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Human Papillomavirus Infection and Skin Cancer Risk in Organ Transplant Recipients

      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.

      Keywords

      Abbreviations

      EV
      epidermodysplasia verruciformis
      HPV
      human papillomavirus

      Risk of skin cancer in the immunocompetent population

      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 I.
      • Shalom D.
      • Marks R.M.
      • Frankel S.J.
      Non-melanoma skin cancer.
      ;
      • Goldberg L.H.
      Basal cell carcinoma.
      ;
      • Marks R.
      Squamous cell carcinoma.
      ). 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 D.S.
      • Stern R.S.
      Nonmelanoma cancers of the skin.
      ). Exposure to sunlight is generally considered to be the most important risk factor for nonmelanoma skin cancers (
      • Brash 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.
      ;
      • Marks R.
      Squamous cell carcinoma.
      ). Infection with human papillomaviruses (HPV), however, may also be important, especially for the development of squamous cell carcinomas (
      • Pfister H.
      • ter Schegget J.
      Role of HPV in cutaneous premalignant and malignant tumors.
      ).

      Risk of warts and skin cancer in organ transplant recipients

      Warts and squamous cell carcinomas are by far the most important cutaneous clinical problem in organ transplant recipients (
      • Boyle 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.
      ;
      • Barr 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.
      ;
      • Hartevelt 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.
      ;
      • Bouwes Bavinck J.N.
      • Vermeer B.J.
      • van der Woude F.J.
      • et al.
      Relation between skin cancer and HLA antigens in renal-transplant recipients.
      ;
      • Glover M.T.
      • Niranjan N.
      • Kwan J.T.C.
      • Leigh I.M.
      Non-melanoma skin cancer in renal transplant recipients: extent of the problem and a strategy for management.
      ;
      • Hardie I.R.
      Skin cancer in transplant recipients.
      ). In organ transplant recipients the most important risk factor for skin cancer is the immunosuppressive therapy.
      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 S.A.
      • Storm H.H.
      • Lamm L.U.
      • et al.
      Cancer risk after renal transplantation in the nordic countries.
      ;
      • Hartevelt 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.
      ;
      • London N.J.
      • Farmery S.M.
      • Will E.J.
      • Davison A.M.
      • Lodge J.P.A.
      Risk of neoplasia in renal transplant patients.
      ). 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 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.
      ;
      • Ferrándiz C.
      • Fuente M.J.
      • Ribera M.
      • Bielsa I.
      • Fernández M.T.
      • Lauzurica R.
      • Roca J.
      Epidermal dysplasia and neoplasia in kidney transplant recipients.
      ;
      • Bouwes 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.
      ;
      • Lampros T.D.
      • Cobanoglu A.
      • Parker F.
      • Ratkovec R.
      • Norman D.J.
      • Hershberger R.
      Squamous and basal cell carcinoma in heart transplant recipients.
      ). 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.

      Postulates for an oncogenic role of HPV infection

      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 H.
      • ter Schegget J.
      Role of HPV in cutaneous premalignant and malignant tumors.
      ;
      • Walboomers J.M.
      • Jacobs M.V.
      • Manos M.M.
      • et al.
      Human papillomavirus is a necessary cause of invasive cervical cancer worldwide.
      ;
      • zur Hausen H.
      Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis.
      ). 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 H.
      • ter Schegget J.
      Role of HPV in cutaneous premalignant and malignant tumors.
      ). 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 H.
      • ter Schegget J.
      Role of HPV in cutaneous premalignant and malignant tumors.
      ). Arguments in favor of and against a possible role of HPV infection in relation to skin cancer are discussed later in this review.

      Hpv16 infection and the risk of cervical carcinoma

      Risk of cervical carcinoma in the immunocompetent population

      During the past 20 y, several types of HPV have been identified that cause specific types of cancers (
      • zur Hausen H.
      Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis.
      ). High-risk HPV types like HPV16 are a necessary cause of squamous cell carcinoma of the cervix (
      • Walboomers J.M.
      • Jacobs M.V.
      • Manos M.M.
      • et al.
      Human papillomavirus is a necessary cause of invasive cervical cancer worldwide.
      ). 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 H.
      Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis.
      ). 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 H.
      Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis.
      ).

      Risk of anogenital warts and cervical carcinoma in organ transplant recipients

      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 V.
      • Kay S.
      • Lee H.M.
      Immunosuppression as a high-risk factor in the development of condyloma acuminatim and squamous neoplasia of the cervix.
      ;
      • Alloub M.I.
      • Barr B.B.B.
      • McLaren K.M.
      • Smith I.W.
      • Bunney M.H.
      • Smart G.E.
      Human papillomavirus infection and cervical intraepithelial neoplasia in women with renal allografts.
      ;
      • Kelly G.E.
      • Sheil A.G.R.
      • Rose B.R.
      • Caterson R.
      • Pearse E.
      • Thomson C.H.
      • Cossart Y.E.
      HPV infection in the lower genital tract of women undergoing hemodialysis and women with renal allografts.
      ;
      • IARC
      Human papillomaviruses.
      ;
      • Euvrard S.
      • Kanitakis J.
      • Chardonnet Y.
      • et al.
      External anogenital lesions in organ-transplant recipients. A clinicopathologic and virologic assessment.
      ). 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 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.
      ), and in a Nordic cohort a standardized incidence ratio of 8.6 was found (
      • Birkeland S.A.
      • Storm H.H.
      • Lamm L.U.
      • et al.
      Cancer risk after renal transplantation in the nordic countries.
      ).

      Epidemiology of cutaneous hpv infection in organ transplant recipients

      High incidence of warts and skin cancer

      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 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.
      ;
      • Penn I.
      • Brunson M.E.
      Cancers after cyclosporine therapy.
      ;
      • Bouwes Bavinck J.N.
      • Vermeer B.J.
      • van der Woude F.J.
      • et al.
      Relation between skin cancer and HLA antigens in renal-transplant recipients.
      ,
      • Bouwes Bavinck J.N.
      • van Zuuren E.J.
      • ter Schegget J.
      Cutaneous warts and carcinomas.
      ;
      • Bouwes Bavinck J.N.
      • Vermeer B.J.
      • Claas F.H.J.
      • ter Schegget J.
      • van der Woude F.J.
      Skin cancer and renal transplantation.
      ;
      • Bouwes Bavinck J.N.
      • Berkhout R.J.M.
      HPV infections and immunosuppression.
      ;
      • Pfister H.
      • ter Schegget J.
      Role of HPV in cutaneous premalignant and malignant tumors.
      ;
      • Harwood C.A.
      • McGregor J.M.
      • Proby C.M.
      • Breuer J.
      Human papillomavirus and the development of non-melanoma skin cancer.
      ,
      • Harwood 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.
      ;
      • Jensen P.
      • Hansen S.
      • Moller B.
      • et al.
      Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens.
      ;
      • Wieland U.
      • Ritzkowsky A.
      • Stoltidis M.
      • et al.
      Communication. Papillomavirus DNA in basal cell carcinomas of immunocompetent patients: an accidental association?.
      ). Sooner or later after the transplantation, almost all patients will experience warts.

      A diverse group of HPV types can be detected

      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 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.
      ) 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 C.
      • Chardonnet Y.
      • Allibert P.
      • Euvrard S.
      • Schmitt D.
      • Mandrand B.
      Detection of mucosal human papillomavirus types 6/11 in cutaneous lesions from transplant recipients.
      ;
      • Tieben L.M.
      • ter Schegget J.
      • Minnaar R.P.
      • et al.
      Detection of cutaneous and genital HPV types in clinical samples by PCR using consensus primers.
      ,
      • Tieben L.M.
      • Berkhout R.J.M.
      • Smits H.L.
      • et al.
      Detection of epidermodysplasia verruciformis-like human papillomavirus types in malignant and premalignant skin lesions of renal transplant recipients.
      ;
      • Berkhout R.J.M.
      • Tieben L.M.
      • Smits H.L.
      • Bouwes Bavinck J.N.
      • Vermeer B.J.
      • ter Schegget J.
      Nested PCR approach for detection and typing of epidermodysplasia verruciformis-associated human papillomavirus types in cutaneous cancers from renal transplant recipients.
      ,
      • Berkhout 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.
      ;
      • de Jong-Tieben L.M.
      • Berkhout R.J.M.
      • Smits H.L.
      • Bouwes Bavinck J.N.
      • Vermeer B.J.
      • van der Woude F.J.
      • ter Schegget J.
      High frequency of detection of epidermodysplasia verruciformis-associated human papillomavirus DNA in biopsies from malignant and premalignant skin lesions from renal transplant recipients.
      ,
      • de Jong-Tieben L.M.
      • Berkhout R.J.M.
      • ter Schegget J.
      • et al.
      The prevalence of human papillomavirus DNA (EV-HPV) in benign keratotic skin lesions of renal transplant recipients with and without a history of skin cancer is equally high: a clinical study to assess risk factors for keratotic skin lesions and skin cancer.
      ;
      • McGregor J.M.
      • Proby C.M.
      The role of papillomaviruses in human non-melanoma skin cancer.
      ;
      • Shamanin V.
      • zur Hausen H.
      • Lavergne D.
      • et al.
      Human papillomavirus infections in nonmelanoma skin cancers from renal transplant recipients and nonimmunosuppressed patients.
      ;
      • Arends M.J.
      • Benton E.C.
      • McLaren K.M.
      • Stark L.A.
      • Hunter J.A.
      • Bird C.C.
      Renal allograft recipients with high susceptibility to cutaneous malignancy have an increased prevalence of human papillomavirus DNA in skin tumours and a greater risk of anogenital malignancy.
      ;
      • de Villiers E.M.
      • Lavergne D.
      • McLaren K.
      • Benton E.C.
      Prevailing papillomavirus types in non-melanoma carcinomas of the skin in renal allograft recipients.
      ;
      • Höpfl R.
      • Bens G.
      • Wieland U.
      • Petter A.
      • Zelger B.
      • Fritsch P.
      • Pfister H.
      Human papillomavirus DNA in non-melanoma skin cancers of a renal transplant recipient: detection of a new sequence related to epidermodysplasia verruciformis associated types.
      ;
      • Bens G.
      • Wieland U.
      • Hofmann A.
      • Hopfl R.
      • Pfister H.
      Detection of new human papillomavirus sequences in skin lesions of a renal transplant recipient and characterization of one complete genome related to epidermodysplasia verruciformis-associated types.
      ;
      • Harwood C.A.
      • Spink P.J.
      • Surentheran T.
      • et al.
      Detection of human papillomavirus DNA in PUVA-associated non-melanoma skin cancers.
      ,
      • Harwood 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.
      ;
      • Forslund O.
      • Antonsson A.
      • Nordin P.
      • Stenquist B.
      • Hansson B.G.
      A broad range of human papillomavirus types detected with a general PCR method suitable for analysis of cutaneous tumours and normal skin.
      ).

      Multiple HPV types can be found in single lesions

      Frequently, there are multiple HPV types present in single skin biopsy specimens of organ transplant recipients (
      • Berkhout 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.
      ;
      • Harwood 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.
      ). 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 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.
      ).
      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 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.
      ) (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 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.
      ). The prevalence rate of 75% in basal cell carcinomas, however, was much higher in this study (
      • Harwood 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.
      ).
      Figure thumbnail gr1
      Figure 1HPV in different skin lesions. Percentages of HPV DNA in squamous cell carcinomas (SCC), Bowen's disease (MB), basal cell carcinomas (BCC), actinic keratoses (AK), hyperkeratotic papillomas (HP), and normal skin (NS) as tested with PCR that are specific for EV-HPV types of subgroup A, B, and C, and other cutaneous HPV types: S (for explanation, see text).
      Modified from
      • Berkhout 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.
      .
      Latent infection with EV-HPV seems to be widespread. The hair follicle region might be the reservoir of EV-HPV (
      • Boxman 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.
      ,
      • Boxman 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.
      ,
      • Boxman 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.
      ).

      Arguments in favor of a role of ev-hpv infection in skin cancer oncogenesis

      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 G.
      Epidermodysplasia verruciformis.
      ). 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 G.
      Epidermodysplasia verruciformis.
      ). 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 H.
      • ter Schegget J.
      Role of HPV in cutaneous premalignant and malignant tumors.
      ).
      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 A.
      • Fuchs P.
      • Shell H.
      • Pfister H.
      Papillomavirus DNA in warts of immunosuppressed renal allograft recipients.
      ;
      • Rüdlinger R.
      • Smith I.W.
      • Bunney M.H.
      • Hunter J.A.A.
      Human papillomavirus infections in a group of renal transplant recipients.
      ;
      • van 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.
      ;
      • Barr 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.
      ;
      • Dyall-Smith D.
      • Trowell H.
      • Mark A.
      • Dyall-Smith M.
      Cutaneous squamous cell carcinomas and papillomaviruses in renal transplant recipients: a clinical and molecular biological study.
      ;
      • de Jong-Tieben L.M.
      • Berkhout R.J.M.
      • ter Schegget J.
      • et al.
      The prevalence of human papillomavirus DNA (EV-HPV) in benign keratotic skin lesions of renal transplant recipients with and without a history of skin cancer is equally high: a clinical study to assess risk factors for keratotic skin lesions and 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 (
      • Bouwes Bavinck J.N.
      • de Boer A.
      • Vermeer B.J.
      • et al.
      Sunlight keratotic skin lesions and skin cancer in renal transplant recipients.
      ;
      • de Jong-Tieben L.M.
      • Berkhout R.J.M.
      • ter Schegget J.
      • et al.
      The prevalence of human papillomavirus DNA (EV-HPV) in benign keratotic skin lesions of renal transplant recipients with and without a history of skin cancer is equally high: a clinical study to assess risk factors for keratotic skin lesions and skin cancer.
      ) and a strong association exists within organ transplant recipients between the number of HPV-induced warts and the development of skin cancer (Figure 2) (
      • Bouwes Bavinck J.N.
      • Vermeer B.J.
      • van der Woude F.J.
      • et al.
      Relation between skin cancer and HLA antigens in renal-transplant recipients.
      ;
      • Bouwes Bavinck J.N.
      • de Boer A.
      • Vermeer B.J.
      • et al.
      Sunlight keratotic skin lesions and skin cancer in renal transplant recipients.
      ;
      • de Jong-Tieben L.M.
      • Berkhout R.J.M.
      • ter Schegget J.
      • et al.
      The prevalence of human papillomavirus DNA (EV-HPV) in benign keratotic skin lesions of renal transplant recipients with and without a history of skin cancer is equally high: a clinical study to assess risk factors for keratotic skin lesions and skin cancer.
      ).
      Figure thumbnail gr2
      Figure 2Association between keratotic skin lesions and skin cancer. Mean number of keratotic skin lesions in organ transplant recipients with and without squamous cell carcinoma (SCC) and basal cell carcinoma (BCC).
      Modified from
      • de Jong-Tieben L.M.
      • Berkhout R.J.M.
      • ter Schegget J.
      • et al.
      The prevalence of human papillomavirus DNA (EV-HPV) in benign keratotic skin lesions of renal transplant recipients with and without a history of skin cancer is equally high: a clinical study to assess risk factors for keratotic skin lesions and skin cancer.
      .
      In addition, DNA of the epidermodysplasia-verruciformis associated subgroup of HPV (EV-HPV) can frequently be detected in biopsies of premalignant lesions and nonmelanoma skin cancers of organ transplant recipients (
      • de Jong-Tieben L.M.
      • Berkhout R.J.M.
      • Smits H.L.
      • Bouwes Bavinck J.N.
      • Vermeer B.J.
      • van der Woude F.J.
      • ter Schegget J.
      High frequency of detection of epidermodysplasia verruciformis-associated human papillomavirus DNA in biopsies from malignant and premalignant skin lesions from renal transplant recipients.
      ,
      • de Jong-Tieben L.M.
      • Berkhout R.J.M.
      • ter Schegget J.
      • et al.
      The prevalence of human papillomavirus DNA (EV-HPV) in benign keratotic skin lesions of renal transplant recipients with and without a history of skin cancer is equally high: a clinical study to assess risk factors for keratotic skin lesions and skin cancer.
      ;
      • Harwood C.A.
      • Spink P.J.
      • Surentheran T.
      • et al.
      Degenerate and nested PCR. a highly sensitive and specific method for detection of human papillomavirus infection in cutaneous warts.
      ,
      • Harwood 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.
      ) and EV-HPV infection in organ-transplant recipients may persist for many years, suggesting that organ transplant recipients are prone to persistent cutaneous HPV infection (
      • Berkhout 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.
      ;
      • de Jong-Tieben L.M.
      • Berkhout R.J.M.
      • ter Schegget J.
      • et al.
      The prevalence of human papillomavirus DNA (EV-HPV) in benign keratotic skin lesions of renal transplant recipients with and without a history of skin cancer is equally high: a clinical study to assess risk factors for keratotic skin lesions and skin cancer.
      ).

      Arguments against a role of ev-hpv infection in skin cancer oncogenesis

      There are several arguments against a direct causative role of EV-HPV infection in skin cancer oncogenesis. In a recent case-control study, the prevalence of EV-HPV DNA in benign keratotic skin lesions was equally high in organ transplant recipients with and without a history of skin cancer, i.e. 55 and 53% in the two groups, respectively (
      • de Jong-Tieben L.M.
      • Berkhout R.J.M.
      • ter Schegget J.
      • et al.
      The prevalence of human papillomavirus DNA (EV-HPV) in benign keratotic skin lesions of renal transplant recipients with and without a history of skin cancer is equally high: a clinical study to assess risk factors for keratotic skin lesions and skin cancer.
      ) and the detection rate and spectrum of HPV infection in hyperkeratotic papillomas, actinic keratoses and squamous cell carcinomas is similar (
      • Berkhout 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.
      ). The existence of one single or of a few oncogenic EV-HPV types seems unlikely (
      • Berkhout 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.
      ).
      In addition, HPV DNA is not detectable in outgrowing cells from explant cultures of malignant and premalignant skin lesions of organ transplant recipients established at the air–liquid interface, indicating that EV-HPV positive keratinocytes do not efficiently proliferate in vitro, or HPV DNA is present in only a few basal cells, making it improbable that these cells are located at the outgrowing margins (
      • Boxman I.L.A.
      • Mulder L.H.C.
      • Vermeer B.J.
      • Bouwes Bavinck J.N.
      • ter Schegget J.
      • Ponec M.
      HPV DNA is not detectable in outgrowing cells from explant cultures of skin lesions established at the air–liquid-interface.
      ).
      In skin samples of patients with psoriasis and bullous diseases HPV5 DNA can also frequently be detected (
      • Favre M.
      • Orth G.
      • Majewski S.
      • Baloul S.
      • Pura A.
      • Jablonska S.
      Psoriasis a possible reservoir for human papillomavirus type 5, the virus associated with skin carcinomas of Epidermodysplasia Verruciformis.
      ;
      • Favre M.
      • Majewski S.
      • Noszczyk B.
      • Maienfisch F.
      • Pura A.
      • Orth G.
      • Jablonska S.
      Antibodies to human papillomavirus type 5 are generated in epidermal repair processes.
      ), and epidermal repair in patients with extensive second-degree burns is associated with the generation of anti-HPV5 antibodies (
      • Favre M.
      • Majewski S.
      • Noszczyk B.
      • Maienfisch F.
      • Pura A.
      • Orth G.
      • Jablonska S.
      Antibodies to human papillomavirus type 5 are generated in epidermal repair processes.
      ). EV-HPV have also been detected in recurrent cutaneous and mucosal lesions of a stoma-carrier (
      • Wieland U.
      • Gross G.E.
      • Hofmann A.
      • Sohendra N.
      • Berlien H.P.
      • Pfister H.
      Novel human papillomavirus (HPV) DNA sequences from recurrent cutaneous and mucosal lesions of a stoma-carrier.
      ). Therefore, the frequent presence of EV-HPV in squamous cell carcinomas of organ transplant recipients does not indicate that these HPV types are necessarily causatively involved in cutaneous oncogenesis.
      Recently, in the immunocompetent population no statistically significant differences could be detected between the presence of HPV DNA in basal cell carcinomas and normal skin nor between antibody prevalence in basal cell carcinoma patients and dermatologically healthy individuals (
      • Wieland U.
      • Ritzkowsky A.
      • Stoltidis M.
      • et al.
      Communication. Papillomavirus DNA in basal cell carcinomas of immunocompetent patients: an accidental association?.
      ). This suggests that the occurrence of human papillomavirus-DNA in basal cell carcinoma does not reflect a major etiologic role of human papillomavirus in this specific skin cancer in immunocompetent hosts (
      • Wieland U.
      • Ritzkowsky A.
      • Stoltidis M.
      • et al.
      Communication. Papillomavirus DNA in basal cell carcinomas of immunocompetent patients: an accidental association?.
      ).

      Interaction between exposure to sunlight and ev-hpv infection in relation to skin cancer

      The oncogenic mechanisms of EV-HPV types remain uncertain in contrast to those of the HPV types involved in anogenital malignancy, but there appears to be a crucial additional requirement for UV radiation (
      • Harwood C.A.
      • McGregor J.M.
      • Proby C.M.
      • Breuer J.
      Human papillomavirus and the development of non-melanoma skin cancer.
      ,
      • Harwood C.A.
      • Spink P.J.
      • Surentheran T.
      • et al.
      Degenerate and nested PCR. a highly sensitive and specific method for detection of human papillomavirus infection in cutaneous warts.
      ). A higher prevalence of EV-HPV DNA was found in benign skin lesions from sun-exposed sites, but only in patients with a history of skin cancer (
      • de Jong-Tieben L.M.
      • Berkhout R.J.M.
      • ter Schegget J.
      • et al.
      The prevalence of human papillomavirus DNA (EV-HPV) in benign keratotic skin lesions of renal transplant recipients with and without a history of skin cancer is equally high: a clinical study to assess risk factors for keratotic skin lesions and skin cancer.
      ).
      Ultraviolet light may exert its harmful effect by inducing DNA damage and/or by inducing local immunologic unresponsiveness (
      • Kripke M.L.
      Ultraviolet radiation and immunology: something new under the sun-presidential address.
      ). Sun exposure might directly activate functions of HPV or sun exposure may enhance HPV replication in the host by inducing (local) immunosuppression and/or inactivating of keratinocyte growth regulating host genes (e.g., p53). In this respect it is important to note that the E6 protein from a range of cutaneous HPV types effectively inhibits apoptosis in response to UV damage (
      • Jackson S.
      • Storey A.
      E6 proteins from diverse cutaneous HPV types inhibit apoptosis in response to UV damage.
      ). This occurs in both p53 null and wild-type cells and does not require p53 degradation (
      • Jackson S.
      • Storey A.
      E6 proteins from diverse cutaneous HPV types inhibit apoptosis in response to UV damage.
      ). As EV-HPV is widely distributed it can be hypothesized that individuals who are infected by EV-HPV are at an increased risk of developing solar keratoses and squamous cell carcinomas by the inhibition of UV-induced apoptosis (Figure 3).
      Figure thumbnail gr3
      Figure 3Possible interaction between exposure to sunlight and EV-HPV infection. Inhibition of apoptosis in response to UV damage by the E6 protein from a range of cutaneous HPV types may play a key role in providing a survival advantage to genetically damaged keratinocytes, resulting in actinic keratoses and squamous cell carcinoma.
      Finally, it cannot be excluded that HPV infection by itself is not a direct causative factor but, when present, it modifies the risk of UV-light induced skin cancer.

      The possible role of p53 in hpv-related oncogenesis

      The p53 tumor suppressor gene is a transcriptional activator involved in the control of the cell cycle (
      • Brash 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.
      ). Like in the immunocompetent population, the high prevalence of p53 immunostaining in premalignant and malignant skin lesions of organ transplant recipients supports a role for p53 protein in skin cancer (
      • McGregor J.M.
      • Farthing A.
      • Crook T.
      • Yu C.C.W.
      • Dublin E.A.
      • Levison D.A.
      • MacDonald D.M.
      Posttransplant skin cancer: a possible role for p53 gene mutation but not for oncogenic human papillomaviruses.
      ,
      • McGregor J.M.
      • Berkhout R.J.M.
      • Rozycka M.
      • ter Schegget J.
      • Bouwes Bavinck J.N.
      • Brooks L.
      • Crook T.
      P53 mutations implicate sunlight in post-transplant skin cancer irrespective of human papillomavirus status.
      ;
      • Ferrándiz C.
      • Fuente M.J.
      • Fernandez-Figueras M.T.
      • Bielsa I.
      • Just M.
      p53 immunohistochemical expression in early posttransplant-associated malignant and premalignant cutaneous lesions.
      ;
      • Hudson A.R.
      • Antley C.M.
      • Kohler S.
      • Smoller B.R.
      Increased p53 staining in normal skin of posttransplant, immunocompromised patients and implications for carcinogenesis.
      ).
      Degradation of the tumor suppressor gene p53 induced by the E6 protein of genital oncogenic HPV types is also an important mechanism for human papillomavirus-induced carcinogenesis (
      • Storey A.
      • Thomas M.
      • Kalita A.
      • et al.
      Role of a p53 polymorphism in the development of human papillomavirus-associated cancer.
      ). A common genomic polymorphism occurs at codon 72 of the p53 gene, and in vitro the codon 72 Arginine variant appears to be particularly susceptible to degradation (
      • Storey A.
      • Thomas M.
      • Kalita A.
      • et al.
      Role of a p53 polymorphism in the development of human papillomavirus-associated cancer.
      ). In a large study with organ transplant recipients, however, the p53 codon 72 Arginine allele did not confer susceptibility to the development of skin tumors after renal transplantation (
      • Marshall S.E.
      • Bordea C.
      • Wojnarowska F.
      • Morris P.J.
      • Welsh K.I.
      p53 codon 72 polymorphism and susceptibility to skin cancer after renal transplantation.
      ). Also in the immunocompetent population no association was found between arginine homozygosity of codon 72 in the p53 gene and the development of cutaneous squamous cell carcinoma, basal cell carcinoma, or malignant melanoma (
      • Bastiaens M.T.
      • Struijk L.
      • Tjong-A-Hung S.P.
      • et al.
      Cutaneous squamous cell carcinoma and p53 codon 72 polymorphism: a need for screening?.
      ). In accordance with this observation it has been shown that the E6 protein of EV-HPV type 8 does not form a complex with p53 (
      • Steger G.
      • Pfister H.
      In vitro expressed HPV 8, E6 protein does not bind p53.
      ).

      Synthesis/Proposed Mechanism

      It is conceivable that the development of squamous cell carcinomas in organ transplant recipients is the result of a complex interplay between EV-HPV infection, exposure to UV radiation, genetic predisposition, immune response, and possibly other factors, such as tobacco smoking, etc. The role of EV-HPV infection in the development of skin cancer in this complex interplay is still unclear. Although HPV infection may play a role in the development of squamous cell carcinomas, its role in the development of basal cell carcinomas remains highly speculative. HPV, no doubt, profit considerably from immunosuppression, as is indicated by the large number of warts in organ transplant recipients and, additionally, these HPV may profit from UV-light-induced immunosuppression.
      The equally high prevalence of EV-HPV infection in patients with and without a history of skin cancer and the fact that, until now, no high-risk oncogenic EV-HPV types could be identified, are arguments against a direct causative role of EV-HPV infection in skin cancer oncogenesis and indicate that besides EV-HPV infection, other factors, such as sun exposure, may be crucial.
      We hypothesize that EV-HPV infection is a (possibly necessary) cofactor in the complex interplay between environmental and genetic factors causing cutaneous squamous cell carcinoma. In this regard, inhibition of apoptosis in response to UV damage by the E6 protein from a range of cutaneous HPV types may play a key role in providing a survival advantage to genetically damaged keratinocytes, which cells otherwise would have been destroyed by apoptotic defense mechanisms.

      ACKNOWLEDGMENTS

      The authors are indebted to Drs F.J. van der Woude, B.J. Vermeer, E.J. van Zuuren, F.H.J. Claas, J.P. Vandenbroucke, R.G.J. Westendorp, H. Pfister, P. Fuchs, L. Gissmann, L.M. de Jong-Tieben, R.J.M. Berkhout, H.L. Smits, I.L.A. Boxman, R. Broer, I.R. Hardie, and A. Green for their contribution to important parts of the studies that were performed with the organ transplant recipients.

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