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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.

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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.

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A neoplasia intraepitelial cervical grau II (NIC II) é um estágio intermediário do desenvolvimento do câncer do colo do útero, que apesar de ser considerada uma lesão precursora do câncer apresenta altas taxas de regressão. As limitações inerentes ao diagnóstico histopatológico, principalmente nessa categoria diagnóstica, podem comprometer o manejo clínico adequado. A fim de melhorar a confiabilidade do diagnóstico da biópsia cervical, alguns biomarcadores estão sendo estudados, como o p16 e o Ki-67. Objetivo: compreender o significado da expressão de p16 e Ki-67 nas biópsias cervicais com diagnóstico de NIC II. Materiais e métodos: Foram analisadas 104 biópsias de colo uterino com diagnóstico original de NIC II, provenientes do Departamento de Anatomia Patológica e Citopatologia (DAPC) do Instituto Nacional de Saúde da Mulher, da Criança e do Adolescente Fernandes Figueira, da Fundação Oswaldo Cruz (IFF/Fiocruz) no período de janeiro de 2006 a dezembro de 2016 com diagnóstico de peça cirúrgica ou exames de seguimento clínico até um ano após o diagnóstico inicial de NIC II. A expressão dos biomarcadores p16 e Ki-67 foi avaliada qualitativamente por um grupo de patologistas experientes e quantitativamente pelo método de quantificação digital e comparadas com os resultados de padrão ouro. Resultados: Cento e quatro casos de biópsia de colo uterino com diagnóstico original de NIC II foram incluídos no estudo. A concordância interobservador na avaliação das biópsias na coloração de rotina e nas imunomarcações se manteve substancial, sendo a classificação dicotômica de p16 mais reprodutível do que a classificação histológica convencional. A avaliação qualitativa e quantitativa das marcações imuno-histoquímicas foram equivalentes. O status de p16 não apresentou relação com o diagnóstico de padrão ouro, mas apresentou alta sensibilidade e alto valor preditivo negativo para o diagnóstico de NIC III no padrão ouro. Em contrapartida, o status de Ki-67 apresentou associação com o padrão ouro e mostrou ser um biomarcador específico e com alto valor preditivo negativo para NIC II e alto valor preditivo positivo para NIC II ou mais grave. O uso da classificação dicotômica para p16 na rotina clínica causaria grande quantidade de sobretratamentos, enquanto que o uso do Ki-67 causaria subtratamento mais frequentemente. Conclusão: O biomarcador p16 não se apresentou como um bom preditor de lesão de maior gravidade no padrão ouro, causando mais casos de sobretratamento devido a sua alta sensibilidade. A aplicabilidade de Ki-67 para definição de conduta é limitada devido a sua baixa sensibilidade, apesar da alta especificidade e de sua associação com o padrão ouro, induzindo maior número de casos subtratados.

Cervical intraepithelial neoplasia grade II (CIN II) is an intermediate state of cervical cancer development, despite being considered a cancer precursor lesion that has high regression rates. The limitations inherent to histopathological diagnosis, especially in this diagnostic category, may compromise adequate clinical management. In order to improve the diagnostic reliability of cervical biopsy, some biomarkers are being studied, such as p16 and Ki-67. Objective: The aim of the study is to understand the significance of p16 and Ki-67 expression in cervical biopsies diagnosed with CIN II. Materials and methods: We analyzed 104 cervical biopsies with original diagnosis of CIN II from the Department of Pathological Anatomy and Cytopathology (DPAC) of the National Institute of Women, Child and Adolescent Health Fernandes Figueira, of the Oswaldo Cruz Foundation (IFF/Fiocruz), of the period from January 2006 to December 2016 with diagnosis of surgical specimen or clinical follow-up examinations until one year after the initial diagnosis of CIN II. The expression of the biomarkers p16 and Ki-67 was evaluated qualitatively by a group of experienced pathologists and quantitatively by the digital image analysis method. Results: One hundred and four cases of cervical biopsy diagnosed with CIN II were included in the study. Interobserver agreement of cervical biopsies evaluation in the routine staining and immunostaining remained substantial, with the dichotomous classification of p16 being more reproducible than conventional histological classification. The qualitative and quantitative evaluation of immunohistochemical staining was equivalent. The status of p16 was not related to the diagnosis of gold standard, but performed a high sensitivity. In contrast, Ki-67 status was associated with the gold standard and showed to be a specific biomarker. The use of dichotomous classification for p16 in the clinical routine could cause a large amount of overtreatment, whereas use of Ki-67 could cause undertreatment more frequently. Conclusion: The p16 biomarker did not perform to be a good predictor of greater severity in the gold standard, leading to overtreatment due to its high sensitivity. The applicability of Ki-67 to the definition of clinical conduct is limited due to its low sensitivity, despite the high specificity and its association with the gold standard, inducing a greater number of undertreated cases.

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