¿Permiten la citología, el genotipado y la anoscopia de alta resolución establecer un protocolo para la detección precoz del carcinoma epidermoide de canal anal en población de riesgo? / Do cytology, genotyping, and high resolution anoscopy allow to establish a protocol for early detection of squamous cell carcinoma of the anal canal in risk population?

Introducción: El cáncer anal ha experimentado un aumento de incidencia en los últimos años. Está mediado por el VPH y precedido de cambios precancerosos planteando la posibilidad de dirigir los esfuerzos preventivos hacia los grupos de alto riesgo. Sigue siendo controvertida la indicación de cribado y los métodos de detección ideales. Objetivo: Validar las pruebas de cribado implementadas en la actualidad comparadas con la biopsia como "gold standard". Material y Métodos: Estudio transversal con recogida de datos prospectiva, en una cohorte de hombres VIH+ que tienen sexo con hombres, pertenecientes al Hospital Gregorio Marañón e Infanta Leonor en un periodo de 2 años. Resultados: Se seleccionaron 179 pacientes con 286 visitas a la consulta de screening en las que se llevaron a cabo 3 pruebas de cribado en paralelo (citología anal, genotipado del VPH y anoscopia de alta resolución (AAR) con toma de biopsia dirigida sobre zona sospechosa o aleatoria). La sensibilidad y especificidad para la detección de displasia de alto grado y cáncer y su grado de concordancia con la biopsia fue la siguiente: citología 3,23%/94,43% (k: 0,03), genotipado de VPH de alto riesgo 90,32%/27,45% (k: 0,05), AAR 32,26%/87,45 (k: 0, 17) siendo el rendimiento diagnóstico de las tres pruebas muy bajo. Conclusión: La citología presenta un rendimiento diagnóstico muy bajo comparado con el genotipado que representa el mayor. A la luz de nuestros resultados, los protocolos clínicos tal y como vienen desarrollándose en la actualidad deberían de ser abandonados.

Introduction: The incidence of anal cancer has increased in recent years. It is mediated by HPV and preceded by precancerous changes, raising the possibility of directing preventive efforts towards high-risk groups. The indication of screening remains controversial and which methods would be the ideal ones. Objective: To validate the screening tests established actually, comparing it with the biopsy considered as the "gold standard". Materials and Methods: A cross-sectional study was performed, with prospective data collection in a cohort of VIH+ patients, who have male homosexual anal relations, belonging to Gregorio Marañón and Infanta Leonor Hospitals in a period of 2 years. Results: A total of 179 patients were selected with 286 visits to the screening Outpatient Clinic in which 3 parallel screening tests were performed (anal cytology, HPV genotyping and high resolution anoscopy (AAR) with a biopsy directed on a suspicious or random area). The sensitivity and specificity for the detection of high-grade dysplasia and cancer and their degree of agreement with the biopsy was as follows: cytology 3.23%/94.43% (k: 0.03), high HPV genotyping. risk 90.32%/27.45% (k: 0.05), AAR 32.26%/87.45 (k: 0, 17), the diagnostic accuracy of the three tests being very low. Conclusion: Cytology shows a very low diagnostic accuracy compared to the genotype that represents the highest one. In light of our results, clinical protocols as they are currently being developed should be abandoned.

Epidemiological dynamic modeling of human papillomavirus-related diseases to assess vaccination strategies in Argentina

Our objective was to develop and test a dynamic simulation model of human papillomavirus (HPV)- related diseases to assess rational vaccination strategies in Argentina. A dynamic stochastic transmission model for hetero- and homosexual transmission of HPV oncogenic and low-risk oncogenic types among females and males was developed. The model included HPV transmission and vaccination, the natural history of HPV-related diseases, disease outcomes, and cervical cancer screening. Considering all cervical cancers, covered or not by the current quadrivalent vaccine, the existing coverage rate would lead to 60% reduction in the global incidence of cervical cancer at 25 years, and to 79% at 50 years. Isolated current female vaccination without a screening program would need around 100 years to eliminate cervical cancer from the local population. Current coverage rate would lead to 59% reduction of vulvar cancer, 76% of vaginal cancer, 85% of anal cancer, and 87% of oropharyngeal cancer, estimated over a 25-year time prospect. Female HPV vaccination within the context of current cervical cancer screening should reach a minimum long-term mean coverage of 60% of girls, receiving at least a two-dose vaccine schedule, to significantly reduce or virtually eliminate cervical cancer at 50 years. Including vaccination to boys to improve herd immunity did not influence the incidence of cervical cancer over time, as long as female coverage did not fall below 50%. Regarding vulvar, vaginal, anal, penile, and some oropharyngeal cancers, current girls-only based vaccination could virtually eliminate these cancer types after 35-40 years, both in women and men.

Se desarrolló un modelo de simulación dinámica de enfermedades relacionadas con papilomavirus humano (VPH) para evaluar estrategias de vacunación. Se desarrolló un modelo dinámico estocástico para transmisión hetero/homosexual de VPH oncogénicos y de bajo riesgo oncogénico, entre mujeres y hombres. El modelo incluyó transmisión y vacunación contra VPH, historia natural de enfermedades relacionadas con VPH, mortalidad y programas de detección de cualquier cáncer de cuello uterino (CCU); teniendo en cuenta todos estos, con o sin vacunación cuadrivalente con la cobertura actual, la reducción sería 60% en la incidencia global de CCU en 25 años, y de 79% en 50 años. Vacunando solo mujeres, sin programa de detección precoz, necesitaría unos 100 años para eliminar el CCU localmente. La tasa de vacunación actual determinaría 59% de reducción del cáncer de vulva, 76% del cáncer vaginal, 85% del cáncer anal y 87% del cáncer orofaríngeo, a 25 años. La vacunación de mujeres, con el cribado actual del CCU, deberá alcanzar una cobertura media mínima a largo plazo del 60% de las niñas, con al menos dos dosis de vacunas, para reducir significativamente o eliminar el CCU en 50 años. La vacunación en niños para mejorar la inmunidad de grupo no influiría en la incidencia del CCU de n o caer la cobertura femenina por debajo de 50%. Con respecto a cánceres de vulva, vagina, ano, pene y algunos orofaríngeos, la vacunación actual solo en niñas podría eliminar virtualmente estos tipos de cáncer después de 35-40 años, tanto en mujeres como en hombres.

Detección temprana de la displasia anal con citología (PAP) y anoscopía de alta resolución (AAR) en la población de riesgo: experiencia inicial / Early detection of anal dysplasia with cytology (PAP) and high resolution anoscopy (AAR) in the population at risk: initial experience

Antecedentes: La incidencia del carcinoma de células escamosas anal (CCE) aumentó drásticamente, es de 35/100.000 habitantes en los hombres que tienen sexo con hombres (HSH), similar a la del cáncer del cuello uterino antes del Papanicolaou (PAP). En forma análoga a la pesquisa del cáncer cervical, el PAP anal y la anoscopía de alta resolución (AAR), se utilizan para la detección temprana de las lesiones precursoras del CCE. Objetivo: Evaluar los hallazgos de la citología anal y la AAR en una población de alto riesgo para desarrollar displasia y CCE. Diseño: Observacional, descriptivo, transversal, prospectivo. Población: Pacientes de alto riesgo (individuos HIV positivos, hombres que tienen sexo con hombres (HSH), mujeres con antecedentes de cáncer o displasia del tracto genital inferior, individuos con antecedentes de HPV anal o genital) que concurrieron al Consultorio de Detección Temprana de la Displasia Anal, entre 1 abril y 30 junio 2012. Método: Tacto rectal, anoscopía convencional, PAP anal y AAR, con biopsia dirigida de lesiones sospechosas. Comparación de la citología con la histología...

Background: The incidence of anal squamous cell carcinoma (SCC) has increased dramatically, with an incidence of 35/100.000 inhabitants in men who have sex with men (MSM), similar to that of cervical cancer before the Papanicolaou (PAP). In analogy form to screening of cervical cancer, anal PAP and high resolution anoscopy (HRA) are used for early detection of SSC precursor lesions. Objective: To assess the findings of anal cytology and HRA in a high risk population for developing dysplasia and SCC. Design: Cross-sectional, descriptive, prospective, study. Population: High-risk patients (HIV- positive individuals, men who have sex with men, women with previous cancer or dysplasia of the lower genital tract, individuals with previous anal or genital condylomata) who attended the Anal Dysplasia Early Detection Clinic between April 1-June 30, 2012, were included. Methods: Digital rectal examination, conventional anoscopy, anal PAP and HRA, with biopsies of suspected areas was performed...

Carcinoma de ano, pene, vulva y vagina: ¿son enfermedades de transmisión sexual? / Anogenital neoplasms: are sexually transmitted diseases?

Introducción: La infección por virus papiloma humano (VPH) sería factor causal de cánceres de ano, pene, vulva y vagina. Objetivo: Analizar la evidencia actual en cuanto a infección por VPH y su rol carcinogénico en estas neoplasias. Metodología: Búsqueda de la literatura para identificar artículos sobre la transmisión sexual como factor de riesgo en cánceres anogenitales. Resultados: En lesiones premalignas y malignas anogenitales se encuentra en gran frecuencia el DNA de VPH, especialmente tipo 16. Se ha demostrado que la vacunación contra VPH previene el desarrollo de lesiones preinvasoras anales; en cambio, ni la vacuna ni la circuncisión parecen ser factores protectores contra cáncer de pene. Discusión: No hay estudios prospectivos que permitan establecer una relación causal entre VPH y cánceres anogenitales, lo que impide la elaboración de estrategias de prevención. El manejo de ciertos factores de riesgo sugeridos previamente en la literatura no reduce el riesgo de cáncer anogenital.

Introduction: Human papillomavirus (HPV) infection has been suggested as a causal factor of anal, penile, vulvar and vaginal cancers. Objective: To analyze current evidence about HPV infection and its carcinogenic role in these neoplasms. Methodology: Literature search to identify articles about sexual transmission as a risk factor in anogenital cancers. Results: In premalignant and malignant anogenital lesions, an important presence of HPV DNA is often found, specially type16. It has been demonstrated that HPV vaccine prevents premalignant anal lesions; however, this vaccine and circumcision do not seem to be protective against penile cancer. Discussion: There are no prospective studies that had established a causal relationship between HPV and anogenital cancers. This keeps off the development of adequate prevention strategies. Management of certain previously suggested risk factors do not reduce the risk of anogenital cancer.

Morphometric analysis of dendritic cells from anal mucosa of HIV-positive patients and the relation to intraepithelial lesions and cancer seen at a tertiary health institution in Brazil / Análise morfométrica das células dendríticas da mucosa anal de pacientes HIV-positivos e relação com as lesões intraepiteliais e o câncer numa instituição de saúde terciária no Brasil

PURPOSE: To morphometrically quantify CD1a+ dentritic cells and DC-SIGN+ dendritic cells in HIV-positive patients with anal squamous intraepithelial neoplasia and to evaluate the effects of HIV infection, antiretroviral therapy and HPV infection on epithelial and subepithelial dendritic cells. METHODS: A prospective study was performed to morphometrically analyze the relative volume of the dendritic cells and the relationship between anal intraepithelial neoplasia and cancer in HIV-positive patients from the Tropical Medicine Foundation of Amazonas, Brazil. All patients were submitted to biopsies of anorectal mucosa to perform a classic histopathological and immunohistochemical analysis, employing antibodies against CD1a and DC-SIGN for the morphometric quantification of dendritic cells. RESULTS: HIV-negative patients displayed a CD1a DC density significantly higher than that of HIV-positives patients (3.75 versus 2.54) (p=0.018), and in patients with severe anal intraepithelial neoplasia had correlated between DC CD1a density with levels of CD4 + cells (p: 0.04) as well as the viral load of HIV-1 (p: 0.035). A not significant rise in the median density of CD1a+ DC was observed in the HIV positive/ HAART positive subgroup compared to the HIV positive/ HAART negative subgroup. The CD1a+ DC were also significantly increased in HIV-negative patients with anorectal condyloma (2.33 to 3.53; p=0.05), with an opposite effect in HIV-positive patients. CONCLUSIONS: Our data support an enhancement of the synergistic action caused by HIV-HPV co-infection on the anal epithelium, weakening the DC for its major role in immune surveillance. Notoriously in patients with severe anal intraepithelial neoplasia, the density of CD1a+ epithelial dendritic cells was influenced by the viral load of HIV-1. Our study describes for the first time the density of subepithelial DC-SIGN+ dendritic cells in patients with anal severe anal intraepithelial neoplasia and points to the possibility that a specific therapy for HIV induces the recovery of the density of epithelial DC.

OBJETIVO: Quantificar morfometricamente as células dendríticas DC CD1a+ e DC DC-SIGN+ em pacientes HIV positivos portadores de neoplasia escamosa intraepitelial anal e avaliar os efeitos da infecção pelo HIV, da terapia antirretroviral e da infecção pelo HPV sobre as células dendríticas epiteliais e subepiteliais. MÉTODOS: Um estudo prospectivo foi realizado para analisar morfometricamente o volume relativo das células dendríticas e as relações entre neoplasia intraepitelial anal e o câncer em pacientes HIV positivos da Fundação de Medicina Tropical do Amazonas, Brasil.Todos os pacientes foram submetidos a biópsia da mucosa retal para realizar uma análise clássica histopatológica e imunohistoquímica utilizando anticorpos contra anti-CD1a e anti-DC-SIGN, para a quantificação morfométrica das células dendríticas. RESULTADOS: Os pacientes HIV negativos apresentaram densidade das DC CD1a+ significativamente maior do que a dos pacientes HIV positivos (3,75 versus 2,54) (p:0,018), e os pacientes com severa apresentaram correlação das DC CD1a com os níveis de células TCD4(p:0,04) assim como a carga viral do HIV-1 (p:0,035). Observamos no subgrupo HIV-positivo/HAART positivo elevação não significativa na mediana da densidade das DC CD1a+ em relação ao grupo HIV-positivo/HAART negativo. As DC CD1a+ também se elevaram nos pacientes HIV negativo portadores de condiloma anorretal(2,33 para 3,53; p:0,05), com efeito inverso nos pacientes HIV positivos. CONCLUSÕES: Nossos dados confirmam a potencialização da ação sinérgica representada pela coinfecção HIV-HPV sobre o epitélio anal, fragilizando as DC em sua função primordial de vigilância imune. Notoriamente nos pacientes com neoplasia intraepithelial anal grave, a densidade das DC CD1a+ epiteliais sofreu influência da carga viral do HIV-1. Nosso estudo descreveu pela primeira vez a densidade das DC subepiteliais DC-SIGN+ em pacientes com neoplasia intraepithelial anal severa e apontamos para a possibilidade de que a terapia específica para o HIV induza a recuperação da densidade das DC epiteliais.

HPV infection and intraepithelial lesions from the anal region: how to diagnose?

In the last years, the prevalence of HPV infection in the anal region has increased, especially in some groups like homosexual and HIV-positive people. Since this infection can be associated with the development of squamous anal cancer due to its progression from HPV infection to anal intraepithelial neoplasia (AIN) and finally to cancer, the screening and evaluation of these conditions are important. Anal cytology and high resolution anoscopy are good methods that are available and can be used. Although useful, these methods should be performed correctly and not indiscriminately in all patients. Patients for whom anal cytology screening is recommended are: HIV-infected patients, homosexuals, women who present with high-grade vulvar squamous intraepithelial neoplasia, vulvar cancer or cervical cancer. An abnormal anal cytology should be further evaluated with high resolution anoscopy.

Diagnostic methods for prevention of anal cancer and characteristics of anal lesions caused by HPV in men with HIV/AIDS

Abnormalities found with anuscopy under colposcopic vision, anal cytology and anal biopsy were evaluated in 21 men with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) at the Federal University of Pernambuco Hospital in Brazil. Mean age was 38.4 ± 6.0 years, and mean time of HIV infection was 8.3 ± 5.1 years; 95.2 percent of the patients had been on highly active antiretroviral therapy (HAART) for an average of 6.6 ± 4.5 years. Mean CD4+ cell count was 482.2 ± 173.75 cells/mm³, and 80.9 percent presented a HIV viral load of < 5,000 copies/mL. Reported sexual preference was 52.4 percent homosexuals, 28.6 percent bisexuals, and 19.0 percentheterosexuals; 81 percent reported having had receptive anal intercourse and 61.9 percent reported more than 10 sexual partners of the same sex. Results of anuscopy under colposcopic vision revealed 17 (81.0 percent) low-grade lesions and/or condylomata or micropapillae and four (19.0 percent) high-grade lesions with or without condylomata. Among the 21 anal cytology examinations, seven (33.3 percent) revealed low-grade squamous intraepithelial lesions (LSIL); three (14.3 percent) presented atypical squamous cells of undetermined significance (ASCUS) and 11 (52.4 percent) were normal. Seventeen patients were submitted to anal biopsy with the following findings: three patients (17.6 percent) with normal epithelium, one (5.9 percent) with infection by HPV, three (17.6 percent) with condylomatas, two (11.8 percent) with AIN 1, four (23.6 percent) with AIN 2, three (17.6 percent) with AIN 3, and one (5.9 percent) with PAIN 2. Anuscopy under colposcopic vision was found to be useful for detecting anal lesions and for guiding anal biopsies. Anal cytology was less useful, as it underestimated the frequency of lesions.

Citologia anal para rastreamento de lesões pré-neoplásicas / Anal cytology for screening of pre-neoplasic lesions

OBJETIVO: Avaliar se a citologia anal com escova pode servir para rastreamento das lesões clínicas e subclínicas provocadas pelo HPV. MÉTODOS: Colhemos citologia anal, com escova, do canal anal de 102 doentes HIV-positivo com queixas proctológicas. Eram 86 homens e 16 mulheres com média etária de 37 anos. Destes, 33 negavam infecção pelo HPV, 14 haviam tratado verrugas, 28 tinham condilomas externos, sete apresentavam lesões internas e 20 os tinham em associação. O material foi enviado para exame de papanicolaou e coloração pela hematoxilina-eosina. Avaliamos as contagens de linfócitos T CD4+ para observar se o estado imunológico determinou as displasias mais avançadas. RESULTADOS: Somente um exame não pôde ser aproveitado. Os demais revelaram padrões celulares que variaram da normalidade até NIAa, incluindo a presença do HPV. Ocorreram 30 NIAs de baixo e 13 de alto grau em todos os grupos de doentes, com ou sem infecção pelo HPV. Em um dos doentes com NIAa e sem história prévia de infecção pelo HPV, e com úlcera no canal anal, a biópsia revelou carcinoma espinocelular invasivo. As médias de células T CD4+ nos portadores de NIA de baixo grau foi 281/mm³ e naqueles com NIAa foi 438/mm³. A análise estatística mostrou diferença significante, revelando que, ao contrário do esperado, displasias menos acentuadas acometem doentes com contagens menores de linfócitos T CD4+. Esse fato demonstra que a imunidade sistêmica isolada parece não interferir na gênese dessas lesões, sugerindo que aspectos da imunidade local devam ser estudados. A avaliação estatística feita com a tabela 2x2 revelou sensibilidade de 74 por cento e especificidade de 61 por cento. CONCLUSÃO: Acreditamos que a citologia anal possa servir para esse rastreamento, selecionando os doentes para colposcopia anal e biópsias.

BACKGROUND: High grade intra-epithelial neoplasias (HAIN) are probable precursors of anal carcinoma, with association to high-risk types of Human Papillomavirus (HPV). This progression could be related to severity of the dysplasia and, albeit not yet confirmed, treatment of these lesions would prevent the evolution to cancer. Standardization and improvement of screening methods should therefore be essential to treat or prevent precursor lesions, mainly in patients at risk such as seropositives to Human Immunodeficiency Virus (HIV). The aim of this study was to evaluate if anal cytology, with a cytobrush, could be useful to screen clinic and pre-clinic lesions provoked by HPV. METHODS: Brushes were used to obtain smears from the anal canal of 102 HIV-positive patients with proctologic complaints. There were 86 males and 16 females with a mean age of 37 years. HPV infection was denied by 33 patients, 14 had treated anal warts in the past, 28 had condylomas in the anal verge, seven had internal clinical lesions and 20 had both internal and external condylomas. The smears were submitted to Pappanicolaou and hematoxilin-eosin stains to identify cytological changes including HAIN. T CD4+ lymphocyte counts were also evaluated to check if the immunologic status caused more advanced dysplasia. RESULTS: One smear only proved insufficient. All the others revealed cellular patterns varying from normality to HAIN. Low grade AIN (LAIN) occurred in 30 and HAIN in 13 patients. One patient with HAIN, without a history of HPV infection in the past, presented an anal canal ulcer which at biopsy was diagnosed as invasive squamous-cell carcinoma. T CD4+ cells averaged 281/mm³ for LAIN patients and 438/mm³ for HAIN patients. Analyses disclosed a statistical difference, showing that despite expectations, more advanced dysplasias occurred in patients with higher counts of T CD4+ cells. This fact demonstrated that isolated systemic immunity did not...

Ki-67 expression in anal intraepithelial neoplasia in AIDS

CONTEXT: AIDS is one of the most important risk factors for progression and recurrence of anogenital condyloma. In a previous work, we observed that patients with warts and high-grade AIN (HAIN) had recurrences more frequently than did patients with warts without AIN. The mechanisms of this increased incidence of high-grade lesions in AIDS are not known. OBJECTIVE: We studied the expression of the proliferative marker Ki-67 by immunohistochemical methods, in specimens of anal condyloma from HIV+ patients to clarify whether its expression can be associated to the grade of AIN. DESIGN: A retrospective study of hiltological specimens. SETTING: University referral unit. SAMPLE: 34 patients were divided into two groups: (1) condylomas with low grade AIN (LAIN), with 25 patients; and (2) condylomas with HAIN, with 9 patients. In this latter group we examined two areas: 2A (HAIN area) and 2B (LAIN area). MAIN MEASUREMENTS: The immunohistochemical reaction for Ki-67 was done on histological sections. Slices were lightly stained with hematoxylin, to help us in Ki-67 positive cell counting. The percentage of Ki-67 marked nuclei was calculated. We applied one-way variance analysis for statistics. RESULTS: The mean number of Ki-67 positive cells in group 1 was 19.68 + or - 10.99; in group 2 (area A) it was 46.73 + or - 10.409; and in area B it was 36.43 + or - 14.731. There were statistical differences between groups 1 and 2A and between groups 1 and 2B. Ki-67 positive cells predominated in the lower layer in LAIN. Positive Ki-67 cells were found in all layers in group 2A, and in group 2B they predominated in the two lower or in all layers of the epithelium. CONCLUSIONS: Our results suggest that LAIN areas (using routine staining techniques) in HAIN can have a biological behavior more similar to HAIN

Características clínicas asociadas de 41 pacientes con carcinoma epidermoide del ano, estudiados en un centro de cáncer / Associated clinical characteristics of 41 patients with squamous cell carcinoma of the anus studied in a cancer center

Objetivo: Conocer las características clínicas asociadas en un grupo de pacientes con cáncer epidermoide del ano (CEA). Antecedentes. El CEA se asocia a un patrón de carcinogénesis viral de transmisión sexual. Material y métodos. Se analizaron las variantes demográficas, la determinación de VIH-1, los hábitos sexuales y la presencia de condilomas acuminados anales de los pacientes con CEA que se trataron durante 1994 y 1995. Resultados. Se analizaron 41 pacientes, 26 mujeres y 15 hombres con un promedio de edad de 61 y 45 años respectivamante. De los pacientes analizados, 23 pacientes practicaron el coito anal (56 por ciento); 17 (41 por ciento) tuvieron condilomas acuminados y doce (29 por ciento fueron VIH-1 (+); estas características se observaron con mayor frecuencia en los hombres (p< 0.001). En los pacientes que practicaron el coito anal se observó una mayor frecuencia de condilomas acuminados y de positividad al VIH-1 que en los que la negaron (p< 0.001 en ambos). Los pacientes seropositivos al VIh-1 practicaron el coito anal y tuvieron con mayor frecuencia condilomas acuminados que los seronegativos (p< 0.001) en ambos). Conclusión. El CEA se presenta a una edad más temprana en los hombres que en las mujeres. En la población masculina se encontró una alta frecuencia de homosexualidad de condilomas acuminados y de seropositividad al VIH-1. Estas observaciones sugieren un mecanismo de carcinogénesis diferente en ambos sexos