Buschke-Loewenstein tumour infiltrating pelvic organs.

We report a 42-year-old HIV-negative patient with a 12-year history of exceptionally extensive genital warts and coexisting verrucous carcinoma of the anogenital region (Buschke-Loewenstein tumour). Masses of both tumour and viral papillomas infiltrated the external genitalia, perineum and buttocks, pelvic diaphragm and parts of the lesser pelvis, as well as the urethra, prostate and parts of the urinary bladder, necessitating repeated surgical intervention and plastic reconstruction. Adjuvant interferon-alpha therapy was given without any lasting effects. Human papillomavirus type 6 was detected by DNA in situ hybridization and Southern blot analysis.

NK-cell activity in patients with HPV16-associated anogenital tumors: defective recognition of HPV16-harboring keratinocytes and restricted unresponsiveness to immunostimulatory cytokines.

Peripheral blood mononuclear cells (PBMC) from patients with active HPV16-associated pre-malignant and malignant anogenital lesions display a significantly decreased NK-cell activity against HPV16-harboring SKv keratinocytes (NK/SKv) while their cytotoxicity against erythroleukemic K562 cells (NK/K562) remains unaffected. A similar defect can also be seen in some healthy individuals displaying no symptoms of HPV infection (low responders). Analysis with specific Leu IIa monoclonal antibodies (MAbs) has revealed that all patients as well as weakly responding control subjects had normal numbers of circulating CD16+ NK cells. However, PBMC from patients with active disease and weakly responding controls displayed a significantly decreased ability to bind SKv cells. Binding of K562 was in the normal range. In patients in whom the lesions were successfully removed or regressed spontaneously (patients with no lesions), NK/SKv activity did not differ from that of normally responding healthy subjects and the ability of their PBMC to bind SKv cells was unaffected. To determine whether an abrogated NK/SKv cytotoxicity may be corrected by NK-cell stimulatory cytokines. PBMC were pre-incubated overnight with IL-2 and interferon-alpha. Both cytokines stimulated NK/K562 activity in all tested groups. Significant stimulation of NK/SKv activity was observed in PBMC from normal and weakly responding controls as well as patients with no lesions. No increase could be seen in patients with active disease. Evaluations of NK-cell activity before and after surgical removal or spontaneous regression of the lesions showed normalization of primarily depressed NK/SKv activity. Malignant progression was associated with a significant drop in SKv cell killing. Our results suggest that abrogation of NK-cell activity against HPV16-harboring targets in patients with HPV16-associated anogenital neoplasia is associated with restricted inability to recognize the disease-specific target cells, and may depend on persistence of the lesions.

Dual infection with human papillomavirus in a population with overt genital condylomas.

BACKGROUND: Multiple human papillomavirus (HPV) genotypes have been demonstrated in individual patients; usually, different genotypes occur in different anatomic sites. OBJECTIVE: Our purpose was to evaluate the prevalence of multiple HPV types from the same anatomic site. METHODS: During the course of a study evaluating topical versus ablative therapy for external genital HPV, sequential biopsies on patients with external genital warts were performed. HPV DNA content was determined by Southern hybridization. Ninety-two specimens from 63 patients (48 women, 15 men) with genital warts were evaluated. RESULTS: Dual infection with two HPV genotypes was documented in each of four specimens (6.3%). Sequential biopsy specimens from the same anatomic site in the same person revealed dual infection in 5 of 12 sampled patients (41%). Overall, 14% of patients had dual genitourinary HPV infection. CONCLUSION: Counseling and follow-up of long-term complications, such as transmission and the risk of subsequent genitourinary carcinoma, should be performed on all patients with HPV because of the possibility of undetected HPV DNA types in the individual patient.

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.

Squamous cell carcinoma of the scrotum associated with human papillomaviruses.

A 53-year-old man presented with recurrent squamous cell carcinoma, and dysplasia of the scrotum and penis. Risk factors included psoralen and ultraviolet radiation therapy for psoriasis, and x-ray therapy for primary lymphoma of the groin. Three different human papillomavirus types were documented using the polymerase chain reaction in distinct anatomical areas. The scrotal carcinoma was associated with human papillomavirus type 18, while regions of dysplasia contained either type 18, 16 or 6/11. Diagnosis of squamous dysplasia and carcinoma of the scrotum in men with psoriasis is complicated by chronic active inflammation, and molecular biological methods may be necessary to detect human papillomavirus infected cells.

Dual genitotropic human papillomavirus infections in genital warts.

BACKGROUND AND METHODS: We have carried out a prospective study of dual genitotropic human papillomavirus (HPV) infections by means of two different DNA detection methods in biopsy specimens obtained from patients who were examined for genital warts at the STD clinic of the School of Medicine in Seville, between January 1990 and December 1991. RESULTS: 100 patients with a clinical diagnosis of condilomata acuminata were seen during the study period. DNA of the genitotropic HPV 6/11, 16/18 and 31/33/35 was detected by an in situ hybridisation method in 75 (77%) of the 98 evaluable samples; one of the genotypes tested in 59 (61%) samples, and two or more genotypes tested in the remaining 16 (15%) samples. In 21 (98%) of the 23 negative samples by in situ hybridisation, we were able to detect DNA of genital HPV using a polymerase chain reaction amplification method (PCR). Among the 34 samples where PCR was applied we confirmed the presence of two different HPV genotypes in eight samples. CONCLUSIONS: The frequency of dual infections with human genitotropic papillomavirus in genital warts was 8%, although we believe that this rate should be higher as we have not used the PCR method in all of the samples.

Detection of human papillomavirus DNA in the urogenital tracts of men with anogenital warts.

Increasing evidence suggests that human papillomavirus (HPV) infection of the female anogenital tract is multifocal. Less is known of the distribution of HPVs in men. To investigate this, a prospective study was conducted of 116 men consecutively attending a clinic for ablative treatment of anogenital warts. Wart tissue, urethral swabs, and urine were obtained from each patient. HPV DNA was extracted from the specimens and amplified using the polymerase chain reaction (PCR). HPV types 6, 11, 16, 18, 31, and 33 were identified using Southern blotting of the PCR product, followed by hybridization. HPV DNA was detected in 112 (96.6%) of 116 wart specimens and there was urethral infection with HPV in 26 (22.4%) of the men. Eleven (61.1%) of 18 urethral specimens taken with a loop and 22 (20.0%) of 116 urethral specimens taken using a cotton-tipped swab contained HPV DNA. One (6.3%) of 16 urine samples tested contained HPV DNA. HPV types 6 and 11 were found in the urethra most commonly when warts were seen near the urinary meatus, although HPV occurred in the urethras of men without clinically apparent meatal warts. The proportion of urethral samples with HPV DNA, including HPV types 16, 18, 31, and 33, was independent of the location of visible warts at the time of sampling.

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.

Papillomaviruses in human disease: Part II. Molecular biology and immunology of papillomavirus infections and carcinogenesis.

As summarized in the last issue of the EJM, human papillomaviruses induce a great variety of neoplastic lesions of mucosal epithelia and the skin. Particular types of these viruses are associated with specific human cancers, most notably anogenital carcinomas. These tumours account for about fifteen percent of the whole worldwide cancer burden. However, recent epidemiological studies revealed that papillomavirus infections including those with the cancer-related papillomavirus types are very widespread even among asymptomatic healthy individuals. Here, the current understanding of the molecular events leading to papillomavirus-induced tumours will be reviewed. It is assumed that these tumours arise as a consequence of several molecular modifications of persistently papillomavirus-infected epithelial cells. Experimental studies revealed that the virus types associated with anogenital cancers harbour two potential oncogenes referred to as E6 and E7. These viral genes are consistently expressed in HPV-associated anogenital carcinoma cells. HPV-associated cervical carcinoma cells loose their neoplastic growth properties if the expression of the E6 and E7 genes is inhibited. The proteins encoded by these viral genes thus appear to be ideal targets for a specific pharmacological approach to treat papillomavirus associated cancers or their respective precursor lesions. Recent studies in animals furthermore suggest that active vaccination with the viral oncoprotein E7 prevents growth of papillomavirus associated tumours. Hence, the possibility arises that also in man, vaccination with the viral transforming proteins might prevent the development of papillomavirus associated cancers.

[Typing of human papillomavirus (HPV) in the male and female genitalia]. / Estudo do tipo de papilomavírus humano (HPV) no aparelho genital feminino e masculino.

Diagnosis and typing of HPV was started in November 1990 at the Virology department of the National Health Institute, Lisbon. Eighty one samples from 70 patients were studied, 57 from women observed at the cervico-vulvar out patient unit of the Gynecology department of Sta Maria Hospital, Lisbon, and 13 from male contacts of some of these women. Forty nine women (86%) had colposcopic, histological or cytological evidence of HPV infection. Eleven men (85%) have clinical signs of infection and 2 (15%) had had sexual intercourse with infected partners with clinical evidence of infection. HPV DNA was detected in 43 patients (61%). Forty two were infected with HPV 6/11 (98%) and one with HPV 16 (2%). These preliminary results suggest that genital infection by HPV must also be considered a public health problem in the field of sexually transmitted diseases in Portugal.

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)

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.

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.

Failure to detect human papillomavirus DNA in extramammary Paget's disease.

Ten genital skin specimens, biopsy proven to be Paget's disease, were examined by human papillomavirus (HPV) in situ hydridization in an effort to detect DNA of HPV types 6, 11, 16, 18, 31, 33, and 35. All ten specimens showed no evidence of DNA of these HPV types. Extra-mammary Paget's disease is probably not a result of infection with HPV types 6, 11, 16, 18, 31, 33, or 35.

[Study by in situ hybridization of the prevalence of herpes virus as cofactors of the tumoral development of papillomatous lesions of the anogenital region in seropositive and seronegative men against HIV]. / Etude par hybridation in situ de la prévalence des Herpès virus comme cofacteurs de l'évolution tumorale des lésions papillomateuses du tractus anogénital chez des hommes sérologiquement positifs et négatifs vis-à-vis du HIV.

Infection with specific types of HPV has emerged as necessary but not sufficient factor in the neoplastic transformation of anogenital condylomas. Some viruses (HIV, Herpes viridae: HSV, CMV, EBV) might act as cofactors in the neoplastic changes and cancer. To study the prevalence of these viral pathogens in anogenital lesions, biopsies were obtained from HIV seropositive or seronegative men and tested using in situ hybridization technique. Infection by "high risk" HPV, HSV and CMV are facilitated in patients immunocompromised by HIV. Presence of CMV is more frequent in high risk HPV-induced lesions than in low risk HPV lesions.

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.