CD11c+CD123Low dendritic cell subset and the triad TNF-α/IL-17A/IFN-γ integrate mucosal and peripheral cellular responses in HIV patients with high-grade anal intraepithelial neoplasia: a systems biology approach.

BACKGROUND: The incidence of anal cancer has increased over the past 25 years, and HIV/HPV coinfection is the most important risk factor for anal squamous cell carcinoma. In this study, we demonstrated that the evaluation of systemic and compartmentalized anal mucosa immune response is relevant to differentiating HIV(+) patients at risk of anal intraepithelial neoplasia (AIN). METHODS: A systems biology approach was used to integrate different immunological parameters from anal mucosal tissue and peripheral blood assessed by phenotypic and intracytoplasmic analysis of lymphocytes and dendritic cell subsets. RESULTS: Our data demonstrated that anal mucosal mononuclear cells from AIN(+)HIV(+) patients showed a robust capacity in producing proinflammatory/regulatory cytokines, mainly mTNF-α > IL-4 > IL-10 > IL-6 = IL-17A. Mucosal TNF-α/IFN-γ/IL-17A are selective high-grade squamous intraepithelial lesion (HSIL)-related biomarkers. Higher levels of circulating CD11cCD123cells and CD1a cells along with elevated levels of IFN-γCD4 T cells are major features associated with HSIL in AIN(+)HIV(+) patients. Regardless of the presence of AIN, HIV(+) patients presented a complex biomarker network, rich in negative connections. Among those patients, however, HSIL+ patients displayed stronger positive links between peripheral blood and anal mucosa environments, exemplified by the subnet of IL-17A/TNF-α/CD4IFN-γ/CD11cCD123 cells. CONCLUSIONS: The significant association between HSIL and the levels of TNF-α/IL-17A/IFN-γ along with the different subsets of DCs present in the anal mucosa milieu should be studied in more detail as a way to identify and categorize HIV(+) patients vis à vis the high risk of anal cancer outcome.

Variabilidade interobservadores no diagnóstico de lesões precursoras do câncer anal: estudo do cenário habitual / Interobserver variability in the diagnosis of anal cancer precursor lesions: study of the usual scenario

OBJETIVO: Analisar a variabilidade interobservadores no diagnóstico de lesões precursoras do câncer anal no cenário mais comum de um serviço constituído por patologistas sem experiência prévia no diagnóstico destas lesões. MÉTODOS: Quinhentas e duas lâminas histopatológicas com espécimes anais retirados de 372 pacientes HIV-positivos e HIV-negativos foram analisadas no Departamento de Patologia da Fundação de Medicina Tropical do Amazonas por três patologistas com ampla experiência no diagnóstico de doenças tropicais e infecciosas, mas sem experiência prévia importante no diagnóstico de lesões precursoras do câncer anal. As leituras individuais de cada patologista foram comparadas com a que se seguiu a diagnóstico de consenso em microscópio de ótica compartilhada. Os diagnósticos individuais foram confrontados com os de consenso mediante análise da estatística kappa. RESULTADOS: A concordância absoluta entre cada diagnóstico individual e o de consenso correspondente foi ruim (kappa=-0,002). Considerando os resultados apenas positivos ou negativos para lesões intraepiteliais escamosas anais, obteve-se concordância regular entre os observadores (kappa=0,35), enquanto que a concordância foi moderada quando os resultados histopatológicos foram considerados positivos ou negativos para lesão intraepitelial de alto grau ou câncer (kappa=0,52). CONCLUSÃO: A variabilidade interobservadores no diagnóstico histopatológico do câncer anal e de suas lesões precursoras entre patologistas sem grande experiência na área, apesar de experts em outras, é tal que os diagnósticos neste campo e neste cenário comum devem sempre ser de consenso.

OBJECTIVE: To assess interobserver variability in the diagnosis of anal cancer precursor lesions in the usual scenario of a service consisting of pathologists without previous experience in the diagnosis of these lesions. METHODS: Five hundred and two anal specimens taken from 372 HIV-positive and HIV-negative patients were analyzed at the Pathology Department of the Tropical Medicine Foundation of Amazonas by three pathologists with extensive experience in the diagnosis of infectious and tropical diseases, but without significant prior experience in the diagnosis of anal cancer precursor lesions. The individual readings of each pathologist were compared to the one following the consensus diagnosis in shared optical microscope by kappa statistics. RESULTS: The absolute agreement between each individual diagnosis and corresponding consensus was poor (kappa = -0.002). Considering only the positive or negative results for anal squamous intraepithelial lesions, we obtained a fair agreement between observers (kappa = 0.35), while the agreement was moderate when the histopathological findings were considered positive or negative for high-grade squamous intraepithelial lesion or cancer (kappa = 0.52). CONCLUSION: The interobserver variability in histopathologic diagnosis of anal cancer and its precursor lesions among pathologists with little experience in the area is such that the diagnoses in this field and this scenario should always be a consensus.

Interobserver variability in the diagnosis of anal cancer precursor lesions: study of the usual scenario.

OBJECTIVE: To assess interobserver variability in the diagnosis of anal cancer precursor lesions in the usual scenario of a service consisting of pathologists without previous experience in the diagnosis of these lesions. METHODS: Five hundred and two anal specimens taken from 372 HIV-positive and HIV-negative patients were analyzed at the Pathology Department of the Tropical Medicine Foundation of Amazonas by three pathologists with extensive experience in the diagnosis of infectious and tropical diseases, but without significant prior experience in the diagnosis of anal cancer precursor lesions. The individual readings of each pathologist were compared to the one following the consensus diagnosis in shared optical microscope by kappa statistics. RESULTS: The absolute agreement between each individual diagnosis and corresponding consensus was poor (kappa = -0.002). Considering only the positive or negative results for anal squamous intraepithelial lesions, we obtained a fair agreement between observers (kappa = 0.35), while the agreement was moderate when the histopathological findings were considered positive or negative for high-grade squamous intraepithelial lesion or cancer (kappa = 0.52). CONCLUSION: The interobserver variability in histopathologic diagnosis of anal cancer and its precursor lesions among pathologists with little experience in the area is such that the diagnoses in this field and this scenario should always be a consensus.