HPV prevalence and genotyping in the cervix of Chinese women

Abstract

The role of human papillomavirus (HPV) as an etiologic factor of cervical cancer has been firmly established, and prophylactic vaccines are now available and have been approved in many countries. Vaccination implies a promising future for cervical cancer prevention especially for countries with very limited access to screening. However, the vaccines are not accessible in mainland China at the moment, and much needs to be understood about the potential benefit when HPV vaccines are applied to Chinese women, and to make the vaccines more specific to Chinese women. This article reviews advanced multi-center, hospital/population-based studies of most recent years, and aims to draw a definitive conclusion on HPV prevalence and genotyping in cervical cancer and precancerous lesions in China from the aspect of study population, geographic areas and time period.

Keywords

human papillomavirus (HPV) genotyping / cervical cancer / precancerous lesions / Chinese women

HPV infection in different populations

Human papillomavirus (HPV) prevalence and genotype distribution in the general population

In a rural high risk population (Xiangyuan County, Shanxi Province, China), the HPV prevalence was 20.8% among women aged 35-50 years and 26.3% in an expanded age group (30-50 years) by using Hybrid Capture® 2 (HC2) (Qiagen Gaithersburg, Inc., USA) [1]. This rate was higher (29.6%) in a neighbouring county called Yangcheng in Shanxi Province [2]. A large scale, multi-center study that involved both rural and metropolitan populations evaluated the type-distribution of HPV infection in women aged 15-59 years [3-5]. In this study, a general primer (GP) 5+/6+ mediated polymerase chain reaction assay (PCR) was used to detect a broad spectrum of HPV DNA from exfoliated cell samples. The overall HPV prevalence was 15.2%, ranging from 14.8% (Yangcheng County, Shanxi Province, Rural) to 16.8% (Shenyang City, Liaoning Province, Metropolitan) and 18.4% (Shenzhen City, Guangdong Province, Metropolitan). In two metropolitan populations, HPV infection peaked at the age group older than 45 years, while it peaked at the 35-44 year old age group in the rural population. HPV typing was also performed by reverse line blot hybridization of PCR products and the result is summarized in Table 1. The predominant HPV types are HPV16 (3.7%), HPV58 (2.1%), HPV52 (1.9%), HPV18 (1.1%) and HPV39 (1.1%). A pooled analysis of several cross-sectional studies from 1998 to 2008 also found a similar prevalence of 14.51%, indicating a heavy burden of HPV infection in China [6].

HPV prevalence and genotype distribution in cytologically confirmed abnormal samples

HPV distribution in cytologically confirmed abnormal samples was also investigated. It was found that the overall HPV prevalence was 88.5% in high-grade squamous intraepithelial lesions (HSIL) and 69.3% in low-grade squamous intraepithelial lesions (LSIL). HPV16, 58, 52, and 18 were the predominant types in both HSIL and LSIL with HPV16 (46.7%), HPV58 (16.2%), HPV52 (13.7%), and HPV18 (12.4%) in HSIL and HPV16 (21.0%), HPV58 (18.9%), HPV52 (12.1%) and HPV18 (11.3%) in LSIL. HPV16/18 prevalence in HSIL and LSIL was 59.1% and 32.3%, respectively [7].

HPV prevalence and genotype distribution in histologically confirmed abnormal tissues

A hospital based study on 34 paraffin-embedded blocks of cervical cancer cases, in which type-specific HPV16/18 primers or GP5+/6+ consensus primers or β-globin primers were used to conduct HPV genotyping, reported that the HPV positive rate for invasive cervical cancer (ICC) was 88%, with type 16 accounting for 62% (21/34) and type 18 for 9% (3/34). HPV prevalence was 95% in 22 squamous cervical cancers (SCC) and 16 of them were infected with HPV16. Among 9 adenocarcinoma (ADC) cases, 67% (6/9) were HPV positive, 2 were HPV16 specific, 2 were HPV18 positive, 1 was positive for HPV45 and the rest were infected by un-typed HPV(s) [8]. Another hospital-based study that included 223 SCC tissue samples and in which HPV detection and typing were confirmed by the general primer PCR and sequence-based typing (PCR-SBT) method indicated a 92.8% HPV positive rate, with HPV16 as the dominant genotype (70.4%) [9]. There was also a hospital-based case-control study using MY09/11 and GP5+/6+ for HPV detection and it was found that the HPV prevalence was 68.8% in cervical intraepithelial neoplasia (CIN)1, 80.3% in CIN2, 90.2% in CIN3, 90.9% in cervical cancer in situ, and 89.9% in invasive cervical cancer (ICC). The most common HPV DNA types found in patients with cervical cancer were HPV16 (79.6%), followed by HPV58 (5.92%), HPV33 (3.29%), HPV18 (1.97%), and HPV6 (1.97%) [10]. Recently, a study in the Xinjiang Uygur Autonomous Region using flow-through hybridization and gene chip technology reported that from 100 paraffin-embedded biopsy ADC specimens, HPV prevalence was 61.0% and HPV16, 18 and 68 were the dominant genotypes [11]. Lo et al. reported an overall of 83.7% HPV prevalence in a multi-center study using MY09/11 consensus primers for DNA detection, and found that the HPV prevalence in SCC was 85.2% (623/731) and that in ADC it was 71.6% (53/74). For SCC, the predominant HPV types were HPV16 (81.0%), HPV18 (5.5%), HPV58 (4.0%), and HPV52 (2.6%); for ADC, the most common HPV types were HPV16 (64.2%), HPV18 (28.3%), HPV52 (3.8%), and HPV58 (1.9%) [12]. Most recently, a large scale, multi-center hospital-based study was conducted. This study included 1233 CIN2+ paraffin-embedded biopsy specimens from mainland China and used the highly sensitive SPF 10 LiPA25 for HPV DNA detection [13]. It suggested that HPV prevalence was 97.6% in SCC, 85.3% in ADC; HPV16 (76.7%) and HPV18 (8.0%) were most common types in SCC, followed by HPV31, HPV52, and HPV58. This could draw a definitive conclusion on HPV genotyping of squamous cervical cancer in China.

On the other hand, a population-based case-control study in Shanxi (n = 1997) found an overall HPV prevalence of 97.7% in cervical lesions (HC2) and 100% in CIN3 and cervical cancer, 95.3% in CIN2, 61.4% in CIN1 [1]. Another multi-center study also found that the overall HPV prevalence of women with cervical lesions was 76.4%, and HPV16, HPV58, HPV52, HPV18 and HPV56 were the predominant HPV types in abnormal cervical tissues [3-5]. An HPV prevalence study by HC2s conducted in Shanxi indicated that of 47 women with≥CIN2, HPV was positive in 97.9% (46/47) of them, while it was only 9.8% (253/2578) in 2578 women with≤CIN2 [14]. A meta-analysis synthesized the results of different DNA detection methods (MY09/11, GP5+/6+, TS-only, etc.) and found that the overall HPV prevalence was 82.7% in ICC, and HPV16 and HPV18 were the most common types in ICC, followed by HPV58, HPV52, and HPV31 [7].

HPV infections in different geographic areas of China

Many studies have been conducted to explore HPV type distribution in China in recent years, and the results have varied across geographies. In this paper, we define China into seven distinct geographic regions: Northeast, North, Northwest, Central, Southwest, South, and East China; data will be discussed based on the defined regions.

Northeast China

A study conducted in Shenyang, Liaoning Province, found that the overall HPV prevalence was 16.8% among women aged 15-59, and 13.6% for those without cervical abnormalities. Using GP5+/6+-based PCR assay for HPV DNA detection, HPV16 was the most common type (3.4%), followed by HPV52 (2.5%) and HPV58 (1.9%) [5].

North China

A cross-sectional study in Inner Mongolia from 2001 to 2003 reported an 80% of HPV prevalence among cervical cancers. Using MY09/11 for HPV DNA detection, the predominant HPV types in SCC were HPV16 and 18, with a prevalence of 63.4% and 5.6%, while in ADC, prevalence of HPV16 and 18 was 25% and 75%, respectively [15].

Northwest China

A study conducted in Xinjiang showed a total HPV prevalence of 61.0% in ADC, 60.0% in Han women and 63.3% in Uygurs women. Generally, HPV16, 18, and 68 were the three most important types in HPV positive ADC tissues, with respective rates of 90.4%, 23.8% and 4.7% in the Han and 89.5%, 21.0% and 10.5% in the Uygurs [11].

Central China

High risk areas mainly distribute in central China. A study conducted in the Xiangyuan and Yangcheng counties of Shanxi Province found that HPV prevalence among the general population was 27.5% [2]. Another study that included Xiangyuan county alone found an HPV prevalence of 20.8% among women of 35-45 years old. When different pathology types were considered, HPV prevalence was 14.2% in normal tissues, 61.4% in CIN1, 95.3% in CIN2, and 100% in CIN3 and cancer [1]. A case-control study conducted in Jiangxi from 2000 to 2004 using MY09/11 and GP5+/6+ primers for HPV detection found that HPV prevalence was 68.8% in CIN1, 80.3% in CIN2, 90.2% in CIN3, 90.9% in cervical cancer in situ, and 89.9% in ICC. The most common HPV types in patients with cervical cancer were HPV16 (79.6%), followed by HPV58 (5.92%), HPV33 (3.29%), HPV18 (1.97%), and HPV6 (1.97%) [10].

Southwest China

A study in Sichuan from 2004 to 2006 found that the overall HPV prevalence was 93.2% among 17-71 year old women. When MY09/11 PCR, one-step type-specific primers PCR (TS PCR) and nested TS PCR were used for HPV DNA detection, HPV prevalence became 83.7%, 76.3% and 90.5%, respectively. The positive rate for HPV16, 18, 52, 58, and 59 detected by one-step TS PCR was 58.4%, 7.4%, 3.2%, 6.8%, and 2.1%. When nested TS PCR analysis was used, the detection rates of HPV16, 52, 58, and 59 were increased to 73.7%, 15.8%, 19.5% and 13.2% respectively, while only 2.1% additional specimens were found to be infected with HPV18 [16].

East China

An HPV prevalence study in Shanghai from 2005 to 2006 found that HPV prevalence was 29.1% by HC2 detection, with 68.8% in CIN1, 66.7% in CIN2, 76.5% in CIN3, and 94.1% in cervical cancer [17]. Using MY09/11 primers for HPV detection, another hospital-based study in Zhejiang from 2004 to 2005 reported an overall prevalence of 85.8% in tissues of carcinoma and intraepithelial neoplasia and that of 66.7% in CIN1, 89.9% in CIN2/3, and 98.3% in cervical cancer. The predominant HPV types were HPV16 (45.6%), HPV58 (12.1%), HPV52 (6.3%), HPV33 (4.2%), and HPV18 (1.7%) [18].

South China

An HPV prevalence survey conducted in Shenzhen in 2004 using GP5+/6+ PCR-based assay for DNA detection found an overall HPV prevalence of 18.4% among the general population. The most common HPV types were HPV16, 52, 58, 31 and 39 [4]. Another study in Hong Kong from 1997 to 2007 found that HPV16 was the most common type (61.2%) among SCC cases diagnosed over the past 10 years, followed by HPV18 (17.7%), 52 (14.7%) and 58 (9.9%), whereas HPV18 (56.3%) and HPV16 (50.0%) were the dominant types in adeno/adenosquamous cell carcinoma [19].

In order to draw a definitive conclusion on HPV distribution in cervical cancer in Chinese women, from 2004 to 2006, The Cancer Institute & Hospital, Chinese Academy of Medical Sciences (CICAMS) conducted a multi-center hospital-based study with standard quality control for lab assays. A highly sensitive SPF 10 LiPA25 for HPV DNA detection was used in this study. HPV16/18 were the most important types in SCC in Chinese women and this does not differ significantly across the regions [13]. HPV prevalence and type-distribution by regions is shown in Table 2.

HPV infections in different time periods

HPV type distribution in cervical cancer and its potential variability over time are key issues that influence the cost-effectiveness of HPV vaccines. A meta-analysis summarized the HPV prevalence of different time periods. It indicated an increasing trend of HPV prevalence over time. Among ICC, HPV prevalence was 64.3% before 2000, became 85.0% from 2000 to 2003, and increased to 86.7% from 2004 to 2006 [7]. However, the great improvement in laboratory methods could be the main reason for the increase in the prevalence. The recent multi-center study mentioned above also found that the HPV prevalence was 97.6% in SCC and 85.3% in ADC, by using highly sensitive SPF 10 LiPA25 for HPV DNA detection [13].

Further study

Based on studies mentioned above, definitive conclusions could be drawn for HPV infection in CIN and SCC. However, data on HPV type-distribution are currently not available in ADC biopsy specimens and only a few studies have analyzed and compared the distribution of HPV genotypes in cervical adenocarcinoma in situ and invasive adenocarcinoma.

The contradictory results call for a large scale type-distribution study in ADC using highly sensitive, state-of-the-art PCR methods in China. Reliable data on HPV genotype spectrum in cervical adenocarcinoma is essential for the assessment of the potential benefit of the vaccines and the comparisons of HPV type-distribution in ADC across geographical areas in China and other parts of the world.

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