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Papillomaviruses in non-melanoma skin cancer: epidemiological aspects
seminars in C A N C E R B I OLOG Y, Vol 9, 1999: pp. 397]403 Article No. scbi.1999.0143, available online at http:rrwww.idealibrary.com on
Papillomaviruses in non-melanoma skin cancer: epidemiological aspects Nancy B. Kiviat
Worldwide, non-melanoma skin cancers (NMSCs), which include squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), are the most commonly diagnosed cancers among Caucasians. It is well established that ultraviolet radiation (UVR) plays a central role in the development of these cancers, and more recently, a role for specific genetic mutations in the pathogenesis of BCC has been identified. The possibility that certain types of HPV, either alone or in conjunction with UVR, may play a role in the pathogenesis of these cancers is suggested by several lines of evidence reviewed below.
interest in the hypothesis that certain types of HPV, either alone or in conjunction with UVR, may play a role in the pathogenesis of these cancers.
Incidence of NMSCs Tumor registries do not routinely attempt to track the incidence of NMSC. Most NMSC are diagnosed and treated in dermatologist’s offices, and frequently, the diagnosis is based on clinical impressions, and histologic confirmation is not obtained. Furthermore, few patients ever die or are hospitalized as a direct consequence of BCC or SCC. Not surprisingly, the true incidence of NMSC remains unclear. Estimates of the incidence of BCC and SCC have been based on relatively small case control studies as well as a few population based surveys. Australia has the highest reported incidence of NMSC, with these cancers being reported to be two times more frequent than all other cancers.5 High incidence rates have also been reported from Canada, especially from British Columbia, and from Switzerland.6 NMSC is the most common cancer in the USA. A 1977]1978 population-based survey estimated the annual ageadjusted incidence of these cancers to be 232.6r100,000 in and 3.4r100,000 in whites and blacks, respectively.7 The incidence of squamous and basal cell NMSC has continued to increase steadily over the last decade,8 to what is generally agreed to be epidemic proportions.9,10 Karagas et al examined the incidence of BCC and SCC in New Hampshire between 1979]1980 and 1993]1994 and found that the rates of SCC increased by 235% in men, and by 350% in women. The incidence rates for BCC increased by over 80% in both men and women.11 Other studies in North America12,13 as well as in Europe and Australia have reported rapid increases in NMSC, with annual increases for SCCs ranging from 3 to over 10% annually.13 ] 17
Key words: epidemiology r non-melanoma skin cancer r papillomavirus Q1999 Academic Press
Introduction Worldwide, non-melanoma skin cancers ŽNMSCs., which include squamous cell carcinoma ŽSCC. and basal cell carcinoma ŽBCC., are the most commonly diagnosed cancers among Caucasians.1,2 BCC is approximately three to four times more common in Caucasians than is SCC,3,4 while SCCs are more common in blacks.4 BCCs can be locally aggressive but almost never metastasize, while SCCs, if not detected and treated appropriately in a timely fashion, can metastasize and rarely cause death.3 Over the last 20 years the importance of ultraviolet radiation ŽUVR. in development of these cancers has been well established.1 More recently, specific genetic mutations have been shown to play a central role in BCC. In addition, there is now considerable
From the Department of Pathology, University of Washington, Seattle, WA 98103, USA Q1999 Academic Press 1044-579Xr 99 r 060397q 07 $30.00r 0
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sively reviewed by Kicker et al.6 Overall, SCC andror BCC have been consistently associated with both within-country Žbut not international. latitude of domicile. In addition, studies of populations that have migrated to areas of increased UVR exposure have generally found that such persons develop increased incidence rates of NMSCs. Anatomic site has also been strongly associated with NMSCs by most all studies, with 80% of NMSCs occurring in sun-exposed skin. Furthermore, the amount of pigmentation, or melanin present, as well as the ability to tan, have been well established as important risk factors for development of NMSCs. Clinical evidence of sun damage is strongly related to risk of NMSC, however, occupational exposure to sun, amount of outdoor activity, history of sunburn, or total sun exposure are only weakly associated with risk of NMSC, in part reflecting the difficulty of standardizing measurements of such exposures. Direct evidence of the importance of UVR in the development of NMSC comes from tissue-based studies documenting the presence of specific p53 mutations associated with UVR exposure. P53 mutation consisting of C ª T and C ª A single-based pair changes at dipyrimidine sequences and tandem double CC ª TT mutations are known to be associated with exposure to UVR.32 Similar p53 mutations have been shown to be induced in mice epithelia by exposure to UVB 280᎐320 nm.33,34 The importance of a functional p53 gene for protection against development of skin cancers was recently demonstrated in mice constitutively lacking one or both copies of the functional p53 genes. Both varieties were at increased risk for NMSC. Interestingly, in the heterozygotes, acceleration of oncogenesis was characterized by UV-induced mutations in the remaining p53 allele.35 In human tissue, using direct sequencing, investigators have reported that from 40 to 56% of NMSCs cancers contain p53 mutations.36 ᎐ 40 However, the p53 mutations described above, which are characteristic of sun exposure, have also been described in histologically normal sun-exposed skin Žsometimes referred to as ‘p53 patches’.. These changes may occur in up to 40% of epithelial cells in normal chronically sun-exposed skin,41,42 and so the significance of these specific mutations is unclear. At present, too few specimens lesions and normal skin Žof cases and controls. have been analyzed to determine whether detection of all p53 mutations, a subset of p53 mutations, or mutations at specific sites, is associated with risk of SCC andror BCC.
Mortality and public health impact While it is well documented that the incidence of NMSCs is increasing, morbidity and mortality from these cancers remain low, and, in fact, appear to be decreasing.3 Ninety percent of NMSCs are readily cured if identified and treated in a timely fashion. In the USA, from 1200 18 ᎐2500 7,19 deaths are attributed to NMSC each year. As mentioned above, most deaths and morbidity are associated with SCC.3 While little mortality is associated with either SCC or BCC, the impact of NMSC on public health is considerable. The cost of treating such cancers in the USA annually exceeds $500 million.20 In Australia, with one of the world’s highest age adjusted incidence rate for NMSC, treatment of NMSC exceeds the costs incurred by treatment of breast cancers.21
Ultraviolet radiation (UVR) as a risk factor for NMSC Exposure to UVR has been estimated to account for approximately 90% of NMSC.22 Each of the three types of UVR likely plays a role in the pathogenesis of NMSC.23,24 UVBR Ž290᎐320 nm. induces both photochemical damage to p53 and systemic immunosuppression.25,26 UVAR Ž320᎐400 nm. increases risk of NMSC alone24 or in conjunction with UVB exposure. UVCR Ž200᎐280 nm., a known carcinogen normally filtered out by the ozone layer, may now be playing an increasing role in the pathogenesis of NMSC.27 BBC are generally associated with intermittent low level exposure while SCC is generally thought to be associated with continual exposure to higher levels of UVR.28 The role of UVR in development of NMSC, especially in development of SCC, has been clearly established by a variety of studies in animals.29,30 In humans the importance of UVR in development of NMSC is supported by the fact that several inherited diseases including xeroderma pigmentosum, and albinism, which are characterized by increased sensitivity to UVR damage, are associated with dramatically increased risk of NMSC.31 Clinical observations and epidemiological studies which have examined the relationship between BCCsrSCCs and anatomic site distribution, skin pigmentation, latitude, migration, occupation, and total sun exposure have clearly demonstrated the central role of exposure to UVR in pathogenesis of NMSC in the general population. These studies have been extensively and comprehen398
Papillomaviruses in non-melanoma skin cancer: epidemiological aspects
HPV as a risk factor for development of NMSC
for detection of cutaneous types of HPV, a number of investigators began to develop more appropriate primers sets. With the use of a series of primers with varying degrees of degeneracy, combined with cloning and sequencing, more recent studies examining NMSCs from RTR have consistently identified known and putative HPV types in over 65% of specimens.56,57 Several years ago, two new primer sets were designed specifically to detect cutaneous and EV-specific or EV-related HPV types.56,58,59 The first set of primers covered a highly conserved region of approximately 650᎐700 bp in the open reading frame of the HPV L1 major capsid protein gene. The second set of primers, described by Berkhout et al,60 amplify a region of the L1 open reading frame almost adjacent to the region amplified by the first primer set. The sensitivity of these degenerate primer sets Žin conjunction with cloning and sequencing. was assessed on skin samples from benign and malignant lesions from 25 RTR.61 HPV was detected in over 90% of in situ and invasive SCCs and in 35% of samples of histologically normal tissues. Five types of HPV, types 20, 23, 38, DL40 and DL267 Žrelated to HPV 10 and 38. accounted for 73% of all HPV detected in malignant lesions. Although there have been reports of NMSC in HIV-infected individuals Žwho likewise are known to have difficulty controlling HPV infection., it is not known whether these individuals are at increased risk for NMSC as compared to those without HIV infection, nor have these lesions been extensively analyzed for the presence of HPV DNA.62 Relatively little is known about the prevalence of HPV in either NMSC or histologically normal tissue from immunocompetent individuals. Case reports include the detection of HPV 34, 35 and 16 in neoplastic lesions of the fingers, palmoplantar regions, and nailbeds of immunocompetent persons.63 ᎐ 69 HPV 16, 31, 54, 58, 61 or 73, were detected in 8 of 12 Bowenoid lesions of the hand by Mitsuishi et al.70 Using both STH and PCR Žas described above., Stark et al found HPV in 2 Ž22%. of 9 SCCs and 3 Ž23%. of 13 intraepidermal carcinomas and 1 Ž8%. of 12 uninvolved tissues from immunocompetent patients.71 As is the case with immunosuppressed patients, the role of HPV in individuals without immunosuppression remains unclear in part because of the difficulties with knowing which HPVs to test for. The recent development of new primers designed to detect that group of HPVs known to be associated with skin lesions has allow researchers to begin carrying out studies that will clarify the role of HPV in the
The role of HPV in the pathogenesis of NMSC is relatively well established for NMSC developing in immunosuppressed individuals, but less so for skin cancers in immunocompetent individuals. As discussed below, available data consist of small-tomedium size case series reports. Well designed, case control studies have not yet been undertaken, in part, due to the difficulties associated with detection of HPV in skin samples. Individuals with epidermodysplasia verruciformis ŽEV., an inherited disorder of cell mediated immunity, are known to be unable to adequately control infection with certain cutaneous HPVs Žreferred to as ‘EV-related types’ since many were originally detected in EV skin lesions.. It is well documented that persons afflicted with EV develop a large number of flat atypical warts and that after the age of 30, 40᎐60% of such lesions Žespecially those located in sun-exposed areas. undergo malignant transformation.43,44 Case series show that over 90% of SCC in EV patients contain evidence of HPV Žparticularly EV associated types 5 and 8..45,46 EV HPV types 5 and 8 appear to those types which carry a high risk for development of squamous cell cancers, and examination of the E6 and E2 regions of the genome suggest that these may represent EV-viruses transforming regions.47 Other immunosuppressed persons appear to have a similar propensity to develop NMSC. Renal transplant recipients ŽRTR., who are iatrogenically immunosuppressed, develop large number of warts, and are at particularly high risk for NMSC cancers,48 especially SCC in sun-exposed areas.49 Currently published studies are for the most part case series in which HPV has detected in 0᎐91% of SCCs and BCCs obtained from RTRs.50 ᎐ 55 The variability in detection of HPV largely reflects the initial lack of appropriate probes and primer sets for detection of cutaneous HPV types. Briefly, since HPV cannot be cultured, the discovery of types that are only distantly related to known types Ži.e. most skin types. has presented great difficulties. In studies prior to the early 1990s, researchers were limited to assaying skin lesions for the presence of HPV by low stringency southern transfer hybridization ŽSTH., or in situ hybridization using the limited number of HPV types available at the time as probes. While a number of different HPV types such as HPV 2, 4, 5 and 8 were detected in NMSCs, the majority of cancers examined were HPV negative. As it became evident that the available primers for detection of HPV were of limited interest 399
N. B. Kiviat
pathogenesis of NMSCs in non-immunosuppressed populations. In one recent study,72 biopsies from immunocompetent patients were examined by PCR analysis using the 2 sets of degenerate primers described above. HPV sequences were detected in 57% of skin biopsies of NMSC lesions, and in 35% of biopsies taken from the randomly selected control subjects. At present, it is not clear how cutaneous HPV types increase risk of NMSC. The clearly demonstrated oncogenicity of genital HPV types 16 and 18 73 ᎐ 76 resides in the ability of the HPV 16 or 18 E6 and E7 gene products to bind and degrade p53 via the ubiquitin pathway,77 and the retinoblastoma ŽRb. protein,77 respectively. The cutaneous HPVs which have been tested thus far do not appear able to efficiently degrade wild type p53, and only demonstrate weak binding of Rb. However, since infection with HPV and the presence of p53 mutations appears to be common in the epidermis, it is likely that many cells contain both HPV and p53 mutations and it is possible that these factors act together to produce malignancy. At present, only 31 tumors from renal transplant patients have been tested for both cutaneous HPV types and p53 mutations.78 HPV was detected in 33% of cases, and although a relationship between HPV and p53 mutations was not detected, this study had little power to detect such an association. The fact that HPV DNA was detected in such a low percentage of cancers among transplant recipients suggests that the sensitivity of the HPV assay used was not optimal. As noted above EV patients, as well as RTR, develop cancers in sun-exposed areas. The relationship between detection of HPV, UVR, and cancer has not been adequately documented or explained. Recently, EV types of HPV have been reported to be found in a high percentage of patients with psoriatic skin disease, especially those who have been treated with Psoralen and UVA photo chemotherapy.79 In one study examining the detection of HPV in patients with psoriatic skin disease treated with psoralen UVA phochemotherapy or with topcial preparations, overall HPV detection rates did not differ significantly by treatment group. However, HPV type 5, which is frequently associated with cancers in EV patients, was found to be more frequently detected in those patients treated with psoralen UVA phochemotherapy 80 reported that the promoter activity of HPV 77 Žan HPV type found uniquely in lesions from RTR. is stimulated by UVR. This response is mediated through p53. These findings support the impor400
tance of undertaking clinical studies examining the issue of HPVs and UV radiation as co-factors in development of NMSC. In summary, while available data support the hypothesis that HPV plays a role in the development of NMSC, larger well designed epidemiological studies are now necessary to clarify the role of specific HPV types in the pathogenesis of these cancers.
Mutations at chromosome 9q22 (PTCH gene) and risk of BCC The nevoid basal cell cancer syndrome ŽNBCCS. is a rare, autosomal dominant disorder that results in development of multiple BCCs, developmental abnormalities, and increased risk of other tumors including medulloblastoma.81 It has recently been shown that NBCCS is associated with mutations of a gene which maps to chromosome 9q22.3.81 ᎐ 83 This gene, thought to be a tumor suppressor gene, has strong homology to the Drosophila segment polarity gene, patched ŽPTCH.. PTCH is thought to normally exert a negative control on cell growth, via its interaction with the hedgehog signalling pathway, repressing expression of various hedgehog target genes. There are now data suggesting that approximately 33᎐68% or more of sporadic BCC have inactivation of PTCH 84 ᎐ 87 and that chromosome 9q22 mutations Žinactivation. may be necessary, and perhaps sufficient for development of BCC. However, thus far, appropriately designed case control studies of the role of chromosome 9q22 mutations in the pathogenesis of most BCC have not yet been undertaken. In conclusion, it now appears that there may be a number of different pathways to development of NMSC. Confirmation of these observations by well designed case-control studies and further studies of the molecular biology underlying the pathogenesis of these cancer are necessary to provide knowledge necessary to clarify the role of HPV in these cancers.
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Papillomaviruses in non-melanoma skin cancer: epidemiological aspects
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DNA in a cutaneous invasive cancer. Arch Dermatol 125: 666᎐669 Moy RL, Eliezre YD, Nuovo GJ, Zitelli JA, Bennet RG, Silverstien S Ž1989. Human papillomavirus type 16 DNA in periungual squamous cell carcinomas. J Am Med Assoc 261: 2660᎐2673 Guitart J, Bergfeld WF, Tuthill RJ, Tubbs RR, Zienowicz R, Fleegler EJ Ž1990. Squamous cell carcinoma of the nail bed: a clinicopathological study of 12 cases. Br J Dermatol 123: 215᎐222 McGrae JD Jr, Greer CE, Manos MM Ž1993. Multiple Bowen’s disease of the fingers associated with human papilloma virus type 16. Int J Dermatol 32:104᎐107 Mitsuishi T, Sata T, Matsukura T, Iwasaki T, Kawashima M Ž1997. The presence of mucosal human papillomavirus in Bowen’s disease of the hands. Cancer 79:1911᎐1917 Stark LA, Arends MJ, McLaren KM, Benton EC, Shahidullah H, Hunter JA, Bird CC Ž1994. Prevalence of human papillomavirus DNA in cutaneous neoplasms from renal allograft recipients supports a possible viral role in tumour promotion. Br J Cancer 69:222᎐229 Berkhout RJM, Tieben LM, Smits HL, Bouwes Bavinck JN, vermeer BJ, van der Wolde FJ, ter Schegget J Ž1995. Nested PCR approach for detection and typing of epidermodysplasia verruciformis-associated human papillomavirus types in cutaneous cancers from renal transplant recipients. J Clin Microbiol 33:690᎐695 Lorincz AT, Reid R, Jenson AB, Greenberg MD, Lancaster W, Kurman RJ Ž1992. Human papillomavirus infection of the cervix: relative risk associations of 15 common anogenital types. Obstet Gynecol 79:328᎐337 Kiviat NB Žin press. Human papillomavirus, in Manual of Clinical Microbiology, 7th Edition, Section V. Virology ŽSmith TF, ed... ASM Press, Washington DC. Arends MJ, Donaldson YK, Duvall E, Wyllie AH, Bird CC Ž1993. Human papillomavirus type 18 associates with more advanced cervical neoplasia than human papillomavirus type 16. Hum Pathol 24:432᎐437 zur Hausen H Ž1991. Human papillomaviruses in the pathogenesis of anogenital cancer. Virology 184:9᎐13 Scheffner M, Werness BA, Huibregtse JM, Howley PM Ž1990. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63: 1129᎐1136 McGregor JM, Berkhout RJ, Rozycka M, ter Schegget J, Bouwes Bavinck JN, Brooks L, Crook T Ž1997. p53 mutations implicate sunlight in post-transplant skin cancer irrespective of human papillomavirus status. Oncogene 15:1737᎐1740 Harwood CA, Spink PJ, Surentheran T, Leigh IM, Hawke JL, Proby CM, Breuer J, McGregor JM Ž1998. Detection of human papillomavirus DNA in PUVA- associated non-melanoma skin cancers. J Invest Dermatol:123᎐127 Purdie KJ Ž1999. The promoter of a novel human papillomavirus ŽHPV 77. associated with skin cancer displays UV responsiveness, which is mediated through a consensus p53 binding sequence. EMBO J 18:5359᎐5369 Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley S, Chidambaram A, Vorechovsky I, Holmberg E, Unden AB, Gillies S, Negus K, Smyth I, Pressman C, Leffell DJ, Gerrard B, Goldstein AM, Dean M, Toftgard R, ChenevixTrench G, Wainwright B, Bale AE Ž1996. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 14:841᎐851 Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM, Quinn AG, Myers RM, Cox DR, Epstein EH Jr, Scott MP Ž1996. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 272: 1668᎐1671 Gailani MR, Bale AE Ž1997. Developmental genes and can-
Papillomaviruses in non-melanoma skin cancer: epidemiological aspects
cer: role of patched in basal cell carcinoma of the skin. J Natl Cancer Inst 89:1103᎐1109 84. Gailani MR, Stahle-Backdahl M, Leffell DJ, Glynn M, Zaphiropoulos PG, Pressman C, Unden AB, Dean M, Brash DE, Bale AE, Toftgard R Ž1996. The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nat Genet 14:78᎐81 85. Wolter M, Reifenberger J, Sommer C, Ruzicka T, Reifenberger G Ž1997. Mutations in the human homologue of the Drosophila segment polarity gene patched ŽPTCH. in sporadic basal cell carcinomas of the skin and primitive neuroectoder-
mal tumors of the central nervous system. Cancer Res 57:2581᎐2585 86. Unden AB, Zaphiropoulos PG, Bruce K, Toftgard R, StahleBackdahl M Ž1997. Human patched ŽPTCH. mRNA is overexpressed consistently in tumor cells of both familial and sporadic basal cell carcinoma. Cancer Res 57:2336᎐2340 87. Aszterbaum M, Rothman A, Johnson RL, Fisher M, Xie J, Bonifas JM, Zhang X, Scott MP, Epstein EH Jr Ž1998. Identification of mutations in the human PATCHED gene in sporadic basal cell carcinomas and in patients with the basal cell nevus syndrome. J Invest Dermatol 110:885᎐888
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Papillomaviruses in non-melanoma skin cancer: epidemiological aspects Nancy B. Kiviat
Worldwide, non-melanoma skin cancers (NMSCs), which include squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), are the most commonly diagnosed cancers among Caucasians. It is well established that ultraviolet radiation (UVR) plays a central role in the development of these cancers, and more recently, a role for specific genetic mutations in the pathogenesis of BCC has been identified. The possibility that certain types of HPV, either alone or in conjunction with UVR, may play a role in the pathogenesis of these cancers is suggested by several lines of evidence reviewed below.
interest in the hypothesis that certain types of HPV, either alone or in conjunction with UVR, may play a role in the pathogenesis of these cancers.
Incidence of NMSCs Tumor registries do not routinely attempt to track the incidence of NMSC. Most NMSC are diagnosed and treated in dermatologist’s offices, and frequently, the diagnosis is based on clinical impressions, and histologic confirmation is not obtained. Furthermore, few patients ever die or are hospitalized as a direct consequence of BCC or SCC. Not surprisingly, the true incidence of NMSC remains unclear. Estimates of the incidence of BCC and SCC have been based on relatively small case control studies as well as a few population based surveys. Australia has the highest reported incidence of NMSC, with these cancers being reported to be two times more frequent than all other cancers.5 High incidence rates have also been reported from Canada, especially from British Columbia, and from Switzerland.6 NMSC is the most common cancer in the USA. A 1977]1978 population-based survey estimated the annual ageadjusted incidence of these cancers to be 232.6r100,000 in and 3.4r100,000 in whites and blacks, respectively.7 The incidence of squamous and basal cell NMSC has continued to increase steadily over the last decade,8 to what is generally agreed to be epidemic proportions.9,10 Karagas et al examined the incidence of BCC and SCC in New Hampshire between 1979]1980 and 1993]1994 and found that the rates of SCC increased by 235% in men, and by 350% in women. The incidence rates for BCC increased by over 80% in both men and women.11 Other studies in North America12,13 as well as in Europe and Australia have reported rapid increases in NMSC, with annual increases for SCCs ranging from 3 to over 10% annually.13 ] 17
Key words: epidemiology r non-melanoma skin cancer r papillomavirus Q1999 Academic Press
Introduction Worldwide, non-melanoma skin cancers ŽNMSCs., which include squamous cell carcinoma ŽSCC. and basal cell carcinoma ŽBCC., are the most commonly diagnosed cancers among Caucasians.1,2 BCC is approximately three to four times more common in Caucasians than is SCC,3,4 while SCCs are more common in blacks.4 BCCs can be locally aggressive but almost never metastasize, while SCCs, if not detected and treated appropriately in a timely fashion, can metastasize and rarely cause death.3 Over the last 20 years the importance of ultraviolet radiation ŽUVR. in development of these cancers has been well established.1 More recently, specific genetic mutations have been shown to play a central role in BCC. In addition, there is now considerable
From the Department of Pathology, University of Washington, Seattle, WA 98103, USA Q1999 Academic Press 1044-579Xr 99 r 060397q 07 $30.00r 0
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sively reviewed by Kicker et al.6 Overall, SCC andror BCC have been consistently associated with both within-country Žbut not international. latitude of domicile. In addition, studies of populations that have migrated to areas of increased UVR exposure have generally found that such persons develop increased incidence rates of NMSCs. Anatomic site has also been strongly associated with NMSCs by most all studies, with 80% of NMSCs occurring in sun-exposed skin. Furthermore, the amount of pigmentation, or melanin present, as well as the ability to tan, have been well established as important risk factors for development of NMSCs. Clinical evidence of sun damage is strongly related to risk of NMSC, however, occupational exposure to sun, amount of outdoor activity, history of sunburn, or total sun exposure are only weakly associated with risk of NMSC, in part reflecting the difficulty of standardizing measurements of such exposures. Direct evidence of the importance of UVR in the development of NMSC comes from tissue-based studies documenting the presence of specific p53 mutations associated with UVR exposure. P53 mutation consisting of C ª T and C ª A single-based pair changes at dipyrimidine sequences and tandem double CC ª TT mutations are known to be associated with exposure to UVR.32 Similar p53 mutations have been shown to be induced in mice epithelia by exposure to UVB 280᎐320 nm.33,34 The importance of a functional p53 gene for protection against development of skin cancers was recently demonstrated in mice constitutively lacking one or both copies of the functional p53 genes. Both varieties were at increased risk for NMSC. Interestingly, in the heterozygotes, acceleration of oncogenesis was characterized by UV-induced mutations in the remaining p53 allele.35 In human tissue, using direct sequencing, investigators have reported that from 40 to 56% of NMSCs cancers contain p53 mutations.36 ᎐ 40 However, the p53 mutations described above, which are characteristic of sun exposure, have also been described in histologically normal sun-exposed skin Žsometimes referred to as ‘p53 patches’.. These changes may occur in up to 40% of epithelial cells in normal chronically sun-exposed skin,41,42 and so the significance of these specific mutations is unclear. At present, too few specimens lesions and normal skin Žof cases and controls. have been analyzed to determine whether detection of all p53 mutations, a subset of p53 mutations, or mutations at specific sites, is associated with risk of SCC andror BCC.
Mortality and public health impact While it is well documented that the incidence of NMSCs is increasing, morbidity and mortality from these cancers remain low, and, in fact, appear to be decreasing.3 Ninety percent of NMSCs are readily cured if identified and treated in a timely fashion. In the USA, from 1200 18 ᎐2500 7,19 deaths are attributed to NMSC each year. As mentioned above, most deaths and morbidity are associated with SCC.3 While little mortality is associated with either SCC or BCC, the impact of NMSC on public health is considerable. The cost of treating such cancers in the USA annually exceeds $500 million.20 In Australia, with one of the world’s highest age adjusted incidence rate for NMSC, treatment of NMSC exceeds the costs incurred by treatment of breast cancers.21
Ultraviolet radiation (UVR) as a risk factor for NMSC Exposure to UVR has been estimated to account for approximately 90% of NMSC.22 Each of the three types of UVR likely plays a role in the pathogenesis of NMSC.23,24 UVBR Ž290᎐320 nm. induces both photochemical damage to p53 and systemic immunosuppression.25,26 UVAR Ž320᎐400 nm. increases risk of NMSC alone24 or in conjunction with UVB exposure. UVCR Ž200᎐280 nm., a known carcinogen normally filtered out by the ozone layer, may now be playing an increasing role in the pathogenesis of NMSC.27 BBC are generally associated with intermittent low level exposure while SCC is generally thought to be associated with continual exposure to higher levels of UVR.28 The role of UVR in development of NMSC, especially in development of SCC, has been clearly established by a variety of studies in animals.29,30 In humans the importance of UVR in development of NMSC is supported by the fact that several inherited diseases including xeroderma pigmentosum, and albinism, which are characterized by increased sensitivity to UVR damage, are associated with dramatically increased risk of NMSC.31 Clinical observations and epidemiological studies which have examined the relationship between BCCsrSCCs and anatomic site distribution, skin pigmentation, latitude, migration, occupation, and total sun exposure have clearly demonstrated the central role of exposure to UVR in pathogenesis of NMSC in the general population. These studies have been extensively and comprehen398
Papillomaviruses in non-melanoma skin cancer: epidemiological aspects
HPV as a risk factor for development of NMSC
for detection of cutaneous types of HPV, a number of investigators began to develop more appropriate primers sets. With the use of a series of primers with varying degrees of degeneracy, combined with cloning and sequencing, more recent studies examining NMSCs from RTR have consistently identified known and putative HPV types in over 65% of specimens.56,57 Several years ago, two new primer sets were designed specifically to detect cutaneous and EV-specific or EV-related HPV types.56,58,59 The first set of primers covered a highly conserved region of approximately 650᎐700 bp in the open reading frame of the HPV L1 major capsid protein gene. The second set of primers, described by Berkhout et al,60 amplify a region of the L1 open reading frame almost adjacent to the region amplified by the first primer set. The sensitivity of these degenerate primer sets Žin conjunction with cloning and sequencing. was assessed on skin samples from benign and malignant lesions from 25 RTR.61 HPV was detected in over 90% of in situ and invasive SCCs and in 35% of samples of histologically normal tissues. Five types of HPV, types 20, 23, 38, DL40 and DL267 Žrelated to HPV 10 and 38. accounted for 73% of all HPV detected in malignant lesions. Although there have been reports of NMSC in HIV-infected individuals Žwho likewise are known to have difficulty controlling HPV infection., it is not known whether these individuals are at increased risk for NMSC as compared to those without HIV infection, nor have these lesions been extensively analyzed for the presence of HPV DNA.62 Relatively little is known about the prevalence of HPV in either NMSC or histologically normal tissue from immunocompetent individuals. Case reports include the detection of HPV 34, 35 and 16 in neoplastic lesions of the fingers, palmoplantar regions, and nailbeds of immunocompetent persons.63 ᎐ 69 HPV 16, 31, 54, 58, 61 or 73, were detected in 8 of 12 Bowenoid lesions of the hand by Mitsuishi et al.70 Using both STH and PCR Žas described above., Stark et al found HPV in 2 Ž22%. of 9 SCCs and 3 Ž23%. of 13 intraepidermal carcinomas and 1 Ž8%. of 12 uninvolved tissues from immunocompetent patients.71 As is the case with immunosuppressed patients, the role of HPV in individuals without immunosuppression remains unclear in part because of the difficulties with knowing which HPVs to test for. The recent development of new primers designed to detect that group of HPVs known to be associated with skin lesions has allow researchers to begin carrying out studies that will clarify the role of HPV in the
The role of HPV in the pathogenesis of NMSC is relatively well established for NMSC developing in immunosuppressed individuals, but less so for skin cancers in immunocompetent individuals. As discussed below, available data consist of small-tomedium size case series reports. Well designed, case control studies have not yet been undertaken, in part, due to the difficulties associated with detection of HPV in skin samples. Individuals with epidermodysplasia verruciformis ŽEV., an inherited disorder of cell mediated immunity, are known to be unable to adequately control infection with certain cutaneous HPVs Žreferred to as ‘EV-related types’ since many were originally detected in EV skin lesions.. It is well documented that persons afflicted with EV develop a large number of flat atypical warts and that after the age of 30, 40᎐60% of such lesions Žespecially those located in sun-exposed areas. undergo malignant transformation.43,44 Case series show that over 90% of SCC in EV patients contain evidence of HPV Žparticularly EV associated types 5 and 8..45,46 EV HPV types 5 and 8 appear to those types which carry a high risk for development of squamous cell cancers, and examination of the E6 and E2 regions of the genome suggest that these may represent EV-viruses transforming regions.47 Other immunosuppressed persons appear to have a similar propensity to develop NMSC. Renal transplant recipients ŽRTR., who are iatrogenically immunosuppressed, develop large number of warts, and are at particularly high risk for NMSC cancers,48 especially SCC in sun-exposed areas.49 Currently published studies are for the most part case series in which HPV has detected in 0᎐91% of SCCs and BCCs obtained from RTRs.50 ᎐ 55 The variability in detection of HPV largely reflects the initial lack of appropriate probes and primer sets for detection of cutaneous HPV types. Briefly, since HPV cannot be cultured, the discovery of types that are only distantly related to known types Ži.e. most skin types. has presented great difficulties. In studies prior to the early 1990s, researchers were limited to assaying skin lesions for the presence of HPV by low stringency southern transfer hybridization ŽSTH., or in situ hybridization using the limited number of HPV types available at the time as probes. While a number of different HPV types such as HPV 2, 4, 5 and 8 were detected in NMSCs, the majority of cancers examined were HPV negative. As it became evident that the available primers for detection of HPV were of limited interest 399
N. B. Kiviat
pathogenesis of NMSCs in non-immunosuppressed populations. In one recent study,72 biopsies from immunocompetent patients were examined by PCR analysis using the 2 sets of degenerate primers described above. HPV sequences were detected in 57% of skin biopsies of NMSC lesions, and in 35% of biopsies taken from the randomly selected control subjects. At present, it is not clear how cutaneous HPV types increase risk of NMSC. The clearly demonstrated oncogenicity of genital HPV types 16 and 18 73 ᎐ 76 resides in the ability of the HPV 16 or 18 E6 and E7 gene products to bind and degrade p53 via the ubiquitin pathway,77 and the retinoblastoma ŽRb. protein,77 respectively. The cutaneous HPVs which have been tested thus far do not appear able to efficiently degrade wild type p53, and only demonstrate weak binding of Rb. However, since infection with HPV and the presence of p53 mutations appears to be common in the epidermis, it is likely that many cells contain both HPV and p53 mutations and it is possible that these factors act together to produce malignancy. At present, only 31 tumors from renal transplant patients have been tested for both cutaneous HPV types and p53 mutations.78 HPV was detected in 33% of cases, and although a relationship between HPV and p53 mutations was not detected, this study had little power to detect such an association. The fact that HPV DNA was detected in such a low percentage of cancers among transplant recipients suggests that the sensitivity of the HPV assay used was not optimal. As noted above EV patients, as well as RTR, develop cancers in sun-exposed areas. The relationship between detection of HPV, UVR, and cancer has not been adequately documented or explained. Recently, EV types of HPV have been reported to be found in a high percentage of patients with psoriatic skin disease, especially those who have been treated with Psoralen and UVA photo chemotherapy.79 In one study examining the detection of HPV in patients with psoriatic skin disease treated with psoralen UVA phochemotherapy or with topcial preparations, overall HPV detection rates did not differ significantly by treatment group. However, HPV type 5, which is frequently associated with cancers in EV patients, was found to be more frequently detected in those patients treated with psoralen UVA phochemotherapy 80 reported that the promoter activity of HPV 77 Žan HPV type found uniquely in lesions from RTR. is stimulated by UVR. This response is mediated through p53. These findings support the impor400
tance of undertaking clinical studies examining the issue of HPVs and UV radiation as co-factors in development of NMSC. In summary, while available data support the hypothesis that HPV plays a role in the development of NMSC, larger well designed epidemiological studies are now necessary to clarify the role of specific HPV types in the pathogenesis of these cancers.
Mutations at chromosome 9q22 (PTCH gene) and risk of BCC The nevoid basal cell cancer syndrome ŽNBCCS. is a rare, autosomal dominant disorder that results in development of multiple BCCs, developmental abnormalities, and increased risk of other tumors including medulloblastoma.81 It has recently been shown that NBCCS is associated with mutations of a gene which maps to chromosome 9q22.3.81 ᎐ 83 This gene, thought to be a tumor suppressor gene, has strong homology to the Drosophila segment polarity gene, patched ŽPTCH.. PTCH is thought to normally exert a negative control on cell growth, via its interaction with the hedgehog signalling pathway, repressing expression of various hedgehog target genes. There are now data suggesting that approximately 33᎐68% or more of sporadic BCC have inactivation of PTCH 84 ᎐ 87 and that chromosome 9q22 mutations Žinactivation. may be necessary, and perhaps sufficient for development of BCC. However, thus far, appropriately designed case control studies of the role of chromosome 9q22 mutations in the pathogenesis of most BCC have not yet been undertaken. In conclusion, it now appears that there may be a number of different pathways to development of NMSC. Confirmation of these observations by well designed case-control studies and further studies of the molecular biology underlying the pathogenesis of these cancer are necessary to provide knowledge necessary to clarify the role of HPV in these cancers.
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