This study followed up on patients diagnosed with CIN grade 1–2 using HPV tests performed by physician-, self- and urine sampling, cytology, and histopathology. Positive results of physician- and self-sampling HPV tests in CIN grade 1 cases showed a high rate of progression and persistence. This indicated that self-sampling tests are further useful for predicting the disease progression risk. In contrast, there was no significant difference in HPV results, progression, and persistence rates in CIN grade 2 cases for each collection method. Particularly, many CIN cases progress even if the patient’s HPV status is negative, and careful follow-up may be required even if the HPV test results are negative.
Since CIN is not cancer and occurs more frequently in females of reproductive age, less-invasive treatments are desirable. In addition, it is necessary to note the particular perinatal prognosis. It was revealed that all the excisional procedures such as laser conization, cold knife conization, and loop electrosurgical excision procedure to treat CIN presented similar pregnancy-related morbidity without apparent neonatal morbidity [9]. Therefore, a predictive marker for CIN progression is crucial. The regression rates of CIN grades 1 and 2 were similar in the 2-year follow-up period [10, 11]. Currently, histopathological assessment cannot differentiate high-grade CIN lesions from other lesions or predict whether they may regress spontaneously [10, 11]. Hence, certain prognostic biomarkers may be helpful in this differentiation [10, 12].
Although patients with CIN grade 1 are generally not candidates for resection and should be observed, some reports indicate that only 43% of biopsies initially diagnosed as CIN grade 1 are classified as CIN grade 1 after further examination [13, 14]. Hence, CIN grade 1 must be managed carefully [15]. Hu et al. [16] have shown that the cumulative progression rates to CIN grade 2 among CIN grade 1 cases over 6, 11, and 15 years were 7.5%, 21.4%, and 24.0%, respectively. Furthermore, the regression rates to a normal cervix were 85.0%, 76.7%, and 72.9%, respectively. They further revealed that females with biopsy-confirmed CIN grade 1 with high-risk HPV-positive status at baseline were 6.6 times more likely to develop CIN grade 2 than those without high-risk HPV infection (35.6% vs. 5.4%) [16]. They concluded that clinical follow-up strategies for females with CIN grade 1 could be adjusted according to the patients’ high-risk HPV or cytology status [16]. In contrast, Zhao et al. [17] have reported that in the CIN grade 1 group, cervical cytology alone was more sensitive than HPV testing alone, and co-testing did not significantly improve screening sensitivity. Furthermore, Wang et al. [18] have detected HPV genotypes in low-grade squamous intraepithelial lesions using manual microdissection of formalin-fixed paraffin-embedded tissue specimens. They concluded that patients with cervical biopsy tissue diagnosed with CIN grade 1 and with a negative or only low-risk HPV status could be considered for follow-up. Conversely, in cases of cervical biopsy tissue diagnosed with CIN grade 1 and with positive or high-risk HPV status, surgery or a close follow-up program can be selected [18].
In particular, it has been suggested that CIN grade 2 in young females should not necessarily be treated with resection, and it is critical to properly identify cases at risk of progression [13, 19, 20]. It has been reported that 43% of CIN grade 2 cases regress spontaneously, 35% persist, 22% progress to CIN grade 3, and only 5% progress to invasive cancer [4, 5]. Guedes et al. [4] reported that CIN grade 2 lesions regress without treatment in 1 year, excision of CIN grade 2 may lead to additional morbidity and costs, and tailoring individual management may result in better outcomes. Bukowski et al. [21] performed a prospective study of extended HPV genotyping to characterize the HPV genotype-specific risk of cervical disease progression in the United States. They investigated CIN grade 2 incidence according to HPV genotype in a high-risk colposcopy referral population and found that CIN grade 2 incidence rates were the highest among HPV types 16, 33, and 58 [21]. Demarco et al. [21, 22] reported that the 3-year-risk of CIN grade 3 was highest for HPV 16 (21.9%), HPV 18 (11.5%), HPV 33 and 58 (8.6%), HPV 31 (8.1%), HPV 52 (5.6%), and HPV 45 (5.4%) in their study. Zhang et al.’s [10] study revealed that detecting HPV E6/E7 messenger ribonucleic acid (mRNA) may provide crucial predictive information for CIN grade 2 prognosis. van Baars et al. [13] reported that the combination of the E4 protein of 15 high-risk HPV types (panHPVE4) and p16INK4a may predict the progression or regression of lesions and provide a basis for refining management decisions regarding follow-up and treatment of CIN grades 1 and 2.
There are few reports on the prognostic impact of self- or urine-sampling HPV test results. Stanczuk et al. [23] reported longitudinal data on the CIN progression rate with known HPV results 3–5 years after the HPV self-sampling test result. They revealed that the 5-year risk of CIN grade 2 is low in patients with high-risk HPV-negative females performing self-sampling using a polymerase chain reaction-based test [23]. They further indicated that the 3-year screening interval for females aged ≤49 years and 5 years for females aged ≥50 years are safe for those who test high-risk HPV-negative with self-collected samples [23].
This study had some limitations. First, the follow-up period was short; hence, the disease progression rate may be low. A longer follow-up period may increase the disease progression rate. Second, the rate of CIN grade 2 progression is possibly not the true value because the patients were divided into those who chose surgery at the time of CIN grade 2 diagnosis and those who chose follow-up. Third, due to the small sample size, larger multi-center prospective observational studies with longer follow-up periods are warranted in the future.
In conclusion, this study’s data revealed that in CIN grade 1 cases, the results of self-sampling HPV tests and those sampled by physicians are crucial for predicting disease progression risk. In addition, although HPV is a critical factor in CIN grade 2 progression risk, it is necessary to conduct a follow-up with a full understanding of the progression risk, even if HPV is negative for each sampling method. Hence, we aim to extend the observation period in future research and consider the disease progression risks