Role of the human papillomaviruses in human cancer.

The papillomaviruses associated with human anogenital carcinomas encode two transforming genes, E6 and E7. The oncoprotein products of these two genes complex with the tumor suppressor gene products p53 and pRB, respectively. The loss of the normal function of these tumor suppressor gene products, either as a consequence of their association with E6 and E7 or by mutation, appears to be a common event in human cervical carcinogenesis.

Papillomaviruses in anogenital cancer as a model to understand the role of viruses in human cancers.

Infections with specific types of human papillomaviruses (HPV) have emerged as necessary but not sufficient factors for the development, at least, of the majority of cervical, vulvar, penile, and perianal cancers. Evidence has accumulated for their causal role in the induction of anogenital premalignant lesions. Genetic events underlying the mechanism of anogenital carcinogenesis have become increasingly understood. A host cell-mediated intracellular control down-regulating specific HPV genes (E6, E7) in replicating normal cells appears to be interrupted in cancer cells, probably due to structural modifications of the respective host cell genes acquired in the course of HPV DNA persistence. Since genital HPV infections are ubiquitous, cofactors which modify controlling host cell genes are likely to determine the different geographic rates of cervical cancer incidence.

Papillomavirus infection of the anogenital region: correlation between histology, clinical picture, and virus type. Proposal of a new nomenclature.

The clinical and histologic picture of 84 anogenital condylomatous and condyloma-like lesions of both sexes were analyzed in an effort to establish a correlation to the different papillomavirus (PV) types. The presence of human papillomavirus (HPV)-specific DNA sequences was confirmed through molecular hybridization and the presence of PV structure antigens was verified in thin sections by means of a group-specific anti-PV-antiserum using the peroxidase-antiperoxidase (PAP) technique. Three distinct clinical forms harboring distinct HPV types were distinguished: (1) Condylomata acuminata in which HPV-6 DNA was present in 37 of 59 samples and HPV-11 DNA in only 13 of 59 samples. HPV-16 DNA was not detected at all and 9 condylomatous lesions remained unclassified. (2) Flat condyloma-like lesions, where HPV-6 and HPV-11 were associated with lesions of low epidermal atypia in 8 and in 2 of 18 cases, respectively, and where HPV-16 was associated exclusively with 6 of 18 such lesions with severe atypia, called bowenoid papulosis. (3) Pigmented papules where HPV-16 was detected twice in lesions of bowenoid papulosis and HPV-11 in 2 of the benign pigmented lesions. The fourth clinical manifestation of genital papillomavirus infections--the so-called condylomata plana--was not available for virologic analysis. Histologically 5 different koilocytotic features were determined which could not be correlated either with one of the clinical pictures or with a specific PV type. HPV-16, however, was found frequently in non-koilocytotic lesions exhibiting the features of severe epithelial atypia known in bowenoid papulosis. The existence of PV structure antigens in these lesions could not be verified using the indirect immunoperoxidase--PAP-technique--in contrast to the koilocytotic lesions where clear evidence of the presence of HPV was proved in 36 of 56 (64.3%) of the cases.

In situ hybridization detection of human papillomavirus DNAs and messenger RNAs in genital condylomas and a cervical carcinoma.

Routinely processed formalin-fixed paraffin-embedded sections from anogenital condyloma acuminatum and an invasive squamous cell carcinoma of the cervix were examined by in situ hybridization for the detection of human papillomavirus (HPV) DNAs and messenger RNAs. Asymmetric, single-stranded, tritium-labeled RNA probes for both the coding and the nonsense strands of HPVs 6, 11, 16, 18, and 31 were hybridized and washed under stringent conditions and detected by autoradiography. Type-specific HPV DNAs were detected with specific nuclear localization, while HPV messenger RNAs gave much higher signals and had clear-cut cytoplasmic localization. Cross-hybridization was observed only with closely related viruses. The level of signal obtained seemed to be linked to the degree of cellular differentiation, with koilocytotic cells labeling the most heavily. However, messenger RNA could be detected in even relatively undifferentiated cells within areas of dysplasia and invasive carcinoma. In situ hybridization is a sensitive and specific method for investigation of the dynamic interplay of papillomavirus replication and gene expression, cellular differentiation, and neoplastic transformation.

Sensitivity of digoxigenin and biotin labelled probes for detection of human papillomavirus by in situ hybridisation.

The sensitivity of digoxigenin and biotin labelled DNA probes for the detection of human papillomavirus (HPV) by dot blotting and in situ hybridisation was compared in tissues from cervical, laryngeal, and anogenital neoplasia. Probes were either labelled with digoxigenin by the random primer technique and detected with anti-digoxigenin antibody, or labelled with biotin by nick translation and detected with streptavidin, both methods having a common final visualisation procedure using alkaline phosphatase. Digoxigenin labelled probes proved two to 10-fold more sensitive by quantitative dot blotting and four-fold more sensitive in detecting HPV 16 DNA in a series of 31 anal carcinomas, compared with biotinylated probes. The digoxigenin method also produced less non-specific background staining of tissue sections than biotin labelled probes. It is concluded that digoxigenin DNA labelling and detection provides a simple, reliable, and efficient alternative to the use of biotin or radioactive isotopes for the detection of HPV DNA by in situ hybridisation. Digoxigenin labelled probes also offer the possibility of double labelling in situ hybridisation procedures when used with biotin labelled probes to provide simultaneous identification of different DNA sequences.

Genital tract papillomavirus infection in children.

Genital tract papillomas in five children were examined for the presence of human papillomavirus (HPV) DNA by molecular hybridization. Papillomavirus DNA was detected in each sample and was identified as HPV-6 (three cases), HPV-6 or HPV-11 (one case), or HPV-16 (one case). These viruses are the same as are responsible for genital papillomas (condylomata) of adults. The transmission of adult genital tract viruses to children occurs primarily by a venereal route but may occur by a nonvenereal route.

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.

Immunosuppression in men with bowenoid papulosis.

The immune status of four men with bowenoid papulosis was evaluated. Each case had been refractory to multiple methods of treatment. Three of the men had other infections and demonstrated a depletion of T4-helper cells. Two of these patients were anergic on skin testing, and the third showed weak reactivity. The fourth patient, who had no evidence of additional infections, had a normal T4 value and T4/T8 ratio, but was anergic on skin testing. All the men were serologically negative for human immunodeficiency virus antibodies. One of the immunosuppressed patients developed squamous cell carcinoma of the tongue, which, along with his bowenoid papulosis, contained human papillomavirus 16 DNA. We suggest that patients with persistent bowenoid papulosis be investigated for altered immune status and followed up as potential candidates for the development of epithelial malignant neoplasms.

Human papillomavirus in the male patient.

Human papillomavirus is a double-stranded DNA virus associated with a broad spectrum of clinical states including condylomata acuminata, latent and subclinical infection (acetowhitening), Bowen's disease, and carcinoma of the penis and anus. The virus is transmitted by direct contact with site-subtype specificity; additional studies are needed to elucidate the exact transmissibility and disease course of HPV infection. The association of HPV-16 and HPV-18 with anogenital malignancy increases the importance of treating such infections and raises questions about the role of HPV in oncogenesis. Treatment modalities for HPV include cytotoxic agents, surgical excision, immunotherapy, and laser ablation. Success rates appear best for laser ablation of evident disease. No therapeutic modality appears superior for treating latent disease. The public health ramifications of HPV are vast and warrant investigation to further our scientific and clinical understanding of oncogenesis and its prevention.

Presence of human papillomavirus DNA in condylomata acuminata in children and adolescents.

The presence of human papillomavirus (HPV) DNA of types 6, 11, 16, 18, 31 and 33 was determined by in situ hybridization on archival paraffin-embedded tissue sections in 21 condylomata acuminata observed in patients aged 20 or less. HPV DNA was detected in 17 of 21 cases: all of these contained HPV 6, five also contained HPV 11, and one also contained HPV 16 and 18. HPVs 31 and 33 were not observed. Among 21 cases, 4 cases were in children under 6 yrs one of whom had a history of sexual abuse. The hybridization data indicate that condylomata acuminata in young people are associated with the same HPV types found in anogenital lesions in adults.

[Prevention of genito-anal and bucco-laryngo-esophageal cancers caused by sexually transmitted viruses]. / La prévention des cancers génito-anaux et bucco-laryngo-oesophagiens à virus transmis sexuellement.

Whilst some viruses of the Papilloma family cause warts on the skin, others infect mucosal cells. The types called 6 and 11 produce benign papillomas, called condylomata acuminata, visible to the naked eye, not only on the vulva, vagina, penis (cockscomb), but also in the anus, and occasionally the larynx, mouth (tongue) and oesophagus. Types 16 and 18 cause cervical cancer (generally called in situ) and especially very small flat lesions that can only be seen through the colposcope in women and a lens in men. These flat micro-lesions can also be found on the vulva, vaginal walls and on the glans and, balano-preputial area and shaft in males, the distal urethra, anus, larynx (especially the vocal cords), the mouth and oesophagus. These flat micro-lesions are either early cancers (here the deoxyribonucleic acid (DNA) of the virus 16 and/or 18 is integrated into the cell genome), or precancerous lesion in which case the viral DNA is not integrated. Their malignant transformation is much more frequent at the junction of the glandular and squamous parts of the cervix, than in the vulva or vagina. Co-carcinogenic factors appear to have an important role in the malignant transformation;--as for instance sexually transmissible infections including chlamydiae, bacteria that produce carcinogens such as nitrosamines, herpes virus which is known to cause mutations predisposing to the integration of the Papova viruses, chemical substances applied to the genitalia. The role of low hygiene standards in male sexual partners is the major cause (such men can carry simultaneously several sexually transmissible diseases (STD], who are never examined in search for flat lesions, who do not seek medical advice and have multiple sexual contacts with many women among whom some are more dangerous than prostitutes, especially since the wide use of hormone contraceptives and abortion that has multiplied the incidence of cervical cancer by 3 among the 20 year-old females, by 4 among the 25 year-old ones and by 2.5 among the 30 year-old ones, between 1961-65 and 1982-83. These changes in contraception have now made intra-vaginal ejaculation the rule (this not only carries viruses and other micro-organisms into the female genital tract, but also deposits sperm that contains some thirty factors that suppress local immunity). This with the rise of multiple partners, early sexual activity in particular in girls (hardly post-puberty) explains the increase of the frequency of cervical cancer in younger and younger women.(ABSTRACT TRUNCATED AT 400 WORDS)

Interferon treatment of anogenital human papillomavirus-related diseases.

Because of their antiviral, antiproliferative, and immunoregulatory properties, IFNs are potentially well suited for use in the management of benign HPV-related anogenital diseases. Parenteral and intralesional therapy of condylomata with various natural and recombinant IFN preparations has consistently resulted in beneficial response rates ranging between 40% and 60%, often in patients in whom other therapeutic measures have repeatedly failed. Adverse effects from IFN are dose dependent and generally tolerable at concentrations of IFN found to be effective in the treatment of condylomata, and they are not associated with any known long-term sequelae. When combined with conventional medical and surgical treatment modalities, IFN offers real promise for the control of both extensive primary and recalcitrant HPV-related conditions.

Relation of papillomaviruses to anogenital cancer.

A variety of HPV types infect the anogenital mucosa, giving rise to lesions that differ in clinical appearance, histology, and risk of malignant progression. Human papillomavirus type 16 is distinguished by a strong association with high-grade intraepithelial neoplasia and the greatest prevalence in anogenital malignancy. Most cancers appear to have a multifactorial cause, and HPV infection alone is probably insufficient for malignant transformation. The consistent association between HPV infection and anogenital cancers emphasizes that the papillomaviruses may have a necessary role in carcinogenesis, however. Hence, there is a prospect that vaccination programs may one day allow public health control of HPV infection, thereby eliminating an important risk factor.

Epidemiology of human papillomavirus infections.

Human papillomavirus infection represents the most common mucocutaneous viral infection, and 3% to 5% of all patients have clinically evident warts. Human papillomavirus infections of the genital tract are one of the most common sexually transmitted viral infections in the United States. Data from STD clinics and private physicians' offices reveal that genital warts, one manifestation of genital HPV infection, have been diagnosed more frequently in recent years. With the use of a variety of diagnostic techniques, asymptomatic HPV infection has been identified in men and women and is probably much more common than is clinically apparent infection.

Comparison of four in situ hybridization methods, based on digoxigenin- and biotin-labelled probes, in detecting HPV DNA in male condylomata acuminata.

We have compared the efficacy of digoxigenin- and biotin-labelled probes in detecting HPV DNA by in situ hybridization on paraffin-embedded tissue sections of 57 male condyloma-suspect genital lesions. Each biopsy was hybridized with at least three of the following four methods: digoxigenin-labelled HPV DNA probes (Dig-HPV), biotinylated HPV-DNA probes (Bio-HPV), and two commercial methods (ViraType in situ and PathoGene), both based on biotinylated DNA probes. The hybridization products were visualized with colourigenic enzyme substrates. In most biopsies, the 4 methods gave equal results although cross-hybridization was most often found with the low-stringency ViraType method. Dig-HPV 6/11 probes gave positive results about twice as often as either of the commercial methods. No such difference, however, was found for HPV 16/18 probes. DNA of any type of HPV 6/11, 16/18 or 31/33/35 or 51 was detected in 28/43 (65%) of lesions showing condyloma acuminatum histology but in none of the 14 biopsies with no histological signs of HPV infection. In HPV-positive condylomata with no cellular atypia. HPV 6/11 was detected in 87% (13/15), and HPV 16/18 in 27% (4/15). In biopsies with cellular atypia, HPV types 6/11 were detected in 62% (8/13), HPV types 16/18 in 46% (6/13), and HPV types 31/33/35 or 51 in 50% (6/12). In about 50% of the biopsies where at least one hybridization method gave a positive result, either one of the commercial methods gave a negative result.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship of papillomaviruses to anogenital cancer.

A variety of HPV types infect the anogenital mucosa, giving rise to lesions that differ in clinical appearance, histology, and their risk of malignant progression. HPV-16 is distinguished by a strong association with high-grade intraepithelial neoplasia and the greatest prevalence in anogenital malignancy. Most cancers appear to have a multifactorial etiology, and HPV infection alone is probably insufficient for malignant transformation. However, the consistent association between HPV infection and anogenital cancers emphasizes that the sexually transmitted papillomaviruses may have a necessary role in carcinogenesis. Hence, there is a prospect that vaccination programs may one day allow public health control of HPV infection, thereby eliminating an important risk factor.

Cancer and viruses.

Viruses implicated in the development of human cancers include hepatitis B (and C) viruses in hepatocellular carcinoma; human papillomaviruses in anogenital cancers; Epstein-Barr virus in nasopharyngeal carcinoma and Burkitt's lymphoma; human T-cell leukaemia/lymphoma viruses in adult T-cell leukaemia/lymphoma; and indirectly, human immunodeficiency viruses in Kaposi's sarcoma and B-cell lymphoma. Together, they contribute significantly to the cancer statistics in the Southeast Asian region. Neoplastic proliferation may be instigated by the presence and expression of viral oncogenes which may be integrated into the host genome and/or exist in episomal molecules. Critical viral genes may also interfere with host genes, resulting in the activation of cellular proto-oncogenes and/or the inactivation of anti-oncogenes and their products. The molecular pathogenesis of virally-induced cancers has led to major breakthroughs in the understanding of carcinogenesis at a molecular level. The occurrence of some of these viruses in a significant proportion of normal individuals suggests long latency periods necessitating multi-step co-operating events arising from multi-factorial agents such as host genetic susceptibility, immunological and hormonal status, as well as chemical and physical cocarcinogens in the environment. Successful intervention achieved with effective vaccines such as the hepatitis B vaccine and measures to severe the chain of viral transmission culminating in reduced incidence of the corresponding cancer will provide conclusive evidence for the virus-cancer relationship.

Male genital condylomatosis in partners of females affected with HPV infections. Clinical statistical contribution.

After a brief introduction, the Authors report the results of a clinical-"peniscopic" study of the genital regions in 56 male patients who were partners of females affected with genital condylomatoses. The results obtained show the importance of examining the male genital region under high magnification (peniscopy), especially if we consider recent research which indicates the close relationship between HPV, VIN, CIN and carcinoma of the cervix.

Human papillomaviruses in anogenital warts in children: typing by in situ hybridisation.

OBJECTIVE: To identify the types of human papillomaviruses found in anogenital warts in children and to relate these to clinical and social information. DESIGN: In situ hybridisation using biotin labelled DNA probes to 11 types of human papillomavirus was performed on biopsy specimens from 17 children with anogenital warts. SETTING: Nuffield department of pathology and the department of dermatology, Oxford. PATIENTS: Children in one group were referred by general practitioners or paediatricians to the dermatology department, where biopsies were performed. The other children were seen in four different hospitals, and biopsy specimens were submitted to the laboratory at the physician's or pathologist's request. RESULTS: Of the 17 biopsy specimens, 10 contained cells positive with a probe to a genital human papillomavirus type (types 6 or 11), while six were positive with a skin virus type (types 2 or 3). One was negative. The virus type present bore no relation to the site or appearance of the warts. The virus type did, however, appear to correlate with groups of children. Skin types were commoner in older children (over 4 years), in those with a relative who had skin warts, and in children with warts elsewhere; there was no relation with the child's sex and no suspicion of sexual abuse in these children. These circumstances suggested non-sexual transmission, such as autoinoculation. In contrast, genital types were commoner in girls, in children under 3 years, in children with relatives with genital warts, and in those with no warts elsewhere. Nevertheless, there was suspicion or evidence of sexual abuse in only half these children, suggesting that other routes of transmission--for example, perinatal--might have been implicated. CONCLUSION: Anogenital warts in children may contain either skin or genital wart virus type. Although the type of human papillomavirus present may give some indication of the likely mode of transmission, this can be interpreted only in conjunction with all available clinical and social information. The type of virus does not provide proof of the presence or absence of sexual transmission.

Androscopy for anogenital HPV.

BACKGROUND: Strong evidence now links anogenital intraepithelial neoplasia to the transmission of the human papillomavirus (HPV) through sexual intercourse. While there is increasing research on women with this disease, less is known about their male sexual partners. METHODS: Male patients whose female sexual partners had been diagnosed as having anogenital intraepithelial neoplasia were recruited for the study. The genital regions of the male patients were examined and biopsied with the aid of a colposcope after application of a 5% acetic acid solution. Treatment was based on the specific findings in each patient. RESULTS: Genital lesions were found on 65% of the male patients examined, even though no disease had been detected by the individual. Seventy-nine percent of patients who were compliant with the prescribed treatment protocol had no detectable HPV-related lesions at the time of their last androscopic examination. CONCLUSIONS: Magnified examination of the male genitalia using an androscope following the application of 5% acetic acid solution is an effective method by which the primary care physician can detect and treat male HPV-related anogenital lesions.