Our findings indicated that patients who had never undergone cervical cancer screening or had long intervals between screening were at a higher risk of advanced cervical cancer than those who underwent regular screenings. Furthermore, patients who underwent screening had low awareness regarding the significance of screening; however, most of them were aware of this after being referred to our hospital. Notably, tumor location within the endo-cervical canal and non-SCC histology impeded detection of pre-cancerous or early-stage cancer through cervical cancer screening, even with 2-year intervals. These findings suggest the need to reconsider the strategies for screening participation and accuracy.
As shown in Table 1, patients with invasive cancer who had long intervals between cancer screening or had never undergone cancer screening tended to present advanced disease at the time of diagnosis. This is consistent with previous reports demonstrating that > 50% of patients with cervical cancer never underwent screening or had longer-than-recommended intervals between screenings [14, 15]. Despite extensive efforts in screening programs, the screening rates have remained relatively low. A systematic review showed that organized screening was more effective than opportunistic screening [16]. In our region, local municipalities send an invitation letter to eligible people every 2 years, with those who miss the screening receiving the same letter the following year; however, the screening rate remained low at 42.5% in 2022. Therefore, although organized screening may increase the screening rate to some extent, it was not to a satisfactory level in our medical district. Some studies have highlighted the economic-social barriers to cancer screening, and organized screening could reduce inequity [17, 18]. However, one study reported that household income was not associated with screening rates [19]. This could be attributed to the fact that patients are required to pay 5–10 US dollars out of pocket owing to subsidies provided by the local government. Furthermore, a USA population-based assessment of cervical cancer screening showed that Asian people were less likely to undergo appropriately timed screening compared with White women [15], which suggests that ethnic culture might affect motivation for screening. Taken together, these findings suggest that increasing the screening rate requires a novel recruitment strategy.
In this study, invitation letters were the reason for organized screening among ≈ 50% of the patients who had undergone screening; moreover, ≈ 20% of patients experienced screening provided at the workplace. However, patients in all age groups were hardly aware of the significance of screening (Table 2). As shown in Table 4, after visiting our hospital, most patients became aware of the lack of clinical symptoms at an early stage and the effectiveness of cancer screening, regardless of their age and screening history. Furthermore, individuals (especially those who were elder) had insufficient knowledge regarding HPV, including its transmission route; rate of transmission; effectiveness of vaccination; and association with cervical cancer and other cancers, including vulva, anal, and mesopharyngeal cancers. In the British colorectal cancer screening program, an information booklet about colorectal cancer is sent to eligible people along with the invitation letter. However, 22% of eligible individuals never read this booklet; moreover, 63% and 4% of individuals without and with a screening history never read this booklet, respectively [20]. This indicates that simply sending information regarding cervical cancer and the significance of screening may not effectively incentivize eligible individuals to undergo screening. A previous review found that tailored messages could alter women’s decisions regarding screening participation [21]; furthermore, primary care physicians who can provide familial messages to patients may remove barriers impeding screening participation [22]. Consequently, if possible, in-person conveyance of messages to patients is crucial for promoting health literacy by utilizing available resources, including the primary doctor, phone calls from the screening organizer, and educational events within the local community.
The age of eligibility for cervical cancer screening is another important factor. Both the American College of Obstetricians and Gynecologists recommendation [23] the Ministry of Health, Labor and Welfare in Japan recommend initiation of cervical cancer screening at an age ≥ 20 years every 2 years. This is because invasive cancer is rare among patients aged < 20 years, with the age-adjusted incidence rate of cervical neoplasm peaking at the age of ≈ 40 years. In our study (Table 3), patients who started screening at a younger age were more likely to be diagnosed with at least CIN or early invasive cancer than patients who began screening at an older age. In Australia, where the HPV vaccination program was launched in 2007, a recent simulation based on the declining incidence of cervical neoplasm suggested that the age-adjusted annual incidence of cervical cancer would be as low as four cases in 10,000 women by 2028 with maintenance of the HPV vaccination and HPV testing program [24]. In our study, none of the patients aged 20–29 years was diagnosed with Stage Ib1-4b’ accordingly, expanding the HPV vaccination coverage could reduce the screening frequency among younger generations within a few decades, even in Japan. However, there is controversy regarding the age at which screening is no longer beneficial in older adults. The US Preventive Services Task Force does not recommend routine screening for women aged ≥ 65 years who have normal Pap smear test results and adequately adhered to screening [25]. In a Canadian modeling study utilizing registry and survey data, the lifetime risk of cervical cancer in individuals whose screening history was unknown at the age of 70 years could be reduced from 1/158 to 1/1206 by recall for screening [26]. Moreover, Swedish cancer registry data demonstrated that regular screening reduced the cancer risk among individuals aged ≥ 65 years [27]. Taken together with our findings that elder individuals account for a considerable high percentage of patients with invasive cervical cancers, older people should be encouraged to undergo screening until the HPV-vaccinated generation reaches old age.
In our study, 28 out of 129 patients with Stage 1b1-4b underwent cervical cancer screening within 2 years; further, 60.7% of these patients had a tumor size > 2 cm (Table 5). There was a nearly significant difference in histology findings between patients who had their last screening within 2 years and those with longer intervals. In this study, 9 out of 13 patients who had their last screening within 2 years were aged < 50 years and had non-SCC histology at diagnosis. In patients within this age group, squamocolumnar junction (SC-junction), from which cervical cancer arises, is usually located outside the cervix, and thus allows relatively easy sampling. Previous studies have suggested that cytology has low sensitivity for detecting precancerous lesions of adenocarcinoma [28, 29]; moreover, there is an increase in the worldwide incidence rate of adenocarcinoma against SCC, especially among younger patients [30]. Given that the HPV-positive rate among patients with adenocarcinoma is ≈ 90% [31], the younger generation could be a good candidate for HPV-based screening. However, HPV infection can be transient and CIN can be regressive in younger people. Therefore, patients with HPV-positive results who have negative cytology should adhere to the next HPV test at an adequate interval to avoid unnecessary colposcopy and biopsy, which is further supported by previous findings that a 5-year interval of the HPV test is safer than a 3-year interval of cytology [32]. Tumor location was another significant factor in patients diagnosed within two 2 years of screening. In this study, six out of eight patients with tumors located in the end-cervical canal and a screening interval of ≤2 years were aged > 50 years. Assuming that the SC-junction migrates toward the deep endocervical canal after menopause, the efficacy of cytological screening in these individuals may be lower than that in younger people [33]. As year of 2021, 48 countries have adopted HPV-based screening for primary method [34]. However, the Catalan Institute investigated the HPV genotype in 10,575 cases which demonstrated that HPV was detected 87% in squamous carcinoma and 62% in adenocarcinoma [35] and lower HPV positive in older patients [36]. Consistent with previous findings [37], we found that transvaginal ultrasound examination with a Doppler scan can easily detect cervical lesions. Although the cost-benefit balance must be considered, ultrasound examination with cytology screening could be a tailored option for some patients undergoing cancer screening. Finally, physicians must remind their patients that screening results may be inaccurate. Therefore, even with a negative screening result, patients with self-reported symptoms should consult a physician. Otherwise, a false negative result may lead to advanced disease.