Frequency of post-treatment disease after excisional procedure in stage IA1 squamous cervical carcinoma - a case series.

Early stages of cervical cancer in young women need conservative treatments. Electrosurgical therapies (LLETZ, LEEP, SWETZ, NETZ) have been recommended for these women. However, there are recommendations to perform a second excision when the specimen margins are not free of disease. This can lead to some important complications. This article aims to verify the frequency of residual invasive or microinvasive disease after the excisional procedure in women with IA1CC. Data on women with IA1CC diagnosed between 1990 and 2022, were retrieved from medical records. Post-treatment disease was detected during a second surgical procedure or postoperative follow-up. Among the 69 included women, three (4.3 percent; CI95 percent 0-9.2) had residual microinvasive lesions, while none showed invasive disease during a second procedure or follow-up. Only the age of 37 years or more was significantly related to the presence of preinvasive or microinvasive residual lesions. Nearly 80 percent of the women who underwent a second procedure showed no residual lesions. The absence of invasive disease in a second procedure or during the follow-up of these women and the large proportion of women with no residual lesion questions the need for a new surgical procedure even when the surgical margins of the initial specimen are involved.

Negative histology in cervical specimens obtained with the "see and treat" method among women at a referral center in Rio de Janeiro, Brazil: a cross-sectional study.

BACKGROUND: According to the Brazilian Guidelines on Cervical Cancer Screening, women with cytopathologic diagnosis of high-grade intraepithelial lesion, abnormal colposcopic findings, fully visible squamocolumnar junction and age 25 years or older should be treated at the first visit ("see and treat-S&T"). The main limitation to this approach is the risk of overtreatment, identified by histology without preinvasive lesion. The objectives of this study were to identify the overtreatment rate in women undergoing S&T in cervical cancer prevention at a referral center with extensive experience with the method and to detect possible factors associated with this rate. METHODS: This was a cross-sectional study that analyzed records from a database with 616 women submitted to S&T from 1996 to 2017. Negative histology was defined as the following histopathologic results: human papillomavirus without cervical intraepithelial neoplasia (CIN), inflammatory, low-grade squamous intraepithelial lesion, and CIN 1. RESULTS: Of the 616 women, there were 52 (8.44%, 95%CI 6.25-10.64%) with a histopathologic report without preinvasive cervical lesion. No statistical association was found between this outcome and age or a significant downward trend over time. CONCLUSION: The overtreatment rate in this study can be considered low and consistent with the acceptable rates reported in the literature, reinforcing the prevailing Brazilian guideline, in which the benefits of immediate treatment outweigh the risk of losses following biopsy.

Roles of CDKN1A gene polymorphisms (rs1801270 and rs1059234) in the development of cervical neoplasia.

The CDKN1A gene product is a p53 downstream effector, which participates in cell differentiation, development process, repair, apoptosis, senescence, migration, and tumorigenesis. The objective of our study was investigated the importance of two polymorphisms in the CDKN1A gene, rs1801270 (31C>A) and rs1059234 (70C>T), for the development of cervical lesions in a Southeastern Brazilian population (283 cases, stratified by lesion severity, and 189 controls). CDKN1A genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and/or DNA sequencing. CDKN1A 31A allele presents a genetic pattern of protection for the development of high-grade cervical lesions (CC vs CA genotype: OR = 0.60; 95 % CI = 0.38-0.95; p = 0.029; CA+AA vs CC genotype: OR = 0.60; 95 % CI = 0.39-0.93; p = 0.021). Allele distributions of the CDKN1A 70C>T polymorphism were also different between the two study groups, with the CDKN1A 70T allele being less prevalent among cases. Moreover, the double heterozygote genotype combination 31CA-70CT decreases the chance of developing high-grade squamous intraepithelial lesion (HSIL) and cancer (OR = 0.55; 95 % CI = 0.32-0.93; p = 0.034) by 50 %, representing a protective factor against the development of more severe cervical lesions.

Polymorphism in apoptotic BAX (-248G>A) gene but not in anti-apoptotic BCL2 (-938C>A) gene and its protein and mRNA expression are associated with cervical intraepithelial neoplasia.

HPV is associated with cervical cancer and plays a crucial role in tumor formation. Apoptosis is regulated by different pathways involving genes that either promote (BCL2 gene) or inhibit (BAX gene) cell death. Our goal was to determine whether the BCL2-938C>A (rs2279115) and BAX-248G>A (rs4645878) single nucleotide polymorphisms (SNPs) are associated with squamous intraepithelial neoplasia (SIL) risk, and whether their phenotypic expression was impaired in these lesions. Two hundred and thirty-one cases showing SIL were classified as low SIL (LSIL, n = 101) or high SIL (HSIL, n = 130), and control subjects (n = 266) with no gynecologically proven SIL were recruited. No statistical difference in the genotype and allelic frequency of the BCL-2-938C>A polymorphism was observed among the groups. BCL2-938C/A and A/A homozygotes carriers had higher distribution of BCL-2-expressing cells in stroma in the SIL group. BCL2 mRNA-expression was not correlated with BCL2-938C>A SNPs in both groups. We did find a strong association of the BAX GG genotype and risk for SIL. No difference was observed between LSIL and HSIL groups. In BAX-248G/A and A/A homozygote carriers, the number of BAX-expressing cells was lower the epithelium area in SIL. However, mRNA expression was higher in SIL patients than in the control group. In conclusion, our data provide evidence that allele G carriers in the BAX-248G>A promoter SNP may influence the development of SIL. However, this genotype does not influence the SIL outcome. Additionally, we suggest a possible role of HPV infection in the inhibition of the expression of BAX protein, decreasing cell death, and favoring cervical carcinogenesis.

A comparison between type 3 excision of the transformation zone by straight wire excision of the transformation zone (SWETZ) and large loop excision of the transformation zone (LLETZ): a randomized study.

BACKGROUND: The management of preinvasive cervical lesions has the objective to ensure the absence of invasive lesions and to prevent progression to cancer. Excisional procedures have been preferred to treat these lesions as they report the presence of unsuspected invasive lesions and the status of surgical margins, allowing inferring full excision when such are free of disease. The purpose of this study is to determine whether Straight Wire Excision of the Transformation Zone (SWETZ) is a better alternative than Large Loop Excision of the Transformation Zone (LLETZ-cone) as a type 3 excision of the Transformation Zone (TZ) to reduce incomplete excision and concerning other outcomes of surgical interest. METHOD: Randomized controlled trial including women who needed type 3 excision of the TZ referred to a colposcopy clinic after cytological screening between January 2008 thru December 2011. The interventions were performed using local anesthesia and sedation in an inpatient basis by different experienced surgeons. The study enrolled and randomized 164 women, of which 82 were allocated to each group. After exclusions, 78 remained in SWETZ and 76 in LLETZ-cone groups for the analysis of outcomes of surgical interest and 52 and 54, respectively, for the margins analysis. RESULTS: There was an even distribution between the groups after randomization and exclusions, concerning mean age, parity, current smoking, prior cytological diagnosis and histopathological diagnosis obtained in cone specimen even after exclusions. We observed significantly higher risk of compromised or damaged endocervical margin in specimens resulting from the LLETZ-cone in relation to SWETZ (RR 1.72, 95% CI: 1.14 to 2.6), with an absolute risk reduction (ARR) of 26.4% (95% CI: 8.1 to 44.8) for patients operated by SWETZ. The specimens obtained by SWETZ showed less fragmentation (ARR = 19.8%, 95% CI: 10.3 - 29.3%), but the procedure took longer. There were complications in 5.6% of the procedures, with no significant differences between the groups. CONCLUSION: This study showed a lower proportion of compromised or damaged endocervical surgical margin in specimens resulting from SWETZ in relation to LLETZ-cone. SWETZ demonstrated to be more efficient than LLETZ-cone concerning less fragmentation of the specimen obtained. However, it accounted for longer surgical time. Both techniques showed morbidity TRIAL REGISTRATION: Number at ClinicalTrials.gov: NCT01929993 (June 10, 2012).

Preinvasive and invasive disease in women with cytological diagnosis of high-grade lesion and high-grade lesion cannot exclude microinvasion.

BACKGROUND: Cervical cancer is the third most common cancer in Brazil and has a high potential for prevention and cure. The prevalence of invasive and preinvasive disease in women with cytological diagnosis of high-grade lesion - cannot exclude microinvasion (HSIL-micro) is not known. METHODS: This cross-sectional study used a cytology lab database to identify women with HSIL-micro and HSIL referred to two colposcopic units from June 2006 to December 2012. For each woman with HSIL-micro, four women with cytologic diagnosis of HSIL who met the inclusion criteria were identified. Data were obtained from review of medical records. RESULTS: Forty-seven patients with report of HSIL-micro and 188 patients with report of HSIL were included. The final diagnoses revealed a frequency of preinvasive lesions of 31.9 % (15/47) and 59.6 % (112/188) in patients with HSIL-micro and HSIL, respectively, while the frequency of invasive disease was 63.8 % (30/47) and 11.7 % (22/188), respectively. The HSIL-micro group showed prevalence of preinvasive or invasive disease 6.5 times greater (95 % CI = 1.6-5.7) and, for invasive disease, 2.4 times greater (95 % CI = 1.7-3.6) than the HSIL group. CONCLUSION: Higher risk of preinvasive and invasive lesions in women with cytologic diagnosis of HSIL-micro reinforces recommendations for immediate investigation.

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.

Effects of MDM2 promoter polymorphisms on the development of cervical neoplasia in a Southeastern Brazilian population.

We investigated the importance of two adjacent functional polymorphisms in the Murine Double Minute 2 (MDM2) gene, SNP285 G > C and SNP309 T > G, for the development of cervical lesions in a Southeastern Brazilian population (293 cases and 184 controls). MDM2 genotyping was performed by PCR-RFLP (Polymerase Chain Reaction-Restriction Fragment Length Polymorphism) and/or DNA sequencing. MDM2 SNP309 has potential as a biomarker of cervical neoplasia in non-smokers, patients with family history of cancer, or those who had late sexual debut (>16 years). Besides, this polymorphism may help identify women at risk of developing severe cervical lesion at a young age (<30 years).

Association of CDKN2A polymorphisms with the severity of cervical neoplasia in a Brazilian population.

Variants of p16(INK4a) and p14(ARF), encoded by the CDKN2A locus, may respond differently to the presence of human papillomavirus (HPV). We investigated the potential association of two CDKN2A polymorphisms, 500C > G (rs11515) and 540C > T (rs3088440), with cervical neoplasia in patients with cervical lesions and healthy controls (n = 492). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), single-strand conformation polymorphism (SSCP) and/or DNA sequencing techniques were employed for genotyping. The 500G allele was found higher, whereas the 540T/T genotype was less frequent in patients with more severe lesions. The CDKN2A variants may have the potential to be markers for the management of patients with cervical neoplasia.

Balance of apoptotic and anti-apoptotic marker and perforin granule release in squamous intraepithelial lesions. HIV infection leads to a decrease in perforin degranulation.

Cell-mediated cytotoxicity plays an important role in the regulation to HPV-associated cervical intraepithelial neoplasia. HIV co-infection is related to poorer prognosis and more rapid clinical progression to cancer. We evaluated the presence of cervical inflammatory cells, apoptotic (Bax, Bcl-2, FasL, NOS2, perforin) markers and the degranulating expressing cell marker (CD107a) in low and high squamous intraepithelial lesions (LSIL and HSIL, respectively) from HIV-negative and -positive women. Higher percentage of cervical CD4(+), CD8(+) T cells and macrophage were observed in LSIL and HSIL groups when compared with control, especially in epithelium and basal layer of epithelium. However, progression from LSIL to HSIL did not change the frequency of inflammatory cells. HIV-infection lead to a reduction on cervical CD4(+) T cell infiltration and an increased CD8(+) T cell distribution in LSIL groups. A balance between pro- and anti-apoptotic protein expressions was verified. Bax-expressing cells were present in all groups and were rarely expressed in keratinocytes in the epithelium in LSIL and control groups, but notably decreased in HSIL group. However, its frequency was enhanced in the basal layer of the epithelium meanly in LSIL group. Bcl2-expressing cells in the epithelium and the stroma were enhanced in HSIL group when compared with LSIL group. HIV-infection did not interfere in both expressions NOS2 expression was located on keratinocytes in both LSIL and HSIL groups when compared with control group. There were few FasL cervical expressing cells in all groups. Indeed, perforin was identified in few cervical cells. However, CD107a, a surface marker for cellular degranulation was significantly higher in epithelium, basal layer of epithelium and stroma in LSIL and HSIL, respectively, when compared with control group. These results support that HIV infection may induce reduction on inflammatory cervical cell degranulation corroborating to carcinogenesis process. This is the first description on the role of HIV in downregulation of perforin degranulation in the cervical lesions and it might be related to carcinogenesis.

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.

Conventional cytologic diagnosis of human papillomavirus-induced anal intraepithelial neoplasia: The experience of a referral center in Rio de Janeiro, Brazil.

BACKGROUND: Screening of anal cancer is rarely available or performed in Brazil. This study analyzes the diagnostic performance of conventional cytology (CC) in the prevention of anal cancer in a coloproctology and gynecology outpatient clinics in a public hospital in Rio de Janeiro, Brazil. METHODS: From 2005 to 2017, 1066 conventional cytological samples were collected. We analyze the causes of unsatisfactory samples (11.3%) and compare the cytological diagnoses of 83 samples from persons living with HIV and persons not living with HIV and in specific situations, using as the gold standard high-resolution anoscopy or histopathology in cases biopsied within 6 months after cytology. RESULTS: The sensitivity of cytology with diagnosis of ASC-US for detection of anal intraepithelial neoplasia of any grade was 85%, specificity was 41%, positive and negative predictive values were 64% and 75%, respectively, and positive and negative likelihood ratios were 1.46 and 0.35, respectively. CONCLUSION: Conventional cytology available in resource-limited settings is a simple, noninvasive, low-cost method that proved feasible for outpatient screening of precursor lesions of the anal canal.

Cervical Intraepithelial Neoplasia grade 2 biopsy: Do p16INK4a and Ki-67 biomarkers contribute to the decision to treat? A cross-sectional study.

BACKGROUND: Managing cervical intraepithelial neoplasia grade 2 (CIN2) is challenging, considering the CIN2 regression rate, perinatal risks associated with excisional procedures, and insufficient well-established risk factors to predict progression. OBJECTIVES: To determine the ability of p16INK4a and Ki-67 staining in biopsies diagnosed with CIN2 to identify patients with higher-grade lesions (CIN3 or carcinoma). DESIGN AND SETTING: Cross-sectional study conducted at a referral center for treating uterine cervical lesions. METHODS: In 79 women, we analyzed the correlation of p16INK4a and Ki-67 expression in CIN2 biopsies with the presence of a higher-grade lesions, as determined via histopathology in surgical specimens from treated women or via two colposcopies and two cytological tests during follow-up for untreated women with at least a 6-month interval. The expression of these two biomarkers was verified by at least two independent pathologists and quantified using digital algorithms. RESULTS: Thirteen (16.8%) women with CIN2 biopsy exhibited higher-grade lesions on the surgical excision specimen or during follow-up. p16INK4a expression positively and negatively predicted the presence of higher-grade lesions in 17.19% and 86.67% patients, respectively. Ki-67 expression positively and negatively predicted the presence of higher-grade lesions in 40% and 88.24% patients, respectively. CONCLUSIONS: Negative p16INK4a and Ki67 immunohistochemical staining can assure absence of a higher-grade lesion in more than 85% of patients with CIN2 biopsies and can be used to prevent overtreatment of these patients. Positive IHC staining for p16INK4a and Ki-67 did not predict CIN3 in patients with CIN2 biopsies.

An evaluation of p16(INK4a) expression in cervical intraepithelial neoplasia specimens, including women with HIV-1.

Although several studies have evaluated the role of p16(INK4a) as a diagnostic marker of cervical intraepithelial neoplasia (CIN) and its association with disease progression, studies regarding the role of p16(INK4a) in human immunodeficiency virus (HIV)-infected patients remain scarce. The present study was designed to determine the potential utility of p16(INK4a) as a diagnostic marker for CIN and invasive cervical cancer in HIV-positive and negative cervical specimens. An immunohistochemical analysis of p16(INK4a) was performed in 326 cervical tissue microarray specimens. Performance indicators were calculated and compared using receiving operating characteristics curve (ROC)/area under the curve. In HIV-1-negative women, the percentage of cells that was positive for p16(INK4a) expression was significantly correlated with the severity of CIN (p < 0.0001). A ROC curve with a cut-off value of 55.28% resulted in a sensitivity of 89%, a specificity of 81%, a positive predictive value of 91% and a negative predictive value of 78%. HIV-seropositive women exhibited decreased expression of p16(INK4a) in CIN2-3 specimens compared with HIV-negative specimens (p = 0.031). The ROC data underscore the potential utility of p16(INK4a) under defined conditions as a diagnostic marker for CIN 2-3 staging and invasive cervical cancer. HIV-1 infection, however, is associated with relatively reduced p16(INK4a) expression in CIN 2-3.

Thromboembolic event as a prognostic factor for the survival of patients with stage IIIB cervical cancer.

OBJECTIVE: The purpose of this study was to evaluate the effect of thromboembolic event (TEE) on the prognosis and survival of women diagnosed with the International Federation of Gynecology and Obstetrics (FIGO) stage IIIB cervical cancer undergoing treatment at the National Cancer Institute (Instituto Nacional de Câncer [INCA], Ministério da Saúde), Brazil. METHODS: A total of 1020 women with FIGO stage IIIB cervical cancer (International Classification of Diseases, C53.9), who had received treatment at this institute between 2000 and 2004, were identified. Data were obtained from the hospital cancer registry at INCA. Patients were followed up from the date of their diagnosis of cervical cancer at INCA until their death or last follow-up visit. The date of TEE diagnosis was defined as the date of one of the following tests diagnosing this condition: Doppler ultrasound scan, computed tomography scan, or in 1 single case echocardiography. The Kaplan-Meyer method was used to perform long-term survival analysis. CONCLUSIONS: The presence of TEE in patients with FIGO stage IIIB cervical cancer seems to be indicative of the severity of the disease and poorer prognosis. The most important finding is that in the patients who developed TEE, this complication occurred around the time of diagnosis of progression of the disease. Disease progression may have been the triggering factor for the development of TEE.

A prognostic value of CD45RA+, CD45RO+, CCL20+ and CCR6+ expressing cells as 'immunoscore' to predict cervical cancer induced by HPV.

The interplay between cervical cancer (CC) and immune cells, mainly intratumoral lymphocytes, has a pivotal role in carcinogenesis. In this context, we evaluated the distribution of CD45RA+ and CD45RO+ cells as well as CCR6+ and CCL20+ cells in intraepithelial (IE) and marginal stroma (MS) areas from cervical intraepithelial neoplasia (CIN) I-III, and CC as 'immunoscore' for HPV-induced CC outcome. We observed increased CD45RA+ and CD45RO+ cells distribution in IE and MS areas in the CC group compared to CIN groups and healthy volunteers. Interestingly, there is a remarkable reduction of CCL20+ expressing cells distribution according to lesion severity. The CC group had a significant decrease in CCL20+ and CCR6+-expressing cells distribution in both IE and MS areas compared to all groups. Using the 'immunoscore' model, we observed an increased number of women presenting high CD45RA+/CD45RO+ and low CCL20+/CCR6+ 'immunoscore' in the CC group. Our results suggested a pattern in cervical inflammatory process with increasing CD45RA+/CD45RO+, and decreasing CCL20+/CCR6+ expression in accordance with CIN severity. Taken together, these markers could be evaluated as 'immunoscore' predictors to CC response. A more comprehensive analysis of longitudinal studies should be conducted to associate CD45RA+/CD45RO+ and CCL20+/CCR6+ 'immunoscore' to CC progression and validate its value as a prognosis method.

Accuracy of endocervical cytological tests in diagnosing preinvasive lesions of the cervical canal in patients with type 3 transformation zone: a retrospective observational study.

BACKGROUND: Cervical cancer screening in Brazil is done using Pap smears. Women who are most likely to have a preinvasive lesion or cervical cancer are immediately referred for colposcopy. OBJECTIVE: The aim of this study was to evaluate the diagnostic performance of endocervical cytological tests in diagnosing preinvasive cervical lesions in women with initial high-grade squamous intraepithelial lesions (HSIL), or atypical squamous cells in which high-grade lesions could not be ruled out (ASC-H), or atypical glandular cells (AGC), and whose colposcopy did not show any abnormalities, with no fully visible transformation zone (types 2 and 3). DESIGN AND SETTING: Retrospective observational study conducted in Rio de Janeiro, Brazil. METHODS: Data from women who came to the cervical pathology outpatient clinic between January 2012 and April 2017 were analyzed. The results from endocervical cytological tests were compared with the final diagnosis, which was obtained through examination of a surgical specimen or, among women who did not undergo an excisional procedure, after cytological and colposcopic follow-up for two years. RESULTS: We included 78 women. The sensitivity of endocervical cytological tests was 72.7%; specificity 98.5%; positive and negative predictive values 88.9% and 95.6%, respectively; and positive and negative likelihood ratios 48.7 and 0.28. CONCLUSION: Endocervical cytological tests are simple, inexpensive and noninvasive, and form a reliable method for determining management among patients with HSIL, ASC-H and AGC cytological findings and negative colposcopic findings without visualization of the squamocolumnar junction.

[Parameters for programming line of care procedures for cervical cancer in Brazil]. / Parâmetros para a programação de procedimentos da linha de cuidado do câncer do colo do útero no Brasil.

The study estimated parameters for planning and programming the supply of procedures for screening, diagnostic workup, and treatment of precursor lesions of uterine cervical cancer. These estimates were used as the basis for assessing the adequacy of Brazil's production of procedures performed by the Brazilian Unified National Health System (SUS) in 2017. Estimates were calculated using as the reference the recommended management in the national screening guidelines. Data on screening tests were obtained from the Information System on Uterine Cervical Cancer and the follow-up data from patient charts in a referral center for cervical pathology. Brazil's production of procedures was obtained from data in the Outpatient and Hospital Information Systems of the SUS. For every one hundred thousand women in the target age bracket for screening (25 to 64 years) there was an estimated annual need for 44,134 cytopathology tests, 1,886 colposcopies, 275 biopsies, 236 type 1 and 2 outpatient exicision procedures, 236 type 2 and 3 hospital exicision procedures, and 39 high-complexity referrals for surgery, chemotherapy, and/or radiotherapy. Applying the estimated parameters to the number of women screened in Brazil in 2017, a deficit was identified in all the procedures for adequate follow-up of the women with altered test results, varying from 7% in colposcopies to 74% in type 3 excisions. The results point to the need to expand and upgrade the supply of line of care procedures for cervical cancer. The estimated parameters can support policymakers in programming and implementing organized screening programs.

Estimaram-se parâmetros para planejamento e programação da oferta de procedimentos para rastreamento, investigação diagnóstica e tratamento de lesões precursoras do câncer do colo do útero e, com base nessas estimativas, avaliou-se a adequação da produção nacional dos procedimentos realizados pelo Sistema Único de Saúde (SUS) em 2017. As estimativas foram calculadas utilizando como referencial as condutas preconizadas nas diretrizes nacionais para o rastreamento. Os dados referentes aos exames de rastreamento foram obtidos no Sistema de Informação do Câncer do Colo do Útero, e os dados de seguimento, em prontuários médicos de uma unidade de referência em patologia cervical. A produção nacional dos procedimentos foi obtida a partir de dados dos Sistemas de Informações Ambulatoriais e Hospitalares do SUS. Para cada cem mil mulheres na faixa etária alvo do rastreamento (25-64 anos), estimou-se a necessidade anual de 44.134 exames citopatológicos, 1.886 colposcopias, 275 biópsias, 236 excisões tipo 1 e 2 ambulatoriais, 236 excisões tipo 2 e 3 hospitalares e 39 encaminhamentos para alta complexidade para realização de cirurgia, quimioterapia e/ou radioterapia. Aplicando-se os parâmetros estimados ao número de mulheres rastreadas no Brasil em 2017, identificou-se déficit de todos os procedimentos para o seguimento adequado das mulheres com alterações, variando de 7% nas colposcopias a 74% nas excisões tipo 3. Os resultados apontam necessidade de ampliar e qualificar a oferta de procedimentos da linha de cuidado do câncer do colo do útero. Os parâmetros estimados poderão subsidiar gestores na programação e implementação de programas de rastreamento organizado.

Se estimaron parámetros para la planificación y programación de la oferta de procedimientos, con el fin de detectar, realizar investigación diagnóstica y tratar lesiones precursoras del cáncer de cuello uterino. En base a las mismas, se evaluó la adecuación del protocolo nacional de procedimientos realizados por el Sistema Único de Salud (SUS) en 2017. Las estimaciones se calcularon utilizando como marco de referencia los procedimientos recomendados en las directrices nacionales para la detección de este tipo de cáncer. Los datos referentes a los exámenes de detección se obtuvieron en el Sistema de Información del Cáncer de Cuello de Útero, y los datos de seguimiento en registros médicos de una unidad de referencia en patología cervical. La producción nacional de los procedimientos se obtuvo a partir de datos de los sistemas de información ambulatoria y hospitalaria del SUS. De cada cien mil mujeres, en la franja de edad objetivo de la detección (25 a 64 años), se estimó una necesidad anual de 44.134 exámenes citopatológicos, 1.886 colposcopias, 275 biopsias, 236 escisiones tipo 1 y 2 ambulatorias, 236 escisiones tipo 2 y 3 hospitalarias y 39 derivaciones hacia centros hospitalarios de alta complejidad para la realización de cirugías, quimioterapia y/o radioterapia. Aplicando los parámetros estimados al número de mujeres a quienes se les realizó el examen en Brasil durante 2017, se identificó un déficit de todos los procedimientos para un seguimiento adecuado de las mujeres con alteraciones, variando de un 7% en las colposcopias, a un 74% en las escisiones tipo 3. Los resultados apuntan la necesidad de ampliar y dotar la oferta de procedimientos en la línea de cuidados del cáncer de cuello uterino. Los parámetros estimados podrán ayudar a los gestores en la programación e implementación de programas organizados de detección.

TNFR1 single nucleotide polymorphisms are not associated with cervical HPV-induced pre-malignant lesion but regulate in situ cervical TNFR1 expression.

TNF-α is involved in HPV infection control by triggering cell signaling through binding in specific receptors TNFR1 and TNFR2. Genetic polymorphisms in these receptors may influence TNF-α signaling. Herein, we investigated TNFR1 rs767455 and rs2234649 single nucleotide polymorphisms, and TNFR1 protein expression in cervical squamous intraepithelial lesions (SIL) to identify their role in cervical pre-malignant development. SIL patients (n = 179) and healthy volunteers (n = 227) were enrolled for TNFR1 genotyping analysis by PCR-RFLP in blood samples and TNFR1 protein expression in cervical tissue by immunohistochemistry. No statistical differences regard genotypes and allelic frequencies for both polymorphisms were observed. Cervical TNFR1-expressing cells were rare in epithelium and basal layer regardless the groups. However, a progressive increase in infiltrating cells was observed in the stromal area, mainly in high SIL (HSIL) group compared to low SIL (LSIL, p < 0.001) and control (p < 0.001) groups. TNFR1-expressing cells frequency was higher in TNFR1 rs767455AG/GG (p < 0.001), and in rs2234649AA (p < 0.001) genotypes carries in HSIL subgroup. These data indicated that TNFR1-expression is abrogated in cervical epithelium, where HPV-induced pre-malignant lesion occurs, increasing its frequency in inflammatory cells in stroma, and is genetically controlled by TNFR1 rs767455AG/GG and rs234649AA genotypes. These biomarkers may be useful to identify cervical precancerous lesions progression.

Cervical Intraepithelial Neoplasia grade 2 biopsy: Do p16INK4a and Ki-67 biomarkers contribute to the decision to treat? A cross-sectional study

ABSTRACT BACKGROUND: Managing cervical intraepithelial neoplasia grade 2 (CIN2) is challenging, considering the CIN2 regression rate, perinatal risks associated with excisional procedures, and insufficient well-established risk factors to predict progression. OBJECTIVES: To determine the ability of p16INK4a and Ki-67 staining in biopsies diagnosed with CIN2 to identify patients with higher-grade lesions (CIN3 or carcinoma). DESIGN AND SETTING: Cross-sectional study conducted at a referral center for treating uterine cervical lesions. METHODS: In 79 women, we analyzed the correlation of p16INK4a and Ki-67 expression in CIN2 biopsies with the presence of a higher-grade lesions, as determined via histopathology in surgical specimens from treated women or via two colposcopies and two cytological tests during follow-up for untreated women with at least a 6-month interval. The expression of these two biomarkers was verified by at least two independent pathologists and quantified using digital algorithms. RESULTS: Thirteen (16.8%) women with CIN2 biopsy exhibited higher-grade lesions on the surgical excision specimen or during follow-up. p16INK4a expression positively and negatively predicted the presence of higher-grade lesions in 17.19% and 86.67% patients, respectively. Ki-67 expression positively and negatively predicted the presence of higher-grade lesions in 40% and 88.24% patients, respectively. CONCLUSIONS: Negative p16INK4a and Ki67 immunohistochemical staining can assure absence of a higher-grade lesion in more than 85% of patients with CIN2 biopsies and can be used to prevent overtreatment of these patients. Positive IHC staining for p16INK4a and Ki-67 did not predict CIN3 in patients with CIN2 biopsies.