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LESÃO DE BAIXO GRAU E INFECÇÃO PELO HPV Prof. Daisy Lima. Dep. Patologia, CCS, UFPE SISTEMA BETHESDA LESÃO I.E. BAIXO GRAU NIC 1 INFECÇÃO PELO HPV SIL DE BAIXO GRAU -NIC 1 CARACTERÍSTICAS CITOLÓGICAS CITOPLASMÁTICAS Células superficiais/intermediárias Citoplasma abundante, transparente Forma poligonal Freqüente associação com coilócitos Prof. Daisy Lima. Dep. Patologia, CCS, UFPE SIL DE BAIXO GRAU – NIC 1 CARACTERÍSTICAS CITOLÓGICAS NUCLEARES Aumento do volume nuclear Hipercromasia Cromatina finamente granular Leve irregularidade nuclear Bi ou multinucleação Prof. Daisy Lima. Dep. Patologia, CCS, UFPE Prof. Daisy Lima. Dep. Patologia, CCS, UFPE Prof. Daisy Lima. Dep. Patologia, CCS, UFPE Prof. Daisy Lima. Dep. Patologia, CCS, UFPE Prof. Daisy Lima. Dep. Patologia, CCS, UFPE Prof. Daisy Lima. Dep. Patologia, CCS, UFPE INFECÇÃO PELO HPV DNA VÍRUS PAPOVA VÍRUS GENOMA Genes “early”(E) Proteínas funcionais Genes “late” (L) Proteínas estruturais Região não codificante URR Prof. Daisy Lima. Dep. Patologia, CCS, UFPE 10 Replication: Individual isolates are highly species specific. All are tropic for squamous epithelial cells (receptors unknown). The virus infects the basal cells of the dermal layer, and early gene expression can be detected in these cells (in situ hybridization). However, late gene expression, expression of structural proteins and vegetative DNA synthesis is restricted to terminally differentiated cells of the epidermis which implies a link between cellular differentiation and viral gene expression. Early Proteins: Non-structural regulatory proteins, including trans-acting transcriptional regulators (E2, E7). Late Proteins: The structural proteins L1 and L2. TIPOS DE INFECÇÃO CLÍNICA – condiloma acuminado LATENTE – só detectada pelas técnicas de biologia molecular SUBCLÍNICA – colposcopia e microscopia Prof. Daisy Lima. Dep. Patologia, CCS, UFPE . INFECÇÃO PELO HPV 11 MANIFESTAÇÕES CLÍNICAS Lesions: Condylomata acuminata are dry, friable ("cauliflower-like") lesions that occur in the perineal area, glans penis, perianal area, vulva, urethral area and intra-urethral area. * LOCALIZAÇÃO PREFERENCIAL E MULTICENTRICIDADE DAS LESÕES * INFECÇÃO CLÍNICA - CONDILOMA ACUMINADO * INFECÇÃO LATENTE * NÃO DIAGNOSTICADA PELOS MÉTODOS CONVENCIONAIS * INFECÇÃO SUBCLÍNICA * LESÕES COLPOSCÓPICAS * ALTERAÇÕES CITO/HISTOPATOLÓGICAS CLÁSSICAS/ * ALTERAÇÕES CITO/HISTOPATOLÓGICAS SUTIS . BIOLOGIA DA INFECÇÃO Epidemiology: This STD is not a reportable disease, but may be the most common STD in the US. It is estimated that there are between 500,000 to 1 million cases per year. Prof. Daisy Lima. Dep. Patologia, CCS, UFPE EXEMPLOS DE HPV DE ALTO E BAIXO RISCO BAIXORISCO 6,11,42,43,44,53,54,57e 66 ALTO RISCO 16*,18,31,33,35,39,45,51,52,56,58,59 e 68 INFECÇÃO PELO HPV GENES “EARLY” E1 replicação viral E2 controle na síntese de E6 e E7 E4 coilocitose? E5 transformação maligna? E6, E7 transformação malígna Prof. Daisy Lima. Dep. Patologia, CCS, UFPE 14 In HPVs: E2 binds to the early promoter and decreases expression of E6/E7; loss of E2 is thus the first stage in transformation. E6 binds to p53 via a cellular protein ("p100") and targets it for degradation via the ubiquitin pathway. E7 binds pRB and prevents phosphorylation. This would normally result in apoptosis BUT: Both E6 and E7 interact with a number of cellular proteins which influence the outcome of infection INFECÇÃO PELO HPV GENES “LATE” L1 * L2 Prof. Daisy Lima. Dep. Patologia, CCS, UFPE PROTEÍNAS DO CAPSÍDEO VIRAL INFECÇÃO PELO HPV RELAÇÃO COM CÂNCER DE COLO CO-FATORES Fatores genéticos – mutação no gene do folato (metabolismo do folato) Imunossupressão Contraceptivos orais – podem causar ou agravar deficiência de ácido fólico Fumo – mutações, destruição ác. fólico Deficiências vitamínicas Infecções concomitantes - HSV Prof. Daisy Lima. Dep. Patologia, CCS, UFPE 16 1. Atipia de células escamosas de significado indeterminado - ASCUS # Conceito. # Freqüência: média de 2,9%. # Associação com lesão intraepitelial escamosa: 10 a 43%, com 5 a 10% dos casos sendo de alto grau. # Falta de reprodutibilidade no diagnóstico citológico de ASCUS. # Associação com infecção pelo HPV. # Subclassificação na categoria ASCUS: natureza reativa ou pré-malígna. # Importância de ASCUS em células metaplásicas - relação com lesão intraepitelial escamosa de alto grau em 23% dos casos. Predisposing Genetic Factors *New studies point to genetic predisposing factors that may influence HPV's behavior more than environmental factors such as multiple sex partners, smoking, etc. (Magnusson PK 2000). The common inherited folate gene mutation, MTHFR 677 C-->T , which greatly impairs folate metabolism, has recently been found in association with cervical and endometrial neoplasms (Piyathilake CJ, 2000, Thomson SW, 2000, Kim YI, 2000, Esteller M, 1997). Recent studies have also identified zinc gene mutations occurring on particular chromosomes where HPV often inserts itself (see Zinc-Cancer & Zinc-HPV). Prof. Daisy Lima. Dep. Patologia, CCS, UFPE CÉLULAS DA CAMADA BASAL INFECÇÃO LATENTE AMADURECIMENTO EPITELIAL INFECÇÃO PRODUTIVA LISE E RUPTURA CELULAR LIBERAÇÃO DO VÍRUS BIOLOGIA DA INFECÇÃO PELO HPV VÍRUS EPISSOMAL 17 CÉLULAS EPITELIAIS DA CAMADA BASAL (CÉLULAS NÃO PERMISSIVAS) vírus epissomal (infecção latente) AMADURECIMENTO EPITELIAL (‘CÉLULAS PERMISSIVAS). multiplicação viral (infecção produtiva). LISE E RUPTURA CELULAR --------- LIBERAÇÃO DO VÍRUS integração do genoma viral ao genoma celular CÉLULAS EPITELIAIS DA CAMADA BASAL. EXPRESSÃO DESREGULADA DOS ONCOGENES E6 E E7-------- ONCOPROTEÍNAS VIRAIS INTERAGEM COM PROTEÍNAS SUPRESSORAS DE TUMORES ( p53 e pRB). PROLIFERAÇÃO CELULAR DESCONTROLADA E PROGRESSÃO MORFOLÓGICA HPV types associated with malignancy (HPV 16 and 18) have different characteristics compared with those types associated with benign lesions (HPV 6 and 11). One of the important steps in progression to cancer is the disruption of the activity of two host tumour suppressor proteins; namely p53 and the retinoblastoma protein (pRb). Tumour suppressor gene products have the normal task of halting cell growth. The HPV E6 gene product binds p53 and the HPV E7 gene product binds pRb. However the E6/E7 proteins of HPV 16 and HPV 18 have a much higher affinity for the tumour suppressor gene products than the E6/E7 proteins of HPV 6 and 11. This difference helps explain the difference in the transforming abilities of the virus associated with benign and malignant lesions. If the function of p53 is disrupted then the cell cycle does not pause to allow repair of damaged DNA. This results in an accumulation of mutations in the cells and it is postulated that eventually one of the proto-oncogenes will mutate. Proto-oncogenes are genes involved in normal cell growth and division. When mutated they promote uncontrolled cell growth and are known as oncogenes. In the "normal" life cycle of the virus the production of E6 and E7 are controlled by the E2 gene product. However in cancers the E2 gene is disrupted during integration of the viral genome into the host cell. This results in uncontrolled production of E6 and E7 for interaction with the tumour suppressor gene products. Once again integration is mainly observed with the HPV types associated with malignancy ie HPV 16 and 18. Prof. Daisy Lima. Dep. Patologia, CCS, UFPE CÉLULAS BASAIS INTEGRAÇÃO VIRAL EXPRESSÃO DESREGULADA DE E6 E E7 INTERAÇÃO COM p53 e pRB PROL. CEL. DESCONTROLADA E PROG. MORFOLÓGICA BIOLOGIA DA INFECÇÃO PELO HPV SÍTIO DE ABERTURA DO DNA E1-E2 E2 INATIVADO 18 HPV types associated with malignancy (HPV 16 and 18) have different characteristics compared with those types associated with benign lesions (HPV 6 and 11). One of the important steps in progression to cancer is the disruption of the activity of two host tumour suppressor proteins; namely p53 and the retinoblastoma protein (pRb). Tumour suppressor gene products have the normal task of halting cell growth. The HPV E6 gene product binds p53 and the HPV E7 gene product binds pRb. However the E6/E7 proteins of HPV 16 and HPV 18 have a much higher affinity for the tumour suppressor gene products than the E6/E7 proteins of HPV 6 and 11. This difference helps explain the difference in the transforming abilities of the virus associated with benign and malignant lesions. If the function of p53 is disrupted then the cell cycle does not pause to allow repair of damaged DNA. This results in an accumulation of mutations in the cells and it is postulated that eventually one of the proto-oncogenes will mutate. Proto-oncogenes are genes involved in normal cell growth and division. When mutated they promote uncontrolled cell growth and are known as oncogenes. In the "normal" life cycle of the virus the production of E6 and E7 are controlled by the E2 gene product. However in cancers the E2 gene is disrupted during integration of the viral genome into the host cell. This results in uncontrolled production of E6 and E7 for interaction with the tumour suppressor gene products. Once again integration is mainly observed with the HPV types associated with malignancy ie HPV 16 and 18. E2 é responsável por reprimir a transcrição ddos genes virais E6 e E7. Uma vez que o E2 é inativado pela abertura da molecula virótica, há uma superexpressão dos genes E6 e E7. O potencial oncogênico do virus é relacionado aos produtos destes genes, que interagem e inativam proteínas celulares derivadas dos genes supressores de tumores p53 e p105-RB, ale´m de promover a degradação destes genes bloqueando a sua ação. A oncogenicidade portanto vais depender diretamente do grau de afinidade entre as proteinas dereivadas dos genes supressores de tumores e as proteínas virais derivadas de E6 e E7. O resultado da integração do virus é a a imortalização das células em que o HPV é integrado. Prof. Daisy Lima. Dep. Patologia, CCS, UFPE E6 P53 E7 pRb Genes que controlam o crescimento celular X Não interrupção do ciclo celular Acúmulo de mutações Não reparação do DNA lesionado (PROTOONCOGENES) ONOGENES CRESCIMENTO CELULAR DESCONTROLADO H P V 19 HPV types associated with malignancy (HPV 16 and 18) have different characteristics compared with those types associated with benign lesions (HPV 6 and 11). One of the important steps in progression to cancer is the disruption of the activity of two host tumour suppressor proteins; namely p53 and the retinoblastoma protein (pRb). Tumour suppressor gene products have the normal task of halting cell growth. The HPV E6 gene product binds p53 and the HPV E7 gene product binds pRb. However the E6/E7 proteins of HPV 16 and HPV 18 have a much higher affinity for the tumour suppressor gene products than the E6/E7 proteins of HPV 6 and 11. This difference helps explain the difference in the transforming abilities of the virus associated with benign and malignant lesions. If the function of p53 is disrupted then the cell cycle does not pause to allow repair of damaged DNA. This results in an accumulation of mutations in the cells and it is postulated that eventually one of the proto-oncogenes will mutate. Proto-oncogenes are genes involved in normal cell growth and division. When mutated they promote uncontrolled cell growth and are known as oncogenes. In the "normal" life cycle of the virus the production of E6 and E7 are controlled by the E2 gene product. However in cancers the E2 gene is disrupted during integration of the viral genome into the host cell. This results in uncontrolled production of E6 and E7 for interaction with the tumour suppressor gene products. Once again integration is mainly observed with the HPV types associated with malignancy ie HPV 16 and 18. Prof. Daisy Lima. Dep. Patologia, CCS, UFPE I. PATOGÊNESE DA INFECÇÃO PELO HPV GLANDULAR ESCAMOSO NEUROENDÓCRINO LATENTE OU ABORTIVA LATENTE OU ABORTIVA LESÃO DE BAIXO GRAU OU LATENTE INFECÇÃO PELO HPV CÉLULAS PRECURSORAS COM CAPACIDADE PROLIFERATIVA DIFERENCIAÇÃO – CONTROLE DA EXPRESSÃO DO GENS DO HPV 20 *Adaptado ds Thomas Bonfiglio. Gynecologic cytopathology, 1997. INFECÇÃO PELO HPV CARACTERÍSTICAS CITOLÓGICAS (0,5-3%) Coilocitose Disqueratose Anfofilia Prof. Daisy Lima. Dep. Patologia, CCS, UFPE CAVITAÇÃO PERINUCLEAR NÚCLEOS VOLUMOSOS, CROMATINA “BORRADA” BI/MULTINUCLEAÇÃO Prof. Daisy Lima. Dep. Patologia, CCS, UFPE Prof. Daisy Lima. Dep. Patologia, CCS, UFPE Prof. Daisy Lima. Dep. Patologia, CCS, UFPE Prof. Daisy Lima. Dep. Patologia, CCS, UFPE 25 0-10898-01 Prof. Daisy Lima. Dep. Patologia, CCS, UFPE Prof. Daisy Lima. Dep. Patologia, CCS, UFPE Prof. Daisy Lima. Dep. Patologia, CCS, UFPE Prof. Daisy Lima. Dep. Patologia, CCS, UFPE Prof. Daisy Lima. Dep. Patologia, CCS, UFPE Prof. Daisy Lima. Dep. Patologia, CCS, UFPE
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