The role of p16 as putative biomarker for cervical neoplasia: A controversial issue? / O Papel da Proteina p16 como marcador putativo para neoplasia cervical: um tema controverso?

INTRODUCTION: Protein p16 has been extensively studied as a potential biomarker for precursor lesions to distinguish cervical Intraepithelial neoplasia (CIN) from their mimics. However, the use of p16 as prognostic biomarker for diagnosis of cervical cancer and precancer is controversial. This study focuses on the assessment of peer-reviewed scientific data related to the use of p16 to predict disease severity and its controversies. METHODS: We reviewed publications in MEDLINE/PubMed assessing the clinical, diagnostic and prognostic significance of p16 in CIN and cervical cancer; we included publications from 2009 to June 2017. RESULTS: The use of p16 as a prognostic marker is still unreliable, although it could be a useful tool for diagnosis of Cervical Intraepithelial Neoplasia lesions with undetermined morphology. Moreover, p16 appears to be a specific marker of high-risk oncogenic HPV infection. CONCLUSION: This review shows the potential utility and drawbacks of p16 for clinical practice and the diagnosis of cervical cancer. Further studies are required to substantiate the role of p16 in conjunction with other more sensitive and specific biomarkers for diagnosing CIN and predicting its progression.

INTRODUÇÃO: A proteína p16 tem sido estudada como um biomarcador potencialmente específico de lesões cervicais precursoras e como uma forma de diferenciar as lesões parecidas com Neoplasia intra-epitelial cervical (NIC). Contudo existem várias controvérsias sobre a utilização de p16 como um biomarcador prognóstico e como uma ferramenta para o diagnóstico de câncer cervical e de lesões pré-câncer. O objetivo deste estudo foi a revisão de dados científicos por pares de bases, relacionados com a utilização da p16 e suas controvérsias. MÉTODOS: O estudo foi projetado como uma revisão da literatura das publicações do Medline/PubMed que avaliam o significado clínico, diagnóstico ou prognóstico do p16 em lesões de NIC e no câncer cervical no período de janeiro de 2009 a junho de 2017. RESULTADOS: o uso do p16 como um marcador prognóstico ainda não é confiável, apesar de que a p16 poderia ser uma ferramenta útil para o diagnóstico em lesões de NIC com morfologia indeterminada. Além disso, a p16 parece ser um marcador específico de infecção por HPV de alto risco oncogênico. CONCLUSÃO: A presente revisão mostra a potencial utilidade da proteína p16, bem como os inconvenientes para uso clínico-patológico e diagnóstico no câncer cervical. Contudo são necessários mais estudos para fundamentar o papel da p16 em conjunto com os outros biomarcadores mais sensíveis e específicos para diagnosticar NIC e prever a sua progressão.

HPV vaccines: their pathology-based discovery, benefits, and adverse effects.

The discovery of the human papillomavirus (HPV) vaccine illustrates the power of in situ-based pathologic analysis in better understanding and curing diseases. The 2 available HPV vaccines have markedly reduced the incidence of cervical intraepithelial neoplasias, genital warts, and cervical cancer throughout the world. Concerns about HPV vaccine safety have led some physicians, health care officials, and parents to refuse providing the recommended vaccination to the target population. The aims of the study were to discuss the discovery of HPV vaccine and review scientific data related to measurable outcomes from the use of HPV vaccines. The strong type-specific immunity against HPV in humans has been known for more than 25 years. Multiple studies confirm the positive risk benefit of HPV vaccination with minimal documented adverse effects. The most common adverse effect, injection site pain, occurred in about 10% of girls and was less than the rate reported for other vaccines. Use of HPV vaccine should be expanded into more diverse populations, mainly in low-resource settings.

Immunohistochemical expression of cyclin D1, p16Ink4a, p21WAF1, and Ki-67 correlates with the severity of cervical neoplasia.

High-risk human papillomaviruses are closely associated with cervical cancer and its precursor lesions through interactions between the E6 and E7 oncoproteins and the cell-cycle regulatory proteins, such as p53 and pRb, respectively. As other molecules involved in the cell-cycle control seem to be important for human papillomavirus (HPV)-mediated cervical carcinogenesis, we have analyzed the expression of p53, p21, p16, cyclin D1, and Ki-67 and the presence of HPV (HPV pool and HPV-16) by immunohistochemical studies using tissue microarray in low squamous intraepithelial lesions (n=50), high squamous intraepithelial lesions (n=98), and cervical carcinoma (n=18). We have found a significant increase in the expression of p16 and p21 (P<0.001) from low- to high-grade lesions and cancer. In contrast, cyclin D1 expression showed a significant decrease in more severe lesions (P<0.001). p16, Ki-67, p21, and p53 positivity increased with the cell-layer level and the lesion severity, with stronger correlations being observed for p16 and Ki-67. High positivity for HPV pool (96.3%) and HPV-16 (77.5%) immunostaining was detected in all cases, with an association between p16 and cyclin D1 expression and HPV-16 infection. Our tissue microarray results corroborate the usefulness of the immunohistochemical assessment of cell-cycle biomarkers in distinguishing different groups of precursor lesions of the cervix and cervical carcinoma.

A comparative analysis of clinical and molecular factors with the stage of cervical cancer in a Brazilian cohort.

UNLABELLED: Cell cycle protein expression plays an important role in the pathophysiology of cervical cancer. However, few studies have attempted to correlate the use of these biomarkers with the clinical progression of the tumor. OBJECTIVES: 1) To analyze the expression of Ki-67, p53 and p16(INK4a) in cervical cancer, 2) to correlate the relative expression of these proteins as well as clinical parameters with the stage of disease, and 3) to determine the HPV DNA prevalence and subtype distribution. METHODS: Tissue Micro-Arrays (TMA) from patients with invasive cervical cancer (ICC) and controls were analyzed. HPV DNA detection was done by PCR and in situ hybridization. Ki-67, p53 and p16(INK4a) were analyzed by immunohistochemistry; clinical data was derived from the chart review. RESULTS: Advanced tumor stage (III and IV) was strongly associated (p<0.005) with advanced age (>55 years old), with more than four pregnancies and with the lack of formal education. HPV DNA was found in 94.3% of cases with the most prevalent types being HPV16 (67.5%), followed by HPV33 (12.0%) and HPV35 (3.6%). High expression of Ki-67 and p16 was more common in the advanced FIGO stages (p = 0.023). Women with HPV16 tended to be younger (50.9 years; SE 1.9) compared to women with other types (59.9 years; SE 2.8). CONCLUSION: We found that Ki-67 and p16 expression were independently associated with the tumor stage. We also noted that about 1/3 of the cervical cancers in this Brazilian cohort were not associated with HPV types directly targeted by the current HPV vaccines.

Incidence of genital warts in adolescents and their association with cervical intraepithelial lesions.

OBJECTIVES: To estimate the incidence of genital warts in adolescents and analyze their relationship with the development of cervical squamous intraepithelial lesions (SIL). STUDY DESIGN: From 1993 to 2006 we followed 846 adolescents in the gynecology clinic of a public hospital in Rio de Janeiro. They were sexually active, had a normal smear test and no genital warts upon recruitment and completed two years of follow-up. Data were analyzed using EPI-INFO software. The research was approved by the hospital Ethics Committee. RESULTS: The mean age at recruitment was 15.8 ± 1.4 years and at first intercourse was 14.7 ± 1.6. Sixty-three (7.4%) adolescents presented condylomata, 5.6% (48/846) during the first year of sexual activity and 1.8% (15/846) during the second year. Within two years, 20.5% (174/846) of the patients had an abnormal smear test. Seventy percent (44/63) of the patients with genital warts developed a SIL. The association between warts and SIL showed a RR=4.2(3.3-5.3). CONCLUSIONS: The incidence of condylomata was one third of the incidence of SIL and was higher during the first than in the second year of sexual activity. Adolescents with genital warts had a fourfold increase in risk of SIL and therefore should be carefully followed up.

Papilomavírus humano (HPV) em mulheres submetidas a rastreamento para câncer de cérvice uterina, Belém - Pará - Brasil / Papillomavirus (HPV) in women screened to servical uterine cancer, Belém - Pará - Brazil

Introdução: o papilomavírus humano (HPV) é reconhecido como o agente causal do câncer de colo uterino. Objetivo: determinar a prevalência de infecção genital por HPV e sua correlação com o resultado do exame citopatológico. Métodos: estudo transversal com 1.021 mulheres de 30 a 45 anos submetidas a rastreamento para câncer de cérvice uterina. As participantes responderam a questionário-padrão e amostras de colo uterino foram encaminhadas para análise citopatológica e para pesquisa de HPV. Resultados: a prevalência de HPV foi de 12,4% sendo de 8,7% nas com citologia negativa e 43,4% nas com citologia alterada, correspondendo a 28,9% nas com ASCUS/AGUS, 60% nas com lesão LSIL, 90% nas com HSIL e 100% nas com carcinoma invasor e com adenocarcinoma in situ. A chance de se detectar HSIL foi cerca de 94 vezes maior nas mulheres infectadas por HPV. Analisando somente as 116 mulheres infectadas e com HPV tipificado, observou-se que a frequência de HPV oncogênico foi de 79,3% (em 71,8% das com citologia negativa e em 91,1% das com citologia com anormalidades), sendo a chance de se detectar anormalidades no exame citopatológico cerca de quatro vezes maior na presença de HPV de alto risco. O HPV 16 foi o tipo mais frequente, detectado em 24,4% das amostras de mulheres com alterações citológicas e em 7,0%das com citologia negativa. Multi-infecção foi detectada em 5,7% das mulheres com anormalidades à citopatologia e em 1,1% das com citologia negativa.Conclusão: o estudo demonstra forte associação entre HPV e anormalidades citológicas.

Introduction: human papillomavirus (HPV) is the agent of cervical uterine cancer. Objective: determine the prevalence of genital infection due to HPV and their correlation with results in the oncotic cytology. Methods: in a cross-sectional study, 1021 women, age 30 to 45 years were enrolled and submitted to cervical cancer screening. All patients answered a standard protocol. Samples of the uterine cervix were sent to citopathological analysis and to identification of HPV. Results: prevalence of HPV was 12.4%; in women with normal cervical cytology the prevalence of HPV was 8,7% compared to 43,4% in women with altered cervical cytology (28.9% among women with ASCUS/AGUS; 60.0% among women with LSIL; 90.0% among women with HSIL and 100.0%both in women with invasive carcinoma and in situ adenocarcinoma). Chance of detection of HSIL was 94 times higher in women who had HPV in theuterine cervix. A separate analysis including only the 116 HPV infected women revealed that HPV oncogenic types corresponded to 79.3% of the cases(71.8% in women with negative cervical cytology and 91.1% in women with altered cervical cytology). The frequency of oncogenic HPV types in 116 women infected with HPV was 79.3% [71.8% in women with negative citology and 91.1% in women with abnormalities in the citology exam). The odds to detect abnormalities in the citopatology exam was four times greater in the presence of HPV of high risk. HPV 16 was the most frequent type observed(24.4% of women with abnormal cytology and in 7,0% of those with negative cytology). Multiinfection was detected in 5.7% of women with abnormal cytology and in 1.1% with negative cytology. Conclusion: in this study, HPV infection and abnormal cytological findings in the uterine cervix were frequently observed and there was an association between them.

Cell-cycle and suppressor proteins expression in uterine cervix in HIV/HPV co-infection: comparative study by tissue micro-array (TMA).

BACKGROUND: The oncoproteins of human papillomavirus (HPVs) directly effect cell-cycle control. We hypothesize that regulatory and cell cycle protein expression might be additionally modified in the cervix of HIV/HPV co-infected women. METHODS: We analyzed the expression of Rb, p27, VEGF and Elf-1 transcriptor factor by immunohistochemistry in 163 paraffin-embeded cervical samples using Tissue Micro-Array (TMA) and correlated this to HIV-1 and HPV infection. RESULTS: HIV/HPV co-infection was associated with a significant increase in expression (p < 0.001) of VEGF and p27 in both low and high grade CIN when compared to the cervices of women infected by HPV alone. Decreased Rb expression was evident with increased CIN grade in the cervices of women infected with HPV alone (p = 0.003 average of cells/mm2 in CIN I: 17.9, CIN II/III: 4.8, and tumor 3.9). Rb expression increased 3-fold for both low and high grade CIN with HPV/HIV-1 co-infection compared to HPV infection alone but did not reach statistical significance. There was a significant increase in Elf-1 expression in HPV+/HIV- women with CIN II/III and tumor (average of cells/mm2 in CIN I: 63.8; CIN II/III: 115.7 and tumor: 112.0, p = 0.005), in comparison to controls. CONCLUSION: Co-infection of HPV and HIV leads to significant increase in the VEGF and p27 expression when compared to HPV+/HIV-negative infection that could facilitate viral persistence and invasive tumor development.

Lesões intra-epiteliais no colo uterino em pacientes infectadas pelo HIV / Cervical intraepithelial lesions among HIV infected patients

Avalia a prevalência de lesões escamosas intra-epiteliais cervicais em pacientes infectadas pelo HIV atendidas em rede pública na cidade do Rio de Janeiro

Prognóstico da doença pré-invasiva do colo uterino em mulheres infectadas pelo HIV: evidências extraídas da literatura médica e discussão quanto à efetividade de seu tratamento / Prognosis of preinvasive disease of the cervix in HIV infected women: evidence from the literatire and discussion of its treatment effectiveness

A infecção pelo HIV tem acometido progressivamente mais mulheres. Com o melhor manejo clínico da infecção e com o advento da terapia anti-retroviral potente, doenças cronicas têm se tornado relevantes. Este é o caso das doenças pré-invasivas cervicais. Várias evidências mostram que estas lesões são mais prevalentes, incidentes e recorrentes após tratamentos convencionais em mulheres HIV positivas

Lesões intra-epiteliais cervicais de alto grau em pacientes infectados pelo HIV / High-grade cervical intraepithelial lesions among HIV infected patients

Estuda a prevalência de lesões intra-epiteliais cervicais de alto grau e a influência de variáveis clínicas, laboratoriais e comportamentais em pacientes infectadas pelo HIV

Fatores envolvidos na associaçäo lúpus eritematoso-neoplasia cervical / Involved factors in the association lupus erythematosus-cervical neoplasia

A partir da observaçäo de vários autores da maior freqüência de neoplasia cervical (NC) em pacientes portadoras de lúpus eritematoso (LE), foram acompanhadas 113 pacientes portadoras de doença do tecido conjuntivo (DTC), sendo 81 portadoras de LE. Este grupo näo era altamente exposto à NC por fatores epidemiológicos prévios; a forma de tratamento näo foi significativamente diferente entre as pacientes afetadas; näo foi evidenciada a participaçäo do HPV nas pacientes com NC de forma relevante; a prevalência de NC em portadoras de DTC foi de 21,24% e de 27,16% nas portadoras de LE; o risco relativo de pacientes portadoras de LE apresentarem NC foi de, aproximadamente, 22 vezes. Säo necessários estudos adicionais para melhor avaliaçäo da influência do tratamento e de fatores próprios do LE capazes de participar na patogenia da NC