International investigations, including cohort studies, have failed to establish consistent evidence for an association between PID and ovarian cancer [6, 7, 24, 25]. This large-scale nationwide population-based study shows that compared with women without PID, women with PID are at higher risk of developing ovarian cancer and that this risk increases over time. Another large nationwide population-based cohort study suggests that there is no increased risk for ovarian, breast or uterine cancer among women with PID , in contrast to other researchers, who have described an increased risk of serous borderline ovarian tumors, but not of the mucinous type, in women with a history of PID. Likewise, Rasmussen and colleagues have reported finding a positive association between low-grade, borderline ovarian tumors and PID in a pooled analysis of evidence from 13 case-control studies conducted between 1989 and 2009 , and a large Italian case-control study performed between 1983 and 1991 has shown an increased risk of ovarian cancer in women with a history of PID . Interestingly, a meta-analysis of studies stratified by race has found a significant positive association between PID and ovarian cancer in studies conducted among Asian women, but only a slightly significant association amongst Caucasians . One population-based cohort study that included 34 years of follow-up data from all women in Denmark (n = 1,318,929) showed a statistically significantly increased risk of serous ovarian cancer in women with a PID history, although there was no statistically significant relationship between PID and overall ovarian cancer .
Evidence from two independent case-control studies supports the association between PID and ovarian cancer, showing that antibodies against Chlamydia trachomatis infection may double the risk of ovarian cancer . One research group has suggested that not only does PID increase the risk for developing ovarian cancer, but also that the risk increases with the number of PID episodes . A more recent study has reported that the risk of high-grade serous ovarian cancer was increased in women with a diagnosis of PID and also in those with a personal history of breast cancer . Interestingly, that study found that the risk for developing high-grade serous ovarian cancer reduced with increased parity, but not in women with a personal history of breast cancer. There are no large-scale, long-term follow-up studies that have examined the relationship between previous PID and ovarian cancer in Taiwan or other Asian countries. Although one research group from Taiwan has reported finding a significant association between PID and ovarian cancer, the 3-year follow-up is probably insufficient time to accurately determine cancer formation .
The evidence from our large nationwide study with approximately 10 years of follow-up reveals that PID is a significant risk factor for ovarian cancer and that women aged 40 years and older with PID are at greater risk of developing ovarian cancer than younger-aged women. An increased risk of ovarian cancer associated with PID supports the hypothesis that inflammatory processes may contribute to the etiology of ovarian cancer [30, 31]. Since women with a history of PID appear to be at high risk for ovarian cancer, screening these women for ovarian cancer may be an effective way to detect and treat the disease early. Prophylactic salpingo-oophorectomy is recommended for the prevention of ovarian cancer in high-risk women; there is no proven overall survival benefit in women with average risk for ovarian cancer, in whom the procedure has been associated with a significant increase in mortality from cardiovascular disease [32, 33]. Prophylactic hysterectomy with bilateral salpingo-oophorectomy has proven to be an effective way of preventing ovarian cancer in women with the Lynch syndrome .
Our study also reveals an increased risk of ovarian cancer in women with histories of endometriosis, infertility, Lynch syndrome, or breast cancer, in line with evidence from large cohort studies. For instance, the risk of epithelial ovarian cancer in women with a history of endometriosis is around 1.3–1.9 times higher than the risk among women without any such history [35, 36] The lifetime risk of ovarian cancer is 10–12% in women with the Lynch syndrome . A multinational pooled analysis of infertility and fertility drug use in eight ovarian cancer case-control investigations reported that infertility increases the overall risk of ovarian cancer, whereas no association was observed between use of ovulation-inducing medications and ovarian cancer . Other researchers have also reported that infertility alone is an independent risk factor for the development of ovarian cancer . Finally, a personal history of breast cancer has been associated with a 3-fold increase in the rate of high-grade serous ovarian cancer .
Prevention of ovarian cancer is an important issue. Our study data are useful for clinicians wishing to counsel patients about the prevention and treatment of PID. The prevention of PID, including sex education and information, and the promotion of condom use, is an important issue for infectious diseases as well as future cancer risk . Our study findings show that among important risk factors for ovarian cancer, the most important was PID.
The strengths of our study include its population-based design, the use of well-established cohort data, a large nationwide sample and an approximate 10-year follow-up period that identifies PID as a crucial risk factor in the development of ovarian cancer. Some limitations must be noted with this study. First, the NHIRD database does not code for the severity of PID, nor does it provide details of the pathogenesis and microbiology of PID, what types of infertility, or details about the cell types of ovarian cancers. Thus, we were unable to analyze any details concerning the pathophysiological relationship between ovarian cancer and PID. Second, the NHIRD registry lacks detailed records about laboratory results, parity, health-related habits or personal histories of patients, such as oral contraception use, family history and gynecological history, some of which are recognized risk factors for ovarian cancer. Third, the general incidence of PID may be underestimated if calculations fail to account for women with subclinical PID, or if women with PID fail to make a hospital visit due to personal or cultural reasons . Fourth, this study was based on inpatient and outpatient data on the NHIRD database. Although the annual coverage rate of the NHI program has been estimated at 99.6%, under lack of 100% coverage, some bias may still exist of the general population. Fifth, comorbidities that happen prior to diagnosis of PID but after entry to the cohort study was not able to involved in this study. Sixth, the mean follow-up time is about 10 years, some of the ovarian cancer happened at advanced age might be miss.