[Clinical algorithm of cutaneous extragenital wart treatment]. / Klinischer Algorithmus zur Therapie von kutanen, extragenitalen HPV-induzierten Warzen.

Various human papillomavirus of the genera α-, ß-, γ-, µ- and η-papillomavirus induce type-specific extragenital warts. Plantar, common and plane warts are the most common types. The closely related Alpha-papillomaviruses HPV 2, 27 and 57 are responsible for the majority of therapy-resistant common warts. A wide armamentarium of surgical, physical, chemical or drug therapies is available but no modality cures all patients. In order to avoid overtreatment it is mandatory to differentiate between indolent warts which will spontaneously resolve, warts which cause acute discomfort and warts without any tendency to heal spontaneously. HPV type, wart type, localization, size, disease duration as well as age and immune status are parameters influencing self-healing and should be considered when choosing the appropriate wart therapy.

[Human papillomavirus-associated warts in organ transplant recipients. Incidence, risk factors, management]. / Humane Papillomvirus-assoziierte Warzen bei organtransplantierten Patienten. Inzidenz, Risikofaktoren, Management.

Human papillomaviruses infect the squamous epithelia of the skin and cause warts, and are occasionally found in squamous cell carcinomas. Since cell-mediated immunity plays a crucial role in the control of HPV-infections, organ transplant recipients, unable to mount an adequate T-helper 1 cell-mediated immune surveillance, frequently develop widespread and resistant induced warts. Skin tumors, especially squamous cell carcinomas, are the most common post-transplantation neoplasm. Warts, actinic keratoses and invasive squamous cell carcinomas are known to develop at the same time in the areas. The role of HPV in the development of invasive squamous cell carcinoma under immunosuppression, remains to be elucidated in respect to common risk factors and increased numbers of warts potentially identifying patients at increased risk for carcinoma. We prospectively studied 1690 organ transplant recipients in the dermatology clinic at the Charité University Hospital in Berlin, to evaluate risk factors being involved in the development of HPV-induced warts and to assess a potential association of with the development of non-melanoma skin cancers in this population. The cumulative incidence of warts steadily increased throughout the post-transplant years. The presence of more than 10 verrucae was associated with the development of actinic keratoses, invasive squamous cell carcinoma and basal cell carcinoma. This study shows clear evidence that certain risk factors of skin carcinogenesis in organ transplant recipient such as increased age at transplantation, a high dose of immunosuppression related to a specific type of graft and use of azathioprine or cyclosporine are strongly associated with an increased incidence of warts. Furthermore, HPV-induced verrucae vulgares could be used as a potential predictor for the development of coincidental non melanoma skin cancer in organ transplant recipients and therefore could serve as an early identification marker of skin cancer high-risk patients. The challenging management of warts in organ transplantation patients is reviewed.

Detection of papillomavirus DNA in human semen.

Human papillomavirus DNA has been detected in the semen of three patients, two of whom have severe chronic wart disease. These data support the contention that sexual transmission of human papillomavirus DNA could occur via semen, a possibility suggested by epidemiological data on the sexual transmission of human papillomavirus.

A verrucous plaque of the eyebrow.

Phaeohyphomycosis is a rare dematiaceous fungal infection requiring surgical excision or appropriate systemic antifungal therapy. The objective of this study is to report a case of phaeohyphomycosis of the right eyebrow successfully treated with surgical excision. We performed an excision of a dermal plaque of phaeohyphomycosis using 4-mm margins on the right brow extending onto the right forehead. An island pedicle flap was used to close the defect. Histopathologic evaluation confirmed the presence of numerous dematiaceous fungal organisms fully consistent with phaeohyphomycosis, and the margins were verified to be free of fungal organisms. Culture of a central portion of the excised lesion confirmed that the causative organism was a saprophytic fungus. Adjuvant systemic antifungal therapy was offered to the patient, but because of financial resources, the patient did not desire any further treatment. The patient remains free of the organism and has healed well, without complications. Phaeohyphomycosis can be effectively treated with excision alone, and when located in a risky anatomic location, such as near the orbit, adjuvant treatment with systemic antifungals may be warranted to prevent recurrence.

Primary tissue culture of human wart-derived epidermal cells (keratinocytes).

The formation of human skin warts may depend on transformation by human papilloma virus or result from a productive virus infection. To explore this problem, methods were developed for the primary tissue culture of epidermal cells (keratinocytes) derived from wart tissues and normal skin. Wart-derived keratinocytes continued to proliferate for periods exceeding 3 months, but the patterns of cell growth were identical to normal keratinocytes. Electron microscopic and immunohistologic examination of wart-derived cultures did not evidence virion assembly.

New human papilloma virus isolated from epidermodysplasia verruciformis lesions.

Human papilloma virus (HPV) was isolated from red plaques of a patient (N. F.) with epidermodysplasia verruciformis. Electron microscopic examination showed characteristic particles of papilloma virus as icosahedrons about 45 nm in diameter. DNA was extracted from these particles, and closed-circular DNA (Form I) was purified by centrifugation in CsCl containing ethidium bromide. The molecular weight of the DNA was about 5.0 x 10(6). A physical map of the HPV DNA was constructed using several restriction enzymes. The restriction endonuclease cleavage pattern of the HPV DNA was different from those of other types of HPV reported thus far, suggesting that the isolate was a new, as yet unclassified, HPV.

Cutaneous Chromoblastomycosis Mimicking Tuberculosis Verrucosa Cutis: Look for Copper Pennies!

Chromoblastomycosis is a rare chronic fungal infection of skin and subcutaneous tissue. It is primarily a disease of tropical and subtropical regions and affects mainly the agricultural workers following trauma with vegetable matter. Cutaneous Chromoblastomycosis may clinically mimic cutaneous tuberculosis as both the condition usually presents with hyper pigmented verrucous lesion of skin. Here in we report a case of chronic cutaneous Chromoblastomycosis in a middle aged woman from north eastern part of India, who was initially misdiagnosed as Tuberculosis verrucosa cutis. In histopathology characteristic brown colored spores of the fungus (also known as copper pennies) were seen within dermal abscess. The organism isolated from culture of the biopsy material was Fonsecaea pedrosoi thus confirming our diagnosis of cutaneous chromoblastomycosis. The patient responded well to oral Itraconazole. The dermatologists and pathologists should be aware of this condition especially when dealing with verrucous lesion of the skin. The pathologists should search for fungal spores in cutaneous lesion with pseudoepitheliomatous hyperplasia and dermal abscess.

Correlation between content of viral DNA and evidence of mature virus particles in HPV-1, HPV-4, and HPV-6 induced virus acanthomata.

In HPV-1 and HPV-4 induced warts as well as in HPV-6 positive condylomata acuminata the quantity of viral DNA encapsulated into virus particles was determined and compared to the total amount of viral DNA present in the papillomas. As shown by filter hybridization using 3H-labeled viral DNA molecularly cloned in Escherichia coli, the amount of total viral DNA found in HPV-1 or HPV-4 induced skin warts is similar. HPV-4 DNA, however, is encapsulated into virus particles with less efficiency. HPV-6 DNA can be detected only at minute amounts in condylomata acuminata and the percentage of DNA recovered from virions is extremely low.

Correlation between human papillomavirus (HPV) type and histology of warts.

Forty warts from different patients and of different clinical type were examined histologically and virologically. Eight lesions were found to be associated with human papillomavirus type 1 (HPV 1), 15 tumors were induced by HPV 2, HPV 3 was detected 4 times, HPV 4 twice, and HPV 6 eleven times. HPV 3, HPV 4, and HPV 6 induced warts revealed a correlation between histology and virus type. They are characterized by the so called "edematous type clear cells". In HPV 3 associated flat warts pycnotic nuclei were mainly localized in the center of large vacuoles. In genital warts sickle shaped nuclei were pushed to the margin of the vacuolized cells. The histology of HPV 1 and HPV 2 induced warts was more heterogenous. With one exception HPV 1-induced lesions represented typical myrmecia warts, varying in the number and shape of inclusion bodies. HPV 2 associated common warts, however, revealed 3 very distinct histologic features: (1) Inclusion wart typical for HPV 1, (2) Classical common wart with marked condensation of keratohyalin granules, (3) Warts with extreme vacuolization of squamous and granular cells leading to a honeycomb-like picture.

Butcher's wart virus (HPV 7) infections in non-butchers.

The analysis of a total of 654 benign and malignant lesions of the skin, genitalia, lungs and bronchi, intestine, kidneys, bladder, mammae, and of the head and neck region, resulted in the identification of human papilloma virus 7 (HPV 7) infections in 3 individuals. One of these was an ordinary "butcher's wart," whereas the other 2 patients have never been involved in meat-handling or farming. One of the latter revealed extensive verrucosis of hands, feet, axilla, neck, and face, persisting for about 27 years, with new lesions arising in the neck region. Particularly the new lesions showed filiform morphology. The second patient has, for a period of more than 2 years, been showing filiform papillomas in the face which recurred after surgical removal. These 2 patients appear to represent the first cases of HPV 7 infections in non-butchers or non-meathandlers.

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.

Characterization of human papillomavirus 3 in warts of a renal allograft patient.

Multiple flat wart-like lesions of a renal allograft recipient were shown to contain HPV 3 or a serologically crossreacting virus by indirect immunofluorescence with monospecific animal antisera against HPV [1--5]. The patient's serum revealed virus specific antibodies (immunofluorescence titer 1/80). Papillomaviruses were isolated and after in vitro iodination 3 major proteins (MW 70.000, 56.000 and 43.000) were detected by SDS polyacryalmide gel electrophoresis. DNA was extracted from the warts and cleaved with the restriction endonuclease Hae III. Distinct bands were discernible within the background of cellular DNA and these fragments were identified as papillomavirus DNA by blot hypbridization with 32P-labeled viral DNA.

Identification of papillomaviruses in butchers' warts.

We have studied the papillomaviruses found in the hand warts of 60 butchers, most of them from 2 distant slaughterhouses. Warts differing in morphology and location were studied separately. The viruses were identified by molecular hybridization, restriction enzyme analysis and immunofluorescence. Four known human papillomaviruses (HPV-1, HPV-2, HPV-3, HPV-4) were detected and one hitherto unknown papillomavirus was identified in 9 butchers. The DNA of the latter virus did not anneal with any of the RNAs complementary to either HPV-1 to HPV-5 or bovine papillomavirus type 1 (BPV-1) DNAs, and showed a Hind II + III restriction enzyme cleavage pattern distinct from those of known HPVs and BPVs. This virus showed distinct antigenic properties, as shown by immunofluorescence, using HPV-1, -2, -3, -5, and BPV-1 antisera. It may represent a new type of human papillomavirus (HPV-7) or a yet unidentified animal papillomavirus. In addition, 6 butchers were found to be infected with a papillomavirus, distinct from the known skin HPVs and from BPV-1, which could not be characterized by restriction enzyme analysis. Eleven butchers were found to be infected by 2 viruses. A characteristic histological pattern was found to be associated with the different papillomaviruses.

Characterization of two HPV-3 related papillomaviruses from common warts that are distinct clinically from flat warts or epidermodysplasia verruciformis.

We have recently identified two unusual human papillomavirus (HPV) isolates while engaged in an ongoing study of wart disease in meat handlers and veterinarians. The papillomas from which these two viruses were isolated clinically resembled verruca vulgaris rather than either flat warts or epidermodysplasia verruciformis (EV). These two previously uncharacterized HPVs were molecularly cloned and characterized with respect to known HPVs. The genomes of the two viruses exhibited dramatically different restriction endonuclease cleavage patterns but were found to have significant sequence homology to each other, as well as to HPV-3 and a new virus isolated from a patient with EV. Neither of the two new HPV isolates exhibit detectable sequence homology under stringent conditions of hybridization or share similar restriction endonuclease cleavage patterns with previously characterized HPV types 1,2,4,5,6b, or a previously isolated HPV from meat handlers.

The virus of epidermodysplasia verruciformis: electron microscopic and fluorescent antibody studies.

Five cases of epidermodysplasia verruciformis were studied for viral particles and antigens. In all benign lesions tested, viral particles and antigens were observed by electron microscopy of ultrathin sections and/or tissue extracts and by fluorescent antibody staining with an antiserum against human wart virus. Both viral particles and antigens were observed in the cells of the stratum granulosum and the stratum corneum and not in those of deeper layers. Viral particles and antigens were observed in nuclei. Viral particles resembled morphologically the virus of common human warts. In two, one on the forehead and the other on the inner aspect of the upper thigh, of six lesions showing the histology of early malignancy, viral particles were observed by electron microscopy of ultrathin sections and/or tissue extracts. Four advanced malignant lesions, two primary ulcerated squamous cell carcinomas and two recurrent carcinomas, were similarly studied. In none of them, were viral particles or antigens detected. These results suggest that (1) the virus of epidermodysplasia verruciformis is related with that of common human warts both morphologically and antigenically, (2) at least some of the virus-induced lesions of epidermodysplasia verruciformis become malignant, and (3) when the lesions are completely replaced with malignant cells, neither viral particles nor antigens are recognizable in them.

A new type of human papillomavirus associated with oral focal epithelial hyperplasia.

Lesions from 10 patients suffering from focal epithelial hyperplasia (FEH) of the oral mucosa, including those of 4 Greenlandic Eskimos, were investigated for the presence of human papillomavirus (HPV) DNA sequences by blot hybridization experiments. Two distinct HPVs were detected in the DNA extracted from these lesions, and their genomes were molecularly cloned and characterized. One of these HPVs, detected in 4 patients, was found to be identical with HPV13, whose association with FEH was already known. The other one, detected in 6 patients, was only weakly related to HPV13 and to the other HPVs associated with lesions of the mucous membranes, and constituted a new HPV type, tentatively named HPV32. Lesions from other types of oral papillomas, obtained from 14 additional patients, were also analyzed. Human papillomavirus DNA sequences were detected in the DNA preparations extracted from 5 specimens: HPV6 DNA in a condyloma and in a papilloma, 2 as yet uncharacterized HPV DNAs in 2 papillomas, and HPV32 DNA in a papilloma which showed histologic similarities to FEH. Thus, it seems likely that FEH of the oral mucosa is a disease associated with 2 specific HPVs--HPV13 and HPV32.

Viral diseases of the skin, 1975: a 25-year perspective.

Most of the major advances in modern virology during the past 25 years have been due principally to the development of refined laboratory techniques and tools and have provided a fund of new knowledge and information about the nature of viral infection and pathogenesis. One group of viruses of interest to dermatologists, the herpesviruses, is undergoing intensive biochemical investigation to determine whether it is carcinogenic. As a result of the success of the World Health Organization's campaign to eradicate smallpox, it is predicted that by the end of 1976, smallpox will have been eradicated. Other viruses of dermatologic interest which are now being studied include the agents of warts, molluscum contagiosum, cat-scratch disease, and enteroviruses. Current research in the field of viral chemotherapy may provide the basis for successfully treating these diseases in the future.

Human papillomaviruses: pediatric perspectives on a family of multifaceted tumorigenic pathogens.

As summarized here human papillomaviruses are associated with a wide spectrum of epithelial lesions, ranging from benign warts to invasive carcinomas. They have been difficult to study in part because they have not yet been propagated in tissue culture. Fortunately advances in molecular biology have allowed characterization of HPV genomes and identification of some HPV gene functions. In addition to their clinical importance HPVs represent an important tool for exploring virus-cell interactions, gene expression, cellular differentiation and cancer. HPV infections are not only common but also difficult to treat and prevent. Depending on the HPV type and location, the modes of HPV transmission may involve casual physical contact, sexual contact and perinatal vertical transmission. HPV DNA genomes replicate at a low copy number in basal cells and, as most clinicians know, are difficult to eradicate. There is often a long latent period and subclinical infections, and HPV DNA can be found in normal tissue adjacent to lesions. HPVs can cause widely disseminated lesions, especially in the immunocompromised host and in epidermodysplasia verruciformis. Aside from the rare carcinomas, the most serious life-threatening HPV-induced illness in children is recurrent respiratory papillomatosis. Somewhat surprisingly in malignant lesions HPV DNA is also found as fragments incorporated into the cellular genome. Unlike retroviruses such as human immunodeficiency virus which integrate into the cellular genome as part of their life cycle, HPV integration is a terminal event for viral replication. Such integration may be critical, however, for viral-induced abnormal cell growth. Perhaps the most important implication of the finding that some anogenital cancers are in part sexually transmitted infectious diseases is that they may be preventable. The data overwhelmingly suggest that avoidance of exposure to HPV via abstinence or monogamy in both partners markedly reduces the risk of cervical cancer. A more realistic goal, however is prevention of HPV transmission by the use of barrier method contraceptives, which may be protective against development of cervical carcinoma. The America Association of Pediatrics Committee on Adolescents has outlined the obligation of pediatricians to be actively involved in adolescent education on sexually transmitted diseases. Certainly a fundamental knowledge of HPV epidemiology, the risks of HPV-related sequelae and prevention of HPV infection are important considerations for adolescent sexuality. Although helpful, such awareness alone falls far short of making an impact on sexual behaviors. A significant reduction in HPV infection rates could be achieved only by inundating adolescents at an early age with a highly visible society-wide campaign directed at these issues.

Ribavirin mitigates wart growth in rabbits at early stages of infection with cottontail rabbit papillomavirus.

The challenge to develop antiviral agents effective against DNA viruses such as human papillomavirus (HPV) has been dependent on finding an animal model which mimics the human forms of the disease. We have used an existing model system for the purpose of measuring the effect of antiviral drugs on the inhibition of growth of these lesions. This was based upon domestic rabbits which efficiently grow cutaneous papillomas (warts) when infected with cottontail rabbit papillomavirus (CRPV). One agent which had shown significant success in achieving these goals was ribavirin. Ribavirin was administered intradermally shortly prior to infection at multiple sites with CRPV. Following daily injections of this drug for eight weeks, we have shown a dose-dependent response which had markedly reduced the number of warts, the time of first appearance of warts and reduced the tumor mass as compared to placebo-treated control animals. At the highest dose of ribavirin tested, 30 mg/kg/day, compared to controls, the average reduction in the number of warts was 52%, the average time of first appearance of warts was 49% longer, and the average mass of the warts was reduced by 98%. No detectable antibodies to CRPV were observed in any of the animals. The only side effects which were observed was focal alopecia, and a decrease in body growth upon prolonged treatment, both of which were completely reversible. Pharmacokinetic studies established the metabolism of ribavirin over a 24-h period of time. Ribavirin administered beginning 12 or 30 days post-infection, while not reducing the number of warts, slightly retarded the growth of warts as determined by date of first appearance of warts and mass of warts.