Infections of the esophagus: an update on risk factors, diagnosis, and management.

Infectious esophagitis is a leading cause of esophagitis worldwide. While esophageal infections have traditionally been associated with immunocompromised patients, these disorders are becoming increasingly recognized in immunocompetent individuals. The three most common etiologies of infectious esophagitis are Candida, herpes simplex virus, and cytomegalovirus. Human papilloma virus infection can also involve the esophagus in the form of ulcerative lesions and papillomas. Less common etiologies include various other fungal, bacterial, and viral organisms. This review provides a comprehensive update on risk factors, diagnosis, and management of both common and less common infections of the esophagus.

[HPV infection in oral, pharyngeal and laryngeal papillomas]. / HPV-Infektion in oralen, pharyngealen und laryngealen Papillomen.

BACKGROUND: HPV infections play a major role in the pathogenesis of squamous cell carcinomas of the head and neck. Regarding benign papillomas, the role of HPV is still uncertain. MATERIALS AND METHODS: To clarify this issue, 100 exophytic papillomas of the oral cavity, pharynx and larynx were subjected to histopathological and molecular pathological examination. Excision biopsies were taken from 62 male and 38 female patients with an age range of 18 to 87 years. Biopsies were tested for p16 expression by immunohistochemistry and analyzed for HPV subtypes 6/11 (low-risk), 16/18 and 31/33/53 (high-risk) by chromogenic in situ hybridization. RESULTS: HPV infections were verified molecularly in 34 % of biopsies; in all cases with the low-risk HPV subtypes 6/11. Only one case showed infection with both 6/11 and 31/33/53 subtypes, but not subtype 16/18; whereas expression of p16 was found in 67 %. The rate of positive molecular verification of HPV infection (in situ hybridization) was highest in the laryngeal lesions with 61.1 %, followed by the oral cavity with 52.9 %, and lowest in pharyngeal lesions (21.5 %). Recurrent papillomas were seen in 18 cases (18 %), of which 14 were molecularly positive for HPV (in situ hybridization). A correlation between inflammatory infiltration and HPV infection could be verified in 82 %. CONCLUSION: Our data demonstrate an important role of HPV infection for the development of benign papillomas of the head and neck region. Furthermore, there is a positive correlation between HPV infection and recurrent papillomas. Therefore, a molecular morphological HPV analysis of papillomas could provide important prognostic data.

[Laryngeal papillomatosis: problem update].

The objective of the present overview was to analyse the available data on etiology, pathogenesis, diagnostics, and treatment of laryngeal papillomatosis. It is shown that the pathogenetic mechanism underlying the development of this pathology is related to cell proliferation mechanisms. The human papilloma virus is most effectively identified by the polymerase chain reaction technique in combination with in situ hybridization. It is expected that new and more informative criteria for diagnostics, treatment,and prognosis of laryngeal papillomatosis will be proposed based on recent progress in molecular biology, morphology,and immunology. Different variants of the therapeutic strategy for the treatment of laryngeal papillomatosis are described.Modern practice of the management of laryngeal papillomatosis takes advantage of the three main approaches and/or their combination. First, further improvement of surgical techniques, such as the application of endoscopic devices and surgical lasers.Second, the search for new pharmaceutical agents (indole-3-carbinol, cidofovir, antiviral medicines, etc.) most frequently used for adjuvant therapy. Third, the development of new vaccination methods. Besides these three approaches, photodynamic therapy and the use of ionizing radiation are currently being studied as the tools for the treatment of extensive and recurrent laryngeal papillomatosis as well as the methods of laser-induced interstitial thermotherapy.

Antimicrobial susceptibility of Treponema phagedenis-like spirochetes isolated from dairy cattle with papillomatous digital dermatitis lesions in Japan.

The minimal inhibitory concentrations (MICs) of 23 Treponema phagedenis-like spirochetes isolated from dairy cattle with papillomatous digital dermatitis (PDD) lesions in Japan were investigated by a broth microdilution method using 15 antimicrobial agents. Although all MIC values showed a monomodal distribution, the MICs of the antimicrobial agents for 90% (MIC(90)) of the isolates tested varied among the agents examined. The MIC(90) values for penicillin G, ampicillin, and erythromycin were <0.06 microg/ml. In contrast, the MIC(90) values for kanamycin, streptomycin, rifampicin, sulfamethoxazole, trimethoprim, and colistin were >128 microg/ml. Oxytetracycline, lincomycin, enrofloxacin, chloramphenicol, ceftiofur, and gentamicin showed intermediate values, i.e., 0.5~32 microg/ml. The present study suggested that no isolate had acquired resistance to the antimicrobial agents examined, although they may have natural resistance to some agents. Furthermore, the in vitro antimicrobial susceptibility data would provide helpful information for PDD treatment and the development of a selective medium for isolating the organism effectively.

Immunologic relatedness of papillomaviruses from different species.

An antiserum prepared by immunization of a rabbit with sodium dodecyl sulfate-disrupted virions from a pool of plantar warts was cross-reactive with virus-positive papillomas of other animal species by both indirect immunofluorescence tests on frozen sections of wart tissues and peroxidase-antiperoxidase tests of sections of Formalin-fixed tissues. The antiserum stained plantar warts, common warts, and skin lesions of epidermodysplasia verruciformis, all from humans; bovine fibropapilloma, experimentally produced with bovine types 1 and 2; and transmissible canine oral papillomas. The staining was localized to nuclei of the upper granular layers of the peithelium and was similar in distribution to the pattern produced by antiserum specifically prepared against that papillomavirus. The antiserum did not stain virus-negative warts, or cells infected with simlan virus 40, human polyomavirus BK, and murine polyomavirus. These data suggested that papillomaviruses share a common internal antigen unrelated to a similar antigen described previously for the polyomaviruses (which include simian virus 40 and polyomavirus subgroups).

Alimentary fibropapilloma in cattle: a spontaneous tumor, nonpermissive for papillomavirus replication.

Fibropapillomatosis of the upper alimentary canal of cattle is described. The tumors, found in the esophagus, esophageal groove, and rumen, showed involvement of the subepithelial fibroblasts as well as of the squamous epithelial layer. Although the fibropapilloma cells harbored multiple episomal copies of the genome of bovine papillomavirus type 2 (BPV-2) easily detected by hybridization techniques, no mature virus could be isolated from these lesions or seen by electron microscopy, and no viral antigen could be detected by immunohistochemical methods. It would appear, therefore, that within the limitations of the techniques employed the alimentary canal epithelium and the underlying fibroblasts, while allowing BPV-2 DNA replication, are nonpermissive for the expression of the viral vegetative functions and that transformation of the epithelial cells, like transformation of fibroblasts, can take place in the absence of infectious viral progeny.

Use of interferon-alpha in recurrent respiratory papillomatosis: 20-year follow-up.

OBJECTIVES: The aim of this study was analysis of the results of use of interferon-alpha (IFN-alpha) in patients with recurrent respiratory papillomatosis (RRP) and correlation of the results with human papillomavirus (HPV) type. METHODS: A multicenter prospective series (42 patients from 22 hospitals) yielded 20 years of follow-up of patients with RRP and HPV typing who were treated with IFN-alpha in doses of 3 MU/m2 3 times per week. RESULTS: During long-term follow-up (mean +/- SD, 172 +/- 36.8 months), the rate of event-free survival evaluated by Kaplan-Meier analysis was 42.8%, and the overall survival rate was 82.6%. The HPV typing revealed an association of HPV 11 with a more aggressive disease course (64% of HPV 11 patients versus 24% of HPV 6 patients), a lower incidence of long-term response to IFN-alpha therapy (14% of HPV 11 patients versus 64% of HPV 6 patients), and a higher incidence of malignant transformation and mortality during follow-up (36% and 24%, respectively, of HPV 11 patients versus 0% of HPV 6 patients). CONCLUSIONS: The obtained results revealed maximal effectiveness of IFN-alpha therapy in RRP patients with HPV 6 as compared with HPV 11. The association of HPV 11 with a worse long-term response to IFN-alpha therapy and a higher incidence of malignant transformation and mortality is clinically important and indicates the necessity of HPV typing in RRP patients after the first biopsy.

The search for a culture system for papillomavirus.

Papillomaviruses induce tumors of keratinocytes. Vegetative viral DNA replication and virion assembly are seen in those cells which are in the process of keratinizing or are keratinized. To date, no cell culture system has been developed that permits expression of the complete viral life cycle. Keratinocytes infected in culture may harbor the virus as a stable, replicating episome, but they do not support vegetative viral growth, nor do they become immortalized or transformed. The major obstacle in using keratinocyte cultures may be related to a dual need for transformation and full differentiation. Some animal papillomaviruses have been shown to be capable of transforming cultured murine fibroblasts. The fibroblast model is useful for identifying the viral-transforming gene(s) and their products.

Influence of schedule and mode of administration on effectiveness of podofilox treatment of papillomas.

We investigated the timing of podofilox delivery to see how it correlated with papilloma size. We looked at times ranging from once per week (morning and afternoon) to five times per week (morning and afternoon). We also looked at delivery systems that might enhance the effectiveness of the drug by increasing penetration of the overlying cutaneous horn. These included soaking prior to drug administration, the use of a grooved needle subsequent to drug administration, and the various possible combinations of these techniques. We found that the timing of treatments had relatively little effect on the size of the papillomas. For example, at the end of ten weeks, the geometric mean diameter (GMD) (mm) of the papillomas treated five times per week and induced by a 10(-1) dilution of the virus (group B) was 18. Likewise the GMD (mm) of papillomas treated once per week was 18 (group D). On the other hand, we found that soaking plus the use of a grooved needle plus podofilox resulted in the curing of all lesions induced by a 10(-2) virus dilution and of most induced by the 10(-1) dilution, whereas soak plus podofilox or podofilox alone were not as effective in curing the lesions. Podofilox plus needle approached the soak plus podofilox plus needle in effectiveness. Treatment schedule was not a critical determinant of podofilox effectiveness. Therapeutic benefits were enhanced by hydration of the overlying cutaneous horn and penetration with a grooved needle.

Papillomavirus in cervical condylomas with and without associated cervical intraepithelial neoplasia.

The aim of this study was to analyze the cytohistologic features of cervical condylomas with respect to the presence of associated cervical intraepithelial neoplasia (CIN) and to evaluate whether or not the prevalence of virus antigen, as detected by immunologic staining with peroxidase-antiperoxidase technique, varies with the histologic appearance of the lesions. In a series of 94 histologically confirmed condylomas of the cervix, almost half (43) had features of CIN grades 1 and 2, corresponding to mild and moderate dysplasia. The prevalence of papillomavirus antigen decreased markedly as the features of associated dysplasia became more severe. The antigen prevalence was 82% in pure condylomas, 32% in condylomas with CIN 1, and 0% in condylomas with CIN 2. The evidence that virus production decreased as the lesion became more severe does not preclude papillomavirus etiology for the CIN lesions. Cells transformed by papillomavirus may be expected to cease production of virus particles even as they continue to harbor the viral genome.

Analysis of oral papillomas, leukoplakias, and invasive carcinomas for human papillomavirus type related DNA.

Five papillomas, five leukoplakias, and six carcinomas were investigated for the presence of papillomavirus group-specific antigens and viral DNA. Viral proteins were identified with genus-specific papillomavirus antibodies. Cloned human papillomavirus (HPV) 11 and 16 DNA were used as probes in Southern blot hybridization at conditions of different stringency in order to determine viral DNA. Four of five papillomas, four of five leukoplakias, and three of six carcinomas reacted with HPV DNA probes and revealed some stained cells after exposure to HPV antibodies. HPV type 16 was found in one carcinoma and HPV type 11 was demonstrated in another case of carcinoma.

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.

The presence of human papillomavirus in sinonasal papillomas, demonstrated by polymerase chain reaction with consensus primers.

The frequency of human papillomavirus (HPV) in sinonasal papillomas seems to vary considerably. The highest frequencies have been reported by investigators using in situ DNA or RNA hybridization. Few studies have used polymerase chain reaction, and in these reports the frequency of HPV detection is rather low. We have investigated the presence of HPV in sinonasal papillomas using the polymerase chain reaction with a set of degenerated consensus primers, which amplify the vast majority of the known HPV types. Human papillomavirus was found in three of 14 papillomas. By in situ hybridization the same three papillomas were positive for HPV type 6/11.

Prognostic importance of human papilloma virus typing in squamous cell papilloma of the bronchus: comparison of in situ hybridization and the polymerase chain reaction.

Thirty-one solitary bronchial squamous cell papillomas (SCPs) with variable degrees of dysplasia, one combined with larynx papilloma and small cell carcinoma in the contralateral lung, and 12 papillomas combined with invasive squamous cell carcinomas (SCCs) were investigated for the presence of human papilloma virus (HPV) DNA by in situ hybridization (ISH) and the polymerase chain reaction (PCR). Benign SCPs showed an association with HPV type 11 and rarely with type 6, whereas type 16 or 18, sometimes in combination with type 31/33/35, was found in SCPs associated with SCCs. In one patient HPV type 18- and 31/33/35-positive benign SCP preceded the recurrence of HPV 18-positive SCP (this time combined with carcinoma) by 2 years. Patients with SCP exhibiting HPV 16 or 18 positivity are at high risk for the development of SCC. Virus typing seems to be a better prognostic indicator than grading of dysplasia or age relationship. Virus typing by the PCR is more sensitive compared with ISH, but positive cells cannot be determined; ISH is less sensitive than the PCR but permits a definite designation of the cell types that have integrated HPV sequences into their DNA. Our data suggest that HPV typing should be performed in every bronchial SCP.

Sinonasal papillomas and human papillomavirus: human papillomavirus 11 detected in fungiform Schneiderian papillomas by in situ hybridization and the polymerase chain reaction.

A series of 19 paraffin-embedded sinonasal papillomas (four squamous papillomas, three fungiform papillomas, nine inverted papillomas, and three cylindrical cell papillomas) were investigated for evidence of human papillomavirus (HPV) infection using immunohistochemistry (polyclonal antibody to HPV capsid antigen), in situ hybridization (DNA probes for HPV 6/11, 16/18, and 31/33/35), and the polymerase chain reaction (primers and probes for HPV 6, 11, 16, 18, and 33). All three fungiform papillomas were positive by all three techniques: immunohistochemistry, in situ hybridization for HPV 6/11, and the polymerase chain reaction for HPV 11. None of the other lesions contained detectable HPV using the specific probes included in this study. These results support the continued classification of fungiform papilloma as a distinctive variant of schneiderian papilloma characterized by a predominantly exophytic growth pattern and an association with HPV 11.

Squamous papillary neoplasia of the adult upper aerodigestive tract.

Selected papillary squamous tumors of the upper aerodigestive tract (UADT) mucosa in adult patients do not have well-defined histologic criteria and the clinical behavior is poorly understood. To better characterize this spectrum of neoplasms, UADT papillary neoplasms were evaluated by routine histology, determination of cellular DNA content using Feulgen-stained tissue sections, and the typing of human papillomavirus (HPV) by in situ hybridization. Solitary papillomas were studied in two patients; there was no recurrence in either case, both had normal DNA content, and one was typed as HPV-6 while the other was typed as HPV-11. Seven adult patients with recurrent papillomatosis and at least one biopsy with dysplasia/atypia were identified (mean age at diagnosis, 13.3 years; mean age at last contact, 42.7 years). Six of seven patients had abnormal DNA cellular content in foci of epithelial atypia. In all biopsies evaluated, the papillomas of the seven patients were consistently typed as either HPV-6 or HPV-11. Six patients with malignant papillary neoplasms also had abnormal DNA cellular content, but none revealed evidence of HPV type 6, 11, 16, or 18 by in situ hybridization of tissue sections. In many of the recurrent papillomas, the degree of epithelial atypia encountered was pronounced and was commonly misdiagnosed as carcinoma in situ or papillary carcinoma. The aneuploid DNA content of these foci of atypia reflected the abnormal cellular appearance and partially explained the overdiagnosis of malignancy. However, none of the seven patients were treated for malignant disease and none progressed to invasive carcinoma, with an average follow-up period of almost 30 years. We conclude that histologic and cytologic atypia in HPV-containing papillomatosis may be appreciable. The aneuploid DNA content may represent premalignant conditions and the patient may be at an increased risk for the subsequent development of squamous cancer. However, none of the seven patients with recurrent papillomatosis developed any evidence of malignancy. In addition, none of the patients with papillary carcinomas had previous recurrent papillomatosis.

Human papilloma virus associated with solitary squamous papilloma complicated by bronchiectasis and bronchial stenosis.

A 28-year-old man presented with recurrent pneumonias for 6 years. Chest radiograph and computed tomography showed localized bronchiectasis of the anterior segment of the left upper lobe. Bronchoscopy showed bronchial stenosis without an endobronchial lesion. After 6 weeks of antibiotic treatment, the patient had a recurrent pneumonia and underwent left upper lobectomy that showed a solitary squamous papilloma. In situ hybridization studies of the papilloma were reactive for human papilloma virus subtypes 6/11.

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.

Development of high-grade lymphoma in Helicobacter pylori-infected C57BL/6 mice.

Helicobacter pylori infection is associated with chronic gastritis, peptic ulcer disease, gastric adenocarcinoma and MALT lymphoma. Mice with H. pylori infection develop severe gastritis and atrophic changes in their stomachs after 6 months. We followed H. pylori-infected animals for 13 months to find out whether dysplasia, carcinoma or lymphoma developed. Six-week-old C57BL/6 mice were infected with the CagA-positive and VacA-positive H. pylori mouse-passaged strain 119/95, fed a low antioxidant diet, and kept in microisolated cages. Histopathological changes were examined after 13 months' infection. All H. pylori-inoculated mice (n = 5) developed a gastric squamous papilloma with nagging of the lamina muscularis after 13 months. Three out of five animals developed high-grade B-cell lymphoma derived from a MALT lymphoma at the squamous-corpus border with manifestations also in the liver, spleen and kidney. There was a suspicion of local gastric lymphoma in the two remaining mice but with no significant changes in the liver, spleen or kidney. The normal control mice showed no pathological changes in any of these organs. It is concluded that this mouse model with infection by the CagA-positive, vac-toxin-producing H. pylori strain 119/95 is suitable for use in the study of lymphoma development and also development of squamous cell papilloma with proliferative features.

Hirsutoid papillomas of vulvae: absences of human papilloma virus (HPV) DNA by the polymerase chain reaction.

We have analyzed the specimens from 16 women with hirsutoid papillomas of the vulvae for the presence of HPV DNA using the polymerase chain reaction. The subjects' ages ranged from 27 to 43 years. In all cases, smooth or filiform papules were symmetrically located on the inner surface of both labia minora. Histologically, the lesions consist of acanthosis or papillomatosis without koilocytes and mitotic activity. Eight of 16 specimens were studied by transmission electron microscopy (TEM). No HPV granules were found in the nuclei of keratinocytes. HPV DNA could not be detected in all specimens. Positive controls were present in each assay. These results suggest that the papules of hirsutoid papillomas of the vulvae are unrelated to HPV. Chronic irritants and inflammation may play an important role in pathogenesis.