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Department of Virology, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Virology, Academic Medical Center, Amsterdam, The Netherlands
Department of Virology, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Virology, Academic Medical Center, Amsterdam, The Netherlands
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.
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 (
). 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 (
). 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 (
). 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 (
). 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 (
). 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 (
). 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 (
). 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 (
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 (
). In an Australian cohort of transplant recipients a standardized incidence ratio for cervical cancer of 3.3 was calculated compared with the normal population (
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 (
). 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) (
) 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 (
Detection of epidermodysplasia verruciformis-like human papillomavirus types in malignant and premalignant skin lesions of renal transplant recipients.
Nested PCR approach for detection and typing of epidermodysplasia verruciformis-associated human papillomavirus types in cutaneous cancers from renal transplant recipients.
High frequency of detection of epidermodysplasia verruciformis-associated human papillomavirus DNA in biopsies from malignant and premalignant skin lesions from renal transplant recipients.
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.
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.
Human papillomavirus DNA in non-melanoma skin cancers of a renal transplant recipient: detection of a new sequence related to epidermodysplasia verruciformis associated types.
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.
). 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 (
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%) (
) (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 (
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).
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) (
). 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 (
). 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 (
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 (
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 (
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) (
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 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).
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 (
High frequency of detection of epidermodysplasia verruciformis-associated human papillomavirus DNA in biopsies from malignant and premalignant skin lesions from renal transplant recipients.
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 EV-HPV infection in organ-transplant recipients may persist for many years, suggesting that organ transplant recipients are prone to persistent cutaneous HPV infection (
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 (
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, 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 (
). 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 (
). 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 (
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 (
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.
). 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 (
). 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 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 (
). 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 (
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 (
). 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 (
). 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 (
). 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 (
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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Human papillomavirus infection and cervical intraepithelial neoplasia in women with renal allografts.
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.
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.
Nested PCR approach for detection and typing of epidermodysplasia verruciformis-associated human papillomavirus types in cutaneous cancers from renal transplant recipients.
Human papillomavirus DNA in non-melanoma skin cancers of a renal transplant recipient: detection of a new sequence related to epidermodysplasia verruciformis associated types.
High frequency of detection of epidermodysplasia verruciformis-associated human papillomavirus DNA in biopsies from malignant and premalignant skin lesions from renal transplant recipients.
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.
Detection of epidermodysplasia verruciformis-like human papillomavirus types in malignant and premalignant skin lesions of renal transplant recipients.
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