Cervical Squamous Intraepithelial Lesions Are Associated with Differences in the Vaginal Microbiota of Mexican Women.

Cervical cancer is an important health concern worldwide and is one of the leading causes of death in Mexican women. Previous studies have shown changes in the female genital tract microbe community related to human papillomavirus (HPV) infection and cervical cancer; yet, this link remains unexplored in many human populations. This study evaluated the vaginal bacterial community among Mexican women with precancerous squamous intraepithelial lesions (SIL). We sequenced the V3 region of the 16S rRNA gene in cervical samples from 228 Mexican women, including 121 participants with SIL, most of which were HPV positive, and 107 healthy women without HPV infection or SIL. The presence of SIL was associated with changes in composition (beta diversity) and with a higher species richness (Chao1). A comparison of HPV-positive women with and without SIL showed that microbiota changes occurred even in the absence of SIL. Multivariate association with linear models (MaAsLin) analysis yielded independent associations between HPV infection and an increase in the relative abundance of Brachybacterium conglomeratum and Brevibacterium aureum as well as a decrease in two Lactobacillus iners operational taxonomic units (OTUs). We also identified a positive independent association between HPV-16, the most common HPV subtype linked to SIL, and Brachybacterium conglomeratum. Our work indicates that HPV infection leading to SIL is primarily associated with shifts in vaginal microbiota composition, some of which may be specific to this human population. IMPORTANCE Human papillomavirus (HPV) plays a critical role in cervical carcinogenesis but is not sufficient for cervical cancer development, indicating the involvement of other factors. The vaginal microbiota is an important factor in controlling infections caused by HPV, and, depending on its composition, it can modulate the microenvironment in vaginal mucosa against viral infections. Ethnic and sociodemographic factors influence differences in vaginal microbiome composition, which underlies the dysbiotic patterns linked to HPV infection and cervical cancer across different populations of women. Here, we provide evidence for associations between vaginal microbiota patterns and HPV infection linked to ethnic and sociodemographic factors. To our knowledge, this is the first report of the species Brevibacterium aureum and Brachybacterium conglomeratum linked to HPV infection or squamous intraepithelial lesions (SIL).

The Role of the Cervicovaginal Microbiome on the Genesis and as a Biomarker of Premalignant Cervical Intraepithelial Neoplasia and Invasive Cervical Cancer.

The microbiome is able to modulate immune responses, alter the physiology of the human organism, and increase the risk of viral infections and development of diseases such as cancer. In this review, we address changes in the cervical microbiota as potential biomarkers to identify the risk of cervical intraepithelial neoplasia (CIN) development and invasive cervical cancer in the context of human papillomavirus (HPV) infection. Current approaches for clinical diagnostics and the manipulation of microbiota with the use of probiotics and through microbiota transplantation are also discussed.

Analysis of the cervical microbiome and potential biomarkers from postpartum HIV-positive women displaying cervical intraepithelial lesions.

The cervical microbiota composition and diversity of HIV-positive women in the postpartum period is unknown. Using a high-throughput bacterial 16S rRNA gene sequencing, we identified four community state types (CSTs). CST III (Lactobacillusdominant) and CST IV (IV-A, IV-B.1, IV-B.2; high-diversity) were found in 41% and 59% of samples, respectively. We did not find association of any CST to postpartum period (six or twelve months), HPV infection or cytology (normal or lesion). However, five bacterial genera were associated with cervical lesions (Gardnerella, Aerococcus, Schlegelella, Moryella and Bifidobacterium), with significant odds ratio (OR) of 40 (2.28-706) for the presence of Moryella and 3.5 (1.36-8.9) for Schlegelella. Longitudinal analysis of samples at postpartum that regressed (lesion to normal), progressed (normal to lesion) and maintained the cytology (lesion or normal) evidenced Gardnerella with a significantly higher abundance in regressing lesions. In the current study, we report the first data on the cervical microbiota of HIV-positive women in the postpartum period. Consistent with previous studies of HIV-negative cohorts, HIV-positive women present a stable cervical microbiota of high-diversity in the postpartum period. Our results highlight that specific microbiota species may serve as sensors for changes in the cervical microenvironment associated with cervical lesions.

Detection of Actinomyces spp. in cervical exudates from women with cervical intraepithelial neoplasia or cervical cancer.

PURPOSE: Under certain circumstances, Actinomyces behaves as an opportunistic microorganism and can cause actinomycosis, a chronic and inflammatory granulomatous infection. The purpose of this project was to detect the presence of Actinomyces in cervical exudates from women with cervical intraepithelial neoplasia (CIN) and women with cervical cancer. METHODOLOGY: Cervical samples from 92 women were divided into three groups: CIN, cervical cancer and healthy women. Metagenomic DNA extraction was performed following the Qiagen QIAamp Mini Kit protocol. A specific fragment (675 bp) was amplified by PCR in order to detect the presence of Actinomycetales. Samples in which Actinomycetales was detected were subjected to separate amplification reactions with primer pairs for A. israelii, A. viscosus, A. meyeri and A. odontolyticus. Amplified products were observed by 2 % agarose gel electrophoresis. RESULTS: Actinomyces were found in 10 % of women with CIN, 36.6 % of women with cervical cancer and 9 % of healthy women. The species identified in this study were A. meyeri in 14/92 samples (15.2 %), A. viscosus in 10/92 samples (10.8 %), A. odontolyticus in 4/92 samples (4.3 %) and A. israelii in 6/92 samples (6.5 %). CONCLUSION: Patients with cervical cancer had a higher prevalence of the presence of Actinomyces compared to the CIN and control groups. This is the first study in which a deliberate search of this genus has been performed in women with cervical pathologies. The use of specific primers for each species facilitated their detection in comparison with traditional isolation methods. More information is necessary to understand the molecular mechanisms involved in the complex role that bacterial communities may play in the development of cancer (and vice versa).

Cryptococcus laurentii fungaemia in a cervical cancer patient

ABSTRACT Infections caused by emerging Cryptococcus non-neoformans species are being reported with increasingly frequency. Here, we present a case of fungaemia byCryptococcus laurentii in a woman receiving aggressive immunosuppressive therapy for cervical neoplasia. Three venous blood samples were aseptically collected on consecutive days and C. laurentiiwas isolated and identified through phenotypic and molecular methods. After central venous catheter removal and appropriate antifungal therapy, the patient showed significant improvement and blood culture became negative. Thus, patients following immunosuppressive therapies and using invasive medical devices are at risk of C. laurentii blood infections.

Cryptococcus laurentii fungaemia in a cervical cancer patient.

Infections caused by emerging Cryptococcus non-neoformans species are being reported with increasingly frequency. Here, we present a case of fungaemia by Cryptococcus laurentii in a woman receiving aggressive immunosuppressive therapy for cervical neoplasia. Three venous blood samples were aseptically collected on consecutive days and C. laurentii was isolated and identified through phenotypic and molecular methods. After central venous catheter removal and appropriate antifungal therapy, the patient showed significant improvement and blood culture became negative. Thus, patients following immunosuppressive therapies and using invasive medical devices are at risk of C. laurentii blood infections.

Uterine cervical ectopy during reproductive age: cytological and microbiological findings.

Cervical ectopy is common in adolescents, pregnant women, and those taking high doses of estrogen-containing contraceptives. The majority of cases have spontaneous reversion, but some cases can be persistent. Studies suggested that the adequacy of a Pap smear could be affected and there is an increased risk cervical infections. This study is a cross-sectional study conducted from December 2009 to February 2011 with 457 women with cervical ectopy and 736 without ectopy. Cervical samples were collected in vials for analysis by ThinPrep cytology (Hologic, Marlborough, MA). The Mann-Whitney test and Fisher's exact test (95% CI) were applied. The study was approved by the ethics committee of the Federal University of Ceará. The mean ages of the study group and control group were 28.7 (±14.8) and 33.6 (±7.5) years old, respectively (P < 0.0001). Negative diagnosis for malignancy and intraepithelial lesion was present in 399 (87%) cases and 705 (96%) in the study and control groups, respectively (P < 0.0001). Shift in the flora suggestive of bacterial vaginosis (BV) was observed more frequently in the study group: 74 (16.2%) than in the control group: 86(11.7%) (P = 0.017). The differences among the other morphotypes showed no significance. The smears were atypical in 12.7% (58/457) of the patients from the study group and in 4.2% (31/736) in the control group (P < 0.001; RR = 3 [2.033-4.712]). The association between ectopy and inflammatory cytology, the presence of the shift in the flora suggestive of BV and cytological atypia is evident.

Molecular detection of HPV and Chlamydia trachomatis infections in Brazilian women with abnormal cervical cytology.

The question of whether Chlamydia trachomatis (Ct) is a cofactor for human Papillomavirus (HPV) in cervical carcinogenesis is still controversial. We conducted a molecular detection study of both infections in 622 Brazilian women, including 252 women with different grades of abnormal cervical cytology and cervical cancer (CC; cases) and 370 women with normal cytology (controls). Although Ct infection did not seem related to CC carcinogenicity, women with abnormal cytology had a significant high rate of Ct infection. Therefore, it is important to adopt protocols for diagnosis and treatment of this bacterium in conjunction with screening for CC in this population.

Presence of high-grade intraepithelial lesions among women deprived of their liberty: a documental study.

The aim of this study was to analyze the results of the Pap smears of women deprived of their liberty. It is a retrospective, documental study, with a quantitative approach, performed in a female prison of Ceará, Brazil, with a sample of 672 patient records. Regarding the microbiological findings, it was verified that the main cervical-vaginal colonization was by bacilli suggestive of Gardnerella/Mobiluncus (21.8%), followed by Trichomonas vaginalis (12%), and Candida sp (5.8%). The frequencies of samples with atypical cells presented rates of 4.1% for Atypical Cells of Undetermined Significance; 3.2% for Low-grade Intraepithelial Lesions; and 2.5% for High-grade Intraepithelial Lesions. The importance of screening for cervical cancer in female prisons was highlighted, as well as the inclusion of the nurse in this environment, ensuring individualized, quality care for women deprived of their liberty.

Presence of high-grade intraepithelial lesions among women deprived of their liberty: a documental study / Presença de lesões intraepiteliais de alto grau entre mulheres privadas de liberdade: estudo documental / Presencia de lesiones intraepiteliales de alto grado a las mujeres privadas de libertad: estudio documental

The aim of this study was to analyze the results of the Pap smears of women deprived of their liberty. It is a retrospective, documental study, with a quantitative approach, performed in a female prison of Ceará, Brazil, with a sample of 672 patient records. Regarding the microbiological findings, it was verified that the main cervical-vaginal colonization was by bacilli suggestive of Gardnerella/Mobiluncus (21.8%), followed by Trichomonas vaginalis (12%), and Candida sp (5.8%). The frequencies of samples with atypical cells presented rates of 4.1% for Atypical Cells of Undetermined Significance; 3.2% for Low-grade Intraepithelial Lesions; and 2.5% for High-grade Intraepithelial Lesions. The importance of screening for cervical cancer in female prisons was highlighted, as well as the inclusion of the nurse in this environment, ensuring individualized, quality care for women deprived of their liberty.

Objetivou-se analisar os resultados dos exames citopatológicos de mulheres privadas de liberdade. Estudo documental, retrospectivo, com abordagem quantitativa, desenvolvida em uma penitenciária feminina do Ceará, Brasil, com amostra de 672 prontuários. Quanto aos achados microbiológicos, foi verificado que a principal colonização cérvico-vaginal foram os bacilos sugestivos de Gardnerella/Mobiluncus com 21,8%, seguidos de Trichomonas vaginalis 12,% e Candida sp em 5,8%. As frequências de amostras com atipias celulares mostraram índices de 4,1% para atipias de significado indeterminado; lesões intraepiteliais de baixo grau 3,2% e lesões intraepiteliais de alto grau 2,5%. Conclui-se sobre a importância do rastreio do câncer cervical nos presídios femininos, bem como a inserção do enfermeiro nesse ambiente, garantindo cuidado individualizado e de qualidade para as mulheres privadas de liberdade.

El objetivo fue analizar los resultados de la prueba de Papanicolaou de mujeres privadas de libertad. Tipo de estudio documental, con un enfoque cuantitativo, desarrollado en una cárcel de mujeres en Ceará-Brasil, con muestra de 672 archivos. En cuanto a los resultados microbiológicos se comprobó que el principal colonización de cáncer cervical-vaginal fueron los Bacilos sugestivos de Gardnerella/Mobiluncus con 21,8%, seguido de Trichomonas vaginalis 12% y Cándida sp 5,8%. Las frecuencias de las muestras con atipia celular se registraron tasas de 4,1% para Atipias de significado indeterminado; Lesiones Intraepiteliales de bajo grado 3,2% y Lesiones Intraepiteliales de alto grado 2,5%. La conclusión es la importancia de la detección del cáncer cervical en las cárceles de mujeres, así como la inclusión de los enfermeros en este entorno al tiempo que garantiza una calidad y una atención individualizada a las mujeres presas.

Dysbacteriosis and squamous (pre)neoplasia of immigrants and Dutch women as established in population-based cervical screening.

We examined the statistical relationships between dysbacteriosis and (pre)neoplasia related to age and ethnicity from the cervical screening of almost half a million smears. Data from 445,080 smears were coded according to KOPAC (the Dutch national cervical smear coding system) with nine grades. Prevalence per 100,000 smears and relative risks (RR) were calculated for dysbacteriosis and for squamous abnormalities. Patients were stratified by their probable country of origin. Dutch women had an RR of 0.92 for dysbacteriosis. Surinamese women had the highest RR for dysbacteriosis (RR = 2.36) and Moroccan women had the lowest (RR = 1.00). The same trends were seen for the risks of squamous abnormalities. The data for Turkish women follow the patterns of those for Surinamese women. The RR of dysbacteriosis is highest at 50 yr (1.28) and lowest at 35 yr (0.86). When dysbacteriotic and non-dysbacteriotic smears were compared, dysbacteriosis was observed more frequently in smears with squamous abnormalities (4.1% vs. 2.2%). Dysbacteriosis may warrant more intensive cytological surveillance and changes in lifestyle.

Chlamydia trachomatis and Human papillomavirus infections in cervical disease in Argentine women.

OBJECTIVES: To examine the prevalence of Human papillomavirus and Chlamydia trachomatis DNA in cervical samples among women with normal and abnormal cervical cytology from La Plata, Argentina. METHODS: Two hundred and seventy-nine women (200 with cervical neoplasia or ICC and 79 women with normal cytology) provided cervical samples for the detection of HPV and C. trachomatis DNA by PCR-based assays. RESULTS: HPV DNA increased with the cervical lesion severity, ranging from 30% among women with normal cytology to 99-100% among women with HSIL or ICC. C. trachomatis DNA prevalence increased from low levels in women with normal cytology (11%) to 47% in those with HSIL, but was uncommon among ICC patients (20%). Among women with normal cytology, C. trachomatis prevalence was higher in HPV DNA positive (12.5%) than HPV DNA negative women (10.9%), but this difference was not significant. CONCLUSIONS: HPV prevalence in the general population is slightly higher than those reported for other developing countries. C. trachomatis DNA positivity was associated with a higher risk of both LSIL and HSIL lesions, but not with ICC.

Risk factors for squamous intraepithelial lesions (SIL) of the cervix among women residing at the US-Mexico border.

It is now well established that cervical cancer is caused by oncogenic human papillomavirus (HPV) infections that commonly infect women worldwide. What remains to be understood are the factors that contribute to cervical cancer in the presence of HPV infection. We conducted a case-control analysis of women recruited at the US-Mexico border to simultaneously evaluate factors associated with 3 cytologic outcomes: atypical squamous cells of undetermined significance or atypical glandular cells of undetermined significance (ASCUS/AGUS), low grade squamous intraepithelial lesions (LSIL) and high grade squamous intraepithelial lesions (HSIL). A cross-sectional binational study of 2059 women ages 15-79 years was conducted between 1997 and 1998. A significant difference in the distribution of cytologic categories by country was observed (3.0% vs. 0.7% HSIL among Mexican vs. US women, respectively). The only factors independently associated with all 3 cytologic outcomes were HPV infection and viral load. A linear increase in risk with increasing viral load was observed for each of the 3 outcome variables, with the strength of this association increasing with cytology abnormality. In addition to HPV infection, parity and Mexico as a country of residence appear to be associated with LSIL and HSIL, respectively. Factors associated with cytologic outcomes in analyses limited to women with HPV infection were similar to results obtained in models where HPV infection was included as a covariate. Future work is needed to evaluate the predictive value of HPV viral load utilizing more specific and quantitative measures.

Chlamydia trachomatis, herpes simplex virus 2, and human T-cell lymphotrophic virus type 1 are not associated with grade of cervical neoplasia in Jamaican colposcopy patients.

BACKGROUND: A few recent studies have suggested that other sexually transmitted infections may increase the likelihood of a human papillomavirus (HPV) infection progressing to high-grade cervical neoplasia and cancer. GOAL: The goal was to assess whether exposures to Chlamydia trachomatis, human T-cell lymphotrophic virus type 1 (HTLV-I), and/or human simplex virus type 2 (HSV-2) are greater in colposcopy patients with cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) than in patients with low-grade cervical neoplasia (CIN1). STUDY DESIGN: Sequential patients (n=447) attending a colposcopy clinic in Kingston, Jamaica, a country with high cervical cancer rates and high HTLV-I prevalence, were tested for (1) HPV DNA by L1 consensus primer (MY09/11) polymerase chain reaction assays, (2) C trachomatis DNA by ligase chain reaction, (3) C trachomatis antibodies by both microimmunofluorescence and a peptide (VS4) enzyme linked immunosorbent assay (ELISA), (4) HTLV-I antibodies by ELISA confirmed by western blotting, and (5) HSV-2 antibodies by a recombinant HSV-2-specific ELISA. Odds ratios and 95% confidence intervals were estimated with use of multinomial logistic regression models. RESULTS: HPV DNA detection was associated with grade of cervical neoplasia but other evaluated sexually transmitted infections were not. CONCLUSIONS: HTLV-I, C trachomatis, and/or HSV-2 were not associated with severity of cervical neoplasia in Jamaican women.

Gardnerella vaginallis: a cofactor in cervical neoplasia?

Gardnerella vaginalis has been associated with cervical lesions. This agent produces nitrosamines that are transformed into carcinogenic derivatives by the cell metabolism. On the other hand, it seems that G. vaginalis can act synergistically with oncogenic agents, such as papillomarivus. The present paper, a five-year study, reports a significantly higher incidence of G. vaginallis infection (p<0.01) in patients whose PAP smears showed features of CIN. Comparing the incidence of this agent in the three grades of CIN cases, a higher incidence in the CIN I group (p<0.001) was observed. We emphasize the importance of PAP and clinical follow-up in patients with G. vaginalis infection in order to search for CIN features.

Squamous intraepithelial lesions in cervical smears of human immunodeficiency virus-seropositive adolescents.

Various authors have reported a high rate of human papillomavirus (HPV) infection and HPV-related neoplasias in human immunodeficiency virus (HIV)-seropositive women. On the other hand, young women are most susceptible to cervical infection because of immaturity of the cervix, as it appears that HPV has more access to the basal cells of the differentiating epithelium. The purpose of the present work was to study cervical smears of 82 adolescent HIV-seropositive women (13-21 years of age) to search for cytological evidence of cervical intraepithelial neoplasias. Twenty-one cases showed characteristic features of HPV infection and squamous intraepithelial lesions (SIL; 25.6%). Sixteen cases aged from 17 to 21 years (mean age 19.5 years) had low-grade SIL (LSIL; 19.5%) and five cases aged from 18 to 21 years (mean age 20.2 years) had high-grade SIL (HSIL; 6.1%). There was no significant difference between the mean age of patients with LSIL and HSIL. Two cases had atypical squamous cells of undetermined significance (ASCUS). In the present work it was found that HIV-seropositive adolescents have a high risk for preneoplastic lesions of the cervix (25.6%) as well as a high incidence of more aggressive lesions (6.1% of HSIL) when compared to the general population of adolescents. As it can be assumed that, if the age of acquisition of the infection in both groups (in the general population and HIV-seropositive women) is the same, it is probable that HIV infection in adolescents not only increases the frequency of HPV infections but also facilitates the evolution to more aggressive preneoplastic lesions of the cervix due to HPV.

A sero-epidemiological study of the relationship between sexually transmitted agents and cervical cancer in Honduras.

To investigate a possible cause-and-effect relationship between sexually transmitted diseases and cervical cancer, we performed a sero-epidemiological study on the presence of antibodies against a number of sexually transmitted agents (STAs) in patients with cervical cancer and their matched controls. In this study, we used serological techniques to investigate the presence of antibodies to cytomegalovirus, herpes simplex virus type 2, human immunodeficiency virus, Chlamydia trachomatis, Treponema pallidum and human papillomavirus (HPV) early protein E7 in sera from patients with cervical cancer, cervical intra-epithelial neoplasia and individually matched, healthy controls. The presence of antibodies to infectious agents other than HPV appeared not to be associated with risk of cervical neoplasia in either univariate or multivariate analysis. After adjustment for cytology, schooling and presence of HPV DNA in cervical scrapes, there was a significantly higher prevalence of antibodies to HPV-16 E7 protein in sera from patients with cervical cancer (OR = 3.6, 95% CI 1.0-12.9) than in healthy controls. The highest antibody prevalence was found among HPV-16 DNA-positive cervical cancer patients (33%). Our results indicate that in these study groups past infections with the STA considered seems to be of no apparent relevance for cervical carcinogenesis and that the HPV-16 anti-E7 response appears to be associated with cervical cancer.

[Association of Chlamydia trachomatis and human papilloma virus as predisposing factors in cervical intraepithelial neoplasia]. / Asociación de Chlamydia trachomatis y virus del papiloma humano como factores predisponentes en la etiopatogenia de la neoplasia intraepitelial cervical.

Human papilloma virus (HPV) has a predisposing association as cofactor in etiopathology of cervicouterine cancer; it is known also that viral infection is not enough, and there are other agents, as Chlamydia trachomatis. The objective of this study was to investigate the association of these cofactors as predisposal for intraepithelial cervical neoplasia (NIC). Prospectively, at Clinica de Colposcopia, Hospital de Ginecología y Obstetricia "Luis Castelazo Ayala", IMSS, 37 patients with cytologic, colposcopic and histological diagnosis of CIN pure or associated to HPV, underwent endocervical cytologies, and by immunofluorescence method, using monoclonal antibodies of conjugated fluoresceine, it was tried to demonstrate Chlamydia trachomatis, presence. From all patients, 12(32,4) were positive for Chlamydia trachomatis, significant percentually, and with Xi square of 0.32, non significant for this group of population. It is concluded that there is an important association of Chlamydia trachomatis and HPV, which should be taken into consideration in diagnosis and treatment of intraepithelial cervical neoplasia.

[Chlamydia trachomatis and cervix dysplasia]. / Chlamydia trachomatis y displasia cervical.

Fifty patients between 18 and 70 years of age from Gynecology and Obstetrics Department, Hospital General "Gonzalo Castañeda" ISSSTE, were studied. Patients were referred for bearing positive cytology with mild, moderate and severe dysplasia; also intentional search for Chlamydia trachomatis was made, both in cytology as well as with the immunofluorescence method, and also directed biopsy. A positive association was found in 10 patients (20%) proving that Chlamydia trachomatis is a promotor and modifier of cervical atypia.

[Cervical intraepithelial neoplasia: Chlamydia trachomatis and other co-factors]. / Neoplasia intraepitelial cervical: Chlamydia trachomatis y otros co-factores.

The incidence of Chlamydia trachomatis (Ct) in patients with diagnosis of Cervical Intraepithelial Neoplasia (CIN) was studied in one hundred eighty patients. The Chlamydiazyme test was performed in all of them. Endocervical samples were taken from 103 patients with CIN and 77 women who sought medical attention for different gynecological reasons (CG). Twenty three tests (12.8%) were positive; 15 of them had CIN (14.6%) and 8 were from the control group (10.4%). It was found a statistical significant difference between NIC III and early intercourse, NIC III and age, NIC and vaginal douches and, among NIC and number of pregnancies and deliveries. There was not a significant difference among Ct and early intercourse, number of sexual partners, pregnancies, deliveries, vaginal douches, oral contraceptives (OC), and vaginal discharge. No statistically significant differences were found between NIC and number of sexual partners, and OC and vaginal discharge. The low incidence of Ct in patients with CIN does not mean that Ct does not play a role in the origin and development of the cervical pathology.