[Computer-assisted diagnostics in cervical cytology]. / Computerassistierte Diagnostik in der Zervixzytologie.

Computer assistance has the ability to reduce screening errors. In cervical cytology only two systems are available: BD FocalPoint™ (BD) utilizes algorithms for image recognition to analyze thin-layer specimens (Surepath) and conventional slides. The ThinPrep® imaging system (Hologic) is based on the densitometric measurement of nuclei and requires a thin-layer preparation. The BD FocalPoint™ system assigns specimens according to declining probability of an abnormality to one of six groups. A further option is location-guided screening (LGS) where the 15 fields of view which are most relevant are presented on a computerized microscope. Several studies indicate that this mode is at least equivalent to manual screening with conventional and surepath (SP) slides. For the ThinPrep® imaging system which only uses the LGS mode the majority of available studies found a significantly higher sensitivity for histologically confirmed grade 2 cervical intraepithelial neoplasia (CIN 2 +). However, most were retrospective or parallel studies. Both systems allow a significantly higher productivity but require a higher technical expenditure.

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.

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.

Presence of human papillomavirus in genital tumors.

Human papillomavirus (HPV) types 16 and 18 have been identified in two different human cervical carcinomas. The viral DNAs were molecularly cloned and used as probes to screen a large number of genital tumors by Southern blot analysis. HPV-16 or HPV-18 sequences, respectively, were found in a high percentage of cervical carcinomas, but only in a small number of condylomata acuminata or flat condylomas. The majority of the latter lesions, however, contained HPV-6 or HPV-11 sequences, respectively, which in contrast were detected only rarely in carcinomas in situ or invasively growing carcinomas. A similar distribution of the different papillomaviruses was observed when cell swabs taken from the cervix were tested by in situ hybridization.

Localization of human epidermal growth factor receptor in cervical intraepithelial neoplasias.

Immunohistochemical staining of epidermal growth factor receptor (EGF-R) with a monoclonal antibody was performed in 43 biopsies of cervical tissue. The distribution of the receptors in normal cervical tissue differs from that of cervical intraepithelial neoplasia (CIN) and squamous cell carcinoma of the cervix. Whereas the staining reaction in normal squamous epithelium was confined to the basal and deep parabasal cell layer, in all cervical intraepithelial neoplasias, with or without human papilloma virus association, a homogeneous EGF-R staining reaction could be observed throughout the entire lesion. This means that the dysplasia cells of a CIN I-III, like the tumor cells of a squamous cell carcinoma, have a raised EGF-R content, which in the normal squamous epithelium is usually only found in the basal and deep parabasal cells that are capable of dividing. No EGF-R staining reaction could be detected in the higher, differentiated cell layers of the normal squamous epithelium of the cervix.

Identification of human papillomavirus in cervical swabs by deoxyribonucleic acid in situ hybridization.

A series of 47 lesions diagnosed cytologically as cervical intraepithelial neoplasia (CIN) III in 22 cases, CIN I/II in 13 cases, and 12 cases showing abnormal smears consistent with human papillomavirus infection were analyzed. Thirty-six cases with negative cytology were used as the control group. Sixty-eight percent of CIN III were positive for a mixture of human papillomavirus 16 and human papillomavirus 18, 18% reacted with human papillomavirus 6 or 11, and 14% were negative. Of the group with CIN I/II or with abnormal Papanicolaou smears, approximately one-third contained human papillomavirus 6 (11) and one-third human papillomavirus 16 and 18. Only 11% of the samples from the control group hybridized with human papillomavirus 6 (11), the others were negative with either probe. The data obtained by the rapid in situ hybridization of cervical cells are in agreement with the presence of human papillomavirus 16 and 18 in a high proportion of cervical carcinoma and carcinoma in situ lesions. Thus, the method can be applied to test the hypothesis that a lesion containing human papillomavirus 16/18 positive cells has a higher risk of progressing to cancer than a lesion harboring human papillomavirus 6 or 11.

Human papillomavirus DNA in invasive carcinoma of the vagina.

The presence of human papillomavirus (HPV) DNA in invasive carcinomas of the vagina, in their lymph node metastases, and in corresponding normal tissue was investigated by Southern blot hybridization with 32P-labeled HPV DNA. Tumor tissue from ten of 18 patients with vaginal carcinoma contained HPV DNA. Three of the 18 patients had a history of cervical neoplasia more than 14 years before the diagnosis of vaginal carcinoma. Five of 15 primary squamous cell carcinomas, one primary adenocarcinoma, and a vulvar recurrence of a vaginal squamous carcinoma contained HPV 16. A primary squamous carcinoma yielded HPV-related sequences. The HPV copy number varied from 0.5 to 50 per cellular genome. Four histologically positive inguinal lymph nodes from three patients contained HPV DNA. In six tumor-free control tissues from four patients, no HPV DNA was detected. No relationship was established between HPV positivity, HPV type, or copy number of the tumor and the grade of differentiation or keratinization or the clinical stage. After a median follow-up of 13 months, five of nine HPV-positive patients were alive without recurrence, whereas all seven HPV-negative patients had died because of disease. The results of this study indicate a possible major role of HPV in the development of vaginal cancer.

Bowenoid papulosis. Presence of human papillomavirus (HPV) structural antigens and of HPV 16-related DNA sequences.

This study reviews 39 cases of anogenital bowenoid papulosis lesions in 22 individuals of both sexes that were analyzed clinically, histologically, immunocytochemically, and virologically. Macroscopically, three different types of lesions were demonstrated: erythematous macules; papules (lichenoid and/or pigmented papules); and leukoplakialike lesions. Microscopically, bowenoid papulosis fulfills the criteria of a squamous cell carcinoma in situ. Much like oral precancers, three distinct growth patterns (flat, endophytic, and exophytic) could be differentiated, which did not correlate with the clinical aspect of the lesions. In only two (5.12%) of the 39 cases of bowenoid papulosis could structural antigens of papillomaviruses be detected immunocytochemically (peroxidase-antiperoxidase technique). The DNA from 12 lesions that were analyzed for the presence of papillomavirus-specific sequences hybridized stringently in all cases with the human papillomavirus 16 specific DNA probe labeled with phosphorus 32.

Human papillomavirus, type 16, DNA in multicentric anogenital neoplasia associated with idiopathic panmyelopathy. A case report.

A 27-year-old woman suffering from panmyelopathy for six years presented with a cervical low grade squamous intraepithelial lesion (SIL), vulvar high grade SIL and perianal squamous cell carcinoma with an inguinal metastasis. Southern blot hybridization with 32P-labeled human papillomavirus (HPV) DNA revealed HPV 16 DNA in varying copy numbers in material from the four locations. HPV 16 genomes persisting after surgery on the perianal tumor area were no longer detectable after betatron radiotherapy.

Human papillomavirus standardization and DNA cytophotometry in cervical intraepithelial neoplasia.

Human papillomavirus (HPV) standardization and DNA cytophotometry were carried out in 29 cases of cervical intraepithelial neoplasia (CIN) grades I-III. A prognostically unfavorable DNA distribution pattern with an aneuploid stemline was found in 14 of the 16 dysplasias with HPV types 16 and 18, while in 11 of 13 dysplasias with HPV types 6 and 11 there was a favorable DNA distribution with a euploid-polyploid stemline. Among 178 colposcopically, cytologically and histologically confirmed cervical lesions, there was a statistically significant incidence of HPV 16/18 infections in severe dysplasias and carcinomas, while HPV 6/11 was found predominantly in mild cervical lesions. It seems that CIN can be divided into high- and low-risk lesions not only by the degree of severity and the DNA distribution pattern but also by HPV typing.

[Status of papillomaviruses and their diagnosis in preventive screening]. / Der Stellenwert der Papillomviren und ihrer Diagnostik bei der Vorsorge.

Cervical carcinoma and its precursors are discriminated by their epidemiology from other malignant diseases. Human papillomavirusus (HPV) have been identified as the central etiologic factor in these diseases. Certain HPV gene products are tumor specific antigens in cervical cancer which leads to new perspectives in prevention and therapy. HPV testing is a realistic option in screening, triage and follow-up of cervical cancer and its precursors which has shown significant advantages over traditional methods in numerous large studies and proven cost effectiveness in recent model simulations.

Short version of the German evidence-based Guidelines for prophylactic vaccination against HPV-associated neoplasia.

Persistent infection with HPV 16 and 18 has been causally associated with the development of cervical cancer and its precursor lesions as well as with other carcinomas and their precursors, e.g. some vulvar and vaginal cancers. Furthermore HPV 6 and 11 are responsible for anogenital condylomata acuminata in more than 90% of cases. With the recently developed prophylactic bivalent (HPV 16 and 18) and quadrivalent (HPV 6, 11, 16 and 18) vaccines, it is possible to prevent infection of the cervical epithelium and other squamous epithelia, the development of premalignant lesions and, in the case of the quadrivalent vaccine, the development of condylomata acuminata. The following paper represents a summary of the full-text version of the German evidence-based Guidelines, including all evidence-based recommendations regarding the safety as well as the efficacy of the vaccines in preventing CIN, VIN/VaIN, genital warts and other HPV-associated lesions.

[Detection of human papilloma virus (HPV) DNA in vulvar cancers]. / Nachweis von humaner Papilloma-Virus(HPV)-DNA in Vulvakarzinomen.

Using Southern Blot hybridization 18 invasive malignant tumours of the vulva and 2 intraepithelial vulvar neoplasias were tested for the prevalence of HPV-DNA. In 6 of 11 primary squamous carcinomas, including one carcinoma of the Bartholinic gland, HPV 16 could be identified. Contrarily, in all seven recurrent vulvar tumours examined, including 5 squamous carcinomas, 1 fibrosarcoma and 1 zylindroma, no HPV-DNA was found. No correlation existed between HPV status of the tumours and grade of differentiation or keratinization, or the tumour-stage and lymph-node status. In one tumour-invaded lymph-node HPV 16 was detected as in the corresponding primary tumour. 12 samples from tumour free abdominal skin considered as corresponding normal tissue specimens were negative for HPV-DNA. A correlation between clinical course of the disease and HPV status of the primary tumours was not observed.

[Focal epithelial hyperplasia (Heck disease). Contribution on its viral origin]. / Fokale epitheliale Hyperplasie (Morbus Heck). Beitrag zur viralen Genese.

Demonstration of human papilloma virus DNA (HPV-DNA) in the lesions of focal epithelial hyperplasia in an 11-year-old Turkish girl provides further proof of its viral cause. In this case characterization of HPV-DNA showed a reaction with that of type 13 and 18. This previously undescribed variant is probably the expression of a new HPV type.

[Alpha interferon in condylomata acuminata and juvenile diabetes mellitus]. / Interferon-alpha bei Condylomata acuminata und juvenilem Diabetes mellitus.

Persistent condylomata acuminata in a 21-year-old patient with diabetes mellitus were treated with highly purified interferon-alpha (IFN-alpha) obtained by recombinant DNA technology. Daily dose was 1.5 X 10(6) IU, given subcutaneously. Already during treatment the condylomata regressed. Two weeks after the end of therapy, i.e. after a total dose of 10.5 X 10(6) IU IFN-alpha, all condylomata had completely receded. Blood glucose levels remained constant with concomitant insulin therapy. Toxic side-effects or antibodies to IFN-alpha were not observed.