Original article
Cervical intraepithelial neoplasia grade 2 or worse in Galicia, Spain: HPV 16 prevalence and vaccination impactNeoplasia intraepitelial cervical de grado 2 o peor en Galicia (España): prevalencia de HPV 16 e impacto vacunal

https://doi.org/10.1016/j.eimc.2013.09.011Get rights and content

Abstract

Introduction

The etiology of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) can influence the efficacy of Public Health preventive strategies. This study aimed to determine the high-risk papillomavirus (HR-HPV) prevalence in CIN2+ cases in unvaccinated women in Galicia (Spain), the expected impact of bivalent vaccination, and the distribution of HPV 16 in squamous lesions.

Material and methods

Ninety-four histologically confirmed cases of CIN2+ (2009–2010) were retrospectively studied: 23 CIN2, 58 CIN3− squamous carcinoma in situ (CIN3-CIS), 5 adenocarcinoma in situ (AIS), and 8 invasive squamous cervical cancer (SCC). Linear Array HPV Genotyping Test (Roche Diagnostics, Mannheim, Germany) was performed on the cervical specimens. Bivalent vaccination impact was calculated, based on regional vaccination coverage data, local HR-HPV prevalence, and reported efficacy (direct and cross-protection) of the vaccine.

Results

HR-HPV prevalence was 96.8%. The most frequent genotypes were HPV 16 (48.8–58.2%) and HPV 31 (9.3%–12.1%), considering single infections or single-multiple infections, respectively (hierarchical attribution). In squamous lesions, HPV 16 prevalence in women younger than 45 years of age increased in severe lesions (CIN3-CIS/SCC, OR 4.2), and was higher than in older women (OR 5.5). The vaccine could reduce the cumulative incidence of CIN2+ by 50.6% (direct protection), or by 62.7% (direct and cross-protection).

Conclusion

HPV vaccination could have a great impact in women younger than 45 years of age due to the high prevalence of HPV 16 in their lesions.

Resumen

Introducción

La etiología de la neoplasia intraepitelial cervical de grado 2 o peor (CIN2+) influirá en la eficacia de las estrategias preventivas de Salud Pública. Se pretende conocer la prevalencia de papilomavirus de alto riesgo (VPH-AR) en CIN2+ en mujeres no vacunadas en Galicia (España), el impacto esperado de la vacunación bivalente y la distribución del VPH 16 en lesiones escamosas.

Material y métodos

Se estudiaron retrospectivamente 94 casos confirmados histológicamente de CIN2+ (2009-2010): 23 CIN2, 58 CIN3− carcinoma escamoso in situ (CIN3-CIS), 5 adenocarcinoma in situ (AIS) y 8 carcinoma escamoso invasivo (CES). Se utilizó Linear Array VPH Genotyping Test (Roche Diagnostics, Mannheim, Alemania) en muestras cervicales. El impacto de la vacunación se calculó según la cobertura vacunal autonómica, la prevalencia local de VPH-AR y datos publicados de eficacia (protección directa y cruzada).

Resultados

La prevalencia de VPH-AR fue del 96,8%. Los genotipos más frecuentes fueron HPV 16 (48,8-58,2%) y HPV 31 (9,3-12,1%) considerando infecciones simples o infecciones simples-múltiples, respectivamente (atribución jerárquica). En lesiones escamosas, la prevalencia de VPH 16 en mujeres de hasta 45 años aumentó con la severidad de las lesiones (CIN3-CIS/CES; OR 4,2) y fue mayor que en las mujeres mayores (OR 5,5). La vacuna podría reducir la incidencia acumulada de CIN2+ un 50,6% (protección directa) o un 62,7% (protección directa y cruzada).

Conclusión

La vacunación frente al VPH podría tener un gran impacto en mujeres menores de 45 años debido a la alta prevalencia de VPH 16 en las lesiones que presentan.

Introduction

The knowledge of a 99.7% worldwide HPV prevalence in cervical carcinomas1 and the fact that persistence of a high risk human papillomavirus (HR-HPV) infection is essential for the development, maintenance and progression of high-grade cervical intraepithelial neoplasia (CIN)2, 3 have changed cervical cancer prevention. Several longitudinal, randomized-controlled trials4, 5, 6 have demonstrated improved prevention of high-grade CIN and cervical cancer with the introduction of HPV testing in cervical screening. In the particular case of Galicia (Spain), an organized cervical cancer screening protocol was introduced by Galician Public Health Service in 2008 according to European and National recommendations (www.sergas.es). In brief, it was a Pap-based screening program. In case of detection of low-grade or high-grade cytological alterations women were referred to colposcopy. The HPV DNA testing was used as a triage test for colposcopy referral in case of atypical squamous cells of undetermined significance (ASC-US) in women older than 25 years of age.

Two HPV vaccines, namely Merck’ Gardasil® and GSK’ Cervarix®, approved by Federal Drug Administration (FDA) in 2006–2007 protect against acquisition of infections with oncogenic HPV types 16 and 18 and their lesions,7, 8 which are responsible for about 70% of all cervical cancers.9 In September of 2008, free vaccination of girls aged 14 years against HPV 16 and 18 with the bivalent vaccine was introduced in Galicia (Spain). The impact of the vaccination on cervical cancer incidence is expected to take several decades to manifest itself.

The implementation of any new intervention requires surveillance in the general population to measure its efficacy. To provide a baseline HPV-type specific prevalence in precancerous and cancerous cervical lesions is essential for future comparisons in order to evaluate the impact of screening protocols and vaccination in cervical cancer prevention.

In this way, a retrospective study was performed in order to know the HPV prevalence in histologically confirmed cases of moderate-grade CIN or worse (CIN2+) which were detected in Galicia, Spain, prior to widespread HPV vaccination, the expected impact of bivalent vaccination in these cervical lesions and the distribution of HPV 16 in squamous lesions.

Section snippets

Patients, ethical statement and epidemiological data

We conducted a retrospective study including consecutive cases of CIN2+ diagnosed during 2009–2010 in women attending the Gynecological Unit of Meixoeiro Hospital (University Hospital of Vigo, Galicia, Spain) for cervical cancer screening. Women had not been vaccinated with any HPV vaccine at time of diagnosis. Ninety-four women agreed to be enrolled.

This study received approval from the ethics committee of clinical investigation of Galicia (Santiago de Compostela, Spain). All study

Results

A total of 94 women between 18 and 82 years of age at CIN2+ diagnosis time (mean age 37.5 years. 95% CI, 35.1–39.8) were included in this study. Histological diagnoses were: CIN2 (n = 23), CIN3-CIS (n = 58), AIS (n = 5) and SCC (n = 8). Presence of HR-HPV was detected in 91/94 (96.8%) CIN2+ cases: 43 (47%) single infections and 48 (53%) multiple infections. Type-specific prevalence is shown in Table 2. HPV 16 and 31 were the most frequent genotypes in single and multiple infections. Genotypes other

Discussion

This study provides data for the local distribution of HPV genotypes among unvaccinated women with CIN2+ in Galicia, Spain. This knowledge could be useful for future evaluations of the impact of the bivalent vaccination that was introduced recently, allow identification of local problems of primary or secondary prophylaxis, of HPV transmission and special needs of Public Health Service interventions.

The data confirmed that HPV 16 is found in the majority of cervical dysplasia, especially in

Conclusions

Although HPV 16 is the most frequent genotype in CIN2+, other genotypes not included in the vaccine like HPV 31, 33, 35, 45, 51, 52, 56 and 58 are also common, suggesting that the development of new vaccines against a higher number of genotypes is important. HPV vaccination could have a great impact in women younger than 45 years of age because of the high prevalence of HPV 16 in their lesions. Presence of multiple high-risk genotypes in CIN2+ might influence the vaccination impact.

Funding

This work was supported by Conselleria de Sanidade, Galicia, Spain.

Conflict of interest

The authors declare no conflict of interest.

Acknowledgements

We thank Malvar A (Department of Epidemiology, Galician Public Health Service, Spain) for critical review of the manuscript. We thank Biomedical Foundation of the University Hospital of Vigo, Spain for the statistical analysis and the English revision of the manuscript. We are also grateful to Taboada P (Peixe Software, SLNE, Spain) for the online software donation for data collection.

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