[Modern biomarkers for precancerous lesions of the uterine cervix : Histological-cytological correlation and use]. / Moderne Biomarker bei Präkanzerosen der Cervix uteri : Histologische-zytologische Korrelation und Einsatz.

The correlation between the cytological findings from the PAP smear and the histological outcome in cases where the cytological findings must be histologically verified, is an integral component of the German screening program for cervical cancer. These data are collected nationwide as part of a benchmarking process by the individual Associations of Statutory Health Insurance Physicians (KV) in the federal states and reported to the National Association of Statutory Health Insurance Physicians (KBV) in Berlin. In most cases there is a good correlation between cytology and histology but in some cases either a different grade of severity of cervical intraepithelial neoplasia (CIN) is found or the histological findings are negative. The reasons for a lack of correlation can be insufficient sampling in the cytology or the biopsy or a misinterpretation of the individual findings. Although the findings from H&E sections are considered to be the gold standard in the histological evaluation, it has long been known that the interobserver agreement in these preparations is only moderate. A significant improvement becomes apparent, firstly by the classification of cervical cancer precursors into low-grade and high-grade groups and secondly by the targeted application of biomarkers, in particular p16 and Ki-67, according to the recommendations of the lower anogenital squamous terminology standardization (LAST) project. The biomarkers p16 and Ki-67 should be used in the differential diagnostics between reactive and reparative alterations and for further differentiation of a CIN grade 2 but not to confirm a CIN grade 3. It is still unclear whether p16 is suitable as a prognostic marker for low-grade lesions.

Incidence of genital warts in adolescents and young adults in an integrated health care delivery system in the United States before human papillomavirus vaccine recommendations.

BACKGROUND: Information on genital wart incidence in adolescents and young adults before human papillomavirus (HPV) vaccination is important for understanding the impact of the vaccine on the epidemiology of this early outcome of HPV infection. METHODS: The study population included 11- to 29-year-old enrollees of Northern California Kaiser Permanente between July 1, 2000, and July 1, 2005, before the availability of the HPV vaccine. We identified genital warts with an algorithm combining genital wart-specific International Classification of Diseases, Ninth Revision, Clinical Modification codes (078.10, 078.11, and 078.19) with physician-recorded anatomic locations. We calculated sex- and age-specific incidence rates of genital warts and described the specific anatomic location of presentation, as well as recurrences of genital warts. RESULTS: We identified 1,682 cases of genital warts among 181,264 individuals. The incidence rate was highest among women (6.3/1000 person-years) and men (2.9/1000 person-years) aged 20 to 24 years old. Among women (n = 96,792), 63.4% of the 1240 incident genital wart cases occurred on the vulva and 21.1% on the cervix. Among men (n = 84,472), 91.6% of the 442 incident genital wart cases did not have a specific anatomic location recorded. Most people with an incident genital wart diagnosis (87.2%) did not have a recurrence during the observation period. CONCLUSIONS: Our study found that the incidence of genital warts was highest among persons aged 20 to 24 years using a unique method to identify the location of the wart. Information on incidence of genital warts before vaccine use provides baseline data that can be used to measure HPV vaccine impact.

Distinctive immunohistochemical profile of penile intraepithelial lesions: a study of 74 cases.

Several classification schemes for penile precancerous lesions have been proposed, but none of them seems to correlate with the current understanding of penile cancer pathogenesis. Recently, a system, which takes into account morphologic features and purported etiopathogenesis, was proposed, separating penile intraepithelial neoplasia (PeIN) in differentiated and warty/basaloid subtypes. This study was designed to seek an immunohistochemical profile that can be helpful in the classification and differential diagnosis of penile epithelial abnormalities and precancerous lesions using the aforementioned system. The immunohistochemical panel included stains for p16, p53, and Ki-67. For p16 immunostaining, only full-thickness positivity in all epithelial cells was considered as positive; for p53 and Ki-67 immunostaining, patchy or diffuse nuclear positivity above the basal layer was considered as positive. Seventy-four lesions in 59 patients were selected and classified as follows: differentiated PeIN, 34 cases; squamous hyperplasia (SH), 21 cases; basaloid PeIN, 15 cases; and warty PeIN, 4 cases. The mean age of patients was 64 years. Forty-two lesions (56.8%) were located in the glans and 32 (43.2%) in the foreskin. Overexpression of p16 was useful for distinguishing SH from warty/basaloid PeINs (0% vs. 94.7%, P<0.0001) but not SH from differentiated PeINs (0% vs. 5.9%, P=0.519). In addition, p16 allowed the distinction of differentiated and warty/basaloid PeINs (5.9% vs. 94.7%, P<0.0001). Immunohistochemistry results for p53 allowed the separation of SH and differentiated PeIN (9.5% vs. 44.1%, P=0.0078) and SH and warty/basaloid PeIN (9.5% vs. 55.6%, P=0.0042). Ki-67 immunostain was useful for distinguishing SH from differentiated PeIN (52.6% vs. 89.7%, P=0.0062) and SH from PeIN with warty and/or basaloid features (52.6% vs. 100%, P=0.0011). There seems to be a distinctive immunohistochemical profile for associated and precursor epithelial lesions of the penis. SH was p16 and p53 negative, with variable Ki-67 positivity. Differentiated PeIN was p16 negative and Ki-67 positive, with variable p53 positivity. Basaloid and warty PeINs were consistently p16 and Ki-67 positive, with variable p53 positivity. The use of a triple p16/p53/Ki-67 immunohistochemical panel was found to be helpful in the classification, differential diagnosis, and morphologic standardization of penile intraepithelial lesions.

Distinctive association of p16INK4a overexpression with penile intraepithelial neoplasia depicting warty and/or basaloid features: a study of 141 cases evaluating a new nomenclature.

From the pathogenic point of view, penile cancers may be grouped in human papillomavirus-related and unrelated tumors, each one of them with distinctive morphologic features. The former are predominantly composed of small, undifferentiated basaloid cells, with more or less prominent koilocytic changes, and the latter of keratinizing differentiated squamous cells. The same cellular types are observed in precancerous lesions. On the basis of these observations, we constructed a novel nomenclature for penile precancerous lesions and classified them as penile intraepithelial neoplasia (PeIN) of differentiated, warty, basaloid, and warty-basaloid types. The aim of this study was to test the usefulness of immunohistochemical p16 overexpression, considered as a surrogate for high-risk human papillomavirus infection, using this classification system. We pathologically evaluated 141 patients with PeIN, associated (123 cases) and unassociated (18 cases) with invasive cancer. Distribution of PeIN types was: differentiated, 72%; basaloid, 9%; warty-basaloid, 7%; warty, 4%; and mixed, 7%. There was a striking similarity in the morphology of in situ and invasive squamous cell carcinomas. Differentiated PeIN was commonly associated with usual, verrucous, papillary, and other low-grade keratinizing variants of squamous cell carcinoma whereas in basaloid and warty carcinomas the presence of in situ lesions with similar morphology was habitual. We evaluated p16 overexpression using a 4-tiered (0, 1, 2, and 3) pattern-based system. To properly distinguish differentiated PeIN from in situ lesions with warty and/or basaloid features only pattern 3, which requires full-thickness staining in all epithelial cells, was considered positive. Using this approach, there was a significant association of the negative patterns and differentiated PeIN and of the positive pattern and warty, basaloid, and warty-basaloid PeIN (P<0.0001). Basaloid variant had the strongest association. The sensitivity rate of p16 positivity for discriminating types of PeIN was of 82%, with a specificity of 100% and an accuracy of 95%. Lichen sclerosus was identified in 42 cases and their epithelial component was p16 negative in all cases. Although more studies are necessary to confirm these observations, p16 overexpression seems to be a useful tool for discriminating differentiated from warty, basaloid, and warty-basaloid PeIN.

Actualización en verrugas genitales externas: diagnóstico, clasificación y tratamiento / Updates in external genital warts

La infección genital por virus papiloma humano constituye la infección de transmisión sexual más frecuente en la actualidad. Las verrugas genitales externas se presentan en cuatro formas clínicas diferentes: condilomas acuminados, verrugas queratóticas, verrugas papulares y verrugas planas. Las diversas alternativas terapéuticas para verrugas genitales externas se pueden clasificar en dos grandes grupos: aquellas autoaplicadas por el paciente y las aplicadas por el médico. Entre las alternativas autoaplicadas destacan Imiquimod, con tasas de curación entre 37 por ciento y 85 por ciento y recurrencias entre 5 por ciento y 19 por ciento, y la Podofilotoxina, con tasas de curación entre 45 por ciento y 88 por ciento y recurrencias entre 0 por ciento y 91 por ciento. Entre las alternativas aplicadas por el médico, tenemos métodos químicos y métodos de remoción. Entre los métodos químicos destaca Podofilina, con tasas de curación entre 19 por ciento y 80 por ciento y recurrencia entre 23 por ciento y 70 por ciento; entre los métodos de remoción destaca la crioterapia, con tasas de curación entre 60 por ciento y 97 por ciento y recurrencias de 80 por ciento.

The human papilloma virus genital infection constitutes the most frequent sexual transmission infection of our time. The clinical manifestations of external genital warts vary in four different types: acuminated condyloma, keratolic warts, papular warts and flat genital warts. The diverse therapeutic alternatives for external genitals warts can be classified in two large groups: those applied by the patient, and those applied by the physician. Among the alternatives applied by the patient, both Imiquimod, with clearance rates between 37 percent - 85 percent and recurrence between 5 percent - 19 percent; and Podofillotoxin 0.5 percent solution, with clearance rates between 45 percent - 88 percent, and recurrence between 0 percent-91 percent stand out. Among the alternatives applied by physicians, we have chemical methods and removal methods. In chemical methods Podofillin stands out with clearance rates between 19 percent - 80 percent and recurrence between 23 percent - 70 percent; among removal methods, cryotherapy is the most important, with clearance rates between 60 percent - 97 percent, and recurrence of 80 percent.

[Clinical features and epidemiological survey of perianal warts in 72 males].

OBJECTIVE: To investigate the clinical features and epidemiological data of 72 cases of male perianal warts. METHODS: Seventy-two cases of perianal warts in our clinic dated from June, 2004 to April, 2006 were enrolled in the study, whose clinical information and epidemiological data were collected and analyzed. RESULTS: Perianal warts were most commonly seen in young and middle-aged men aged from 18 to 45, only 12.5% of whom had homosexual behaviors. Sauna was another predisposing factor of perianal warts in males in China (chi2 = 5.03, P < 0.05). Primary eruptions of the anus and rectum, like perianal pruritus, eczema, anus fissure, and haemorrhoids, often impaired the local integrity of skin/mucosa. Classical condyloma acuminate was found in 61 (84.72%) of patients, who were susceptive to the infections of HPV 6/11, and were flat condylomas related to HPV16/18. Cryotherapy was believed to be one of the most efficient therapeutic choices for flat perianal warts. Suppression of cellular immune response was identified in the patients by comparison between the subgroups of peripheral T cells and the normal control. CONCLUSION: Sauna is an essential predisposing factor of perianal warts in males, while anus sexual intercourse is not the main route of HPV infection. Classical condylomata acuminate constitute the majority of the eruptions, and flat condylomata come next. The study also provides some useful data for understanding the clinical and epidemiological features of perianal warts in Chinese males for the sake of prevention and treatment of the disease.

Infección vaginal por el virus del papiloma humano / Vaginal infection for human papilloma virus

Se estudiaron 25 mujeres con lesiones papilares de vagina en el servicio de ginecología y reproducción humana Hospital Carlos J Bello de la Cruz Roja Venezolana, entre octubre de 1996 y diciembre de 1997. Se tomaron dos muestras de dicha lesión, una de ellas para determinar la presencia de algunas de las secuencias de ADN asociadas al virus 6,11,16,18,31.33 ó 35 mediante la técnica de reacción en cadena de la polimerasa y la otra fue procesada por antomía patológica según la metodología tradicional. Once muestra de total pacientes estudiadas coincidieron con el diagnóstico histológico sugestivo de infección por el virus (44 por ciento). En 8 de las muestras estudiadas (32por ciento), se encontró la presencia de alguna de las secuencias de ADN asociadas a los tipos de virus anteriormente nombrados. De las 11 biopsias sugestivas de infección por el virus 3 resultaron positivas para ADN del virus (27 por ciento). De las 8 biopsias donde se encontró presencia de alguna de las secuencias de ADN estudiadas, 3 (38 por ciento) coincidieron con el diagnóstico histológico sugestivo de infección. La citología ex-endocervical resultó negativa, en todas las muestras para la sospecha de infección en el virus

Submicrostructure and typing of female genital condylomata.

Thirty biopsies from female genital condylomata were examined by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) to study structural characteristics and typing of condylomata. It was found that cytoplasmic clearing was marked in acuminate condylomata, diffuse interstitial and epithelial proliferation in nodular condylomata (flat condylomata), and invagination of the lesions into the interstitial tissue or glandular ducts in endophytic condylomata. In nodular condylomata, SEM also showed some structural features similar to those of intra-epithelial neoplasia. Microridges on the surface of squamous cells had villiform of granular changes. On the surface of a percentage of squamous or columnar cells, there were holes with a diameter of about 3 to 5 microns. A number of giant cells were seen among other cells. The cervical squamatization zone contained groups of special cells covered with dense microvilli. TEM of nodular condylomata revealed some pictures resembling active proliferation of tumor cells, such as enlarged or irregular nuclei (large N/C ratio), evaginated or invaginated nuclear membranes, condensed chromatin attached to the inner part of the nuclear membrane, transparent nucleoplasm, and frequent nucleosomes and karyokinesis. Virus particles with the morphological characteristics of HPV (naked hexagon-like particles with an average diameter of 45-50 nm) were seen in some nuclei with markedly condensed chromatin. It is suggested that HPV-induced genital condylomata, especially nodular one (flat condylomata), entail a potential progression to malignancy.

Children with condylomata acuminata.

BACKGROUND: The modes of transmission of genital human papillomavirus (HPV) infection in children are controversial. Studies have varied in reporting suspicion of sexual abuse in children with condylomata acuminata from zero to 90.9%. Possible modes of transmission include sexual, from mother to infant in utero, passage through an infected birth canal, infection of a nongenital type virus to the genital area, and nonsexual acquisition from a fomite. METHODS: Seven children, ranging in age from 2 to 12 years, who had genital HPV infections were assessed for sexual abuse. An interview with each child was conducted and an examination with a colposcope of the external genitalia was performed. A shave biopsy of a representative genital lesion was obtained. The tissue was sent for HPV typing. RESULTS: Six of the children had perianal warts; the seventh had a labial lesion. Five of the children (71%) had been sexually abused as determined by the history, physical examination, or an investigation by Child Protective Services. Five had HPV type 6 or 11, one had HPV type 16 or 18, and one had a novel HPV type. CONCLUSIONS: Genital types of HPV (6 or 11, 16 or 18, and others) should alert the family physician to proceed with a careful assessment for sexual abuse. This study supports the findings of other reports that genital HPV infection can be the result of sexual abuse and points out the usefulness of HPV typing.

[Colposcopy of the vulva]. / La vulvoscopie.

A detailed colposcopy study of the cervix, vagina and vulva was conducted in 365 women referred for genital human papillomavirus (HPV) lesions, abnormal cervico-vaginal smear or cervical intraepithelial neoplasia (CIN). Valvuloscopic abnormalities, all biopsied, were found in 144 women, i.e. 40% of the population studied. Five types of vulvoscopic abnormalities are described: diffuse acidophilia (55% of abnormalities), acidophilic maculae (17%), micropapillae (20%), papulae (4%) and leucoparakeratosis (4%). Histological examination of the biopsy specimens obtained from 144 women with abnormal vulvoscopy showed 55 typical flat condylomas (38%), 50 probable flat condylomas (35%) and no signs of condyloma in 38 cases (27%). It also revealed the presence of four vulvar intraepithelial neoplasias (VIN) stages 2-3, all of them associated with typical or probable condyloma. Comparison between the 144 abnormal vulvoscopies and a series of 14 normal vulvoscopies made it possible to establish a significant correlation between the presence of valvuloscopic abnormalities and the finding of histological signs of typical or probable flat condyloma. The vulvoscopic images of subclinical vulvar HPV infection, but apart from papulae and, to a lesser extent, leucoparakeratosis, correlations between vulvoscopic and histological images were imprecise.

[Assessment of human papilloma virus colposcopic findings of the cervix (in the Italian colposcopic classification]. / L'inquadramento dei reperti colposcopici da HPV in sede cervicale (nella classificazione colposcopica italiana).

HPV-induced flat condylomatosis is not only much more frequently observed on the hexocervix than the florid type, but it also induces colposcopic changes in the epithelium without completely altering its morphology. HPV-induced changes have now been largely identified and are recognisable in colposcopy. They can therefore be classified in the various patterns that characterise colposcopically the transformation epithelium, with undeniable advantages not only from the point of view of their correct classification but also from that of their prognostic evaluation. This is important because viral modifications ANTZ have a different diagnostic and prognostic significance from those observable in the notice squamous epithelium. A classification proposal of the various findings of flat HPV condylomatosis based on italian colposcopic classification is therefore presented.

Vulvo-vaginal condylomatosis and relapse: combined treatment with electrocauterization and beta-interferon.

The therapeutical effectiveness of beta-interferon and the possibility of reducing the incidence of relapses were evaluated by selecting three groups of patients affected with three forms of condylomatosis and submitting then to various treatments. In the first group of sixty patients treated with beta-interferon, we obtained the best results in micro-condylomatosis (a 100% response), while florid condylomatosis responded less well to the treatment (72% with no response). In the second group of ten patients, electrocoagulation of florid condylomata determined a complete response (CR) in seven cases (70%). Moreover, immunoperoxidase identified three case of sub-clinical infection, two of which relapsed. In the third group of ten patients, we combined electrocoagulation with beta-interferon. This combination showed the effectiveness of beta-interferon in decreasing relapses. This result is evident if we consider that only one out of four patients with immunoperoxidase-positive biopsy relapsed.

Discrimination between precancerous and cancerous lesions of the uterine cervix by DNA measurements on tissue sections.

Morphologically typical uterine cervical biopsies were separated into normal cervices, condylomas and cervical intraepithelial neoplasias (CIN) grades I, II and III. At least 100 nuclei per lesion were measured on 4 micron Feulgen-stained sections using a Zeiss microspectrophotometer, with a variant of the plug method used to compute the nuclear DNA content. DNA distribution histograms were then decomposed into subsets of diploid, tetraploid, octoploid and aneuploid cells. The decomposition, which assumed a log-normal model of polydiploidy distribution, led to the identification of six indices: (1) the percentage of diploid cells, (2) the percentage of tetraploid cells, (3) the percentage of octoploid cells, (4) the percentage of aneuploid cells with DNA contents less than tetraploidy, (5) the percentage of aneuploid cells with DNA contents between tetraploidy and octaploidy and (6) the percentage of aneuploid cells with DNA contents greater than octoploidy. These indices, along with the mean nuclear radius, the 5c exceeding rate and the 2c deviation index, generated a nine-dimensional space. Two methods of discriminant analysis on this space showed discriminating powers of 78.22% and 87.13%, respectively, as compared to the original diagnoses. The most discriminating variable in both analyses appeared to be the percentage of octoploid cells.

Condylomatous lesions associated with precancerous changes and carcinomas of the uterine cervix.

The present communication is a comparative survey of the histological specimens derived from the dysplastic or neoplastic lesion of the uterine cervix of 400 women comprising two age-matched series (200 women in each) collected from two Finnish hospitals. Special emphasis was placed on the detection of the newly described condylomatous lesions (flat, inverted, papillomatous) and the possible variations in their biological behavior in the two series. The biological behavior of the condylomatous lesions (the distribution into the three types, their high frequency in young women, and their relationship to different degrees of epithelial atypia) was not significantly different in the two series studied. The main difference between the series was in the frequency of the condylomatous lesions which was markedly higher (p less than 0.005) in the material made up of women in eastern Finland. The results suggest that condylomatous lesions caused by human papilloma virus (HPV) are ubiquitous and characterized by a rather constant biological behavior. The reasons behind the observed local variations in their frequency remain obscure and advocate an epidemiological study combined with virological assays to be done among the patients with precancerous lesions of the uterine cervix to gain further data on the role of HPV in human squamous cell carcinogenesis.

Condylomatous tumours of vulva, vagina, and penis. Relation between histological appearance and age.

Among 237 cases of condyloma diagnosed in Uganda between 1964 and 1975 seven types of lesions were defined. Three of these were found within a wide age range in both young and elderly people, namely, the common (49.4%) and the flat (2.0%) condyloma acuminatum, and condyloma acuminatum of irregular outline (13.5%). Four variants, on the other hand, fell into different age groups. Condyloma acuminatum, showing marked cell death (5.1%) and observed exclusively among girls in the first decade of life, displayed numerous aciophil bodies, presumably reflecting single cell necroses. Condylomata acuminata showing marked acanthosis (16.9%) were found in patients between 12 and 30 years, dysplastic condylomata acuminata (5.9%) between 20 and 62 years, and proliferative (giant) condylomata acuminata (7.2%) between 31 and 80 years of age. In the latter two groups of lesions, the inflammatory stromal infiltrate was more prominent, but cytoplasmic vacuolation, often believed to be a sign of viral infection, was seen less frequently than in the remaining types. In young people, the features seen resemble, therefore, a cytocidal and/or vacuolating viral infection, whereas the dysplastic and proliferative changes observed in older patients are compatible with malignant transformation being under way.