Cervical cancer is the second most common cancer in women worldwide, and 80% of cases occur in developing countries [1]. Certain types of human papillomavirus (HPV) are the principal cause of invasive cervical cancer and cervical intraepithelial neoplasia [1]. More than 80 HPV types have been identified and subdivided into low-risk types, which are found mainly in genital warts, and high-risk types, which are frequently associated with invasive cervical cancer [2,3,4]. Most HPV infections are self-limiting and spontaneously regress within 1 to 2 years as a result of cell-mediated immunity. In one study, two-thirds of adolescents infected with low-risk HPV types spontaneously cleared their infections by 12 months, as did over 50% of those infected with high-risk HPV types [5]. In another follow-up study of adolescents and young women with low-grade squamous intraepithelial lesion (LSIL), 91% of HPV-infected individuals cleared their infections after 36 months of follow-up and only 5% to 10% of HPV infections progressed to persistent infection [6]. Persistent infection with certain HPV genotypes is an important factor in the development of cervical cancer. HPV 16 and HPV 18 are the most prevalent types and account for more than 70% of all invasive cervical cancers [7]. Infection with HPV 16 or HPV 18 tends to persist longer than infection with other HPV types [8], and persistence of infection with a high-risk HPV is a requirement for the development of cervical neoplasms such as cervical intraepithelial neoplasia (CIN) 2/3 and invasive cervical cancer. There is a marked difference between the HPV types associated with CIN grades 1, 2, or 3, and the relationship between the natural history of HPV and low-grade CIN has not been fully elucidated. In addition, previous meta-analyses reported a significant regional variation in overall prevalence and type distribution of HPV [9]. Although the most prevalent type worldwide is HPV 16 followed by HPV 18, in Asia HPV 58 is the most prevalent type [10]. In this study, we report the regression or persistence of specific human papilloma-virus genotypes in Korean women with low-grade CIN.

Among 137 patients who were initially enrolled, 21 patients with a minimum follow-up period of less than 8 months were excluded and a total of 116 patients were finally included and followed up in this study. Table 1 shows the demographic characteristics of patients. Median follow-up period was 16 months. Thirty patients were diagnosed with LSIL. Of them, biopsy was taken in 24 patients, including 6 normal, 17 CIN1, and 1 koilocytotic atypia. The remaining 6 did not take biopsies; 4 of them because of follow-up loss, 2 were taken only colposcopy. Individual Pap smear results and corresponding biopsy results were shown in Table 2.

This study evaluated the prevalence and type-specific persistence of HPV in women with low-grade CIN in Korea. Although many previous studies have discussed the relationship between HPV infection and CIN or invasive cervical cancer, our understanding remains incomplete [3]. One limitation of these studies is the crudeness of the information. Because there are many variables that might affect the results, it is difficult to explain the geographic variation in cervical cancer incidence and the variability reported in different countries. Another limitation is that individual susceptibility to HPV was not considered in many studies [3]. There is a clear need for further research to understand the factors that determine whether a woman with HPV infection will clear the infection or become a persistent carrier. The results of this study provide a more complete understanding of the natural history of HPV infection.

HPV 53 was the most prevalent type in the present study, which is somewhat unusual compared with previous reports. An international meta-analysis showed that 70% of cases of invasive cervical cancer were associated with infection with HPV 16 (55%) or 18 (15%), and the next most common types were HPV 31, 33, 45, 52, and 58, which accounted for an additional 18% of cases. The most common HPV types in patients with HSIL were similar to those in patients with invasive cancer [13]. The prevalence of invasive cancer and HSIL is especially high in Asian patients with HPV 58 and 52 [14]. In a similar study of LSIL, HPV 16 was clearly the most prevalent HPV genotype worldwide and HPV 53 and 66, the so-called probable HR types, were relatively common in LSIL but were rarely found in invasive cancer and exhibited a squamous cell carcinoma/LSIL ratio lower than that for LR HPV type 6 [15]. In a large cohort study in Korea, the most prevalent HPV types were HPV 58, 16, 52, and 18, which together accounted for 73.9% of the HR HPV infections detected [16]. These discrepancies might be because the present cohort was collected at single medical center and has a relatively small sample size.

Although the most prevalent genotype in this study was HPV 53, HPV 16 was the most persistent HPV type. Together, HPV 16 and HPV 18 account for 35% of HPV-positive LSILs but nearly 70% of worldwide cervical cancers [2,14]. In prospective studies, HPV 16 infection was found to be more persistent and more likely to lead to progression to CIN3 than other HR HPV genotypes [17,18,19,20]. Although the degree of difference varies between genotypes, all HPV genotypes except HPV 16 and 18 were found to be unclearly relate to cervical cancers compared with LSIL [14]. In meta-analysis of Korean data, HPV 16, 58, and 18 were the three most common types in high-grade lesions, accounting for 62.0% of all high-grade lesions cases and 31.4% of low-grade lesions [16]. This result suggests that HPV genotyping might have a diagnostic role in separating LSIL cases with HPV 16 and 18 from LSIL cases with other HR genotypes.

Multiple HPV infections were common in this cohort, especially double infection (46.2%). According to previous studies, although there is no concrete evidence that previous infection can modulate the risk of secondary infection with HPV, already infected women are more likely to get another HPV infection than those who are not infected [20]. One previous study reported that women with HPV 58 were seven times more likely to get HPV 16 or 18 infections than uninfected women [21].

This is a prospective study designed to determine the natural history of HPV in Korea. The small sample size, the fact that it is not representative of the general Korean population, and the relative short duration of follow up are limitations of our study. However, our data suggest that distinction between HR HPV genotypes might explain the progression of LSIL and might be useful in the management of LSIL in clinical practice. The persistence of certain HR HPV types may explain the role of HPV in the pathogenesis of cervical cancer development from precancerous lesions. Further studies with a larger sample size and longer follow-up are needed to demonstrate whether persistence of specific HR HPV types is directly correlated with progression of low-grade lesions.