia.
    Radović-Kovacević V, Pekmezović T, Adanja B, et al. Survival analysis in patients with cutaneous malignant melanoma. Srpski Arhiv Za Celokupno Lekarstvo 1997;125(5-6):132–137.
    • The most common sites,
    • in decreasing order, are:
    • trunk (43.5%)
    • extremities (33.9%)
    • acral sites (11.9%)
    • and head and neck (10.7%)
    From: http://esubart.info/diseases-and-conditions/skin-diseases-and-conditions/page/3/
  • 4. Epidemiologic data
    • However, increased incidence of melanoma is partly due to early detection, especially thin melanomas.
    MacKie RM. Melanoma and the dermatologist in the third millennium. Arch Dermatol 2000;136(1):71–73.
    • Melanoma incidence has continued to increase significantly during the last half of 20th century wherever available data exist.
    Richert SM, D'Amico F, Rhodes AR. Cutaneous melanoma: patient surveillance and tumor progression. JAAD 1998;39(4):571–577.
  • 5. The highest incidence rates in fair-skinned populations of Australia (especially in Queensland) and New Zeland (20–50 per 100 000), America (10–20 per 100 000), and Europe (5–20 per 100 000).
    • In the United States, the incidence of melanoma has more than tripled in the white population during the last 20 years, and melanoma currently is the sixth most common cancer.
    Epidemiologic data: GLOBOCAN 2000 IARC. Cancer incidence, mortality and prevalence worldwide, version 1.0.cancerbase no. 5. Lyon: IARC Press; 2001. Czarnecki D, Meehan CJ. Is the incidence of malignant melanoma decreasing in young Australians? JAAD 2000; 42(4):672–674. ethnic group
    • The incidence of malignant melanoma appears to be lower and stable in dark-skin individuals (Africans, Native Americans, Asians, and Hispanics).
    • Decreased incidence reported from some countries is probably partly due to an influx of low risk immigrants.
    Hall HI, Miller DR, Rogers JD et al. Update on the incidence and mortality from melanoma in the United States. JAAD 1999; 40 (1):35–42. RacLennan R, Green AC, McLeod GR, Martin NG. Increasing incidence of cutaneous melanoma in Queensland, Australia. J Nat Canc Inst 1992; 84(18):1427–1432.
  • 6. Epidemiologic data: age Lasithiotakis KG, Petrakis IE, Garbe C. Cutaneous melanoma in the elderly: epidemiology, prognosis and treatment. Mel Res 2010;20:163-170. Kelly JW. Melanoma in the elderly. A neglected public health challenge. Med J Aust 1998;169(8): 403-4.
    • With increased life expectancy of the elderly population, melanoma will be a public health challenge.
    • The incidence of cutaneous melanoma in patients older than 65 years is up to 10 times higher than in patients younger than 40 years, reaching 100 cases per 100.000 in high-incidence regions of Australia.
    • The increase of the incidence rates of melanoma during the last 30 years has been consistently higher for elderly people all over the world.
    Jemal A, Devesa SS, Hartge P, Tucker MA. Recent trends in cutaneous melanoma incidence among whites in the United States. J Natl Cancer Inst 2001; 93:678–683.
    • In Europe, Australia and United States, the highest incidence rates have been observed in patients older than 60 years old, predominantly males.
    Marrett LD, Nguyen HL, Armstrong BK. Trends in the incidence of cutaneous malignant melanoma in New South Wales, 1983–1996. Int J Cancer 2001; 92:457–462.
  • 7. Epidemiologic data: sex
    • The incidence of melanoma is similar in men and women, although there are reports that the incidence may be higher in women.
    • The most recent analysis of global cancer statistics for melanoma demonstrated a prevalence of 37.7 cases per 100,000 men and 29.4 cases per 100,000 women in Australia and New Zealand, compared with 6.4 cases per 100,000 men and 11.7 cases per 100,000 women in North America.
    Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. Mar-Apr 2005;55(2):74-108
    • Sex is an independent prognostic factor in surviving melanoma.
    • The sex difference in survival with a better outcome for women is confined to melanoma patients of 60 years and younger. In addition, in younger age groups, male patients present with prognostically unfavorable features of primary melanoma .
    Mervic L, Leiter U, Meier F, et al.Sex differences in survival of cutaneous melanoma are age dependent: an analysis of 7338 patients. Mel Res 2011; 21(3):244–252. Radović-Kovacević V, Pekmezović T, Adanja B, et al. Survival analysis in patients with cutaneous malignant melanoma. Srpski Arhiv Za Celokupno Lekarstvo 1997;125(5-6):132–137.
  • 8. Curado MP, Edwards B, Shin HR, Storm H, Ferlay J, Heanue M, Boyle P, editors. Cancer incidence in five continents. Vol. IX. Lyon: IARC (IARC Scientific Publications No. 160); 2007. http://www-dep.iarc.fr/CI5_IX_frame.htm Cutaneous melanoma incidence for selected populations of Australia, the US and Europe for the years 1998–2002. Rates standardized according to the world standard population. Data retrieved from the cancer incidence in five continents vol. IX database
  • 9. Cutaneous melanoma incidence rates/100.000 person/year (standardized on global population) for sex and geographical areas. Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2002 Cancer Incidence, mortality and prevalence woeldwide IARC cancer base No.5, version 2.0. IARC press, Lyon, 2004. Geographical areas Incidence rates Men Women Australia/New Zeland 29.4 37.7 North America 11.7 11.4 Western Europe 10.3 7.3 Southern Europe 5.5 6.0 South Africa 4.1 5.4 Eastern Europe 3.8 3.3 Melanesia 2.9 4.8 East Africa 2.3 1.2 South America 2.3 2.4 Central Africa 2.2 2.2 Central America 1.7 1.3 Western Asia 1.5 1.6 Caraibi 1.1 1.0 Western Africa 0.9 1.1 Micronesia o.7 1.2 North Africa 0.5 0.7 South-East Asia 0.5 0.5 South-Center Asia 0.4 0.4 Eastern Asia 0.2 0.3 Polinesia 0.0 5.1
  • 10. Melanoma ETIOPATHOGENESIS Risk factors Melanoma genesis
  • 11.
    • Patient-related risk factors (endogenous)
    • genetic
    • phenotypic
    • Environmental factors
    • (exogenous)
    Risk factors Melanoma skin cancer ethiopatogenesis involves:
  • 12. Genetic risk factors
    • Genetic susceptibility to melanoma has been investigated by several epidemiolgic studies performed on melanoma-prone families.
    • 8-12% of melanomas occur in a familial setting ( familial melanoma ), has an autosomal dominant transmission with incomplete penetrance.
    Newton Bishop JA, Gruis NA. Genetics: what advice for patients with present with a family history of melanoma? Semin Oncol 2007;34:452-59.
    • One of the most significant risk factors for melanoma is a positive family history.
    • It is estimated that approximately 10 %of melanoma cases report a first-or second-degree relative with melanoma.
    Hayward NK. Genetics Of melanoma predisposition. Oncogene 2003; 22(20):3053-62. From: http://63.126.107.29/SOTS/Meetings/Melanoma/05-05-2003/transcripts/03/transcript.htm
  • 13.
    • Familial melanoma is defined by the presence, within the same family, of:
    • at least 2 cases in first-degree relatives
    • ≥ 3 cases in the same side of the family, without respect to the degree of relatedness
    • at least 2 cases in second-degree relatives, one of those with multiple melanoma or with diagnosis received before the age of 40.
    From: http://63.126.107.29/SOTS/Meetings/Melanoma/05-05-2003/transcripts/03/transcript.htm Newton Bishop JA, Gruis NA. Genetics: what advice for patients with present with a family history of melanoma? Semin Oncol 2007;34:452-59. Genetic risk factors
  • 14. Mancini C, Fargnoli MC, Suppa M, et al. Aspetti genetico-molecolari. In: De Giorgi V, Aricò M, Lotti T, eds. Il melanoma.Prevenzione, diagnosi e terapia. Tortona: Fernando Folini; 2008. pp 11-14. melanoma affected woman melanoma affected man = dead Genealogical tree of melanoma-affected family
  • 15. Genetic risk factors Fargnoli MC, Argenziano G, Zalaudek I, et al. High-and low-penetrance cutaneous melanoma susceptibility genes. Expert Rev Anticancer Ther 2006; 6:657-70.
    • Numerous molecular genetic studies have dimonstrated the important role of some susceptibility genes in the pathogenesis of melanoma.
    • To date, mutations of three genes have been demonstrated to predispose to melanoma development:
    • CDKN2A ( cyclin-dependent kinase inhibitor type 2A )
    •  High penetrance gene
    • CDK4 ( cyclin-dependent kinase type 4 )  High penetrance gene
    • MC1R ( melanocortin 1 receptor )  Low penetrance gene
  • 16.
    • The CDKN2A gene acts as a tumor suppressor gene and plays a crucial role in cell cycle regulation and senescence.
    • It encodes for two proteins, p16 INK4A and p14 ARF, which control, respectively, the two important pathways of Rb (Retinoblastoma) and p53 proteins.
    • Germinal mutations of CDKN2A have been identified in 20-40% of melanoma-prone families, and most part of these mutations are missense and localized in the exon 1 α and 2.
    Mancini C, Fargnoli MC, Suppa M, et al. Aspetti genetico-molecolari. In: De Giorgi V, Aricò M, Lotti T, eds. Il melanoma.Prevenzione, diagnosi e terapia. Tortona: Fernando Folini; 2008. pp 11-14. CDKN2A
  • 17. Goldstein AM, Chan M, Harland M et al. High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMel. Cancer Res 2006;66:9818-28.
    • In melanoma-affected families, mutations in CDKN2A which alterate p16INK4A are more frequent (about 38%) than p16INK4A mutations.
    • Among CDKN2A mutations which have been described until today, 70% have been reported one time only, while 30% are recurrent in several melanoma-prone families around the world.
    • Aplotype analysis of these families indicated that they share a common progenitor (“foudator effect”).
    • A significant association between CDKN2A and other tumors, especially pancreatic cancer.
    From: http://www.gla.ac.uk/schools/medicine/medicalsubjects/medicalgenetics/dretobias/ CDKN2A
  • 18. Goldstein AM, Chan M, Harland M, et al. Features associated with germline CDKN2A mutation: A GenoMel study of melanoma-prone families from three continents. J Med Genet 207;44:99-106.
    • Among melanoma-prone families, the probability of finding a CDKN2A mutation increases with:
    • number of affected family member
    • younger age at diagnosis
    • presence of multiple melanoma
    • cases of pancreatic carcinoma
    • within the family
    From: http://63.126.107.29/SOTS/Meetings/Melanoma/05-05-2003/transcripts/03/transcript.htm CDKN2A
  • 19. From: http://63.126.107.29/SOTS/Meetings/Melanoma/05-05-2003/transcripts/03/transcript.htm
    • Mutations of the CDKN2A gene confer susceptibility to familial melanoma.
    • Partial or complete loss of p16 expression has also been identified in sporadic melanomas.
    Bataille V.Genetics of familial and sporadic melanoma. Clinical and Experimental Dermatology 2000; 25(6):464-70. Nagore E, Climent J, Planelles MD, et al. Analysis of the CDKN2A and CDK4 genes and HLA-DR and HLA-DQ alleles in two Spanish familial melanoma kindreds. Acta Dermato-Venereologica 2000;80(6): 440–442. CDKN2A
  • 20.
    • People with CDKN2A mutation have variable risk of melanoma developement according to different areas .
    • Otherwise, CDKN2A mutations have been rarely described in non-familiar melanoma:
    • in 1,2% of patient with sporadic melanoma
    • in 2.9% of patient with multiple melanoma
    Bishop DT, Demenais F, Gldstein AM et al. Geographical variations in the penetrance of CDKN2A mutation for melanoma. J Natl Cancer Inst 2002; 94:894-903. Berwick M,Orlow I, Hummer AJ et al. The prevalence of CDKN2A germ-line muatins and relative risk for cutaneous malignant melanoma: an international population-based study. Cancer Epidemiol Biomarkers Prev 2006;15:1520-5. From:http://www.ricercaitaliana.it/prin/dettaglio_completo_prin-2004061840.htm CDKN2A
  • 21.
    • Proto-oncogene CDK4, localized in the 12q13 region, is rarely responsible of genetic susceptibility to melanoma.
    • Like CDKN2A, it plays a role in the regulation of the G1/S checkpoint of the cellular cicle, trough the binding with p16 INK4A protein.
    From: http://ghr.nlm.nih.gov/gene/CDK4
    • Two germinal mutations of CDK4, within the same codon of the exon 2, have been recently identified in 8 melanoma-prone families.
    Majore S, De Simone P, Crisi A et al. CDKN2A/CDK4 molecular study on 155 Italian subjects with familial and/or primary multiple melanoma. Pigment Cell Melanoma Res 2008;21:209-11. CDK4
  • 22. Mancini C, Fargnoli MC, Suppa M, et al. Aspetti genetico-molecolari. In: De Giorgi V, Aricò M, Lotti T, eds. Il melanoma.Prevenzione, diagnosi e terapia. Tortona: Fernando Folini; 2008. pp 11-14.
    • The Melanocortin-1-receptor (MC1R) gene plays an important role in cutaneous pigmentation
    • MCR1 gene encods for an high-affinity receptor for MSH, the melanocortin whose binding determines eumelanin production.
    • If MCR1 function is altered, there is maily pheomelanin synthesis.
    Rees J. The genetics of sun sensitivity in humans. Am J Hum genet 2004;75:739-51. MC1R
  • 23.
    • MCR1 gene is highly polymorphic, with more than 75 allelic variants expressed in different populations.
    • It is considered a main determinant of the diversity of human pigmentation, with the wild-type MC1R predominantly expressed in Africa, where high eumelanin content in the skin is critical for optimal photoprotection.
    Garcia-Borron JC, Sanchez-Laorden BL, Jimenez-Cervantes C.Melanocortin-1 receptor structure and functional regulation. Pigment Cell Res 2005;18:393–410.
    • Stimulation of eumelanin synthesis by activation of MC1R confers photoprotection; however, the effect of MC1R genotype on melanoma risk is independent of the effect on pigmentation, suggesting that MC1R determines the risk for melanoma by other mechanisms.
    Stratigos AJ, Dimisianos G, et al. Melanocortin receptor-1 gene polymorphisms and the risk of cutaneous melanoma in a low-risk southern European population. J Invest Dermatol 2006;126:1842–1849. MC1R
  • 24.
    • Some MC1R variants, mainly R151C, R160W and D294H, are strongly associated with red hair color (RHC) phenotype .
    •  High penetrance “ R ”.
    • Three other variants (V60L, V92M and R163Q) have a low association, so they are defined NRH C  Low penetrance “ r ”.
    Sturm RA, Box NF et al. Genetic association and cellular funcion of MCR1 variant alleles in human pigmentation. Am NY Acad Sci 2003; 994:348-58.. Kadekaro AL, Leachman S, Kavanagh RJ, et al. Melanocortin 1 receptor genotype: an important determinant of the damage response of melanocytes to ultraviolet radiation. FASEB J 2010;24:3850–3860.
    • Expression of any two of the RHC variants in the homozygous or compound heterozygous state results in loss of function of the receptor, disrupting its ability to signal when bound by its agonists.
    From:http://www.thetech.org/genetics/ask.php?id=301 MC1R
  • 25.
    • In sporadic melanoma, the presence of the RCH
    • variants of MCR1 gene, is associated with poor tanning
    • ability and increased risk of melanoma development,
    • with a major effect in patients who has more than one
    • allelic variant.
    • In familial melanoma, RCH variants can augment the
    • penetrance of CDKN2A mutations, reduce the age of
    • melanoma onset and predispose to multiple melanoma development.
    • Epidemiological studies from different populations have demonstrated that RHC variants are also related to non-melanoma skin cancer, which is independent from skin type and hair color.
    Kennedy C, ter Huurne J, Berkhout M, et al.Melanocortin 1 receptor (MC1R) gene variants are associated with an increased risk for cutaneous melanoma which is largely independent of skin type and hair color. J Investig Dermatol 2001;117:294–300. Fargnoli MC, Argenziano G, Zalaudek I, et al. High-and low-penetrance cutaneous melanoma susceptibility genes. Expert Rev Anticancer Ther 2006; 6:657-70. MC1R
  • 26.
    • It has been also demonstrated that patient with MC1R gene allelic variants have an increased risk of developing a melanoma cancer with somatic mutations of BRAF gene, and this risk is proportional to the number of variants existing in genotype.
    • Moreover, the MCR1/BRAF association seems to be independent from age, phenotype, location and thickness of melanoma and nevi’s number.
    Fargnoli MC, Pike K, Pfeiffer RM, et al. MC1R variants increase risk of melanomas harboring BRAF mutations. J Invest Dermatol 2008; 128(10): 2485–2490. MC1R
  • 27.
    • pigmentation pathway : OCA2
    • cellular grow and differentiation :
    • BRAF, EGF, VDR, EDN
    • DNA repair : XCP, XPD, XRCC3
    • metal detoxification : GSTM1, GSTT1
    Other various low-penetrance genes have been studied, with conflicting results. The investigated genes are involved in: Fargnoli MC, Argenziano G, Zalaudek I, et al. High-and low-penetrance cutaneous melanoma susceptibility genes. Expert Rev Anticancer Ther 2006; 6:657-70. OTHER GENES
  • 28.
    • Although genetic studies have reported a number of loci associated with cutaneous melanoma (CM) risk, a comprehensive synopsis of genetic association studies and a systematic meta-analysis for all eligible polymorphisms have been performed only recently by Chatzinasiou et al .
    • In the main meta-analyses, 4 loci showed genome-wide statistically significant association with cutaneous melanoma and reached strong epidemiological credibility: MC1R , TYR , SLC45A2 and MYH7B/PIGU/ASIP .
    • In the supplementary meta-analyses, also TYRP1
    • and CDKN2A/MTAP resulted to be associated with an
    • increased susceptibility to melanoma.
    Chatzinasiou F, Lill CM, Kypreou K, et al.Comprehensive field synopsis and systematic meta-analyses of genetic association studies in cutaneous melanoma. J Natl Cancer Inst 2011;103(16):1227-35. OTHER GENES
  • 29.
    • Patient-related risk factors (endogenous)
    • genetic
    • phenotypic
    • Environmental factors
    • (exogenous)
    Risk factors Melanoma skin cancer ethiopatogenesis involves:
  • 30. Phenotypic risk factors
    • pale skin
    • red or blond hair
    • numerous freckles
    • tendency to burn and tan poorly
    • presence of more than 50 acquired (common, banal) nevi
    • more than five dysplastic (atypical, Clark’s) nevi
    • large congenital nevi
    • nevi larger than 6 mm
    • Xeroderma pigmentosum
    • older age
    • family history of melanoma
    • actinic keratosis, non melanoma skin cancers
    • scars, Marjolin’s ulcer
    • immunosuppression
    Bandarchi B, Ma L, Navab R, et al. From melancyte to metastatic malignant melanoma. Dermatology Research and Practice 2010: ID 583748 predominantly skin phototype 1–3
  • 31. Phenotypic risk factors Stanganelli I, Palmieri G. Prevenzione primaria e secondaria del melanoma. In: De Giorgi V, Aricò M, Lotti T, eds. Il melanoma.Prevenzione, diagnosi e terapia. Tortona: Fernando Folini; 2008. pp:15-20.
    • People with red/blond/light brown hair, blu/green eyes and pale skin have an higher relative risk (RR) than people with dark brown or black hair/eyes.
    • In particular:
    • RR 3.6 : red hair
    • RR 2.5 : freckles
    • RR 2.0 : blond hair
    • RR 2.1 : phototype I
    • RR 1.7-1.8 : phototype II-III
    • RR 1.5-1.6 : blue/green eyes
  • 32.
    • Patient-related risk factors (endogenous)
    • genetic
    • phenotypic
    • Environmental factors
    • (exogenous)
    Risk factors Melanoma skin cancer ethiopatogenesis involves:
  • 33. Exogenous risk factors
    • Environmental risk factors include :
    • intermittent sun-exposure
    • excessive childhood sun exposure
    • blistering childhood sunburns
    • use of tanning devices (sunbeds)
    • PUVA therapy
    • chemical exposures
    Bandarchi B, Ma L, Navab R, et al. From melancyte to metastatic malignant melanoma. Dermatology Research and Practice 2010: ID 583748 Whiteman DC, Green AC. Melanoma and sun exposure: where are we now? Int J Dermatol 1999;38(7):481–489.
    • The role of chronic sun exposure is controversial. Some studies suggested that total accumulated exposure to sun is a very important factor, whereas long-term correct exposure actually may be protective .
    Ricceri F. De Giorgi V. Lotti . Melanoma:un’ipotesi eretica relativamente alla fotoesposizione cronica. In: De Giorgi V, Aricò M, Lotti T, eds. Il melanoma.Prevenzione, diagnosi e terapia. Tortona: Fernando Folini; 2008. pp:15-20.
    • Ultraviolet (UV) radiation is the major risk factor, and up to 65% of melanomas are sun-related.
  • 34. Exogenous risk factors
    • The Earth's ozone layer blocks 97-99% of this UV radiation from penetrating through the atmosphere. UV radiation is divided into 3 wavelength ranges:
    • UVA rays ( 400 nm–315 nm): they represent the 98.7% of the UV radiation that reaches the Earth's surface. UVA rays cause cells to age and can cause some damage to cells' DNA. They are linked to long-term skin damage such as wrinkles, but are also thought to play a role in skin cancers.
    • UVB rays ( 315 nm–280 nm): they can cause direct
    • damage to the DNA, and are the main rays that cause
    • sunburns. They are also thought to cause most skin cancers.
    • UVC rays ( 280 nm–100 nm): they don't get through our
    • atmosphere and therefore are not present in sunlight.
    • They are not normally a cause of skin cancer.
    Hockberger, PE. A history of ultraviolet photobiology for humans, animals and microorganisms. Photochem. Photobiol. 2002;76 (6): 561–579. From: http://www.anthelios.com/anthelios-uvraydamage.html
  • 35. UVA rays
    • Use of artificial UV tanning devices (sunbeds) consists mainly of repeated exposure to high UVA doses.
    • Epidemiological studies published over the last years confirmed the association between sunbed use and melanoma.
    • A recent study of Autier et al. has demonstrated that UVA could be involved in the occurrence of nonlife-threatening melanoma .
    • The authors also suggest that the increasing use of sunbeds and of sunscreens may partly explain why melanoma incidence increases in most light-skinned populations without concomitant increase in mortality.
    Autier P, Doré JF, Eggermont AM, Coebergh JW. Epidemiological evidence that UVA radiation is involved in the genesis of cutaneous melanoma.Curr Opin Oncol 2011;23(2):189-96.
  • 36.
    • Absorption of UVB by DNA causes damage that, if not repaired, can become initiating mutations in skin cancer. UVB rays cause two types of DNA lesions:
    • the 6–4 photoproducts , generated between adjacent pyrimidine residues.
    • pyrimidine dimers , formed specifically between adjacent thymine or cytosine residues.
    UVB rays Matsumura Y, Ananthaswamy HN. Front Biosci.2002;7:d765–d783 . You YH, Lee DH, Yoon JH, Nakajima S. J Biol Chem 2001;276:4688–94.  
    • Pyrimidine dimers are considered to be more carcinogenic than the 6–4 photoproducts, forming almost three times as often and being repaired less efficiently.
  • 37. Melanoma genesis
  • 38. Nearly 30% of cases derives from melanocytic nevi (ie, common, congenital, and atypical/dysplastic types) The sequence of events in which normal melanocytes transform into melanoma cells, referred to as melanomagenesis , is still poorly understood. Melanomagenesis about 70% of cases arise de novo (ie, not from a preexisting pigmented lesion). Palmieri G, Capone M, Capone M, Main roads to melanoma Journal of Translational Medicine 2009;7:art86 . Primary cutaneous melanoma
  • 39.
    • Melanomagenesis is likely to involve a combination of up- or downregulation of various effectors acting on different molecular pathways, along with a multistep process of
    • progressive genetic mutations that:
    • alter cell proliferation, differentiation, and death
    • impact susceptibility to the carcinogenic effects of UV ray .
    Demierre MF, Nathanson L. Chemoprevention of melanoma: an unexplored strategy. J Clin Oncol 2003;21(1):158-65. From melanocytes to melanoma
    • Alteration of cell cycle proteins (e.g., cyclin D1, pRb, and p16) has a role in transformation and progression in melanocytic tumors.
    • Progressive increase in expression of cyclin D1 and pRb is associated with progression to melanoma cells.
    Karim RZ, Li W, Sanki A, et al. Reduced p16 and increased cyclin D1 and pRb expression are correlated with progression in cutaneous.International Journal of Surgical Pathology 2009; 17(5):361–367.
  • 40.
    • During the early stages of melanomagenesis, melanocytes
    • acquire the ability to proliferate and escape from cell cycle
    • regulation by uncoupling from keratinocytes.
    • This is achieved by downregulating the expression of the adhesion molecules E-cadherin, P-cadherin, and desmoglein in response to the paracrine factor HGF via
    • binding to c-Met and activation of ERK1/2 and IP3 kinase.
    From melanocytes to melanoma
    • Mutations which disrupt MAP kinase ERK1/2 and IP3 kinase pathways of melanocyte homeostasis are common in melanoma: e,g, BRAFV900E mutation causes constitutive activation of BRAF and upstream of ERK1/2, thus increased proliferation and survival .
    Jamal S, Schneider RJ. UV-induction of keratinocyte endothelin-1 downregulates E-cadherin in melanocytes and melanoma cells. J Clin Investig 2002;110:443–452. Sosman JA, Margolin KA. Inside life of melanoma cell signaling, molecular insights, and therapeutic targets. Curr Oncol Rep 2009;11:405–411.
  • 41. From melanocytes to melanoma
    • Further studies showed that overexpression of basic fibroblast grow factor ( b FGF ) in a human xenograft model followed by UVB irradiation gave rise to hyperplastic melanocytic cells with high-grade atypia, reminiscent of lentiginous melanoma.
    Berking C, Takemoto R, Satyamoorthy K, et al. Basic fibroblast growth factor and ultraviolet B transform melanocytes in human skin. Am J Pathol 2001;158:943–953.
    • Overexpression of bFGF concomitantly with endotelin-3 ( ET-3 ) and stem cell factor ( SCF ) followed by UVB exposure, led to the formation of nests of atypical melanocytes representing melanoma in situ.
    Berking C, Takemoto R, Satyamoorthy K, et al. Induction of melanoma phenotypes in human skin by growth factors and ultraviolet B. Cancer Res 2004;64:807–811.
  • 42. Both types of lesions induced by UVB rays, i.e., 6–4 photoproducts (6-4-PP) and pyrimidine dimers (PD) , can lead to genetic mutations such as the C T or CC T T transitions (the latter mutation being the hallmark of UV-induced mutagenesis). Molecular and carcinogenic responses of melanocytes to UV radiation Jhappan C,  Noonan FP, Merlino G. Ultraviolet radiation and cutaneous malignant melanoma. Oncogene 2003; 2 2.
  • 43. From nevi to melanoma
    • Although nevi and melanomas share initiating genetic
    • alterations such as oncogenic mutations in BRAF and
    • NRAS , melanomas often show recurrent patterns of
    • chromosomal aberrations such as losses of chromosomes 6q, 8p, 9p, and 10q along with gains of chromosomes 1q, 6p, 7, 8q, 17q, and 20q.
    • Differences in frequency of BRAF or NRAS mutations are also related to patterns of sun exposure:
    • - BRAF mutations are more common in intermittently UV-exposed skin
    • - KIT mutations are common in chronically sun exposed skin or relatively unexposed skin .
    Palmieri G, Capone M, Capone M, Main roads to melanoma Journal of Translational Medicine 2009;7:art86 . Maldonado JL, Fridlyand J, Patel H, et al. Determinants of BRAF mutations in primary melanomas. J Natl Cancer Inst. 2003;95(24):1878-90 .
    • Otherwise, benign nevi tend to have no detectable chromosomal aberrations by comparative genomic hybridization or karyotyping.
  • 44. Transmission electron micrograph (TEM) of a melanocyte from human malignant melanoma. From: http://www.sciencephoto.com/media/253749/enlarge An overproduction of melanin is indicated by the small black areas around the periphery of the cell. The cell nucleus has the appearance of a fried egg, with a central dark nucleolus .
  • 45. Transmission electron micrograph (TEM) of melanosomes within a malignant melanocyte . From: http://www.sciencephoto.com/media/253750/enlarge
  • 46. Melanoma PREVENTION Primary prevention photoprotection Secondary prevention early diagnosis
  • 47. Photoprotection Behavioral norms Sunscreen use Melanocortin analog administration
  • 48. Behavioral norms
    • The intensity of UV radiations varies with the season, the altitude and latitude, and the time of day.
    • In this range of hours, people with phenotypic risk factors should wear hat and protective clothes, and, in summer months, avoiding sun exposition.
    Stanganelli I, Palmieri G. Prevenzione primaria e secondaria del melanoma. In: De Giorgi V, Aricò M, Lotti T, eds. Il melanoma.Prevenzione, diagnosi e terapia. Tortona: Fernando Folini; 2008. pp:15-20.
    • In our latitudes, the 60% of UV radiation that reaches the Earth’s surface is concentrated in 4 hours, from 11.00 to 15.00, with maximum incidence in summer months.
  • 49. Sunscreen use
    • Is now generally accepted that regular sunscreen use prevents cutaneous squamous cell carcinoma long term, but their effect on melanoma arouses contrasting opinions.
    • Some authors reasoned that sunscreen use may extend sun exposure intended for getting a tan, while it does not necessarily decrease sunburn occurrence. Indeed, nearly 99% of UV radiation that reaches the Earth’s surface is UVA, whereas sunscreen creams are more effective in blocking UVB rays.
    • According to Autier et al ., sunscreen use for tan acquisition would thus lead to similar exposure to UVB and greater exposure to UVA, which could explain the slightly higher melanoma risk often found among sunscreen users.
    Autier P, Doré JF, Eggermont AM, Coebergh JW. Epidemiological evidence that UVA radiation is involved in the genesis of cutaneous melanoma. Curr Opin Oncol. 2011;23(2):189-96.
  • 50.
    • Recently, Green et al . published the results of a complex trial, that has demonstrated for the first time a strong evidence for a reduction in the incidence of invasive melanoma after regular application of broad-spectrum sunscreen in adults.
    • Long-term follow-up of this randomized trial showed that, among adults age 25 to 75 years, regular application of SPF 15+ sunscreen in a 5-year period appeared to reduce the incidence of new primary melanomas for up to 10 years after trial cessation.
    • A protective effect was also evident for invasive melanoma, which showed a 73% decrease in those randomly assigned to daily sunscreen after approximately 15 years of follow-up.
    • The trial was conducted in Queensland, the region with the highest rate of skin cancer in the world and achieved relatively high rates of compliance among the participants assigned to the group using sunscreen.
    Green AC, Williams GM, Logan V and Strutton GM. Reduced Melanoma After Regular Sunscreen Use: Randomized Trial Follow-Up. J Clin Oncol 2011;29(3):257-63.
  • 51. Gimotty PA, Glanz K. Sunscreen and Melanoma: What Is the Evidence? JCO , 2011;29(3):249-250.
    • Highly exposed and at-risk individuals should consider making regular sunscreen use a habit, much like other health routines; in addition, parents should apply sunscreen to their children's skin and should model the practice of sunscreen use.
    Sunscreen use
    • Clinicians should advise patients at high risk for skin cancer because of phenotypic characteristics, who live in or visit sunny climates, and/or who have a family history of melanoma, to routinely and thoroughly apply sunscreen before going outside, and provide them clear instructions regarding the use and re-application of sunscreen.
  • 52.
    • Since decades, there has been interest in targeting the MC1R in a strategy to prevent melanoma.
    • The injective α -MSH analog NDP-MSH was found to reduce the induction of DNA photoproducts in sunexposed human skin . Despite its effectiveness, NDP-MSH was not specific to the MC1R.
    • In the last years, small tetrapeptide analogs of α -MSH
    • for topical application have been developed.
    • These mlecules showed to surpass α -MSH
    • in their potency to stimulate melanogenesis and
    • to reduce UV-induced DNA damage and apoptosis .
    Melanocortin analog Levine N, Sheftel SN, Eytan T, et al. Induction of skin tanning by the subcutaneous administration of a potent synthetic melanotropin. JAMA 1991;266:2730-36 Abdel-Malek ZA, Kadekaro AL, et al. Melanoma prevention strategy based on using tetrapeptide alpha-MSH analogs that protect human melanocytes from UV-induced damage and cytotoxicity. FASEB J 2006;20:1561–63.
  • 53.
    • Some of these peptides proved to be highly selective for the MC1R , which should alleviate any side two that has been tested so far could permeate human skin, suggesting their possible efficacy in a topical application .
    • These analogs are expected to confer photoprotection for
    • individuals with wild-type MC1R, heterozygous for MC1R
    • variants reducing receptor function, or mutant for other
    • melanoma susceptibility genes.
    Melanocortin analog Abdel-Malek ZA, Ruwe A, Kavanagh-Starner R. alpha-MSH tripeptide analogs activate the melanocortin 1 receptor and reduce UV-induced DNA damage in human melanocytes. Pigment Cell Melanoma Res 2009;22:635–644. Demenais F, Mohamdi H, Chaudru V, et al. Association of MC1R variants and host phenotypes with melanoma risk in CDKN2A mutation carriers: a GenoMEL study. J Natl Cancer Inst 2010;102:1568-83.
    • More recently, tripeptide α -MSH analogs were developed and shown to be capable of activating the MC1R and reducing UV-induced DNA damage .
  • 54. [email_address]