Human Papillomavirus Infection and Skin Cancer Risk in Organ Transplant Recipients
2001; Elsevier BV; Volume: 6; Issue: 3 Linguagem: Inglês
10.1046/j.0022-202x.2001.00048.x
ISSN1529-1774
AutoresJan Nico Bouwes Bavinck, Mariet C.W. Feltkamp, Linda Struijk, Jan ter Schegget,
Tópico(s)Polyomavirus and related diseases
ResumoWarts and squamous cell carcinomas are important cutaneous complications in organ transplant recipients. The role of infection with human papillomaviruses (HPV) in the development of cutaneous squamous cell carcinoma is still unclear. An extremely diverse group of HPV types, mainly consisting of epidermodysplasia-verruciformis (EV)-associated HPV types, can be detected in benign, premalignant, and malignant skin lesions of organ transplant recipients. Frequently, there are multiple HPV types present in single skin biopsies. Typically, the prevalence of viral warts rises steadily after transplantation and a strong association exists between the number of HPV-induced warts and the development of skin cancer. The interval between the transplantation to the development of warts is clearly shorter than the interval from transplantation to the diagnosis of the first skin cancer. A comparison of transplant recipients with and without skin cancer, however, showed an equally high prevalence of EV-HPV DNA in keratotic skin lesions in both groups of patients and the detection rate and spectrum of HPV infection in hyperkeratotic papillomas, actinic keratoses, and squamous cell carcinomas was also similar. HPV DNA can frequently be detected in patients with hyperproliferative disorders like psoriasis and antibodies against HPV in patients with regenerating skin (e.g., after extensive second degree burns). Latent infection with EV-HPV seems to be widespread. The hair follicle region might be the reservoir of EV-HPV. The E6 protein from a range of cutaneous HPV types effectively inhibits apoptosis in response to UV-light induced damage. It is therefore conceivable that individuals who are infected by EV-HPV are at an increased risk of developing actinic keratoses and squamous cell carcinomas, possibly by chronically preventing UV-light induced apoptosis. Warts and squamous cell carcinomas are important cutaneous complications in organ transplant recipients. The role of infection with human papillomaviruses (HPV) in the development of cutaneous squamous cell carcinoma is still unclear. An extremely diverse group of HPV types, mainly consisting of epidermodysplasia-verruciformis (EV)-associated HPV types, can be detected in benign, premalignant, and malignant skin lesions of organ transplant recipients. Frequently, there are multiple HPV types present in single skin biopsies. Typically, the prevalence of viral warts rises steadily after transplantation and a strong association exists between the number of HPV-induced warts and the development of skin cancer. The interval between the transplantation to the development of warts is clearly shorter than the interval from transplantation to the diagnosis of the first skin cancer. A comparison of transplant recipients with and without skin cancer, however, showed an equally high prevalence of EV-HPV DNA in keratotic skin lesions in both groups of patients and the detection rate and spectrum of HPV infection in hyperkeratotic papillomas, actinic keratoses, and squamous cell carcinomas was also similar. HPV DNA can frequently be detected in patients with hyperproliferative disorders like psoriasis and antibodies against HPV in patients with regenerating skin (e.g., after extensive second degree burns). Latent infection with EV-HPV seems to be widespread. The hair follicle region might be the reservoir of EV-HPV. The E6 protein from a range of cutaneous HPV types effectively inhibits apoptosis in response to UV-light induced damage. It is therefore conceivable that individuals who are infected by EV-HPV are at an increased risk of developing actinic keratoses and squamous cell carcinomas, possibly by chronically preventing UV-light induced apoptosis. epidermodysplasia verruciformis human papillomavirus Skin cancers are the most common malignant tumors among the Caucasian population. Cutaneous squamous cell carcinoma and basal cell carcinoma, together commonly called nonmelanoma skin cancers, account for almost 90% of cutaneous malignancies (Harvey et al., 1989Harvey I. Shalom D. Marks R.M. Frankel S.J. Non-melanoma skin cancer.Br Med J. 1989; 299: 1118-1120Crossref PubMed Google Scholar;Goldberg, 1996Goldberg L.H. Basal cell carcinoma.Lancet. 1996; 347: 663-667Abstract PubMed Scopus (97) Google Scholar;Marks, 1996Marks R. Squamous cell carcinoma.Lancet. 1996; 347: 735-738PubMed Scopus (99) Google Scholar). Although the annual mortality rate from nonmelanoma skin cancers is relatively low, due to the high prevalence and substantial degree of morbidity, these tumors present a significant and costly health problem (Preston and Stern, 1992Preston D.S. Stern R.S. Nonmelanoma cancers of the skin.N Engl J Med. 1992; 327: 1649-1662Crossref PubMed Scopus (434) Google Scholar). Exposure to sunlight is generally considered to be the most important risk factor for nonmelanoma skin cancers (Brash et al., 1991Brash D.E. Rudolph J.A. Simon J.A. et al.A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma.Proc Natl Acad Sci USA. 1991; 88: 10124-10128Crossref PubMed Scopus (1643) Google Scholar;Marks, 1996Marks R. Squamous cell carcinoma.Lancet. 1996; 347: 735-738PubMed Scopus (99) Google Scholar). Infection with human papillomaviruses (HPV), however, may also be important, especially for the development of squamous cell carcinomas (Pfister and ter Schegget, 1997Pfister H. ter Schegget J. Role of HPV in cutaneous premalignant and malignant tumors.Clinics Dermatol. 1997; 15: 335-347Abstract Full Text PDF PubMed Scopus (111) Google Scholar). Warts and squamous cell carcinomas are by far the most important cutaneous clinical problem in organ transplant recipients (Boyle et al., 1984Boyle J. MacKie R.M. Briggs J.D. Junor B.J.R. Aitchison T.C. Cancer warts, and sunshine in renal transplant recipients: a case-control study.Lancet. 1984; 1: 702-705Abstract PubMed Scopus (234) Google Scholar;Barr et al., 1989Barr B.B.B. Benton E.C. McLaren K. Bunney M.H. Smith I.W. Blessing K. Hunter J.A.A. Human papilloma virus infection and skin cancer in renal allograft recipients.Lancet. 1989; 1: 124-129Abstract PubMed Scopus (267) Google Scholar;Hartevelt et al., 1990Hartevelt M.M. 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Like in the immunocompetent population, exposure to sunlight is believed to be a major risk factor for the development of nonmelanoma skin cancer in organ transplant recipients. In countries with low exposure to sunlight, the cumulative incidence of skin cancer is 10% 10 y after the transplantation and 40% 20 y after the transplantation (Birkeland et al., 1995Birkeland S.A. Storm H.H. Lamm L.U. et al.Cancer risk after renal transplantation in the nordic countries.Int J Cancer. 1995; 60: 183-189Crossref PubMed Scopus (505) Google Scholar;Hartevelt et al., 1990Hartevelt M.M. Bouwes Bavinck J.N. Kootte A.M.M. Vermeer B.J. Vandenbroucke J.P. Incidence of skin cancer after renal transplantation in the Netherlands.Transplantation. 1990; 49: 506-509Crossref PubMed Scopus (568) Google Scholar;London et al., 1995London N.J. Farmery S.M. Will E.J. Davison A.M. Lodge J.P.A. Risk of neoplasia in renal transplant patients.Lancet. 1995; 346: 403-406PubMed Scopus (334) Google Scholar). In Australia, Spain, and the U.S.A., these numbers are even much higher, namely 40% and 70% after 10 and 20 y, respectively (Hardie et al., 1980Hardie I.R. Strong R.W. Hartley L.C.J. Woodruff P.W.H. Clunie C.J.A. Skin cancer in Caucasian renal allograft recipients living in a subtropical climate.Surgery. 1980; 87: 177-183PubMed Google Scholar;Ferrándiz et al., 1995Ferrándiz C. Fuente M.J. Ribera M. Bielsa I. Fernández M.T. Lauzurica R. Roca J. Epidermal dysplasia and neoplasia in kidney transplant recipients.J Am Acad Dermatol. 1995; 33: 590-596Abstract Full Text PDF PubMed Scopus (70) Google Scholar;Bouwes Bavinck et al., 1996Bouwes Bavinck J.N. Hardie D.R. Green A. et al.The risk of skin cancer in renal transplant recipients in Queensland, Australia: a follow-up study.Transplantation. 1996; 61: 715-721Crossref PubMed Scopus (432) Google Scholar;Lampros et al., 1998Lampros T.D. Cobanoglu A. Parker F. Ratkovec R. Norman D.J. Hershberger R. Squamous and basal cell carcinoma in heart transplant recipients.J Heart Lung Transplant. 1998; 17: 586-591PubMed Google Scholar). Many patients develop 10 to more than 100 skin cancers in short time periods. The role of infection with human papillomaviruses in the development of cutaneous squamous cell carcinoma is still unclear. This review focuses on the role of HPV infection in the development of skin cancer in organ transplant recipients and draws a parallel with the development of cervical cancer in HPV16-infected women. Prerequisites for a role of HPV infection in the pathogenesis of cervix carcinoma are (i) that the viral DNA can be detected in the majority of the carcinomas (preferably in high copy numbers), (ii) that the viral genes (most notably the oncogenes) are expressed in the tumor cells, and (iii) that the viral genome persists during metastatic spread of the tumor cells or passage of the cells in vitro (Pfister and ter Schegget, 1997Pfister H. ter Schegget J. Role of HPV in cutaneous premalignant and malignant tumors.Clinics Dermatol. 1997; 15: 335-347Abstract Full Text PDF PubMed Scopus (111) Google Scholar;Walboomers et al., 1999Walboomers J.M. Jacobs M.V. Manos M.M. et al.Human papillomavirus is a necessary cause of invasive cervical cancer worldwide.J Pathol. 1999; 189 (10.1002/(sici)1096-9896(199909)189:1 3.3.co;2-6): 12-19Crossref PubMed Scopus (6612) Google Scholar;zur Hausen, 2000zur Hausen H. Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis.J Natl Cancer Inst. 2000; 92: 690-698Crossref PubMed Google Scholar). This is in contrast to a large series of rather frustrating attempts to demonstrate HPV-DNA in nonmelanoma skin cancers by conventional nucleic acid hybridization techniques (Pfister and ter Schegget, 1997Pfister H. ter Schegget J. Role of HPV in cutaneous premalignant and malignant tumors.Clinics Dermatol. 1997; 15: 335-347Abstract Full Text PDF PubMed Scopus (111) Google Scholar). When discussing a possible role of HPV in skin cancer, one should therefore be prepared to acknowledge a more indirect and maybe transient effect of HPV on the pathogenesis of skin cancer (Pfister and ter Schegget, 1997Pfister H. ter Schegget J. Role of HPV in cutaneous premalignant and malignant tumors.Clinics Dermatol. 1997; 15: 335-347Abstract Full Text PDF PubMed Scopus (111) Google Scholar). Arguments in favor of and against a possible role of HPV infection in relation to skin cancer are discussed later in this review. During the past 20 y, several types of HPV have been identified that cause specific types of cancers (zur Hausen, 2000zur Hausen H. Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis.J Natl Cancer Inst. 2000; 92: 690-698Crossref PubMed Google Scholar). High-risk HPV types like HPV16 are a necessary cause of squamous cell carcinoma of the cervix (Walboomers et al., 1999Walboomers J.M. Jacobs M.V. Manos M.M. et al.Human papillomavirus is a necessary cause of invasive cervical cancer worldwide.J Pathol. 1999; 189 (10.1002/(sici)1096-9896(199909)189:1 3.3.co;2-6): 12-19Crossref PubMed Scopus (6612) Google Scholar). These tumors are characterized by the presence of mostly integrated HPV DNA in all tumor cells. Viral oncogene expression (E6 and E7) can be demonstrated in tumor material. Furthermore, extensive evidence has been presented for an important role of these high-risk HPV types in the pathogenesis of cervical cancer (zur Hausen, 2000zur Hausen H. Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis.J Natl Cancer Inst. 2000; 92: 690-698Crossref PubMed Google Scholar). Transforming properties of the E6/E7 genes have been identified. E6 and E7 expression is required for maintaining the malignant phenotype of cervical carcinoma cell lines and both oncoproteins interact with growth-regulating host-cell proteins. Finally, epidemiologic studies identified these HPV infections as a risk factor for the development of cervical cancer (zur Hausen, 2000zur Hausen H. Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis.J Natl Cancer Inst. 2000; 92: 690-698Crossref PubMed Google Scholar). A number of studies have been conducted to estimate the prevalence of anogenital and cervical lesions among groups of women who are immunosuppressed following organ transplantation (Schneider et al., 1983Schneider V. Kay S. Lee H.M. Immunosuppression as a high-risk factor in the development of condyloma acuminatim and squamous neoplasia of the cervix.Acta Cytol. 1983; 27: 220-224PubMed Google Scholar;Alloub et al., 1989Alloub M.I. Barr B.B.B. McLaren K.M. Smith I.W. Bunney M.H. Smart G.E. 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In an Australian cohort of transplant recipients a standardized incidence ratio for cervical cancer of 3.3 was calculated compared with the normal population (Fairley et al., 1994Fairley C.K. Sheil A.G.R. McNeil J.J. Ugoni A.M. Disney A.P.S. Giles G.G. Amiss N. The risk of ano-genital malignancies in dialysis and transplant patients.Clin Nephrol. 1994; 41: 101-105PubMed Google Scholar), and in a Nordic cohort a standardized incidence ratio of 8.6 was found (Birkeland et al., 1995Birkeland S.A. Storm H.H. Lamm L.U. et al.Cancer risk after renal transplantation in the nordic countries.Int J Cancer. 1995; 60: 183-189Crossref PubMed Scopus (505) Google Scholar). Many organ transplant recipients have a highly increased incidence of both viral warts and squamous cell carcinoma, and DNA of human papillomaviruses can frequently be detected in nonmelanoma skin cancers, raising the question of a possible causal contribution of these viruses to skin carcinogenesis (Boyle et al., 1984Boyle J. 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An extremely diverse group of HPV types consisting of epidermodysplasia-verruciformis (EV)-associated HPV types (e.g., EV-HPV types of subgroup A: HPV5, 8, 12, 14, 19, 20, 21, 25, 36, and 47, EV-HPV types of subgroup B: HPV9, 15, 17, 22, 23, 37, 38, and 47, and EV-HPV types of subgroup C: HPV24) (Berkhout et al., 2000Berkhout R.J.M. Bouwes Bavinck J.N. ter Schegget J. Persistence of human papillomavirus DNA in benign and (pre) malignant skin lesions from renal transplant recipients.J Clin Microbiol. 2000; 38: 2087-2096PubMed Google Scholar) and other cutaneous HPV types (e.g., HPV2, 3, 10, 27, 28, 29, and 58), as well as dozens of putatively new EV and cutaneous HPV types, can be detected in benign, premalignant, and malignant skin lesions of organ transplant recipients. The EV-HPV types prevail in all lesion types (Soler et al., 1993Soler C. Chardonnet Y. Allibert P. Euvrard S. Schmitt D. Mandrand B. 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A broad range of human papillomavirus types detected with a general PCR method suitable for analysis of cutaneous tumours and normal skin.J Gen Virol. 1999; 80: 2437-2443Crossref PubMed Scopus (382) Google Scholar). Frequently, there are multiple HPV types present in single skin biopsy specimens of organ transplant recipients (Berkhout et al., 2000Berkhout R.J.M. Bouwes Bavinck J.N. ter Schegget J. Persistence of human papillomavirus DNA in benign and (pre) malignant skin lesions from renal transplant recipients.J Clin Microbiol. 2000; 38: 2087-2096PubMed Google Scholar;Harwood et al., 2000Harwood C.A. Surentheran T. McGregor J.M. Spink P.J. Leigh I.M. Breuer J. Proby C.M. Human papillomavirus infection and non-melanoma skin cancer in immunosuppressed and immunocompetent individuals.J Med Virol. 2000; 61: 289-297Crossref PubMed Scopus (372) Google Scholar). An approach with PCR techniques for the detection of distinct (sub)groups of genotypically related cutaneous HPV types, i.e., three subgroups of EV-associated HPV types and two groups of other cutaneous HPV types, generally allows a reliable identification of HPV genotypes by direct sequencing of the PCR products, despite the frequent occurrence of multiple infections (Berkhout et al., 2000Berkhout R.J.M. Bouwes Bavinck J.N. ter Schegget J. Persistence of human papillomavirus DNA in benign and (pre) malignant skin lesions from renal transplant recipients.J Clin Microbiol. 2000; 38: 2087-2096PubMed Google Scholar). The frequency of EV-associated HPV and other cutaneous HPV types is similar in biopsy specimens from hyperkeratotic papillomas (78%), actinic keratoses (68%), and squamous cell carcinomas (78%), but appears to be lower in specimens of basal cell carcinomas (36%), benign skin lesions (39%), and clinically normal skin (32%) (Berkhout et al., 2000Berkhout R.J.M. Bouwes Bavinck J.N. ter Schegget J. Persistence of human papillomavirus DNA in benign and (pre) malignant skin lesions from renal transplant recipients.J Clin Microbiol. 2000; 38: 2087-2096PubMed Google Scholar) (Figure 1). Similar prevalence rates were found in another study in which HPV DNA was detected in 84% of squamous cell carcinomas and 88% of premalignant skin lesions (Harwood et al., 2000Harwood C.A. Surentheran T. McGregor J.M. Spink P.J. Leigh I.M. Breuer J. Proby C.M. Human papillomavirus infection and non-melanoma skin cancer in immunosuppressed and immunocompetent individuals.J Med Virol. 2000; 61: 289-297Crossref PubMed Scopus (372) Google Scholar). The prevalence rate of 75% in basal cell carcinomas, however, was much higher in this study (Harwood et al., 2000Harwood C.A. Surentheran T. McGregor J.M. Spink P.J. Leigh I.M. Breuer J. Proby C.M. Human papillomavirus infection and non-melanoma skin cancer in immunosuppressed and immunocompetent individuals.J Med Virol. 2000; 61: 289-297Crossref PubMed Scopus (372) Google Scholar). Latent infection with EV-HPV seems to be widespread. The hair follicle region might be the reservoir of EV-HPV (Boxman et al., 1997Boxman I.L.A. Berkhout R.J.M. Mulder L.H.C. Wolkers M.C. Bouwes Bavinck J.N. Vermeer B.J. ter Schegget J. Detection of human papillomavirus DNA in plucked hairs from renal transplant recipients and healthy volunteers.J Invest Dermatol. 1997; 108: 712-715Crossref PubMed Scopus (271) Google Scholar,Boxman et al., 1999aBoxman I.L.A. Hogewoning A. Mulder L.H.C. Bouwes Bavinck J.N. ter Schegget J. Detection of human papillomavirus types 6 and 11 in pubic and perianal hair from patients with genital warts.J Clin Microbiol. 1999; 37: 2270-2273PubMed Google Scholar,Boxman et al., 1999bBoxman I.L.A. Mulder L.H.C. Russell A. Bouwes Bavinck J.N. Green A. ter Schegget J. Human papillomavirus type 5 is commonly present in immunosuppressed and immunocompetent individuals.Br J Dermatol. 1999; 141: 246-249Crossref PubMed Scopus (50) Google Scholar). The earliest evidence that HPV infection may play a role in skin cancer oncogenesis comes from studies in patients with the rare hereditary syndrome epidermodysplasia verruciformis (EV) (Orth et al., 1987Orth G. Epidermodysplasia verruciformis.in: Salzman N.P. Howley P.M. The Papovaviridae, the Papillomaviruses. New York, Plenum Publishing1987: 199-243Crossref Google Scholar). EV patients acquire characteristic skin warts during childhood and one-third of these patients develop squamous cell carcinomas on sun-exposed skin at young age (Orth et al., 1987Orth G. Epidermodysplasia verruciformis.in: Salzman N.P. Howley P.M. The Papovaviridae, the Papillomaviruses. New York, Plenum Publishing1987: 199-243Crossref Google Scholar). The HPV types found in the skin lesions of these patients by Southern blot hybridization are commonly referred to EV HPV types and include HPV5, 8, 9, 12, 14, 15, 19–25, 36, 38, and 47 (Pfister and ter Schegget, 1997Pfister H. ter Schegget J. Role of HPV in cutaneous premalignant and malignant tumors.Clinics Dermatol. 1997; 15: 335-347Abstract Full Text PDF PubMed Scopus (111) Google Scholar). There are several arguments supporting a causative role of HPV infection in the development of squamous cell carcinomas in organ transplant recipients. The prevalence of viral warts rises steadily after transplantation (Gassenmaier et al., 1986Gassenmaier A. Fuchs P. Shell H. Pfister H. Papillomavirus DNA in warts of immunosuppressed renal allograft recipients.Arch Dermatol Res. 1986; 278: 219-223Crossref PubMed Scopus (63) Google Scholar;Rüdlinger et al., 1986Rüdlinger R. Smith I.W. Bunney M.H. Hunter J.A.A. Human papillomavirus infections in a group of renal transplant recipients.Br J Dermatol. 1986; 115: 681-692Crossref PubMed Scopus (173) Google Scholar;van der Leest et al., 1987van der Leest R.J. Zachow K.R. Ostrow R.S. Bender M. Pass F. Faras A.J. Human papillomavirus heterogeneity in 36 renal transplant recipients.Arch Dermatol. 1987; 123: 354-357Crossref PubMed Scopus (86) Google Scholar;Barr et al., 1989Barr B.B.B. Benton E.C. McLaren K. Bunney M.H. Smith I.W. Blessing K. Hunter J.A.A. Human papilloma virus infection and skin cancer in renal allograft recipients.Lancet. 1989; 1: 124-129Abstract PubMed Scopus (267) Google Scholar;Dyal
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