Daniela Etlinger

Increasing expression of monocarboxylate transporters 1 and 4 along progression to invasive cervical carcinoma.

Solid tumor cells are known to be highly glycolytic and, to prevent apoptosis by cellular acidosis, cells increase proton efflux through pH regulators, such as monocarboxylate transporters (MCTs). However, the role of these membrane proteins in solid tumor development and survival is not fully understood. We aimed to evaluate the expression of the MCT isoforms 1, 2, and 4 in a large series of cervical lesions (neoplastic and non-neoplastic) and assess its clinical-pathologic significance. The series analyzed included 29 chronic cervicitis, 30 low-grade squamous intraepithelial lesions, 32 high-grade squamous intraepithelial lesions, 49 squamous cell carcinomas, 51 adenocarcinomas, and 30 adenosquamous carcinomas of the uterine cervix. Analysis of the expression of MCT isoforms 1, 2, and 4 was performed by immunohistochemistry with specific antibodies. Immunoreactions were evaluated both qualitatively and semiquantitatively. We found a significant increase in MCT expression from preinvasive to invasive squamous lesions and from normal glandular epithelium to adenocarcinomas. This is the first study evaluating the significance of MCT expression in lesions of the uterine cervix, including invasive carcinomas, and the results found herein led us to believe that these membrane proteins are involved in the progression to invasiveness in uterine cervix carcinoma.

Monocarboxylate transporters 1 and 4 are associated with CD147 in cervical carcinoma

Due to the highly glycolytic metabolism of solid tumours, there is an increased acid production, however, cells are able to maintain physiological pH through plasma membrane efflux of the accumulating protons. Acid efflux through MCTs (monocarboxylate transporters) constitutes one of the most important mechanisms involved in tumour intracellular pH maintenance. Still, the molecular mechanisms underlying the regulation of these proteins are not fully understood. We aimed to evaluate the association between CD147 (MCT1 and MCT4 chaperone) and MCT expression in cervical cancer lesions and the clinico-pathological significance of CD147 expression, alone and in combination with MCTs. The series included 83 biopsy samples of precursor lesions and surgical specimens of 126 invasive carcinomas. Analysis of CD147 expression was performed by immunohistochemistry. CD147 expression was higher in squamous and adenocarcinoma tissues than in the non-neoplastic counterparts and, importantly, both MCT1 and MCT4 were more frequently expressed in CD147 positive cases. Additionally, co-expression of CD147 with MCT1 was associated with lymph-node and/or distant metastases in adenocarcinomas. Our results show a close association between CD147 and MCT1 and MCT4 expressions in human cervical cancer and provided evidence for a prognostic value of CD147 and MCT1 co-expression.

Associação entre idade ao início da atividade sexual e subseqüente infecção por papilomavírus humano : resultados de um programa de rastreamento brasileiro

PuRPOse : to investigate women’s age at their first sexual intercourse and its correlation with their present age, human papillomavirus (HPV) infection and cytological abnormalities at Pap smear. MethOds : women from the general population were invited to be screened for cervical cancer and pre-malignant lesions. After answering a behavior questionnaire, they were submitted to screening with cervical cytology and high-risk HPV testing with Hybrid Capture 2 (HC2). This report is part of the Latin American Screening (LAMS) study, that comprises centers from Brazil and Argentina, and the data presented herein refer to the Brazilian women evaluated at the cities of Porto Alegre, Sao Paulo and Campinas. Results : from 8,649 women that answered the questionnaire, 8,641 reported previous sexual activity and were included in this analysis. The mean age at the interview was 38.1±11.0 years and the mean age at the first sexual intercourse was

Simultaneous Chlamydia trachomatis and HPV infection in pregnant women.

Pregnancy is associated with HPV infection and with Chlamydia trachomatis (CT) infection mostly due to the natural immunosuppression. In addition, pregnancy associated to CT infection can lead to adverse conditions to the woman and fetus, and CT is also believed to be a co‐factor in human immunodeficiency virus infection and HPV‐induced cervical cancer. The aim of this study was to establish the odds ratios (OR) of CT infection in to HPV‐infected pregnant women and vice versa of women stratified by age (<25 years) and marital status. This work is part of a national multicentric transversal study carried out in six Brazilian cities supported by the Ministry of Health of Federal Government of Brazil in 2003. Cervical scrapes of 371 pregnant women were sampled. We performed a hybrid capture‐2 technique to diagnose these samples on HPV and CT infection, and the women responded a questionnaire. Significant association was observed between nonstable marital status and hr‐HPV infection [OR = 2.61 (1.38–4.97) P = 0.003)], and age <25 years old [OR = 2.26 (1.09–4.71) P = 0.029]. Nonstable marital status was also associated with lr‐HPV infection [OR = 2.67 (1.59–4.50) P < 0.001), and age <25 years old [OR = 2.55 (1.51–4.32) P < 0.001). Fifty of the 371 pregnant women were infected with hr‐HPV (13.5%) and 111 (30.0%) were infected with lr‐HPV. The coinfections of HPV and CT were found in 31 women, that is, 8.36% of the pregnant women (P < 0.001). The high rate of simultaneous CT and HPV infection in pregnant women favors the recommendation to screen pregnant women for both CT and HPV. Diagn. Cytopathol. 2010.

Deregulated expression of superoxide dismutase-2 correlates with different stages of cervical neoplasia

Objective: Superoxide dismutase-2 (SOD2) is considered one of the most important antioxidant enzymes that regulate cellular redox state in normal and tumorigenic cells. Overexpression of this enzyme may be involved in carcinogenesis, particularly in lung, gastric, colorectal and breast cancer. Methods: In the present study, we have evaluated SOD2 protein levels by immunohistochemistry (IHC) in 331 cervical histological samples including 31 low-grade cervical intraepithelial neoplasia (LSIL), 51 high-grade cervical intraepithelial neoplasia (HSIL), 197 squamous cervical carcinomas (SCC) and 52 cervical adenocarcinomas (ADENO). Results: We observed that SOD2 staining increases with cervical disease severity. Intense SOD2 staining was found in 13% of LSIL, 25.5% of HSIL and 40% of SCC. Moreover, 65.4% of ADENO exhibited intense SOD2 staining. Conclusions: Differences in the expression of SOD2 could potentially be used as a biomarker for the characterization of different stages of cervical disease.

The association of p16INK4A and fragile histidine triad gene expression and cervical lesions

Objective. This cross-sectional study was intended to assess the association between immunohistochemical analysis of p16INK4A and fragile histidine triad (FHIT) and the presence of precancerous cervical lesions. Materials and Methods. Women seen at Pérola Byington Hospital, São Paulo, Brazil, with histologically confirmed cervicitis (n = 31), cervical intraepithelial neoplasia (CIN) 1 (n = 30), CIN 2,3 (n = 30), and cervical cancer (n = 7) had also cervical material collected for liquid-based cytology, human papillomavirus Hybrid Capture 2 (HC2) test, and p16 and FHIT immunohistochemical reactions. Results. p16 and FHIT reactions were scored as the following: <1%, 1% to 5%, >5% to 25%, and >25%. Receiver operating curve analysis was used to select p16 and FHIT score cutoffs for further categorical analyses. All but one of the 37 CIN 2,3/cancer cases had a p16 score of greater than 1% to 5%. Among the 61 cervicitis/CIN 1 cases, 46 (75%) had a p16 score lower than 1% to 5%. In contrast, no association of FHIT expression and severity of cervical lesions could be demonstrated in this data set. Receiver operating curve analyses suggested the score of 1% to 5% for p16 as the cutoff that best discriminates CIN 2,3/cancer from cervicitis/CIN 1. No cutoff for FHIT scores could be suggested with data set. Conclusions. p16, but not FHIT expression, has the potential to be used as complementary diagnostic tool to investigate human papillomavirus-induced cervical lesions, if these results are confirmed in larger studies.

Avaliação crítica das nomenclaturas diagnósticas dos exames citopatológicos cervicais utilizadas no Sistema Único de Saúde (SUS)

PURPOSE: to identify the nomenclature for reporting cervical cytological diagnoses used by laboratories which render services to the Brazilian Unified Health System (SUS) and which participate in External Quality Monitoring (MEQ). To evaluate the information acquired from gynecologists of the SUS regarding the various diagnostic classifications that they receive in the cervical cytology diagnostic reports. METHODS: we evaluated 94 cytology reports issued by laboratories which participate in the MEQ in the State of Sao Paulo, Brazil, and 126 questionnaires applied to gynecologists who work for the SUS. RESULTS: out of the 94 laboratories, 81 (86.2%) use one diagnostic classification: 79 (97.6%) use the Brazilian Nomenclature for Cytological Reports (NBLC), 1 (1.2%) uses the Papanicolaou classification and 1 (1.2%) uses the Richart diagnostic classification. Of the 13 (13.8%) laboratories that use more than one classification, 5 use 2 types and 8 use 3 to 4 types, with 9 including the Papanicolau diagnostic classification. The study showed that 52 (55.3%) laboratories presented more than one descriptive diagnosis in the same report. Out of the 126 gynecologists who filled out a questionnaire evaluating the cytopathology reports, 78 (61.9 %) stated that they received laboratory reports with only one diagnostic classification, 48 (38.1%) received reports with more than one classification and 2 received reports with all 4 classifications. Among the 93 (73.8%) gynecologists who prefer only one classification, 56 (60.2%) claimed that the NBLC contributes to clinical practice, 13 (14.0%) opted for the Richart classification, 8 (8.6%) for the Reagan classification and 16 (17.2%) for the Papanicolaou classification. Out of 33 (26.2%) gynecologists who prefer more than one classification, 5 opted for the 4 classifications. CONCLUSIONS: these data suggest that there is still resistance on the part of pathologists about using the official nomenclature in cytology reports for SUS. There is discrepancy between the information that gynecologists would like to see in the reports and the information provided by the pathologists. Greater efforts should be made to stimulate the use of the official nomenclature.

Asociación entre la expresión génica de p16INK4A, la tríada de histidina frágil y las lesiones cervicales

Objetivo. Este estudio transversal tuvo como objetivo valorar la asociación entre el análisis inmunohistoquímico de p16INK4A y de la tríada de histidina frágil (FHIT) y la presencia de lesiones cervicales precancerosas. Material y métodos. Se estudió a mujeres visitadas en el Pérola Byington Hospital, Sao Paulo, Brasil, que presentaban una cervicitis confirmada histológicamente (n = 31), neoplasia cervical intraepitelial (CIN) 1 (n = 30), CIN 2,3 (n = 30) o cáncer cervical (n = 7), en las que se obtuvieron muestras de material cervical para citología líquida (CL), prueba del virus del papiloma humano Hybrid Capture 2 (HC2), y reacciones inmunohistoquímicas de p16 y de FHIT. Resultados. Las reacciones de p16 y de FHIT se valoraron de la siguiente forma: <1%, 1% a 5%, > 5% a 25%, y > 25%. Se utilizó un análisis de curva de receptor‐operador para elegir los valores de corte de p16 y FHIT para los ulteriores análisis de variables discretas. La totalidad de los 37 casos de CIN 2‐3/cáncer, excepto uno, presentaron una puntuación de p16 de la clase superior a 1% a 5%. De los 61 casos de cervicitis/CIN 1, 46 (75%) tenían una puntuación de p16 de la clase inferior a 1% a 5%. En cambio, no se observó asociación alguna de la expresión de FHIT con la gravedad de las lesiones cervicales en este conjunto de datos. Los análisis de la curva de operador‐receptor sugirieron la puntuación de 1% a 5% para p16 como valor de corte que mejor discrimina entre CIN 2‐3/cáncer y cervicitis/CIN 1. No pudo sugerirse ningún valor de corte para las puntuaciones de FHIT con esta serie de datos. Conclusión. La expresión de p16, pero no en cambio la de FHIT, tiene un potencial de uso como herramienta diagnóstica complementaria para el estudio de las lesiones cervicales inducidas por el virus del papiloma humano, si estos resultados son confirmados por estudios más amplios. ▪