Types of human papillomavirus isolated from Japanese patients with epidermodysplasia verruciformis

Virological studies were performed on 12 patients with epidermodysplasia verruciformis (EV). Three types of lesions were observed: red plaques, pityriasis versicolor (PV)-like macules and plane warts. Human papillomavirus (HPV) 14, 20 and 21 were isolated from the plaques, HPV 3, 14 and 38 from flat warts and HPV 5, 12, 17, 20 and 38 from PV-like lesions. No clear relationship could be established between the different lesions and the types of HPV. Types 17 and 20 have been isolated most frequently from Japanese EV patients and HPV 5, frequently detected in other countries, is less common, whereas HPV 8 has not been isolated. Skin cancers occurred in six of the cases (50%) and all had benign lesions that were PV-like. At least one type of HPV 5, 17 or 20 could be isolated from these benign lesions and HPV 17 or 20 detected in the cancers. These three types of HPV in EV patients appear to be involved in the malignant transformation.     

Human papillomavirus infection in Netherton's syndrome

BACKGROUND: Netherton's syndrome (NS) is a hereditary disorder with dermatological signs (e.g. ichthyosis) and a complex immunological dysfunction. In immunodeficient individuals human papillomavirus (HPV) types are associated with carcinomas on non-mucosal sites. OBJECTIVES: To study the presence of HPV infection in different skin lesions of three male NS patients and to investigate a possible association between HPV and malignancies in NS. METHODS: Patient 1 had extraordinary widespread multiple skin carcinomas on sunlight-exposed areas, as well as common viral warts. Patient 2 showed disseminated viral plane warts that resolved spontaneously, and patient 3 was free of skin lesions suspicious for HPV infection; only pseudoepitheliomatous wart-like lesions as a symptom of ichthyosis were apparent. We performed nested polymerase chain reaction analysis of DNA from benign and malignant skin lesions and HPV-8 serology in these three patients. RESULTS: Antibodies to HPV-8 were not detectable in our patients; however, seven of 22 (31%) biopsies of the three NS patients were positive for HPV DNA. Epidermodysplasia verruciformis (EV) -associated HPV types and normal cutaneous types (HPV-2, HPV-28) were detected. Interestingly, only the patient with cutaneous carcinomas harboured, preferentially in malignant lesions, EV-HPV types (HPV-19, 23, 38 and HPV-RTRX9, closely related to EV-HPVs), whereas plane warts of patient 2 were positive for HPV-28. The pseudoepitheliomatous skin lesions were HPV-DNA negative in all investigated probes. CONCLUSIONS: These data in NS patients further confirm an association of EV-HPVs with non-melanoma skin cancer (NMSC) and suggest a possible carcinogenic role similar to that assumed for NMSC in transplant recipients. A complex immunological disorder facilitating EV-HPV infection, negative HPV serology and photochemotherapy may all have contributed to the unusual occurrence of multiple cancers in one of our NS patients.     

Different papillomaviruses as the causes of oral warts

We have observed four patients with oral papillomas. Two children had oral mucosal lesions characteristic of focal epithelial hyperplasia, a young man had common, wart-like lesions on his hard palate, and a male immunosuppressed renal allograft recipient had condyloma-like lesions on his gingivae. Papillomavirus-like particles were seen by electron microscopy in lesions from both patients with focal epithelial hyperplasia. No structural antigens for human papillomavirus (HPV) 1, 2, 3, or 5 were found by immunofluorescent microscopy, but further evidence of the presence of a papillomavirus was found by immunoperoxidase microscopy using a cross-reacting sodium lauryl sulfate-disrupted bovine papillomavirus 1 anti-rabbit serum sample. The distinct histologic pattern seen in focal epithelial hyperplasia suggests that a yet undescribed HPV type might be associated with this disease. Histologic, ultrastructural, and immunofluorescent microscopy and restriction endonuclease analysis all gave evidence of HPV 2 in the palatal lesions in patient 3. Evidence of papillomavirus antigen was found by immunoperoxidase microscopy in the oral condylomas from our immunosuppressed patient.     

Epidermodysplasia verruciformis occurring in a patient with human immunodeficiency virus: a case report

Epidermodysplasia verruciformis (EV) is an uncommon dermatosis associated with human papillomavirus (HPV) infection in association with defects in cell-mediated immunity. Malignant transformation to squamous cell carcinoma has been associated with lesions caused by HPV-5, HPV-8, and HPV-14. Clinically, the disease may be confused with verruca plana, seborrheic keratosis, and pityriasis versicolor. We present an unusual case of EV occurring in a human immunodeficiency virus (HIV)-positive man and discuss the clinical and histologic findings. Clinically, the patient had 1- to 3-mm hypopigmented smooth macules covering the entire body. Histopathologic examination of the skin biopsy results demonstrated enlarged keratinocytes with prominent blue-gray cytoplasm and clumping of keratohyalin granules within the granular layer of the epidermis. Although EV typically is viewed as a disease of childhood, sometimes presenting in patients with a family history of the disease, it rarely may be seen in immunocompromised adults.     

Human papillomavirus infections in a group of renal transplant recipients

One hundred and twenty renal transplant recipients were investigated. Fifty-eight (48%) were found to have warts, 13 (11%) keratoses and six (5%) to have, or recently to have had cancers. The longer the time of immunosuppression, the greater the prevalence of warts; of those patients who had had their transplant for at least 5 years, 87% had warts. Those with a graft survival time of 10 years or more are at special risk of warts, keratoses and malignancy. Five (10%) of 50 women had genital warts, four of whom had internal lesions (vaginal, cervical or anal) and one developed a carcinoma of the vulva. These findings indicate the advisability of colposcopy for all female renal transplant recipients, a high risk group. Eighty-eight specimens from 42 patients were examined by DNA restriction enzyme analysis and cross hybridization for the presence and type of human papillomavirus (HPV). HPV DNA was detected in 66% of the warts examined, HPV2 and HPV4 occurring most often and HPV1 and HPV3 only infrequently. In sequential specimens from common hand warts of one individual, an HPV was found which could not be precisely identified but was related to HPV4. HPV16 was detected in a vaginal wart from one patient and an HPV6-related virus in a vulval wart of another. HPV DNA of an unknown type was demonstrated in one of 11 keratoses examined. With the probes used to examine the few samples of skin cancers available, HPV16 was found in a squamous cell carcinoma of the vulva, and faint bands from an unidentified type of HPV were detected in two squamous cell carcinomata from a patient's hand. One woman had plaque lesions morphologically and histologically resembling those found in epidermodysplasia verruciformis (EV). HPV5 was identified in these lesions. This is only the third reported case of HPV5, previously thought to be unique to EV, in a renal transplant recipient.     

T cell defect in patients with epidermodysplasia verruciformis due to human papillomavirus type 3 and 5

Most of the patients with epidermodysplasia verruciformis (EV) were anergic to sensitization to dinitrochlorobenzene (DNCB) and were shown to have a decreased number of T lymphocytes and reduced lymphocyte PHA responsiveness. Preserved cell-mediated immunity (CMI) was found only in the abortive cases of EV infected with human papillomavirus type 3 (HPV-3). CMI was impaired to the same extent in patients with EV induced by HPV-3 and HPV-5, and in EV cases with combined infection with both viruses. In contrast to this, malignant transformation, i.e. of Bowen's carcinoma type, was observed only in the 7 patients infected with HPV-5. This could indicate that malignancy in EV is related rather to the oncogenic potential of HPV-5 type than to the extent of T cell defect that was similar in both EV varieties due to HPV-3 and HPV-5.     

Polyclonal antibody to human papillomavirus-related antigens specific to epidermodysplasia verruciformis

We have developed a polyclonal antibody for human papillomavirus (HPV)-related antigens specific to epidermodysplasia verruciformis (EV). Using this antibody, immunohistochemical studies on 12 EV patients were performed. The polyclonal antibody was obtained from rabbits immunized with roughly purified virions of HPV from an EV patient. Sections from 12 EV patients were treated with the polyclonal antibody and then the peroxidase-antiperoxidase method was used to observe the reaction. The observations revealed not only papillomavirus genus-specific common structural antigen (pgs-antigen) but also HPV-related antigens specific to EV. Pgs-antigen was observed in the nuclei of the upper keratinized cells of the benign lesions and HPV-related antigens specific to EV were observed in the nuclei and cytoplasm of both keratinizing cells of the benign lesions and malignant skin tumor cells. HPV-related antigens specific to EV were observed in sections of all 12 EV patients infected by HPV-5, 5-related, 14, 20, 21 and 38, but not in sections of other HPV infections. Using the immunoblot technique, we detected the main papillomavirus structural polypeptide (MW, 58 Kd) and two other unknown proteins (MW, 42 Kd and 33 Kd) in the benign lesion of an EV patient. Two proteins (MW, 42 Kd and 33 Kd) were also detected in the malignant tumor of the EV patients we consider these proteins to be HPV-related antigens specific to EV.     

Skin cancers and HLA frequencies in renal transplant recipients.

An association between HLA DR7 and the development of multiple non-melanoma skin cancer was detected in immunosuppressed patients in southern Australia. The relative risk was 2.6 which was lower than for immunocompetent patients with the same skin cancers. HLA frequencies of renal transplant recipients with multiple skin cancers were determined. The types HLA B27 and HLA Dr7 were found in significantly higher frequency, and there was no absence of HLA A11.     

Human papillomavirus type 5 is commonly present in immunosuppressed and immunocompetent individuals

DNA of a wide spectrum of epidermodysplasia verruciformis-associated human papillomavirus (HPV) types (EV-HPV) has been detected in skin lesions and plucked hairs from both immunosuppressed and a considerable proportion of non-immunosuppressed persons. Recently, the skin of psoriatic patients was claimed to be an important reservoir for a particular EV-HPV type, HPV 5, which is considered as a high-risk HPV type for skin carcinomas. In the present study, we analysed plucked hairs from immunosuppressed renal transplant patients and immunocompetent individuals, utilizing an HPV 5-specific nested polymerase chain reaction. HPV 5 was detected in hairs derived from 14 of 31 (45%) immunosuppressed patients and 21 of 135 (16%) immunocompetent individuals. Both the immunosuppressed and the immunocompetent groups consisted of individuals with and without non-melanoma skin cancer. HPV 5 DNA was detected in similar proportions of hair samples plucked from individuals with and without skin cancer in either group. Our results indicate that HPV 5 is commonly present in the population. The role of HPV 5 in the pathogenesis of skin carcinomas and psoriasis remains to be established.     

Human papillomavirus (HPV) types specific of epidermodysplasia verruciformis detected in warts induced by HPV3 or HPV3-related types in immunosuppressed patients.

Epidermodysplasia verruciformis (EV) is characterized by an abnormal genetic predisposition to infection with specific types of human papillomavirus (HPV). Specific defects of the cell-mediated immunity and/or of the control of HPV infection in keratinocytes are assumed to be involved in the development of the disease. As a model to test this hypothesis, we have studied the prevalence of EV-specific HPV in skin warts of 56 immunosuppressed patients. All main types of cutaneous HPV (HPV1, 2, 3, 4, 10, and 28) responsible for skin warts in the general population were detected by blot hybridization. EV-specific HPV (HPV5, 20, and 23) were detected in three patients. Four additional patients were found infected with HPV49, first characterized in the course of this study, and found to be related to EV HPV. A most important finding was that HPV5, 20, 23, and 49 were always codetected with HPV3 or the related types HPV10 and 28. None of the specimens showed the typical clinical morphology of EV lesions. In none of these specimens was the specific cytopathic effect of EV recognized; instead that of HPV3 and related types was seen. No evidence for productive EV HPV DNA replication was obtained for the three specimens that could be further analyzed by in situ hybridization. Our data suggest that HPV3 infection favors infection with EV HPV in immunosuppressed patients but that the full expression of EV HPV is usually restricted as in the general population.     

Human papillomavirus heterogeneity in 36 renal transplant recipients

Immunosuppressed patients such as renal transplant recipients are prone to increased incidence of wart disease. We examined 48 tissue specimens from 36 renal transplant recipients using human papillomaviruses (HPVs) 1, 2, 3, 4, 5, and 6 in filter hybridization under stringent conditions. The results showed that 90% of the samples contained HPV DNA. Of these 43 positive samples, we found HPV-1 in 2%, HPV-2 in 56%, HPV-3 in 19%, HPV-4 in 47%, HPV-5 in 9%, and HPV-6 in 5%. In several cases, more than one type of HPV DNA was observed. In a few of these cases, the clinical appearance of the lesions differed from what might have been expected, such as those lesions containing HPV-3- or HPV-5-related DNAs.     

Do epidermodysplasia verruciformis human papillomaviruses contribute to malignant and benign epidermal proliferations?

The aim of this review is to present new data on epidermodysplasia verruciformis (EV) and EV human papillomaviruses (HPVs), regarded previously as specific to the disease. Recently introduced highly sensitive molecular methods for virologic studies allow detection of EV HPVs in non-EV populations. In this article, we present the most recent findings on EV and EV HPVs, which shed new light on a possible contribution of EV viruses to malignant and benign epidermal proliferation. We discuss the significance of EV HPV DNA detection in premalignant cutaneous lesions and nonmelanoma skin cancers; however, direct evidence for the causative role of EV HPV is still not available. In psoriasis, a high frequency of EV HPV-5 and other EV HPVs in the skin and the presence of specific HPV-5 antibodies strongly suggest expression of EV HPV proteins in this extensive epidermal proliferation. Epidermodysplasia verruciformis HPV-5 may also be transiently expressed in epidermal repair processes, whereas in psoriasis there is a continuous epidermal proliferation that could result in persistent viral expression. A potential contribution of EV HPVs to the pathogenesis of psoriasis is also supported by the recently disclosed co-localization of susceptibility loci for psoriasis and EV in the same region of chromosome arm 17qter; however, specific genes for both conditions are still not identified.     

Vulval intraepithelial neoplasia and periungual Bowen's disease concordant for mucosal (HPV-34) and epidermodysplasia verruciformis (HPV-21) human papillomavirus types

Human papillomavirus (HPV) infection is associated with genital malignancy and specific cutaneous malignancies. We report a case of an HPV-associated concurrent vulval intraepithelial neoplasia and periungual Bowen's disease in a young immunocompetent Afro-Caribbean woman with no known risk factors for either disease. HPV genotyping studies detected multiple alpha and beta papillomaviruses with concordance for HPV-34 [a high-risk (HR) mucosal type], and HPV-21 [an epidermodyslasia verruciformis (EV) type] in both vulval and finger tissue. Although the HR-mucosal viruses detected are likely to have a pathogenic role in vulval intraepithelial neoplasia, this is the first report of concordance for EV HPV types in both genital and nongenital skin premalignancies. This case, in the context of accumulating epidemiological and experimental data in cutaneous SCC, raises the question of whether EV HPV may contribute to vulval malignancy, and further study is merited.     

Seborrheic Keratosis-like lesions in patients with epidermodysplasia verruciformis

Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by disseminated infection by human papillomavirus (HPV) and malignant transformation of the lesions in about half of the patients. Two phenotypes of EV have been described according to their propensity to develop malignant tumors. The benign form of EV presents a singular type of lesions comprised of flat warts widely disseminated. The malignant form of EV is highly polymorphic and presents as malignant skin tumors, predominantly basal and squamous cell carcinomas, on sun-exposed sites. The seborrheic keratosis-like (SK) lesions in patients of EV have been reported to be associated with the malignant phenotype. In this work, we documented the behavior of SK-like lesions in nine patients with EV, through clinical observations as well as histological and immunohistochemical findings. We suggest that the HPV infection may promote the occurrence of SK-like lesions in EV patients. Despite the fact that we did not observe any malignant transformation of these lesions in our series of patients, this possibility was not completely excluded.     

TP53 polymorphism of exon 4 at codon 72 in cutaneous squamous cell carcinoma and benign epithelial lesions of renal transplant recipients and immunocompetent individuals: lack of correlation with human papillomavirus status

A common polymorphism at codon 72 of exon 4 encoding either arginine or proline has been shown to confer a susceptibility to the development of skin tumor in renal transplant recipients. Moreover, this polymorphism may affect proteolytic degradation of p53 promoted by E6 protein from mucosal human papillomaviruses and represent a risk factor for human-papillomavirus-induced carcinogenesis. In this study, we analyzed the human papillomavirus presence and the TP53 allele distribution in cutaneous squamous cell carcinoma of renal transplant recipients and immunocompetent patients. Fifty-three squamous cell carcinomas from 40 renal transplant recipients, 50 benign epithelial skin lesions from 50 renal transplant recipients with no history of skin cancer, 51 squamous cell carcinomas from immunocompetent patients, and 29 blood samples from immunocompetent individuals without skin cancer were investigated. Human papillomavirus DNA was detected using polymerase chain reaction performed with two pairs of primers (MY09-MY11 and FAP59-FAP64). TP53 allele distribution was studied by denaturing gradient gel electrophoresis assay, followed by sequencing analysis. Human papillomavirus DNA was detected in 64% of squamous cell carcinoma and 79% of benign epithelial lesions from renal transplant recipients (NS) and only in 37% of squamous cell carcinoma from immunocompetent patients (p < 0.05). Mucosal oncogenic human papillomavirus types were predominant in squamous cell carcinoma from both renal transplant recipients and immunocompetent patients. Rate of arginine homozygosity in squamous cell carcinoma from renal transplant recipients was significantly higher (83%) than in immunocompetent patients with or without squamous cell carcinoma (60% and 59%, respectively). Our results suggest that TP53 arginine/arginine genotype could represent a potential risk factor for the development of squamous cell carcinoma in renal transplant recipients compared to immunocompetent patients. No association between TP53 arginine/arginine genotype and human papillomavirus status could be determined, however.     

Human papillomavirus type 16 in bowenoid papulosis, intraoral papillomas, and squamous cell carcinoma of the tongue

A 33-year-old immunosuppressed man developed bowenoid papulosis on his genitalia, velvety papules and plaques in his mouth, and invasive squamous cell carcinoma of his tongue. All three lesions were positive for human papillomavirus type 16 (HPV-16). The case provides further circumstantial evidence for a role of HPV-16 in epithelial neoplasia. The possible roles of a second HPV infection and of immunosuppression are also discussed.     

CO2 laser treatment of warts in immunosuppressed patients

BACKGROUND: A large proportion of chronically immunosuppressed patients suffer from recalcitrant viral warts. Furthermore, the incidence of nonmelanoma skin cancer is clearly elevated in this patient group and human papillomavirus is most likely to play a causal role in these neoplasms. OBJECTIVE: To analyze the effectiveness of treatment of viral warts with the CO(2) laser in immunosuppressed patients. METHODS: Multiple viral warts of 13 patients with immunosuppression, a majority of them renal allograft recipients, were treated with CO(2) laser in local or regional anesthesia. In case of recurrences, the lesions were treated again after 3 months. RESULTS: 12 of 13 patients experienced dramatic improvement after 1-3 treatment sessions, 6 of these patients showed full remission. Side effects such as postoperative pain or scarring were minimal. CONCLUSION: CO(2) laser treatment of recalcitrant warts in immunosuppressed patients shows promising results which are comparable to those in immunocompetent hosts. This offers a welcome enlargement of the array of therapies in this otherwise difficult-to-treat group of patients and may contribute to the reduction of risk factors for nonmelanoma skin cancer.     

Detección del virus del papiloma humano en muestras de cáncer cutáneo no melanoma y piel sana perilesional en pacientes trasplantados renales y pacientes inmunocompetentes

BackgroundThe influence of human papillomavirus (HPV) on the development of nonmelanoma skin cancer (NMSC) is a topic of debate. HPV types from the beta genus (HPV-β) have been most frequently associated with the development of skin cancer.ObjectivesTo analyze the prevalence and range of HPV types in NMSC lesions and healthy perilesional skin in immunodepressed and immunocompetent patients and to evaluate the influence of various clinical factors on the prevalence of HPV in skin cancer.MethodsNested polymerase chain reaction and sequencing were used to detect HPV in 120 NMSC samples obtained by biopsy from 30 kidney transplant recipients and 30 immunocompetent patients. In all cases, a sample was taken from the tumor site and the surrounding healthy skin. Potential confounders were assessed and the data analyzed by multivariate logistic regression.ResultsHPV DNA was detected in 44 (73.3%) of the 60 samples from immunodepressed patients and in 32 (53.3%) of the 60 samples from immunocompetent patients (adjusted odds ratio, 3.4; 95% CI, 1.2-9.6). In both groups of patients, HPV was more common in healthy perilesional skin than in lesional skin. HPV-β was the most common type isolated.ConclusionWe found a wide range of HPV types (mostly HPV-β) in the skin of kidney transplant recipients and immunocompetent patients with skin cancer.     

Detection of a human papilloma virus type 5 DNA in a renal allograft patient from Scotland

A renal allograft recipient with small raised red scaly lesions on a forearm is described. The clinical and histological picture was that of similar lesions reported in some epidermodysplasia verruciformis patients. Virological investigations revealed the presence of human papilloma virus type 5; this is the second report of the occurrence of this type in allograft patients. As human papilloma virus type 5 is known to have malignant potential, clinicians should be on the lookout for these banal-looking and distinctly non-warty lesions in renal transplant recipients. Close follow-up is indicated.     

Low-dose retinoid therapy for chemoprophylaxis of skin cancer in renal transplant recipients

Background Renal transplant recipients have an increased incidence of skin cancers, which may be multiple and aggressive. Objectives The purpose of this study was to examine the chemoprophylactic effects of low-dose etretinate (0.3 mg/kg/day) on skin cancer development in renal transplant recipients and to monitor retinoid toxic effects at this dose. Methods All skin lesions were counted and photographed prior to therapy with etretinate. Patients were assessed at monthly intervals for new skin lesions and for retinoid toxicity. Results Eleven renal transplant recipients participated. There was a significant reduction in the number of skin cancers which occurred during etretinate therapy compared with pre-treatment for 3 and 6 months of treatment, and a trend towards fewer skin cancers in the 12 and 18 month treatment periods. Side-effects were well-tolerated and no significant biochemical effects were observed. Conclusion Low dose etretinate is safe, well-tolerated and partially effective in chemoprophylaxis of skin cancer in renal transplant recipients.