High-Grade Cervical Intraepithelial Neoplasia: Impact of Colposcopic Lesion Area on Systemic Immune Responses

Priscila Thaís Silva Mantoani,1,2 Douglas Côbo Micheli,2 Millena Prata Jammal,2 Julia Hailer Vieira,3 Márcia Antoniazi Michelin,3 Caroline Gabriela Xavier Ferreira,2 Henrique Nascimento Silva,2 Eddie Fernando Candido Murta,2 Rosekeila Simões Nomelini1,2 1Graduate Program in Gynecology and Obstetrics of the Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP), Ribeirão Preto, SP, Brazil; 2Laboratory of Applied Sciences for Women (LaCam)/Department of Gynecology and Obstetrics; Federal University of Triângulo Mineiro, Uberaba, MG, Brazil; 3Research Institute of Oncology (IPON); Discipline of Immunology; Federal University of Triângulo Mineiro, Uberaba, MG, BrazilCorrespondence: Rosekeila Simões Nomelini, Laboratory of Applied Sciences for Women (LaCam)/Department of Gynecology and Obstetrics, UFTM, Av. Getúlio Guaritá, s/n, Bairro Abadia, Uberaba, MG, 38025-440, Brazil, Tel +55 34 3318 5326, Fax +55 34 3318 5342, Email [email protected]: The progression of high-grade cervical intraepithelial neoplasia (CIN) and cervical cancer is accompanied by a reduction in the immune response. The objectives of the study were to determine whether colposcopic lesion area is associated with serum levels of cytokines IL (interleukin) − 1, IL-6, IL-8, IL-10, IL-12 and TNF-α in precursor lesions of cervical cancer.Methods: The study population comprised patients with high-grade squamous intraepithelial lesion who had undergone colposcopy, cervical biopsy, and measurements of serum cytokines by ELISA (Enzyme-Linked Immunosorbent Assay). Genotyping for HPV (human papillomavirus) 16, 18, 45 and 52 was performed by PCR (Polymerase Chain Reaction). ROC (Receiver Operating Characteristic) curves were calculated to determine whether there existed a cut-off value for serum cytokines in patients with colposcopic lesion area smaller vs larger than 1 cm2. For cytokines with significant results, these cut-off values were used to perform the multivariable analysis.Results: There were 71 patients with CIN 2/3. ROC curves were calculated to verify a cut-off value for serum cytokine levels that could be used to distinguish between lesion areas 13.3 pg/mL and IL-12 ≤ 349.6 pg/mL. In the multivariable analysis, the independent variables associated with colposcopic lesion area greater than 1cm2 were IL-1> 13.3 pg/mL and IL-12 ≤ 349.6 pg/mL [OR (95% CI) = 10.10 (1.50– 67.96); OR (95% CI)=10.70 (1.17– 97.45), respectively].Conclusion: Although CIN 2/3 is a local uterine cervix lesion, there is a systemic immunological response. Our results are unprecedented and could be the target of new important studies in public health and cervical cancer prevention.Keywords: uterine cervical dysplasia, cytokines, uterine cervical neoplasm

Prevention of cervical cancer in women with ASCUS in the Brazilian Unified National Health System: cost-effectiveness of the molecular biology method for HPV detection Prevenção de câncer de colo uterino em pacientes com ASCUS no Sistema Único de Saúde: custo-efetividade de método de biologia molecular para HPV

This study aimed to assess the performance of PCR as a means of detecting HPV 16/18 compared to the single probe-based PCR for detecting high-risk HPV, and evaluate these methods for detecting cervical intraepithelial neoplasia (CIN) in follow-ups for ASCUS testing. It also compares the costs of cytology, PCR methods, colposcopy and biopsy in the Brazilian Unified National Health System. Of the 81 patients with ASCUS, 41 (50.6%) tested positive for HPV 16/18 in PCR testing and 47 (58.02%) tested positive for high-risk HPV with single probe-based PCR testing. The negative predictive value was 93.75% for HPV 16/18 PCR and 100% for single probe-based PCR in cases that progressed to high-grade CIN. The annual costs of patient referral were the following: R$2,144.52 for referral of patients with ASCUS cytology for colposcopy; R$6,307.44 for referral of patients with ASCUS cytology and PCR positive for HPV 16/18 or colposcopy; R$3,691.80 for referral of patients with ASCUS cytology with single probe-based PCR positive for high-risk HPV. Therefore, cost per user can be reduced by performing single probe-based PCR for high-risk HPV on patients with ASCUS.<br>Os objetivos deste estudo foram avaliar o desempenho do PCR para detecção de HPV 16/18 versus PCR sonda única para a detecção de HPV de alto risco, avaliar estes métodos na detecção de neoplasia intraepitelial cervical (NIC) no seguimento de ASCUS, e comparar os custos de citologia, métodos de PCR, colposcopia e biópsia no Sistema Único de Saúde. Das 81 pacientes com ASCUS, 41 (50,6$2.144,52, R$6.307,44 e R$3.691,80, respectivamente. Considerando eventual redução dos custos para utilização em grandes quantidades, este método poderia ser realizado em ASCUS