Ovarian cancer is the fifth leading cause of female cancer deaths.1,2 More than 75% of women who present locally advanced or disseminated disease are characterized by a gradual invasion of the surrounding organs and, in high-stage cases, invasion of the peritoneal cavity. The survival rate of patients presenting with widespread metastatic disease is only approximately 20%.3
More than 100 types of human papillomavirus (HPV) are known, and they are categorized into 3 broad categories depending on their oncogenic potential.4 A link between HPV infection and squamous cell cancer of the cervix has been identified.5
Persistent infection with high-risk HPV and the integration of viral genomes into the host genome have been implicated in the etiology of malignant and premalignant diseases of the female lower genital tract.6
The hypothesis that the ovarian squamous cell carcinoma is related to HPV infection was initially proposed by Mai et al.7
The role of HPV in ovarian carcinogenesis remains controversial. This systematic review measures the prevalence of HPV DNA in ovarian cancer.
MATERIALS AND METHODS
We searched MEDLINE, EMBASE, LILACS, the Cochrane Central Register of Controlled Trials, IBECS, BIOSIS, the Web of Science, SCOPUS, Congress Abstracts, and gray literature (Google scholar, the British Library) for articles published from January 1990 to March 2012. We searched using the following terms, both as text words and MeSH (Medical Subject Headings) or equivalent subject heading/thesaurus terms: “ovarian neoplasm,” “ovarian lesions,” or “ovarian masses” and “HPV” or “human papillomavirus.” This sensitive filter was created by combining 3 filters for the studies via the Boolean operators “OR” and “AND.” The search was limited to human studies but had no language restrictions. Three reviewers made preliminary relevance assessments (M.I.R., G.D.S., and L.R.M.). Potentially relevant items were examined by 2 reviewers by obtaining full-text copies of the study reports. Disagreements between reviewers were resolved by the involvement of a third reviewer (P.W.T.A.S).
We included case-control and cross-sectional studies, prospective or retrospective, that evaluated clinical ovarian cancer and provided a clear description of the use of in situ hybridization (ISH), Southern blot hybridization (SBH), and polymerase chain reaction (PCR). All methods were based on assays to identify HPV DNA in ovarian cancer cells. Furthermore, the included articles contained information on the type-specific prevalence of HPV in patients with ovarian cancer. The ovarian lesions were grouped as borderline or invasive ovarian tumors and were compared with benign ovarian lesions. The primary outcome was the prevalence of HPV DNA in ovarian cancer. The second outcome was the odds ratio (OR) from case-control studies calculated to measure the odds of ovarian cancer cells containing HPV DNA. The studies were independently reviewed by 3 investigators (M.I.R., G.D.S., P.W.T.A.S.). The final inclusion and exclusion criteria were defined based on a selection criteria checklist. Disagreements on study inclusion or exclusion were initially solved by consensus, and when consensus was not possible, disagreements were solved by a fourth reviewer (C.S.S.).
Three investigators (L.R.M., M.I.R., P.W.T.A.S.) independently extracted data from the primary studies regarding the prevalence of HPV DNA in ovarian lesions. The assessment of English-language articles was performed by 2 reviewers (B.R.S., G.D.S.), whereas the assessment of non-English articles was independently performed by another reviewer (L.R.M.), following translation when necessary. Any disagreement was resolved by consensus for both English and non-English studies.
Human papillomavirus prevalence rates were expressed as percentages in all cases of HPV DNA testing. Multiple infections were separated into constituent types; therefore, type-specific prevalence represents either single or multiple infections. Case-control studies were sorted according to their ORs, and these studies were pooled with random-effects models. Statistical analysis was performed using REVMAN 5.0.8 The random-effects models used to pool the case-control data were based on the Mantel-Haenszel, DerSimonian, and Laird methods.
The study selection process is summarized in Figure 1. In total, 24 publications were included in this meta-analysis.9– 32 Studies from 11 countries on 3 continents contained data on HPV and ovarian cancer.
One study by Kaufman et al33 in 1987 was excluded because their initial results showed the presence of HPV-6 in 10 of 12 ovarian cancer cases using ISH. However, the authors could not reproduce their results in a later analysis and retracted the first article, suspecting contamination.34
There were 889 ovarian cancer cases in total, and most of the cases came from Asia (45.1%) (Table 1). The mean HPV prevalence in the studied ovarian cancer cases was 17.5% (95% CI, 15.0–20.0), ranging from 0% to 66.7% by region.
The HPV prevalence was lowest in Europe at 4.0% (95% confidence interval [CI], 1.7–6.3), followed by North America at 9.0%(95% CI, 5.1–12.9), and it was highest in Asia at 31.4% (95% CI, 26.9–35.9) (Table 1).
In the publication calendar period, the HPV prevalence was the highest (33.7%; 95% CI, 28.5–39.3) for studies published between 2006 and 2012 (Table 1).
Four HPV types, HPV-6, -16, -18, and -33, were found. Human papillomavirus type 16 was the most common type, with a prevalence of 39.7% (95% CI, 28.1–51.3), followed by HPV-18 (12.2%; 95% CI, 1.8–22.6). Among the 156 cases of positive HPV-DNA found in our study, 65 (41.6%) did not specify the HPV type.
Human papillomavirus was not detected in 4 of 6 studies from Europe,9,15,18,27 in 6 of 8 from North America,12,14,23,25,26,29 and 1 of 10 from Asia (Japan).10
Among the ovarian cancer–positive HPV cases (n = 156), the histological types were as follows: 45 serous cases, 15 mucinous cases, 12 borderline cases, 6 endometrioid cases, 6 undifferentiated cases, 2 mixed cases, and 2 clear cell cases. Other studies did not relate the histological types of ovarian cancer.
In only 4 of the case-control studies from Asia20,21,28 ,31 was it possible to estimate the OR, with 131 cases and 82 controls. These studies showed an OR = 2.48 (95% CI, 0.64–9.57; χ2 = 8.84; P = 0.03; I 2 = 66%) (Fig. 2). In other continents, the OR could not be estimated because we did not find case-control studies, or the studies contained 2 cells with value 0 (zero).
We found evidence of heterogeneity between studies (year, location, methods, and HPV type). The studies were pooled using a DerSimonian-Laird random-effects model.
Human papillomaviruses play a causal role in cervical cancer. Walboomers et al (1999),35 combining the data from previous study (Bosh et al ) and excluding inadequate specimens, found the worldwide HPV prevalence in cervical carcinomas is 99.7%. This infection is additionally detected in other cancers. Li et al (2012),36 in a recent meta-analysis, found the overall HPV prevalence in laryngeal cancer tissues of 28.0%; Hoots et al37 (2009) showed a prevalence of 71% of invasive anal cancers. A study developed in our laboratory showed prevalence of HPV of 23% in breast cancer.38
We showed that 17.5% of ovarian cancer cases additionally reported HPV infection. Human papillomavirus prevalence was highest in Asia at 31.4%. In the present study, 7.9% of ovarian cancer cases were positive for HPV DNA from 1986 to 1999, followed by an increase in positivity between 2000 and 2005 and a decrease after 2006. The highest prevalence was found between 2000 and 2005, which could be explained by the inclusion of 4 studies from China in this period.19,24 ,31,32
The OR indicated a risk factor of (2.48), although the CI was not significant. This lack of significance could be explained by the heterogeneity of the studies, different HPV detection methods (PCR, ISH, SBH), the small number of articles included, or differences between countries.
The role of HPV infection in the development of cancers in the upper genital tract is less clear. Data on HPV DNA detection in ovarian cancers are controversial, and most studies were unable to identify HPV in ovarian tumor tissues.9,12,14,15,18,23,25–27,29 The first report on HPV infection in ovarian cancers was published in 1987,33 although the same authors retracted their results 1 year later, stating that they were in error.34 Other studies have reported that HPV DNA has been found in substantial numbers of ovarian cancer cases.10,11,13,16,17,19–22,24,28,30– 32
Of the 14 positive reports of HPV and ovarian cancer coincidence, 6 were from Chinese women.19,21,22,24 ,31,32 Negative cases have been found principally in European patients, with a HPV prevalence of 4.0%.9,15,18,27 These data confirm the hypothesis of Wu et al31 that the host genetic makeup plays an important role in the susceptibility to HPV infection.
The controversial results from epidemiological studies would indicate that identifying the role of HPV in ovarian cancer tumorigenesis remained a big challenge. Because the ovarian cancer is multifactorial in etiology and HPV infection is related to sexual behavior, a more precise assay should take the covariates such as age, ethnicity, and lifestyle into consideration.
Human papillomavirus intratypic variants in different geographical regions may additionally determine the association between HPV and the ovarian cancer risk. The distribution of HPV variants varied by geographic area, suggesting that the virus and the host have coevolved over time.39–41
The heterogeneity between studies of HPV prevalence by geographical area or country is generally hampered by differences among study populations surveyed, and the variation in HPV types detected across geographical regions. In addition to the host and pathogen genetic variation, the difference of the detection methods used in the studies might also explain data discrepancy.
Hildesheim et al42 (2002) showed that individuals infected with a non-European variant of HPV-16 were associated with 2- to 9-fold increased risk of cervical cancer. Whether this is the case in ovarian cancer needs to be further investigated.
The mechanisms through which HPV affects the upper genitalia are unclear. The endometrium and fallopian tubes are an anatomical continuation of the endocervical glands, and infection may spread via this route. In addition, sperm cells may be responsible for the transfer of HPV; they may carry viruses during passage from the endocervical canal.43, 44
In conclusion, this study is the first meta-analysis to explore HPV infection prevalence in ovarian cancer across 3 continents and publication calendar year. Our study found a high prevalence of HPV-positive DNA in ovarian cancer cases; but the role of HPV in ovarian cancer remains inconclusive. Further studies are needed to control case to answer this question.
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