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.

Human Papillomavirus 16 Lineage D is Associated with High Risk of Cervical Cancer in the Brazilian Northeast Region / Papillomavirus humano 16 da linhagem D associado a alto risco de câncer de colo do útero em região do nordeste brasileiro

Abstract Objective Similar to Human Papillomavirus (HPV) genotypes, different lineages of a genotype also have different carcinogenic capabilities. Studies have shown that specific genotype lineages of oncogenic HPV are associated with variable risks for the development of cervical intraepithelial neoplasia (CIN2/CIN3) and cervical cancer. The present study aimed to analyze the genetic diversity of the HPV16 genotype in women with CIN2/CIN3 and cervical cancer, from the northeast region of Brazil. Methods A cross-sectional multicenter study was conducted in the northeast region of Brazil, from 2014 to 2016. This study included 196 cases of HPV16 variants (59 and 137 cases of CIN2/CIN3 and cervical cancer, respectively). The difference of proportion test was used to compare patients with CIN2/CIN3 and cervical cancer, based on the prevalent HPV16 lineage (p < 0.05). Results According to the histopathological diagnosis, the percentage of lineage frequencies revealed a marginal difference in the prevalence of lineage A in CIN2/CIN3, compared with that in cervical cancer (p = 0.053). For lineage D, the proportion was higher in cancer cases (32.8%), than in CIN2/CIN3 cases (16.9%), with p = 0.023. Conclusion HPV16 lineage A was the most frequent lineage in both CIN2/CIN3 and cervical cancer samples, while lineage D was predominant in cervical cancer, suggesting a possible association between HPV16 lineage D and cervical cancer.

Resumo Objetivo Tanto os tipos quanto as linhagens do Papilomavírus Humano (HPV) parecem ter diferentes capacidades carcinogênicas e estão associados a riscos variados para o desenvolvimento de neoplasia intraepitelial cervical (NIC) e câncer de colo do útero. O presente estudo tem como objetivo analisar a diversidade genética do genótipo HPV 16 nos casos de NIC2/NIC3 e câncer de colo de útero em mulheres da região Nordeste do Brasil. Métodos Estudo transversal de base hospitalar realizado na região Nordeste do Brasil no período de 2014 a 2016. A amostra foi composta por 196 casos da variante HPV-16 (59 casos de NIC2/NIC3 e 137 de câncer do colo do útero). O teste de diferença de proporção foi usado para comparar os grupos NIC2/NIC3 e câncer de colo do útero por linhagem viral em relação à prevalência da linhagem HPV-16. Foi considerada significância estatística o valor de p < 0,05. Resultados As frequências de linhagem por diagnóstico histopatológico mostraram diferença limítrofe da linhagem A no grupo NIC2/NIC3 em relação ao grupo câncer de colo de útero (p = 0,053). Por outro lado, em relação à linhagem D, houve uma proporção maior nos casos de câncer (32,8%) quando comparado ao grupo NIC2/NIC3 (16,9%) e esta diferença se mostrou estatisticamente significante (p = 0,023). Conclusão A linhagem A do HPV-16 foi a mais frequente tanto nas amostras CIN2/CIN3 quanto nas amostras de câncer de colo de útero, enquanto a linhagem D predominou no câncer de colo do útero, sugerindo uma possível associação da linhagem D de HPV-16 com câncer de colo de útero.

Progression of cervical intraepithelial neoplasia grade 2 lesions among Japanese women harboring different genotype categories of high-risk human papillomaviruses / Journal of Rural Medicine

Background: This study aimed to examine whether genotype categories of high-risk human papillomaviruses (HR-HPVs), when divided into HPV16/18, HPV 31/33/45/52/58, and HPV35/39/51/56/59/68, had an effect on the time required for and the proportion of cases that progressed to cervical intraepithelial neoplasia (CIN) grade 3 among women with CIN2.Patients: A total of 160 women aged 20–49 years and having CIN2 were recruited between January 2008 and June 2018. The time required for progression to CIN3 was determined by Kaplan-Meier time-to-event analysis. HPV genotypes were determined using the Linear Array HPV genotyping test.Results: During an average follow-up time of 22 months, 62 (39%) women with CIN2 progressed to CIN3, whereas 34 (21%) eliminated HR-HPVs and became cytologically normal. The majority (63%) of the women harboring HPV16/18 progressed to CIN3 with a 50% progression time of 11 months, whereas 26% of those harboring HPV31/33/45/52/58 progressed to CIN3 with a 50% progression time of 70 months.Conclusion: For every patient diagnosed with CIN2, genotyping to distinguish HPV16/18 from other HR-HPVs should be performed. Therefore, electing a surgical treatment, such as conization, should be considered as the primary option for women who are positive for HPV16/18, particularly when they are likely to be lost for follow-up or are 40 years old or older. In contrast, follow-up cytology should be repeated every 12 months for women harboring non-16/18 HR-HPVs. Those who tested negative for HR-HPV may be followed at the maximum interval of 24 months.

Follow-up after treatment of CIN2～3 / 基础医学与临床

Treatment of CIN2～3 includes cervical ablation,cervical local excision and hysterectomy,while cervical local excision is the standard procedure for CIN2～3.The recurrence rate was 0.7%～21% after surgery treatment of CIN2～3;The high risk factors of recurring are positive margin,serious lesion and age over 40.The follow-up items for postoperation involve cytology,colposcopy,ECC and HPV testing;If there were 2 LSIL or 1 HSIL for cytology,the patients should be given colposcopy examination and ECC.Retreatment must be clinically individual one.It is the same significance for follow-up and treatment of CIN2～3.