Human papillomavirus and squamous cell cancer of the skin--epidermodysplasia verruciformis-associated human papillomavirus revisited.

As squamous cell cancer (SCC) is the most common malignancy in organ transplant recipients, a viral etiology has been proposed. Human papillomavirus (HPV) is found more often in organ transplant recipients than in the general population, but its role in cancer development has been debated for years. As a model of susceptibility of HPV the inherited disease epidermodysplasia verruciformis (EV) has been investigated intensively. EV is an autosomal-recessive skin disease leading to multiple flat warts and pityriasis versicolor-like macules in early youth. EV patients are at great risk of developing skin cancer due to a lack of defense against beta HPV. Beta HPV are causally involved in the formation of skin cancer in patients afflicted with EV. Beta HPV has frequently been detected in SCC and its early lesions such as actinic keratoses. Depending on the methods used, a prevalence of 30-90% has been reported for beta HPV for SCC in organ transplant recipients, while this prevalence in the general population is lower, but still considerable at 50%. Epidemiologic studies in the general population seem to suggest that beta HPV plays a role in the formation of SCC, both for invasive and in situ lesions.

Epidermodysplasia verruciformis associated with plasmablastic lymphoma and hepatitis B virus infection.

Epidermodysplasia verruciformis is a rare genodermatosis characterized by inherited susceptibility to infection with certain papillomaviruses, which leads to the development of disseminated plane wart-like lesions. In some patients, lesions resembling pityriasis versicolor appear. Epidermodysplasia verruciformis has also been reported in immunosuppressed patients, most notably those with HIV infection. The affected patients are predisposed to development of skin and mucosal malignancies. We describe the rare occurrence of plasmablastic lymphoma in a patient with long lasting epidermodysplasia verruciformis and hepatitis B virus infection.

Seroreactivity of 38 human papillomavirus types in epidermodysplasia verruciformis patients, relatives, and controls.

Epidermodysplasia verruciformis (EV) is a rare recessive genodermatosis characterized by high susceptibility to infections with human papillomaviruses (HPVs) of genus beta. Knowledge about seroreactivity against HPV in these patients and their first-degree relatives is scarce. Using multiplex serology, we analyzed antibodies to 38 HPV types from five genera in 32 EV patients, 22 first-degree relatives, and 64 and 44 age- and sex-matched, non-related, healthy controls, respectively. EV patients showed higher seroprevalences than non-related controls with statistically significant odds ratios (ORs) for 5 of 10 investigated alpha (OR range 6.9-21.3), all 16 beta (OR range 12.3-61.3), 3 of 9 gamma (OR range 6.4-11.7), and 1 of 2 micro HPVs (OR 5.8). In comparison to their relatives, antibodies in EV patients were significantly more prevalent for 4 of 16 beta HPVs (OR range 12.5-25.6), but for none of the other genera. A significantly increased seroprevalence in relatives compared with their controls was only seen for HPV 5 (OR 22.1). The considerably elevated HPV seroprevalence in EV patients, especially for beta papillomaviruses (PVs), reflects the high viral load described for these individuals. Whether the observed differences between relatives and healthy controls depend on heterozygosity for EV-associated alleles requires further investigation.

Detection of antibodies against epidermodysplasia verruciformis-associated canine papillomavirus 3 in sera of dogs from Europe and Africa by enzyme-linked immunosorbent assay.

The role of papillomaviruses (PVs) in the development of canine cancers is controversial. However, recently a novel canine PV (CPV3) was detected in a dog affected with a condition reminiscent of epidermodysplasia verruciformis (EV). The aim of the present study was to investigate the seroprevalence of CPV3 by using generic enzyme-linked immunosorbent assays (ELISAs) for the detection of antibodies against either canine oral PV (COPV) or CPV3. Therefore, the capsid proteins of both PV types were expressed as glutathione S-transferase fusion protein antigens and adsorbed to glutathione-casein-coated ELISA plates. After showing that PV type-specific antibodies could be detected in the sera from dogs with confirmed COPV or CPV3 infection, CPV3- and COPV-seropositive samples were detected in two sets of canine sera collected in Switzerland and South Africa, respectively. We found specific antibodies against COPV and CPV3 among the tested sera and also a large number that were positive for both antigens. The seroprevalences of PV antibodies of 21.9% (COPV) and 26.9% (CPV3) among the tested dogs from South Africa were higher than those among the dogs from Switzerland at 10.5% (COPV) and 1.3% (CPV3). Our data suggest a need for further CPV-related seroepidemiological surveys in different countries, especially in the context of clinical manifestations and possible breed predispositions. For this purpose, the newly developed ELISAs can be a useful tool.

Epidermodysplasia verruciformis-associated and genital-mucosal high-risk human papillomavirus DNA are prevalent in nevus sebaceus of Jadassohn.

BACKGROUND: The hamartoma nevus sebaceus (NS) presents at birth or early childhood as a yellowish plaque characterized histologically by variable acanthosis, papillomatosis, sebaceus hyperplasia, and proliferations of adnexal structures. Clinically apparent human papillomavirus (HPV) infection is also recognized by acanthosis and papillomatosis. OBJECTIVE: We sought to determine the prevalence and physical state of HPV DNA in NS. METHODS: DNA was retrieved from 44 formalin-fixed, paraffin-embedded samples of NS (22 with secondary tumors [eg, trichoblastoma, verruca, syringocystadenoma papilliferum] and two epidermal nevi [EN]). Nested polymerase chain reaction with multiple degenerate consensus and type-specific primers and direct sequencing of polymerase chain reaction products was performed. For selected cases, in situ hybridization using probes specific for HPV 5 and 8 and for high-risk genital-mucosal HPV types was performed. RESULTS: HPV DNA was detected in 82% of NS and both EN, and consisted of genital-mucosal HPV types in 52% (HPV 6, 16, and 33) and a diverse variety of epidermodysplasia verruciformis-associated HPV types in 61%, including well-known epidermodysplasia verruciformis HPV types (5, 8, 15, 20, 22, 24, 36, 37, 38, and 80) and putatively novel epidermodysplasia verruciformis HPV types (DL285, DL287, DL436, and alb-1, -2, -3, -5, -6, -7, -8, -10, -11, -12, and -13). HPV coinfection was frequent, found in 48% (two HPV genotypes in 35% and 3 in 13%). Of NS and EN, 42% had HPV genotypes associated with cancer (ie, HPV 5, 8, 16, 20, 33, and 38); the two most commonly identified HPV types where HPV 16 (39%) and HPV 38 (18%). No differences were detected comparing frequency of HPV DNA detected with respect to age or presence of a secondary tumor. Histologically, all NS and EN showed HPV-associated cytopathic effects (ie, perinuclear halos, altered keratohyaline granules). By in situ hybridization, 64% (18/28) were positive, showing a low-intensity, punctate nuclear signal in epidermal and adnexal keratinocytes, indicating viral integration and low viral genome copy number. LIMITATIONS: Absence of adjacent, uninvolved normal-appearing skin control samples. CONCLUSION: HPV DNA is prevalent in NS, and HPV 16, the most frequently detected genotype, appears to be integrated into the host genome. Whether HPV represents a commensal infection caused by localized cutaneous predisposition, or is an essential factor in the pathogenesis of NS is unknown. The high frequency of oncogenic HPV types implicates maternal transmission of HPV and infection of an ectodermal stem cell leading to an epigenetic mosaic and altered skin development manifested along Blaschko's lines.

Human papillomavirus infection and ultraviolet light exposure as epidermoid inclusion cyst risk factors in a patient with epidermodysplasia verruciformis?

Epidermoid inclusion cysts are common lesions with unclear etiology. We sought to examine evidence for human papillomavirus (HPV) infection and ultraviolet light (UV) exposure as risk factors in the formation of epidermoid inclusion cysts. We performed HPV typing of biopsied cysts with polymerase chain reaction for a patient with darkly-pigmented skin, epidermodysplasia verruciformis (EV) and more than 250 photodistributed cysts. HPV types 8 and 6 DNA was demonstrated within biopsy specimens of 3 cysts. In one biopsy specimen, abnormal keratinocytes bridging the follicular infundibulum were seen. We concluded that UV exposure and HPV viral infection may be risk factors for the formation of epidermoid inclusion cysts.

[Epidermodysplasia verruciformis: clinicaland epidemiological features of 45 cases in the Department of Dermatology at the University Hospital Center of Yalgado Ouedraogo, Ouagadougou]. / Epidermodysplasie verruciforme: aspects epidémiologiques et cliniques de 45 cas dans le service de Dermatologie du Centre Hospitalier Universitaire Yalgado Ouédraogo, Ouagadougou.

INTRODUCTION: The epidermodysplasia verruciformis is a rare, autosomic, recessive, genodermatose characterized by a chronic, disseminated, cutaneous infection with human papillomavirus. The majority of these patients have a genetic or acquired immunodeficiency. PATIENTS AND METHODS: This retrospective study was conducted on the records of all patients who presented in our dermatology department with an epidermodysplasia verruciformis in a 13 years and 6 months period, from January 1st, 1992 to June 30th, 2005. RESULTS: We have collected 45 cases of epidermodysplasia verruciformis. They were aged from 3 to 57 years, with a mean of 24.6 years. The most concerned age bracket was that from zero to 9 years. They were 29 women (64.4%) and 16 men (35.6%). The eruption presented as papules of 2 to 3 mm size, associated with hypochromic, finely squamous macules with the same size. We noted three cases of itching. We found 37.7% of family cases. We observed 14 cases of HIV positive patients and one case of cancer. CONCLUSION: This study confirmed that the epidermodysplasia verruciformis was rare. Genetic factors or immunodeficiency would support the appearance of the disease.

Sunlight exposure and (sero)prevalence of epidermodysplasia verruciformis-associated human papillomavirus.

Ultraviolet radiation (UVR) is associated with an increased risk of squamous cell carcinoma (SCC), which is in part due to immunomodulation. In addition, human papilloma virus (HPV), especially the epidermodysplasia verruciformis (EV)-associated types, may be involved. In view of the capacity of UVR to impair host resistance to infections, we investigated the relationship between solar exposure and the prevalence of cutaneous HPV. In a case-control study on skin cancer (320 controls and 156 patients) a lifetime-retrospective questionnaire on sun exposure was administered. The presence of DNA of HPV types 5, 8, 15, 20, 24, and 38 in plucked eyebrow hair and type-specific seroreactivity were assessed and analyzed in relation to estimated exposure. Sunburn episodes in the past, especially at age 13-20 y, appeared to be associated with an enhanced risk of EV-HPV DNA positivity. In contrast, a higher lifetime sun exposure was associated with a lower risk of HPV infection. These results indicate that UVR at erythematogenic doses increases the risk of EV-HPV infection, possibly due to impaired host resistance to HPV and/or a direct effect of UVR on viral replication. The favorable association between lifetime sun exposure and HPV prevalence, however, underscores the enigmatic role of HPV in skin carcinogenesis.

Clinical aspects of epidermodysplasia verruciformis.

Thirteen patients with epidermodysplasia verruciformis (EV) were studied over a period of 7 years. EV is a rare genodermatosis characterized by a generalized infection with a specific group of human papilloma virus (HPV) and a propensity for developing skin malignant tumours in 30%-50% of patients. The diagnosis of EV was confirmed by histopathological and immunohistochemical findings. Three of our patients had the benign form of EV, which is characterized by monomorphous lesions and no malignant changes, whereas 10 had the malignant form, which is characterized by polymorphic lesions and development of cutaneous malignant tumours. All EV patients with the malignant form developed multiple skin tumours (77%). They started to appear at age 20, predominantly on the forehead (50%). Most were squamous cell carcinoma, extremely aggressive and invasive, which provoked metastasis and death in two patients.

Seroreactivity to epidermodysplasia verruciformis-related human papillomavirus types is associated with nonmelanoma skin cancer.

DNA from epidermodysplasia verruciformis-related human papillomavirus (EV-HPV) types is frequently found in nonmelanoma skin cancer (squamous and basal cell carcinoma). Epidemiological studies that investigate the relation between EV-HPV infection and nonmelanoma skin cancer are scarce. We designed a case-control study in which we looked for HPV infection in 540 cases with a history of skin cancer and 333 controls. By measuring seroreactivity to L1 virus-like particles of EV-HPV types 5, 8, 15, 20, 24, and 38 and the genital type HPV16 and by estimating the skin cancer relative risk among HPV seropositives, we analyzed whether EV-HPV serorecognition is associated with nonmelanoma skin cancer. Seroreactivity to five of the six EV-HPV types tested (HPV5, 8, 15, 20, and 24) was significantly increased in the squamous cell carcinoma cases. After adjusting for age and sex, the estimated squamous cell carcinoma relative risk was significantly increased in HPV8 and HPV38 seropositives [odds ratio (OR) = 14.7 (95% confidence interval (CI), 1.6-135) and OR = 3.0 (95% CI, 1.1-8.4), respectively]. The estimated relative risk for nodular and superficial multifocal basal cell carcinoma was also significantly increased in the HPV8 seropositives [OR = 9.2 (95% CI, 1.1-78.2) and OR = 17.3 (95% CI, 2.1-143), respectively] and in the HPV20 seropositives [OR = 3.2 (95% CI 1.3-7.9) and OR = 3.4 (95% CI 1.2-9.5), respectively]. The relative risk of developing malignant melanoma was not increased among HPV seropositives, and no associations were found for HPV16. Restricted analyses among the HPV seropositives only, to exclude distortion by interindividual differences in seroresponsiveness, underscored the significance of our findings. Restricted analyses among patients with skin cancer only, however, revealed that EV-HPV seropositivity was not significantly more present in patients with nonmelanoma skin cancer than in those with melanoma skin cancer. Taken together, our results indicate that EV-HPV serorecognition is nonspecifically associated with nonmelanoma skin cancer and suggest that EV-HPV-directed seroresponses are induced upon skin cancer formation, rather than upon infection.

Epidemiologic aspects of epidermodysplasia verruciformis (L-L 1922) in Japan.

A survey of epidermodysplasia verruciformis (EV), a skin disease caused by human papillomavirus (HPV), was made by means of a questionnaire sent to 92 university hospitals. Replies were obtained from 68 hospitals (74% recovery) reporting 66 patients. Fewer patients were reported from north-eastern Japan than from south-western Japan. Many EV patients were from families of consanguineous marriages (44%), showing a high incidence of intra-familial onset after consanguineous marriages. The complication of malignant tumors was observed in 36 of 62 cases (58%). Malignant tumors of the skin developed at an early age in EV patients. These cancers developed predominantly in exposed areas of the skin (72%). The time from onset of skin lesions to the onset of cancer seemed to be related to the nature of the lesions in EV patients. These findings suggest that the interaction of HPVs, ultraviolet rays and host factors is associated with the development of skin carcinomas.