Combined Oral Contraceptive Use and the Risk of Cervical Cancer: Literature Review / Uso de anticoncepcional oral combinado e o risco de câncer cervical: Revisão da literatura

Abstract Cervical cancer (CC) is caused by persistent infection of human papillomavirus of high oncogenic risk (hr-HPV); however, several cofactors are important in its carcinogenesis, such as smoking, multiparity, and prolonged use of oral hormonal contraceptives (COCs). Worldwide, 16% of women use COCs, whereas in Brazil this rate is of ~ 30%. The safety and adverse effects of COCs are widely discussed in the literature, including the increase in carcinogenic risk. Due to the existence of several drugs, combinations, and dosages of COCs, it is hard to have uniform information in epidemiological studies. Our objective was to perform a narrative review on the role of COCs use in the carcinogenesis of cervical cancer. Several populational studies have suggested an increase in the incidence of cervical cancer for those who have used COCs for > 5 years, but other available studies reach controversial and contradictory results regarding the action of COCs in the development of CC.

Resumo O câncer cervical (CC) é causado pela infecção persistente pelo papilomavírus humano de alto risco oncogênico (hr-HPV); entretanto, vários cofatores são importantes na sua carcinogênese, como tabagismo, multiparidade e uso prolongado de contraceptivos hormonais orais (COCs). No mundo, 16% das mulheres usam AOCs, enquanto no Brasil essa taxa é de ~ 30%. A segurança e os efeitos adversos dos COCs são amplamente discutidos na literatura, incluindo o aumento do risco carcinogênico. Devido à existência de várias drogas, combinações e dosagens de COCs, é difícil ter informações uniformes em estudos epidemiológicos. Nosso objetivo foi realizar uma revisão narrativa sobre o papel do uso de COCs na carcinogênese do câncer cervical. Vários estudos populacionais têm sugerido aumento da incidência de câncer de colo uterino para aquelas que usam COCs há mais de 5 anos, mas outros estudos disponíveis chegam a resultados controversos e contraditórios quanto à ação dos COCs no desenvolvimento do CCU.

Combined Oral Contraceptive Use and the Risk of Cervical Cancer: Literature Review.

Cervical cancer (CC) is caused by persistent infection of human papillomavirus of high oncogenic risk (hr-HPV); however, several cofactors are important in its carcinogenesis, such as smoking, multiparity, and prolonged use of oral hormonal contraceptives (COCs). Worldwide, 16% of women use COCs, whereas in Brazil this rate is of ∼ 30%. The safety and adverse effects of COCs are widely discussed in the literature, including the increase in carcinogenic risk. Due to the existence of several drugs, combinations, and dosages of COCs, it is hard to have uniform information in epidemiological studies. Our objective was to perform a narrative review on the role of COCs use in the carcinogenesis of cervical cancer. Several populational studies have suggested an increase in the incidence of cervical cancer for those who have used COCs for > 5 years, but other available studies reach controversial and contradictory results regarding the action of COCs in the development of CC.

O câncer cervical (CC) é causado pela infecção persistente pelo papilomavírus humano de alto risco oncogênico (hr-HPV); entretanto, vários cofatores são importantes na sua carcinogênese, como tabagismo, multiparidade e uso prolongado de contraceptivos hormonais orais (COCs). No mundo, 16% das mulheres usam AOCs, enquanto no Brasil essa taxa é de ∼ 30%. A segurança e os efeitos adversos dos COCs são amplamente discutidos na literatura, incluindo o aumento do risco carcinogênico. Devido à existência de várias drogas, combinações e dosagens de COCs, é difícil ter informações uniformes em estudos epidemiológicos. Nosso objetivo foi realizar uma revisão narrativa sobre o papel do uso de COCs na carcinogênese do câncer cervical. Vários estudos populacionais têm sugerido aumento da incidência de câncer de colo uterino para aquelas que usam COCs há mais de 5 anos, mas outros estudos disponíveis chegam a resultados controversos e contraditórios quanto à ação dos COCs no desenvolvimento do CCU.

Cytokine profiling of samples positive for Chlamydia trachomatis and Human papillomavirus.

Persistent human papillomavirus (HPV) infection is closely associated with cervical carcinoma. Co-infection in the endocervical environment with other microorganisms, such as Chlamydia trachomatis, may increase the risk of HPV infection and neoplastic progression. While in some individuals, Chlamydia trachomatis infection is resolved with the activation of Th1/IFN-γ-mediated immune response, others develop a chronic infection marked by Th2-mediated immune response, resulting in intracellular persistence of the bacterium and increasing the risk of HPV infection. This work aimed to quantify cytokines of the Th1/Th2/Th17 profile in exfoliated cervix cells (ECC) and peripheral blood (PB) of patients positive for Chlamydia trachomatis DNA, patients positive for Papillomavirus DNA, and healthy patients. Cytokine levels were quantified by flow cytometry in ECC and PB samples from patients positive for C. trachomatis DNA (n = 18), patients positive for HPV DNA (n = 30), and healthy patients (n = 17) treated at the Hospital de Amor, Campo Grande-MS. After analysis, a higher concentration of IL-17, IL-6, and IL-4 (p <0.05) in ECC; INF-γ and IL-10 (p <0.05) in PB was found in samples from patients positive for C. trachomatis DNA compared to samples from healthy patients. When comparing samples from patients positive for HPV DNA, there was a higher concentration of cytokines IL-17, IL-10, IL-6, and IL-4 (p <0.05) in ECC and IL-4 and IL-2 (p <0.05) in PB of patients positive for C. trachomatis DNA. These results suggest that induction of Th2- and Th17 mediated immune response occurs in patients positive for C. trachomatis DNA, indicating chronic infection. Our results also demonstrate a high concentration of pro-inflammatory cytokines in ECC of patients positive for C. trachomatis DNA.

IL-6 and IL-10 in the serum and exfoliated cervical cells of patients infected with high-risk human papillomavirus.

Persistent infection by high-risk human papillomavirus (HR-HPV) is the main cause of cervical cancer and its precursor lesions. While some cytokines help immune cells in virus clearance, others contribute to the persistence of infection and neoplastic progression. Here, the levels of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-10, IL-6, IL-4, and IL-2 were quantified in the serum and exfoliated cervical cells (ECCs) of patients with HR-HPV, and the presence of IL-6+ cells was investigated in uterine cervix biopsies. Cytokine levels in the serum and ECCs of 26 HR-HPV DNA-positive patients and 18 HPV DNA-negative patients were measured using flow cytometry. Fifteen uterine cervix biopsy samples embedded in paraffin were subjected to immunohistochemical analysis for the detection of IL-6+ cells. HR-HPV-positive patients showed increased IL-6 and IL-10 in the ECCs and serum, respectively. Compared with HPV DNA-positive patients, HPV DNA-negative patients had higher levels of IL-6 in ECCs. Patients with multiple infections of HPV had higher levels of IL-6 in their ECCs than those with a single infection. Immunostaining of uterine cervix biopsy samples revealed no differences in IL-6 expression between the different classes of histopathological lesions. However, differences were observed in the expression levels of IL-6 and IL-10 at the systemic and local levels in HR-HPV-positive patients without cervical lesions. Considering the functional characteristics of these cytokines, it can be inferred that such patients are prone to persistent HPV infection.

The Role of Self-Collection by Vaginal Lavage for the Detection of HPV and High-Grade Intraepithelial Neoplasia.

OBJECTIVE: To compare the results of cervical cytology and high-risk HPV tests using samples obtained using two different collection modalities in a population of Brazilian women: self-collection (vaginal lavage) and cervical Pap testing. METHODS: We enrolled 204 women who were aged 18-64 years and had previously obtained abnormal cervical cytology test results; 83.8% of them agreed to participate. The sample was divided into two aliquots: one for the cytological study and one for the molecular analysis of high-risk HPV. RESULTS: Fifty-eight percent of the participants preferred to utilize self-collection as an alternative screening method. However, we noticed that the HPV positivity rate was significantly lower in self-collected samples when compared to those obtained using the conventional collection method (p = 0.035). The cytology tests of the samples obtained via self-collection were sensitive and had a positive predictive value and an area under the curve (AUC) that were significantly lower than those of the Pap test. However, the specificity and negative predictive value of these tests were similar. When compared with the HPV test, the self-collected samples demonstrated lower accuracy in predicting high-grade cervical intraepithelial neoplasia or worse, with a significantly lower sensitivity, positive predictive value, and AUC than the cervical Pap test samples. CONCLUSION: Self-collection by vaginal lavage is simple and well accepted by women. Due to its limitations, however, self-collection by lavage should be utilized with caution.

A Low-Cost HPV Immunochromatographic Assay to Detect High-Grade Cervical Intraepithelial Neoplasia.

OBJECTIVE: To evaluate the reproducibility and accuracy of the HPV16/18-E6 test. METHODS: The study population was comprised of 448 women with a previously abnormal Pap who were referred to the Barretos Cancer Hospital (Brazil) for diagnosis and treatment. Two cervical samples were collected immediately before colposcopy, one for the hr-HPV-DNA test and cytology and the other for the HPV16/18-E6 test using high-affinity monoclonal antibodies (mAb). Women with a histologic diagnosis of cervical intraepithelial neoplasia grade 2 or 3 were considered to be positive cases. Different strategies using a combination of screening methods (HPV-DNA) and triage tests (cytology and HPV16/18-E6) were also examined and compared. RESULTS: The HPV16/18-E6 test exhibited a lower positivity rate compared with the HPV-DNA test (19.0% vs. 29.3%, p<0.001) and a moderate/high agreement (kappa = 0.68, 95%CI: 0.60-0.75). It also exhibited a significantly lower sensitivity for CIN2+ and CIN3+ detection compared to the HPV-DNA test and a significantly higher specificity. The HPV16/18-E6 test was no different from cytology in terms of sensitivity, but it exhibited a significantly higher specificity in comparison to ASCH+. A triage test after HPV-DNA detection using the HPV16/18-E6 test exhibited a significantly higher specificity compared with a triage test of ASCH+ to CIN2+ (91.8% vs. 87.4%, p = 0.04) and CIN3+ (88.6% vs. 84.0%, p = 0.05). CONCLUSION: The HPV16/18-E6 test exhibited moderate/high agreement with the HPV-DNA test but lower sensitivity and higher specificity for the detection of CIN2+ and CIN3+. In addition, its performance was quite similar to cytology, but because of the structural design addressed for the detection of HPV16/18-E6 protein, the test can miss some CIN2/3+ lesions caused by other high-risk HPV types.

Clinical characteristics of women diagnosed with carcinoma who tested positive for cervical and anal high-risk human papillomavirus DNA and E6 RNA.

High-risk human papillomavirus (hrHPV) is an essential cause of cervical carcinoma and is also strongly related to anal cancer development. The hrHPV E6 oncoprotein plays a major role in carcinogenesis. We aimed to evaluate the frequency of hrHPV DNA and E6 oncoprotein in the anuses of women with cervical carcinoma. We analyzed 117 women with cervical cancer and 103 controls for hrHPV and the E6 oncogene. Positive test results for a cervical carcinoma included 66.7 % with hrHPV-16 and 7.7 % with hrHPV-18. One case tested positive for both HPV variants (0.9 %). The samples from the anal canal were positive for HPV-16 in 59.8 % of the cases. Simultaneous presence of HPV in the cervix and anal canal was found in 53.8 % of the cases. Regarding expression of E6 RNA, positivity for HPV-16 in the anal canal was found in 21.2 % of the cases, positivity for HPV-16 in the cervix was found in 75.0 %, and positivity for HPV-18 in the cervix was found in 1.9 %. E6 expression in both the cervix and anal canal was found in 19.2 % of the cases. In the controls, 1 % tested positive for HPV-16 and 0 % for HPV-18. Anal samples from the controls showed a hrHPV frequency of 4.9 % (only HPV16). The presence of hrHPV in the anal canal of women with cervical cancer was detected at a high frequency. We also detected E6 RNA expression in the anal canal of women with cervical cancer, suggesting that these women are at risk for anal hrHPV infection.

Seasonal profile and level of CD4+ lymphocytes in the occurrence of cryptosporidiosis and cystoisosporidiosis in HIV/AIDS patients in the Triângulo Mineiro region, Brazil.

Patients with AIDS are particularly susceptible to infection with intestinal coccidia. In this study the prevalence of infections with Cryptosporidium sp and Cystoisospora belli were evaluated among HIV/AIDS patients in the Triângulo Mineiro region, Brazil. Between July 1993 and June 2003 faecal samples from 359 patients were collected and stained by a modified Ziehl-Neelsen method, resulting in 19.7% of positivity for coccidian (8.6% with Cryptosporidium sp, 10.3% with Cystoisospora belli and 0.8% with both coccidian). Patients with diarrhoea and T CD4+ lymphocyte levels < or =200 cells/mm3 presented higher frequency of these protozoans, demonstrating the opportunistic profile of these infections and its relationship with the immunological status of the individual. It was not possible to determine the influence of HAART, since only 8.5% of the patients positive for coccidian received this therapy regularly. Parasitism by Cryptosporidium sp was more frequent between December and February and thus was characterised by a seasonal pattern of infection, which was not observed with Cystoisospora belli.

Seasonal profile and level of CD4+ lymphocytes in the occurrence of cryptosporidiosis and cystoisosporidiosis in HIV/AIDS patients in the Triângulo Mineiro region, Brazil

Patients with AIDS are particularly susceptible to infection with intestinal coccidia. In this study the prevalence of infections with Cryptosporidium sp and Cystoisospora belli were evaluated among HIV/AIDS patients in the Triângulo Mineiro region, Brazil. Between July 1993 and June 2003 faecal samples from 359 patients were collected and stained by a modified Ziehl-Neelsen method, resulting in 19.7 percent of positivity for coccidian (8.6 percent with Cryptosporidium sp, 10.3 percent with Cystoisospora belli and 0.8 percent with both coccidian). Patients with diarrhoea and T CD4+ lymphocyte levels < 200 cells/mm3 presented higher frequency of these protozoans, demonstrating the opportunistic profile of these infections and its relationship with the immunological status of the individual. It was not possible to determine the influence of HAART, since only 8.5 percent of the patients positive for coccidian received this therapy regularly. Parasitism by Cryptosporidium sp was more frequent between December and February and thus was characterised by a seasonal pattern of infection, which was not observed with Cystoisospora belli.

Pacientes com AIDS são particularmente susceptíveis a infecção por coccídios intestinais e nesse estudo foi avaliada a freqüência de Cryptosporidium sp. e Cystoisospora belli entre pacientes HIV/AIDS na região do Triângulo Mineiro, Brasil. No período de julho de 1993 a junho de 2003, amostras de fezes de 359 pacientes foram submetidas à coloração pelo método de Ziehl-Neelsen modificado, sendo detectada a presença de coccídios em 19,7 por cento destas (8,6 por cento de Cryptosporidium sp, 10,3 por cento de Cystoisospora belli e 0,8 por cento de ambos coccídios). Pacientes com diarréia e níveis de linfócitos T CD4+ < 200 células/mm3 apresentaram maior frequência destes protozoários, demonstrando o perfil oportunista destas infecções e a relação com o status imunológico do indivíduo. Não foi possível determinar a influência da HARRT, pois apenas 8,5 por cento dos pacientes positivos para coccídios fazriam uso regular desta terapia. Parasitismo por Cryptosporidium sp foi mais freqüente no período compreendido de dezembro a fevereiro caracterizando padrão sazonal desta infecção, fato não observado com Cystoisospora belli.

Pelagra endógena e ataxia cerebelar sem aminoacidúria: doença de Hartnup? / Endogenous pellagra and cerebellar ataxia without aminoaciduria: Hartnup disease?

Menino, 7 anos, com história de convulsão, hiperpigmentação cutânea em áreas de exposição solar e episódios recorrentes de ataxia cerebelar. Estabelecido diagnóstico clínico de doença de Hartnup, foi tratado com nicotinamida, com melhora. Análises não confirmaram aminoacidúria ou outras alterações metabólicas. Na doença de Hartnup ocorre defeito no transporte renal e intestinal de aminoácidos neutros, reduzindo triptofano disponível para produção de niacina. Cursa com ataxia cerebelar intermitente, erupções cutâneas pelagróides e distúrbios mentais. Aminoacidúria em cromatografia urinária confirma diagnóstico, porém são descritos casos compatíveis com doença de Hartnup sem aminoacidúria.

A seven-year-old boy with history of convulsion, cutaneous hyperpigmentation in sun-exposed areas and recurrent episodes of cerebellar ataxia is presented. Once established the clinical diagnosis of Hartnup disease, treatment with nicotinamide was started, with improvement. Laboratorial results did not confirm aminoaciduria nor other identified metabolic changes. In Hartnup disease, defective renal and intestinal transport of neutral amino acids occurrs, resulting in reduction of tryptophan to produce to nicotinamide. Symptomatic cases present with intermittent episodes of cerebellar ataxia, pellagra-like skin rash and mental disturbances. Urinary chromatographic amino acid pattern confirms diagnosis; however, cases compatible with Hartnup disease, but without aminoaciduria, have been reported.