The cervical intraepithelial neoplasia grade I (CIN I) shows an important percentual of spontaneous regression (80%) and there is no universal consensus if these lesions should be treated or only monitored. Lesions at risk for progression are precisely those associated with high-risk HPV. Knowing which CIN I are related to these viruses may be one of the determining factors for the decision to treat or not.
To determine the prevalence of high-risk HPV in women with CIN I and to evaluate if there is an association between the presence of the virus and some risk factors.
Cross-sectional descriptive study. We evaluated 55 women with histological diagnosis of CIN I. All of them were previously submitted to HPV-DNA testing.
25 out of 55 (45.5%) women analyzed were positive for high-risk HPV. The virus infection was related with higher level of education, smoking and history of sexually transmitted diseases. Other risk factors like age, number of sexual partners, age at first sexual intercourse, use of hormonal contraceptives, and immunosuppression condition did not show a relation to the high-risk HPV infection.
The prevalence of high-risk HPV in women with histological diagnosis of CIN I was 45.5%. HPV-DNA detection was associated with smoking, history of sexually transmitted diseases, and higher level of education.
As neoplasias intraepiteliais cervicais grau I (NIC I) apresentam um percentual importante de regressão espontânea (cerca de 80%) e não há um consenso universal se essas lesões devam ser tratadas ou apenas acompanhadas. As lesões que apresentam risco de progressão são justamente aquelas associadas aos HPV de alto risco oncogênico. O conhecimento de quais lesões estão relacionadas a esses vírus pode ser um dos fatores determinantes para a decisão de se tratar ou não tais lesões.
Determinar a prevalência do papilomavírus humano (HPV) de alto risco oncogênico em mulheres com resultado histológico de NIC I e verificar a existência da associação entre a presença do vírus e alguns fatores de risco.
Trata-se de um estudo transversal, de caráter descritivo, onde foram avaliadas 55 mulheres com diagnóstico histopatológico de NIC I. Todas foram submetidas ao teste de DNA-HPV previamente.
Das 55 mulheres analisadas, 25 (45,5%) apresentaram HPV de alto risco positivo. A infecção pelo vírus foi associada às mulheres com mais anos de estudo, tabagismo e à história de alguma doença sexualmente transmissível. Outros fatores de risco, como a idade, o número de parceiros sexuais, a faixa etária em que ocorreu a coitarca, o uso de anticoncepcionais hormonais e o estado de imunossupressão, não mostraram relação com a infecção pelo HPV.
A prevalência do HPV de alto risco oncogênico nas mulheres com diagnóstico histológico de NIC I foi de 45,5%. A detecção do vírus foi associada ao tabagismo, à história de doença sexualmente transmissível e a um grau maior de escolaridade.
Cervical cancer is the second most common malignancy in the female population wordlwide (about 471,000 new cases per year). About 80% of them occur in developing countries, where in some regions, it becomes the most frequent one. In Brazil, the cervical cancer is the third most common malignancy among women, being preceded only by breast cancer and colorectal cancer, and the fourth cause of death by cancer among women. The estimate of cervical cancer for 2016 is 16,340 new cases and a mean of 5,000 deaths/year1.
The invasive cervical cancer is preceded by premalignant or precursory lesions, represented by cellular atypia of the cervical epithelium2. As for the etiology, it is currently well established that the human papillomavirus (HPV) is the cause of cervical cancer and their precursory lesions, the high-grade cervical intraepithelial neoplasias (CIN II and III)3,4,5. There are over 45 different genotypes of these viruses infecting the anogenital area, both among men and women, which associate to benign lesions and invasive cancers, though most cases are caused by HPV 16 and 186,7.
The HPV infection is common, especially among young women, and their prevalence is related, mainly, to sexual behavior8,9. The infection alone is not enough to cause cervical cancer. Other factors associated to the host (genetic and immunologic) or environmental (smoking, high-dosage oral contraceptive, diet low in vitamins and oligoelements, sexual activity, pregnancies, among others) also contribute to the progression of HPV lesion inducing carcinoma10. A compulsory phase in the development of this cancers is the integration of the viral DNA to the DNA of host cells, leading to an uncontrolled cell division and the onset of tumor11. This integration happens almost exclusively with the oncogenic high-risk (HR) virus2,12,13,14,15. It is the persistence of the infection by these specific HPV types, especially the 16 and the 18, the factor responsible for the development, maintenance and progression of a CIN for the invasive cancer10,12,13,16.
As the cervical carcinoma is preceded by preinvasive lesions, the best prevention is the diagnosis and treatment of these lesions. There is no doubt that all the cases of high-grade lesions (mainly CIN III) should be treated, since they have great chances of evolving into the invasive form13. However, the low-grade lesion (CIN I) presented an important percentage of spontaneous regression (about 80%)17,18 and there is no universal consensus if these lesions should be treated or just monitored13. The lesions that represent the risk of progressions are precisely those associated to oncogenic HR-HPV13,19. The knowledge of which lesions are related to this virus may be one of the determining factors for the decision of treating or not such lesions.
In order to evaluate the prevalence of the oncogenic HR-HPV in the CIN I and to relate this finding to other possible cofactors associated with the progression of these lesions. It is expected that this study may contribute to establish strategies for a more suited therapeutic planning, avoiding, thus, the treatment of unnecessary cases (overtreatment) or the absence of treatment of the cases of risk for progression into cancer (undertreatment).
It is a prospective, observational, descriptive, and cross-sectional study carried out at the Genital Oncology Clinic of the University Hospital of the Universidade Federal de Santa Catarina (HU/UFSC), evaluating 55 women who had histopathological results for CIN I and who performed the DNA test for oncogenic HR-HPV by the hybrid capture method II (Digene & Co.).
The age of those women were stratified into ≤30 years or >30 years of age, because the presence of oncogenic HR-HPV persisting among women aged over 30 years represents a risk factor for the development of cervical carcinoma, according to various studies (9,16,18.
The educational level was stratified into elementary school and high school/college degree in a same group, since there was only one case with college degree and, for statistical reasons, these two variables were combined. There was no discrimination in relation to the level being complete or incomplete.
The number of sexual partners women had in their lives was subdivided into <3 or ≥3 partners. Several studies have showed that the higher the number of sexual partners, the higher is the prevalence of oncogenic HR-HPV16,18.
Other variables considered to be risk factors for infection by HPV were analyzed such as parity, age at the first sexual intercourse, and current and previous history of sexually transmitted diseases (STDs)9,18,20.
When we analyzed the variable smoking, women who smoke or who have smoked in the past were considered smokers. Similarly, women who use or who have used hormonal contraception were considered users of this method.
Regarding their immunosuppression status, only the presence or absence of HIV infection was considered, since there were no other cases of immunosuppression among these women.
The results of the oncotic colpocytology were based on the Cytological Classification of Bethesda 200121.
The result of the colposcopic evaluation was divided into atypical transformation zone (ATZ) with smaller and greater cervical alterations, depending on the images observed22.
The anatomopathologic results of the biopsy of cervix were classified into CIN I and alterations consistent with HPV.
The data necessary to conduct this study were obtained by means of the information registered in the medical charts of patients who underwent some kind of follow-up or treatment of cervical intraepithelial lesions in the Genital Oncology Clinic of the HU/UFSC. The data collection was based on a semistructured research protocol.
The colposcopy and the cervical biopsy were carried out in the Ginecology Service and the histopathological tests at the Pathological Anatomy Service of the HU/UFSC. The test to detect oncogenic HR-HPV DNA was performed at the
The analysis of the data was carried out by the Epi Info 6.0 software. In order to verify the possible associations between the presence of HR-HPV and the variables, the chi-square (χ2) test was used. The result was considered significant if the probability of error was <5% (p<0.05). When the p-value did not show significance, it was presented as p=NS.
This study was approved by the Human Being Research Ethics Committee of the UFSC.
The HR-HPV was detected in 25 (45.5%) women with CIN I.
The age of the women varied from 14 to 45 years of age. By correlating age and the presence of HR-DNA-HPV, we observed that there was no significant difference between them. However, on analyzing women with positive HR-HPV, a higher prevalence (60%) of the virus among the youngest ones (≤30 years) was observed.
As for the level of education, there was a prevalence twice as high (68.4%) among women with more years of study (high school to college degree) than among those with lower schooling (33.3%), achieving statistical significance, with p=0.012 (
The sexual behavior was assessed as the beginning of sexual activity and the number of partners. Regarding the first sexual intercourse, the prevalence of the virus was 1.7 times higher among women who began their sexual activities after 18 years of age; however, the statistical value was not significant.
With regard to the number of sexual partners, despite not being statistically significant, a greater prevalence of DNA-HPV was observed among the women with three or more partners (58.8%) than among women with less than three (39.5%).
Contrary to what was expected, we found greater HR-HPV detection among women who had two pregnancies or less (50%). This infection was present in 36.8% of the women with more than two pregnancies. However, this difference was not significant.
In relation to the habit of smoking, there was a statistically significant difference between smoking women, who had double the prevalence of HR-HPV (63.6%) in relation to nonsmokers (33.3%) (p=0.027) (
There was no difference regarding the use of oral contraception (OC) and the presence of HR-HPV. More than half of the positive cases (51.4%) were among women using OC.
Of the 55 women, only 8 had the history of STDs (syphilis, anogenital HPV, Chlamydia and Ureaplasma). Of those, seven of them had oncogenic HR-HPV (87.5%), observing a significant difference with p=0.0097 (
When evaluating the presence of immunosuppression, there was no statistical difference, despite the two cases of HIV infection being positive for HR-HPV (100%). The negative HIV women were positive for HR-HPV in 43.4%.
In relation to the previous colpocytologic test of women diagnosed with CIN I, only 16 (29.1%) had agreeable diagnosis. We also observed the subdiagnosis in 58.2% of them and overdiagnosis (high grade lesion) in 12.7%. As the distribution of the cases was small for each result, these data were not subjected to statistical calculation (
We observed great correlation between the colposcopic result of ATZ with minor changes and the histologic result of CIN I (87.3%). There was no statistical difference between women with minor alterations (43.8%) or major alterations in the colposcopy (57.1%) (
The relation between the HPV and cervical cancer is already well established3,4,6,8. However, there is a considerable variation in the literature about the frequency of detection for DNA-HPV among women with precancerous lesions (CIN). This may be explained by the differences of the evaluated populations and by the kinds of studies, which have varying designs, in addition to the difference on sensitivity and specificity of the tests used9. Thus, a great variability in the prevalence of HR-HPV in CIN I is observed, varying from 4125 to 86%2,9,12,28,29,30. Borges
Several studies showed that the CIN I is more prevalent among young women3,9,12. The same occurs with the infection by HR-HPV. Many studies found this greater prevalence among women with less than 30 years of age3,13,14,15,20,31. However, with aging, despite there is a decline of this prevalence, infection by HPV becomes more persistent9,13,14,32,33. In our study, we observed 50% positive results for the HR-HPV for younger women (≤30 years) and 40% for those aged over 30 years. Cohort studies indicate that most infections by oncogenic HPV are transitory and that its lower prevalence in older age may be due to an acquired immunity to the virus through previous exposures and their elimination34. Dalstain
Our study was a cross-sectional observation, in which a single sample was used to characterize the women with HR-HPV; this can mean only transitory infections or reactivation of latent infections. Also, there might have been false-negatives due to an inappropriate sample or due to low levels of the virus, which were undetectable by hybrid capture.
Many sociodemographic and behavioral factors are classically described as risk factors for cervical cancer. Most authors show significance when comparing data related to education, demonstrating that the risk of cervical lesions is increased among women with lower schooling12,35,36. Leal
According to Hernández-Hernández
The relation between the number of sexual partners and the risk of infection by HPV for the development of precursor lesions of cervical cancer is considered an important risk factor by many authors12,34,35,37,38. Ho
Great part of the literature also shows a strong association between the multiple pregnancies and the risk of infections by HR-HPV, as well as risk of invasive cervical cancer9,10,12,39. Adam
As expected, we observed a significantly higher prevalence of HR-HPV (almost double) between female smokers and former smokers. Smoking is one of the most important risk factors for cervical cancer5,9,14,35,40. Moore
The relation between the use of OC and cervical cancer is not a consensus. Most authors consider that the hormonal factor plays a role of cofactor for both the infection by HPV and the progressions of lesions related to the virus3,14. More recent researches demonstrate that the risk for these lesions increase significantly among users of OC for more than 5 years39,41. However, some authors described that there was no correlation between the use of OC with infection by HPV and their manifestations12,15. In the present study, the prevalence of HR-HPV also showed no association with the use of OC, despite a higher rate of the virus (51.4%) being present among its users. Although the HPV has estrogen receptors, it is likely that the relation of OC with this infection and cervical lesions is associated with hormonal concentration.
SDTs have been described as a great risk factor for cervical lesions caused by HPV35. Cavalcanti
Women with immunodeficiency, such as the HIV infection, have increased rates of HPV infection and are more likely to develop high-grade cervical lesions, once that there is a greater tendency to persistently keep the DNA of the HPV15,42,43,44. Branca
The favorable evolution of the low-grade lesions depends on proper handling. Thus, it is important that the investigative methods are reliable, in order to diagnose them at an early stage. However, the citopathologic test is not a perfect screening method. Agorastos
The ideal handling of the CIN I lesions is still not a consensus, once that great part of them regresses without treatment. Another part, however, may persist or even progress17,18,46,47. Most of these studies show that 80% of these lesions will spontaneously regress within 1 year and just 20% of them will persist. Therefore, it is important to identify which are the persistent lesions, once that they are the higher-risk ones for progression to a high-grade lesion13,16. Thus, the use of techniques for the detection of DNA-HPV has been proposed by various authors31,48,49, once that this test has showed increased sensitivity when detecting high-grade lesions with high negative predictive value2,23,24. So, it is argued that those exam would have an important role in the populations with low prevalence of HPV and low risk of cervical cancer, and it may be associated to the cytopathological exam, or even being performed alone26,45.
The prevalence of oncogenic HR-HPV among women with histologically confirmed CIN I was of 45.5%, those being the cases with risk for progression and which should be conducted more cautiously. The detection of the virus was associated to smoking, the history of STDs and a higher schooling level.
Study carried out at the Federal University of Santa Catarina (UFSC) - Florianópolis (SC), Brazil.
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