A potentially oncogenic human papillomavirus (HPV-5) found in two renal allograft recipients

We have observed 2 immunosuppressed renal allograft recipients with skin lesions induced by human papillomavirus type 5 (HPV-5). One recipient had multiple pityriasis versicolor-like (PV-like) skin lesions on his arms and trunk, and multiple Bowenoid in-situ skin cancers. The other had 2 warty lesions on the back of her fingers. Structural antigens of human papillomavirus type 5 (HPV-5) were identified in benign lesions from both patients by immunofluorescence. The histologic and ultrastructural features observed in lesions from both patients were similar to those previously seen in HPV-5-induced lesions occurring in patients with the rare disease epidermodysplasia verruciformis (EV). The severe form of EV is characterized by HPV-5-induced PV-like lesions, multiple skin cancers, and usually depressed cell-mediated immunity. The picture seen in one of our renal allograft recipients recalls this severe form of EV. HPV-5, until now, has been found only in EV patients. The role of this potentially oncogenic virus in skin cancers which are known to occur with increased frequency in immunosuppressed renal allograft recipients must be determined.     

Intralesional injection of bleomycin sulphate into resistant warts in renal transplant recipients versus non-transplant warty patients.

Sixteen adult renal transplant patients and 20 non-transplant patients with warts underwent intralesional therapy with bleomycin sulphate. One unit/ml bleomycin sulphate was injected in 93 warts in renal transplant recipients and 100 warts in non-transplant patients with proven resistance to conventional treatment for at least 6 months. The treatment was compared with a normal saline placebo injected into the paired warts in the same patient. Thirty-four out of 93 warts (37%) in renal transplant recipients vs. 59 out of 100 warts (59%) in non-transplant patients were completely cured after one to three injections. We found bleomycin completely ineffective in 56 warts (60%) in renal transplant recipients, but ineffective in only 17 warts (17%) in non-transplant warty patients. None of the patients treated experienced any side effects except for local pain which was well tolerated, especially by non-transplant patients.     

Human papillomavirus type 1-associated squamous cell carcinoma in a heart transplant recipient.

The occurrence of squamous cell carcinomas in organ transplant recipients with warts represents a good model to study viral carcinogenesis. Most of the cases were reported in renal transplant recipients. We present the case of a heart transplant recipient in whom multiple common warts, preepitheliomatous keratoses, and squamous cell carcinomas developed. The warts began 4 years after the transplantation and the first carcinoma occurred 2 years after the warts, all the lesions being on sun-exposed areas. Histologic signs of human papillomavirus infection were seen in all premalignant and malignant lesions. Furthermore, human papillomavirus type 1 DNA was detected by in situ molecular hybridization within one of the carcinomas. Human papillomaviruses, along with other carcinogenic factors, play an important role in the development of carcinomas, and benign types could be implicated. Further studies are required to evaluate the frequency of cutaneous malignant neoplasms in heart transplant recipients as compared with renal transplant recipients.     

Verruciform Xanthoma: Report of Five Cases

We describe five cases of verruciform xanthoma (VX). The patients, all males, presented with single warty verrucous lesions of 0.5–2 cm size that had been diagnosed clinically as viral warts (four cases) and leukoplakia (one case). Two patients had the lesion in the oral cavity, two on the genital mucosa, and one on the scrotal skin. Histopathology was diagnostic, with verrucous and papillomatous epidermal hyperplasia with the silhouette of a viral wart but with numerous foamy histiocytes packed in the elongated dermal papillae. Columns of deep parakeratosis and neutrophils in the upper spinous layers, with a dermal plasma cell infiltrate were the other histopathologic findings. Excision of the lesions was curative, without recurrences, in the two patients who had lesions in the oral cavity; follow-up was not available in the cases with genital lesions. VX is an uncommon but distinctive clinicopathologic entity affecting the oral and genital mucosa that may be mistaken for benign, premalignant, and malignant conditions. VX can be diagnosed with certainty only on histopathologic examination.     

Subclinical human papilloma virus infection in condylomata acuminata patients attending a VD clinic.

In 37 (77%) of 48 patients with external genital warts, application of 5% acetic acid revealed areas of acetowhite epithelium. The lesions were not clinically apparent before acetic acid was applied but were easily detected without the use of a colposcope. In a control group of 20 patients with chlamydial urethritis and no history of genital warts, none had acetowhite genital lesions. Histological examination of biopsy specimens from the flat acetowhite lesions showed HPV infection with koilocytosis in 29 (78%) and in 3 (8%) intra-epithelial neoplasia grade II-III. Using in situ hybridization with commercially available biotinylated DNA probes, HPV types 16/18 could be detected in 7 (24%) patients with koilocytosis and in 3 (100%) patients with dysplasia. Simultaneous infection with HPV types 6/11, 16/18, and 31/33/35 was found in 8 of the 13 HPV DNA-positive patients. It is concluded that subclinical HPV-induced acetowhite lesions are common among patients with genital warts and that these flat lesions may be associated with a high grade of dysplasia. Consequently, routine use of the acetic acid test on the genital epithelium is recommended in patients with condylomata acuminata in order to diagnose and treat all HPV-infected areas.     

Prevalence of benign cutaneous disease among Oxford renal transplant recipients

Background The burden of malignant and benign cutaneous disease among renal transplant recipients (RTR) is substantial. Little attention is given to non‐malignant skin problems in the literature despite their potential impact on quality of life or on aesthetics – which may contribute to poor compliance with immunosuppressive medications post‐transplantation. Objectives The aim of this study was to examine prevalence of benign cutaneous disease in a group of RTRs and identify risk factors for individual cutaneous conditions. Methods All cutaneous findings were recorded in a single full body skin examination of 308 RTRs. Data on medical, transplant and medication history were obtained from questionnaire and medical records. Odds ratios were calculated to look at associations between benign cutaneous diseases and various potential risk factors after controlling for gender, age, time since transplantation and skin type. Results Cutaneous infections such as viral warts (38%), fungal infection (18%) and folliculitis (27%) were common and usually chronic. A range of pilosebaceous unit disorders were observed with hypertrichosis being strongly associated with ciclosporin (P < 0.0001). Other iatrogenic cutaneous effects included gingival hyperplasia (27%) and purpura (41%). We identified seborrhoeic warts and skin tags in 55% and 33% respectively. Inflammatory dermatoses were rare (< 2%) apart from seborrhoeic dermatitis (9.5%). Discussion In this first comprehensive study on prevalence of benign cutaneous diseases in a UK transplant population, a wide range of skin disorders was identified. It is therefore important that RTRs have access to dermatology services post‐transplantation for appropriate management of benign cutaneous conditions as well as early detection of cutaneous malignancy and education regarding risks of sun exposure.     

Benign Human Papillomavirus Infection in Renal Transplant Recipients

Warts and cutaneous squamous cell carcinomas are common complications of immunosuppression. We studied a total of 189 renal transplant recipients clinically for such lesions. The incidence of warts increased steadily after transplant, such that of patients transplanted for more than 5 years, 92% were found to have warts and 65% had more than five warts each. DNA extracted from scrapings of their warts showed they carried the same human papillomavirus types as the general population, and not the unique set found on patients with epidermodysplasia verruciformis (who share with transplant recipients an increased incidence of warts and squamous cell carcinomas).     

Histologic features of actinic keratoses in solid organ transplant recipients and healthy controls.

BACKGROUND: Squamoproliferative lesions are common in patients who are immunosuppressed, particularly in recipients of solid organ transplants. Histologic features in such biopsy specimens may differ from those of otherwise healthy patients. Actinic keratoses (AKs) in transplant recipients may possess pathologic characteristics that suggest that they arose in an immunosuppressed host. OBJECTIVE: We evaluated 30 randomly selected AKs from 25 recipients of solid organ transplants and compared their histologic features to those of 50 AKs from 45 patients who were not immunosuppressed. METHODS: Tissue samples were categorized by sex, patient age, and site of biopsy. Sixteen separate histologic criteria were evaluated in a blinded fashion in each specimen. Statistical analysis was performed between the two groups with and without controlling for the age of the patient. RESULTS: The transplant group was significantly younger (54.8 years) than the nontransplant group (70.0) and contained more men (88%) than women (51%). AKs from transplant recipients were statistically more likely to demonstrate bacterial colonization, confluent parakeratosis, hyperkeratosis, increased mitotic activity, and verrucous changes. After controlling for age only, hyperkeratosis failed to be more prevalent in the transplant group. CONCLUSION: Certain histopathologic features are more common in AKs of immunosuppressed transplant recipients and may be used to distinguish between those removed from otherwise healthy persons.     

The dysplastic melanocytic nevus: a prevalent lesion that correlates poorly with clinical phenotype

We estimated the prevalence of persons with histologic dysplasia in at least one of two nevi examined by biopsy to be 53% in Utah's caucasians. This apparently high prevalence indicates that such lesions may represent a normal variant of a melanocytic nevus, perhaps those in the process of active proliferation. Regardless of the apparent ubiquity of these lesions, examination of biopsy specimens led to a grading scheme of histologic dysplasia that may reflect chronologic stages in the neoplastic development of melanocytic nevi. Comparison of these histologic findings with the clinical examination yielded the unexpected result that dysplasia and lesion size are independent of each other. Lesions 3 mm in diameter or smaller were as likely to be dysplastic as those much larger. There was, however, a statistically significant relationship between histologic dysplasia of a nevus examined by biopsy and the person's total number of melanocytic lesions. This finding indicates that the pathology grading scheme may be useful. The high prevalence of dysplastic nevi dilutes the clinical significance of a dysplastic nevus as an isolated finding and thereby lessens the importance of pathologic findings in the diagnosis of dysplastic nervus syndrome.     

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.     

Safety and efficacy of 5% imiquimod cream for the treatment of skin dysplasia in high-risk renal transplant recipients: randomized, double-blind, placebo-controlled trial

OBJECTIVE: To evaluate the safety and efficacy of 5% imiquimod cream for cutaneous dysplasia in high-risk renal transplant recipients. DESIGN: A randomized, blinded, placebo-controlled study comparing treated with control skin. SETTING: A specialist organ transplant dermatology clinic. PATIENTS: Twenty-one high-risk patients with skin cancer with comparable areas of clinically atypical skin on dorsal hands or forearms. INTERVENTIONS: Imiquimod or placebo (randomly assigned) applied 3 times a week for 16 weeks to 1 dorsal hand or forearm, with 8 months of follow-up. At week 16, biopsy samples were collected from pre-assigned sites in the treatment and control areas and were examined for dysplasia. MAIN OUTCOME MEASURES: The proportion of patients showing reduced numbers of viral and keratotic lesions and reduced histological severity of dysplasia in the treatment vs control areas at week 16, serum creatinine levels, and tumors developing in the study sites. RESULTS: Fourteen patients receiving imiquimod and 6 receiving placebo completed the study. Seven patients using imiquimod (1 taking placebo) had reduced skin atypia, 7 using imiquimod (none taking placebo) had reduced viral warts, and 5 using imiquimod (1 taking placebo) showed less dysplasia histologically. In 1 year, fewer squamous skin tumors arose in imiquimod-treated skin than in control areas. Renal function was not adversely affected. CONCLUSIONS: Topical 5% imiquimod cream seems to be safe on skin areas up to 60 cm2 in renal transplant recipients. It may be effective in reducing cutaneous dysplasia and the frequency of squamous tumors developing in high-risk patients. Larger studies are required to confirm these results.     

High prevalence of cervical dysplasia in female consorts of men with genital warts

Altogether 51 regular female consorts of men attending a venereal disease clinic for genital warts were examined using colposcopy, vaginal cytology and--when needed--surgical biopsy. Abnormal cytological smears were found in 18 out of 49 consorts (37%), which should be compared with 8 out of 124 (6%) matched female controls from a family planning clinic (p less than 0.001). Possibly premalignant lesions, i.e. atypical condylomata and/or frank dysplasia, were found in 14 (27%) out of 51 consorts. The prevalence of abnormal smears or biopsy-proven dysplasia was approximately the same in consorts with and without external warts. These findings call for close attention to the risk of development of cervical dysplasia in female consorts of men with genital warts.     

Cervical signs of HPV infection in PAP-smear negative women with external genital warts

Forty-eight women with external genital warts, all with normal cervical cytological PAP smears, were examined by means of colposcopy. One cervical biopsy for histological evaluation was taken from each woman, irrespective of the colposcopic findings. Koilocytosis was detected in 18/48 (38%) and dysplasia (CIN-1) in 3/48 (6%) of the patients. The presence of aceto-white lesions on the cervix was significantly associated with abnormal histology; 12 of 17 (71%) aceto-white lesions and 8 to 31 (26%) normal-appearing cervices showed histological changes indicating HPV infection (p less than 0.01). Women with koilocytosis and dysplasia had genital warts for a mean of 201 days compared with 79 days in women with normal cervical histology (p less than 0.01). It is concluded that even the clinically normal appearing cervix frequently is a reservoir for HPV and that colposcopy should be a routine procedure in women with external genital warts, irrespective of the result of the PAP smear, to provide a basis for proper counselling and individual therapy.     

Cytological screening to detect subclinical anal human papillomavirus (HPV) infection in homosexual men attending genitourinary medicine clinic.

Unselected homosexual men attending a department of genitourinary medicine were screened for human papilloma virus (HPV) infection using anal cytology. Satisfactory smears were obtained from 221 patients, and 73 showed cytological abnormality with warty atypia. Abnormal cytology was detected in 55 (31%) of 178 patients in whom there was no macroscopic evidence of anal or perianal warts, and anal cytology may therefore be valuable to detect patients with subclinical condylomatous lesions and may also serve to identify those who possibly have intraepithelial neoplasia.     

Warts as a presenting sign in acanthosis nigricans

Three patients with malignant acanthosis nigricans who presented with widespread warty lesions arc reported. Although many of the lesions appeared similar to viral warts, no evidence supporting a viral aetiology could be found by light or electron microscopy. These cases illustrate a potentially misleading presentation of an important marker of internal malignancy.     

A morphologic, pathologic, and virologic study of anogenital warts in men.

BACKGROUND AND DESIGN--Infection with human papillomavirus (HPV) in the anogenital region is associated with benign papillomas (condyloma acuminatum), subtle verrucous changes, subclinical infection, and malignant lesions. Although both men and women are affected, much of the investigation has been directed toward women in the study of cervical and vulvar carcinoma. The current investigation focuses on HPV infection in men. This study was undertaken to correlate the clinical spectrum of disease in our population of male patients with histopathologic features, immunoperoxidase staining for viral capsid antigen, and viral typing. Genital lesions from 26 patients were examined and tested prospectively over a 1-year period. RESULTS--The 26 lesions examined demonstrated variable morphologic features with regard to location, size, surface characteristics, and color. Histopathologic features were consistent with the diagnosis of venereal warts, but not necessarily diagnostic. Three of five standard histopathologic criteria were present in only 71% of the specimens. Despite the morphologic variability and the indeterminant histopathologic findings, 20 of 23 lesions positive for the genital tract HPV types tested contained HPV types 6 and/or 11. CONCLUSIONS--We conclude that the morphologic appearance of anogenital warts does not necessarily correlate with HPV type. Histopathologic study is helpful in excluding other diagnoses but may be indeterminant in the diagnosis of venereal warts. All men with anogenital warts should be counseled, treated, and undergo follow-up regardless of HPV type.     

Advantage of human papillomavirus typing in the clinical evaluation of genitoanal warts. Experience with the in situ deoxyribonucleic acid hybridization technique applied on paraffin sections

Genitoanal warts are predominantly induced by human papillomavirus (HPV) types 6, 11, 16, and 18. A strong association has been established between infection by HPV 16 and HPV 18 and the subsequent development of cancer in the uterine cervix. Therefore, a clinical challenge exists with respect to identification of patients harboring the latter type of high-risk HPV types. The present study on 108 men with genitoanal warts focuses on whether reliable gross and/or histopathologic criteria exist to predict the presence of HPV 16 and HPV 18 or whether there is a need for HPV typing by deoxyribonucleic acid (DNA) hybridization assay in future epidemiologic studies. The high-risk HPV types were identified in 9 of 91 HPV DNA-positive lesions (11%). The gross appearance of the lesions appeared to be of limited predictive value for the presence of these HPV types. HPV 16 was most common in warts exhibiting some degree of dysplasia (p less than 0.001) and also occurred in the two lesions with a severe dysplasia. Lack of dysplasia correlated with the presence of HPV 6 and/or 11 (p less than 0.01). However, absence of dysplasia did not preclude infection with high-risk HPV types, and a mild to moderate dysplasia was associated with all of the four HPV types studied. Therefore, we emphasize the value of HPV typing in clinical routine in order to trace men harboring the high-risk HPV types 16 and/or 18.     

p53 immunoreactivity in non-melanoma skin cancer from immunosuppressed and immunocompetent individuals: a comparative study of 246 tumours

p53 immunoreactivity was examined in 132 cutaneous non-melanoma tumours from renal transplant recipients and in 114 histologically matched specimens from immunocompetent individuals. Skin lesions examined included 52 viral warts, 50 clysplastic keratoses, 51 intraepidermal carcinomas (IEC), 50 invasive squamous cell carcinomas (SCC) and 43 basal cell carcinomas (BCC). Overall, 51% (51/101) pre-malignant skin lesions and 45% (42/93) non-melanoma skin cancers (NMSC) showed p53 immunoreactivity, with extensive (> 50% cells positive) p53 staining in 27% (27/101) of pre-malignant and 20% (19/93) of malignant lesions. 17% (9/52) viral warts showed p53 immunoreactivity, but this was limited to focal or basal p53 staining. p53 immunoreactivity in all tumours was less in transplant than in non-transplant patients and this reached statistical significance for SCCs (p = 0.03).     

Skin lesions in renal transplant patients after 10-23 years of immunosuppressive therapy

Ninety-eight patients with 10-23 years of uninterrupted immunosuppressive therapy due to renal transplants were investigated for signs of skin disease. Thirty-seven per cent had or had had premalignant or malignant skin lesions. This is significantly different from a control population (p less than 0.0001). There was also a correlation between the length of the immunosuppressive therapy and the risk of acquiring squamous cell skin cancers (p less than 0.05). Fifty-five per cent had common viral warts at the time of the present examination. The duration of immunosuppressive therapy also correlated with the presence of warts (p less than 0.01). Seven patients had mycosis and four patients had seborrheic eczema. In one-third of the patients the skin appeared normal.