Introduction
According to the fifth edition of World Health Organization’s classification system, thymic epithelial tumors are divided into thymoma, thymic carcinoma, and thymic neuroendocrine tumor (NET).1–4 Thymic carcinoma, which is relatively rare, accounts for 5–36% of all thymic epithelial tumors.4,5 Moreover, thymic carcinoma exerts a more severe clinical impact than does thymoma primarily because of its higher tendency to metastasize, resulting in poorer prognosis overall. Thymoma has the highest 5-year survival rate among the aforementioned thymic cancer subtypes, approaching 90%.6 By contrast, thymic NETs, which account for 2–5% of all thymic epithelial tumors, have a more variable 5-year survival rate, ranging from 28 to 75%.4,6
In the United States, data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program database indicate that the age-standardized incidence rates are between 0.13 and 0.15 per 100,000 people for thymoma and 0.02 per 100,000 people for thymic NET.1,6–8 Furthermore, according to the findings of the RARECARE project, the age-standardized incidence rate for thymic epithelial tumors in Europe is 0.17 per 100,000 people.9 Previous studies conducted in Europe and the United States have reported slightly higher incidences of thymic epithelial tumors in men than in women.6,10 Among ethnic groups, Asian Americans and Pacific Islanders have the highest incidence rates of thymic epithelial tumors, followed by African Americans.6 Regarding age, the incidence of thymic cancer is highest in individuals aged between 70 and 74 years.6
In Asia, data obtained from a hospital-based cancer registry and the National Cancer Center in Japan revealed an incidence rate of 0.29 cases per 100,000 person-years for thymic carcinoma.11 The incidence rate of thymic carcinoma in men is approximately twice that in women. The highest incidence rates were observed in men aged between 75 and 79 years and in women aged between 70 and 74 years.11 Furthermore, according to the National Cancer Registry Annual Report 2020, in Taiwan, the age-standardized incidence rate of thymic cancer in men is approximately 1.46 times higher than that in women (2.1 vs 1.44 per 100,000 people).12
Human papillomavirus (HPV) is the primary causative agent of cervical cancer.13 HPV is a small, non-enveloped, circular DNA virus classified under the Papillomavirus genus of the Papovaviridae family.14 Over 200 HPV genotypes have been identified, with significant differences in infection rates and carcinogenicity among different types. According to global epidemiological data, HPV accounts for 31.1% of pathogen-related cancers, ranking second only to Helicobacter pylori, which accounts for 36.3%.15 Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, affects multiple organs including the kidneys, heart, liver, pancreas, and immune system. Immunosuppression is a shared risk factor for both HPV and COVID-19, increasing the risk of persistent HPV infection and severe COVID-19 outcomes.16 Previous studies have demonstrated that HPV is implicated in not only cancers of the female reproductive system but also urogenital, oropharyngeal, breast, colorectal, esophageal, and lung cancers.17–22 In particular, 70% to 80% of cases of oropharyngeal squamous cell carcinoma (OPSCC) in the United States and Europe are associated with HPV. By contrast, in Taiwan, HPV-related OPSCC accounts for only 25–30% of cases.23,24 In addition, HPV is implicated in 50% to 84% of colorectal, rectal, and anal cancers.18,25,26 Furthermore, HPV genotypes 16 and 18 are the primary causative agents of cervical cancer in Western countries, whereas HPV genotypes 52 and 58 are the main causative agents in Taiwan.27–29 In North America and Europe, approximately 85% of OPSCC cases are attributable to HPV genotypes 16 and 18.30 However, a retrospective cohort study conducted at a single medical center in Taiwan revealed that HPV genotype 16 alone and HPV genotype 58 alone accounted for 76.9% and 7.5% of cases, respectively.31,32
Although previous studies have suggested that age and ethnicity lead to differences in incidence rates, some studies have proposed that infection or chronic inflammation is associated with the development of thymoma or thymic carcinoma.5,6,33,34 Malcolm et al observed that thymic hypertrophy, characterized by an increase in the numbers of all types of thymocytes and enhanced cellularity of the cortex and medulla, increased with age in transgenic mice expressing the E7 protein of HPV16 from the keratin 14 promoter.35 However, currently, evidence remains limited to establishing only a correlation between thymic cancer and viral infection, largely because of a lack of large-scale cohort prospective studies. Thus, in the present study, we used a large-scale community-based database to investigate the potential association between HPV and thymic cancer. In addition, we explored whether specific HPV genotypes are linked to thymic cancer.
Materials and Methods
Study Design and Cohort Recruitment
This study used data from the 1991 to 1992 Community-Based Cancer Screening Program in Taiwan. A total of 11,923 women aged 30 to 39 years from 7 townships in Taiwan were enrolled. Because the primary aim of this study was to investigate the effect of HPV on cervical cancer development, individuals with inadequate cervical cell specimens and those with a history of hysterectomy were excluded from the sampling. This process resulted in a final cohort of 10,615 individuals who underwent the Papanicolaou (Pap) smear test (Cervex Brush, Rovers, Netherlands) and HPV DNA testing (ViraPap Kit, Digene Diagnostics, Silver Spring, MD, USA). To examine the correlation between HPV and thymic cancer development in women, individuals with any known history of cancer at the time of screening were further excluded, resulting in a final cohort of 10,558 individuals. Given the community-based design, no formal sample size calculation was performed; all eligible individuals were enrolled without sampling.
Subsequently, well-trained public health nurses administered standardized individual questionnaires to these participants. These questionnaires covered sociodemographic characteristics, dietary habits, cigarette smoking, alcohol consumption, betel nut chewing, history of menarche, menopause, pregnancy, delivery, and oral contraceptive or intrauterine device usage. Cells collected for HPV testing were preserved at −80°C. The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board by the institutional review board (IRB) of Fu Jen Catholic University (no. C112033). All participants provided written informed consent before enrollment, and all data were de-identified prior to analysis.
Methods of HPV DNA Extraction, HPV Polymerase Chain Reaction Assay, and HPV Genotyping
One milliliter of a frozen cervical cell sample was aliquoted into 100-μL volumes before DNA extraction. The methods for DNA extraction and polymerase chain reaction (PCR) employed in this study have been described in previous studies.13,34,36,37 For HPV genotyping, we used the EasyChip HPV blot kit (King Car, Taiwan), which can detect 39 genotypes of HPV [6, 11, 16, 18, 26, 31, 32, 33, 35, 37, 39, 42, 43, 44, 45, 51, 52, 53, 54, 55, 56, 58, 59, 61, 62, 66, 67, 68, 69, 70, CP8061 (71), 72, 74, CP8304 (81), 82, MM4 (82), MM7 (83), MM8 (84), and L1AE5 (85)] through reverse-blot hybridization.36,37
A specimen was considered HPV-positive if it showed positive results in both the EasyChip kit and PCR assays. For specimens initially EasyChip kit testing positive, reconfirmation through additional PCR for genotyping was performed. If a specimen exhibited a consistent gel electrophoresis pattern of HPV DNA but inconsistent genotyping results, it was classified as an equivocal type. Specimens exhibiting consistent positive gel electrophoresis of HPV DNA but a negative result in the EasyChip assay were categorized as other types and not included among the 39 detected genotypes; they were then directly sequenced from the L1 region. Both equivocal and other types were included in the positive group. Each batch of experiments contained 96 samples, namely 89 cervical tissue samples and 7 control samples, to maintain a contamination-free environment, to facilitate reproducibility, and to ensure the accuracy of the results as described previously.13
We classified the HPV genotypes detected using the EasyChip kit in accordance with the classification system established by the International Agency for Research on Cancer (IARC).38 HPV genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59 were categorized as IARC group 1. HPV genotype 68 (2A) and HPV genotypes 26, 53, 66, 67, 70, 73, and 82 (2B) were categorized as IARC group 2. HPV genotypes 6 and 11 were categorized as IARC group 3. Other types that were not considered to be carcinogenic and are unspecified by the IARC but were detected using the EasyChip kit included HPV 32, 37, 42, 43, 44, 54, 55, 61, 62, 69, CP8061 [71], 72, 74, CP8304 [81], MM7 [83], MM8 [84], and L1AE5 [85].
Identification of Patients with Newly Diagnosed Common Female Cancers During Follow-up
We linked data from the National Cancer Registry, National Death Certification Registry, and National Health Insurance database in Taiwan, tracking records up to December 31, 2020. Newly diagnosed primary cancers have been registered in the National Cancer Registry since 1996. Thymus malignant tumors are coded as 164 in the International Classification of Diseases, Ninth Edition. Thymic cancers were diagnosed through histological analysis and further classified in accordance with the International Classification of Diseases for Oncology, Third Edition. Confirmatory cytology and tissue morphology were available for 91.5% to 99.6% of all diagnosed thymic cancers from 1991 to 2020.
Statistical Analysis
For each participant, person-years of follow-up were calculated from the date of recruitment. The cumulative incidence of thymic cancers was determined using the Kaplan–Meier method, with censoring occurring at the date of diagnosis for new thymic cancer cases. Multivariate-adjusted HRs and their corresponding 95% CIs were computed using Cox proportional hazards models for patients who developed thymic cancers to analyze data on the basis of different IARC groups for HPV-positive cases. The HPV genotypes present in patients with thymic cancer during the follow-up period were analyzed and categorized. A P value of <0.05 indicated statistical significance. All statistical analyses were performed using SAS version 9.1.4 (SAS Institute, Cary, NC, USA).
Results
Patient Characteristics
In the CBCS-HPV study, 1170 participants were excluded because of missing data from either Pap smear or HPV testing, and an additional 138 individuals were excluded because they had previously undergone hysterectomy. As a result, 10,615 participants who met the eligibility criteria were enrolled. After the exclusion of individuals with a history of cancer, the final cohort for this longitudinal study contained 10,558 individuals (Figure 1). The mean age of these participants was 46.3 ± 9.7 years, and the prevalence rate of any type of HPV in the cohort was 15.5% (Table 1). Genotype analysis conducted on the participants who tested positive for HPV revealed the following distribution in accordance with the IARC classification system: 64.15%, 21.22%, and 13.05% for IARC groups 1, 2, and 3, respectively (Table S1). In addition, among specific HPV genotypes, the 5 most common were types 52 (2.47%), 16 (2.05%), 11 (1.85%), 18 (1.62%), and 58 (1.34%) (Table S1).
|
Table 1 Basic Characteristics of Patients with and without HPV Infection
|
 |
Figure 1 Flowchart for the selection of eligible participants from the CBCSP-HPV study.
|
Association Between HPV Infection Status and Thymic Cancer
Table 1 lists the basic characteristics of the participants stratified by their HPV infection status. We noted significant differences in alcohol consumption and cigarette smoking between the HPV-positive and HPV-negative groups. Regardless of HPV status, no significant difference in mean age, oral contraceptive use, or betel nut chewing was observed between the HPV-positive and HPV-negative groups. In the follow-up analysis, in addition to the already known relationship between cervical cancer and HPV infection, a slightly increased HR for thymic cancer was observed in the HPV-positive group compared with the HPV-negative group (HR = 2.42, 95% CI = 0.62 to 9.38; Table 2). However, we noted no significant differences in the cumulative incidence rates of thymic cancer between the HPV-positive and HPV-negative groups (Figure 2).
 |
Table 2 Baseline HPV Infection and Subsequent Development of Thymic Cancer
|
 |
Figure 2 Cumulative incidence of thymic cancer by HPV status at study entry.
|
Association Between Different Category of HPV Genotypes and Thymic Cancer
Further analysis of the HPV-positive group revealed that those with HPV genotypes classified as IARC group 3 had a higher HR (11.82, 95% CI = 2.51 to 55.7; Table 2) for thymic cancer incidence. Moreover, we noted a significant difference in the cumulative incidence rates of the participants with HPV genotypes classified as IARC group 3 and the other participants (ie, those who tested negative for HPV and those who tested positive for HPV genotypes not classified in IARC group 3; Figure 3). We comprehensively analyzed the demographic data of 10 participants with thymic cancer (Table 3). None of these participants had a history of tobacco, alcohol, or betel nut use. Moreover, except for thymic cancer, no organ malignancies were identified during the follow-up period. Among 3 participants with HPV positivity, 2 had dual-genotype infections, including one case where HPV genotype 11 was present. Specifically, Case 2 had concurrent infections with IARC group 1 (type 18) and group 3 (type 11) genotypes, whereas Case 3 was infected with an IARC group 3 genotype (type 11) and a non-IARC-classified genotype (type 71). Histologically, Cases 2 and 3 were diagnosed with mixed-type thymoma, whereas Case 1 was diagnosed with an unspecified type of thymic carcinoma. The time from the initial Pap smear to the diagnosis of cancer varied. Case 1 was diagnosed with thymic cancer after a decade of follow-up, whereas Cases 2 and 3 were diagnosed after more than 20 years of follow-up.
 |
Table 3 Multivariable Cox Proportional Hazards Regression Model Analysis of the Associations of IARC HPV Groups with Thymic Cancer Risk
|
 |
Figure 3 Cumulative incidence of thymic cancer in HPV-positive cases classified as IARC group 3 versus other participants.
|
Discussion
This large-scale, community-based cohort study investigated the potential association between HPV infection and thymic cancer development in women. Cervical tissue samples were tested using PCR and gene chip technology to identify HPV exposure and genotype distribution. While no significant overall association was observed between HPV infection and thymic cancer, subgroup analysis revealed a noteworthy link with HPV genotypes classified as IARC group 3.
Importantly, this observed association with IARC group 3 HPV genotypes (HR=11.82) should be interpreted with caution, as it was based on only one case (HPV11 in Case 2). This result should be interpreted as exploratory and hypothesis-generating only, and should be validated in larger studies.
The HPV prevalence in our cohort was 15.5%, slightly lower than the 19.85% reported by Jeng et al in a Taiwan-based urban population using similar molecular detection methods.39 This difference may be attributable to variations in age distribution and geographic settings. Nevertheless, the consistency with contemporary epidemiological trends reinforces the validity of our findings.
Although the present study did not observe a significant association between any type of HPV and thymic cancer development, a subanalysis of HPV genotypes revealed that those categorized in IARC group 3 had a relatively high risk of thymic cancer. Previous studies have reported HPV has been implicated in cervical and various anogenital and oropharyngeal cancers. To the best of our knowledge, this is the first study to indicate a possible association between specific HPV genotype classifications and thymic cancer. Although age and ethnicity are considered as potential risk factors, the number of large cohort studies confirming the relationships of other risk factors with thymic cancer remains lacking. Thus, the present study provides limited evidence for understanding these associations.
Among thymic cancer cases, patients who were HPV-positive were younger (mean age 55.8 years) than their HPV-negative counterparts (mean age 64.0 years), suggesting a potential age-related susceptibility. In the previous study, Cufi et al observed decreased expression of p53, a tumor suppressor, and increased expression of p16CDKN2A, a surrogate marker for HPV infection, in 11 cases of thymoma-associated MG. However, subsequent tests using real-time PCR for HPV DNA yielded negative results.33 The discrepancy may reflect differences in detection methods (immunohistochemistry vs PCR), sample types (thymoma vs thymic carcinoma), or population characteristics. Thus, the relationship between viral infections and thymoma or thymic carcinoma remains inconclusive. Although neither the previous study nor the present study directly detected HPV DNA in thymic tissue, the former suggested a potential association between thymoma, and HPV infection based on p16CDKN2A overexpression identified by immunohistochemistry. In contrast, our study demonstrated a possible association through cohort-based follow-up of HPV infection identified in cervical samples. This limitation underscores the need for tissue-based molecular analysis to validate potential viral involvement in thymic tumorigenesis.
Previous studies have categorized HPV genotypes into high risk (group 1), intermediate risk (group 2), and low risk (group 3) on the basis of the IARC’s risk assessment for cervical cancer. However, the contributions of individual genotypes to cancer risk vary.31,40,41 Notably, 2 of 3 HPV-positive thymic cancer patients carried genotypes 18 and 52, both belonging to IARC group 1. However, a significant association was detected with group 3 genotypes, including HPV 6 and 11, traditionally considered low risk and more commonly linked to benign lesions such as warts. These genotypes have also been sporadically detected in lung as well as head and neck cancers, prompting investigation into possible oncogenic mechanisms.42–44
The observed association with group 3 HPV types raises the question of how low-risk genotypes may contribute to the thymic epithelial tumorigenesis. Several hypotheses have been proposed to explain HPV-driven carcinogenesis in non-mucosal sites. The first theory suggests that HPV is transmitted through mononuclear white cells via the bloodstream or lymphatic system to the target organ, resulting in infection.45,46 Second, the “hit and run” hypothesis posits that HPV initiates carcinogenesis in thymic epithelial tumors, even without the histological evidence of persistent viral infection.47 Thus, even if the virus is cleared by the immune system or remains at a very low viral load in the tissue, it can still lead to the development of cancer in the future. The third theory involves extracellular vesicles containing nucleic acids, proteins, and noncoding RNA, potentially originating from another site of initial infection. These vesicles may transfer to tissues that lack HPV receptors, leading to abnormal cell proliferation.48
The present study had some limitations that should be considered. First, HPV detection was limited to cervical samples at baseline, without direct HPV testing of thymic tissues or longitudinal follow-up for persistent infection. However, these participants who tested positive for HPV were aged between 51 and 64 years. Previous studies have been suggested that, due to immune suppression occurring after the age of 50, the likelihood of transient HPV infection is considered low. Second, the rarity of thymic cancer and small number of cases (n = 10) limited the statistical power of genotype-specific analyses. Third, potential confounding factors such as environmental exposures (eg, radiation) or hereditary predispositions could not be adjusted due to data limitations. Finally, in the absence of direct thymic testing, the possibility of contamination or non-local HPV presence cannot be excluded, and causal inference requires further mechanistic validation.
Conclusions
In this cohort study of adult women, HPV infection was confirmed using cervical DNA analysis, and younger age was observed among thymic cancer patients with HPV positivity. Although no significant increase in overall cancer risk was detected, a potential association between thymic cancer and IARC group 3 HPV genotypes was identified. Given the rarity of thymic cancer and the novelty of these findings, additional multicenter studies and molecular investigations are warranted to clarify the biological plausibility and clinical relevance of this association.
Abbreviations
CI, confidence interval; HR, hazard ratio; NET, thymic neuroendocrine tumor; HPV, human papillomavirus; IRB, institutional review board; OPSCC, oropharyngeal squamous cell carcinoma; Pap, Papanicolaou; PCR, polymerase chain reaction.
Data Sharing Statement
Data is unavailable due to privacy or ethical restrictions.
Ethics Statement
The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board by the institutional review board (IRB) of Fu Jen Catholic University (no. C112033).
Acknowledgments
The authors are grateful to the Fu Jen University Foundation for their helpful comments and recommendations.
Author Contributions
Peng-Tzu Liu: Conceptualization, Formal acquisition, Writing-original draft, Writing-review & editing. Wan-Lun Hsu: Conceptualization, Methodology. Tzu-I Chen: Data curation, Formal analysis, Software. Chung-Ju Chiang: Methodology, Resources, Validation. Mei-Hung Pan: Investigation. Hui-Ling Lee: Supervision. Chia-Chuan Wang: Conceptualization, Supervision. Chien-Jen Chen: Investigation, Supervision. Vinchi Wang: Conceptualization, Supervision. Yong-Chen Chen: Conceptualization, Formal acquisition, Project administration, Writing-review & editing.
All authors made a significant contribution to the work reported, whether in conception, design, data acquisition, analysis, interpretation, or in all these areas. All authors participated in drafting or critically revising the article; gave final approval of the version to be published, agreed on the journal to which the article has been submitted, and agreed to be accountable for all aspects of the work.
Funding
This research was funded by Shin Kong Wu Ho Su Memorial Hospital and the Fu Jen Catholic University Joint Program, grant number 12-SKH-FJU-07. The funding organization played no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.
Disclosure
The authors declare no conflicts of interest in this work.
References
1. Engels EA. Epidemiology of thymoma and associated malignancies. J Thorac Oncol. 2010;5(10 Suppl 4):S260–265. doi:10.1097/JTO.0b013e3181f1f62d
2. Hasserjian RP, Ströbel P, Marx A. Pathology of thymic tumors. Semin Thorac Cardiovasc Surg. 2005;17(1):2–11. doi:10.1053/j.semtcvs.2004.12.002
3. Ströbel P, Marx A, Zettl A, Müller-Hermelink HK. Thymoma and thymic carcinoma: an update of the WHO Classification 2004. Surg Today. 2005;35(10):805–811. doi:10.1007/s00595-005-3047-y
4. Marx A, Chan JK, Coindre JM, et al. The 2015 world health organization classification of tumors of the thymus: continuity and changes. J Thorac Oncol. 2015;10(10):1383–1395. doi:10.1097/JTO.0000000000000654
5. Scorsetti M, Leo F, Trama A, et al. Thymoma and thymic carcinomas. Crit Rev Oncol Hematol. 2016;99:332–350. doi:10.1016/j.critrevonc.2016.01.012
6. Mou H, Liao Q, Hou X, Chen T, Zhu Y. Clinical characteristics, risk factors, and outcomes after adjuvant radiotherapy for patients with thymoma in the United States: analysis of the Surveillance, Epidemiology, and End Results (SEER) Registry (1988–2013). Int J Radiat Biol. 2018;94(5):495–502. doi:10.1080/09553002.2018.1454618
7. Gaur P, Leary C, Yao JC. Thymic neuroendocrine tumors: a SEER database analysis of 160 patients. Ann Surg. 2010;251(6):1117–1121. doi:10.1097/SLA.0b013e3181dd4ec4
8. Hsu CH, Chan JK, Yin CH, Lee CC, Chern CU, Liao CI. Trends in the incidence of thymoma, thymic carcinoma, and thymic neuroendocrine tumor in the United States. PLoS One. 2019;14(12):e0227197. doi:10.1371/journal.pone.0227197
9. Siesling S, van der Zwan JM, Izarzugaza I, et al. Rare thoracic cancers, including peritoneum mesothelioma. Eur J Cancer. 2012;48(7):949–960. doi:10.1016/j.ejca.2012.02.047
10. Sirri E, Kieschke J, Vohmann C, et al. Survival of malignant mesothelioma and other rare thoracic cancers in Germany and the United States: a population-based study. Int J Cancer. 2020;147(6):1548–1558. doi:10.1002/ijc.32931
11. Koizumi T, Otsuki K, Tanaka Y, et al. National incidence and initial therapy for thymic carcinoma in Japan: based on analysis of hospital-based cancer registry data, 2009–2015. Jpn J Clin Oncol. 2020;50(4):434–439. doi:10.1093/jjco/hyz203
12. Health Promotion Administration, Ministry of Health and Welfare (Taiwan), Cancer Registry Annual Report, 2020. Available from: https://www.hpa.gov.tw/File/Attach/16434/File_21196.pdf.
13. Chen HC, You SL, Hsieh CY, et al. Prevalence of genotype-specific human papillomavirus infection and cervical neoplasia in Taiwan: a community-based survey of 10,602 women. Int J Cancer. 2011;128(5):1192–1203. doi:10.1002/ijc.25685
14. Ma X, Wu C, Wu T, Yu X, Song L. Genotypic analysis of human papillomavirus in cervical exfoliated cells from women in Zigong. Virol J. 2025;22(1):40. doi:10.1186/s12985-025-02652-7
15. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–249. doi:10.3322/caac.21660
16. Torge D, Bernardi S, Arcangeli M, Bianchi S. Histopathological features of SARS-CoV-2 in extrapulmonary organ infection: a systematic review of literature. Pathogens. 2022;11(8):867. doi:10.3390/pathogens11080867
17. Ahmed W, Zaib S, Ullah S, et al. Role of human papillomavirus in various cancers: epidemiology, screening and prevention. Mini Rev Med Chem. 2023;23(10):1079–1089. doi:10.2174/1389557523666230213140641
18. Bucchi D, Stracci F, Buonora N, Masanotti G. Human papillomavirus and gastrointestinal cancer: a review. World J Gastroenterol. 2016;22(33):7415–7430. doi:10.3748/wjg.v22.i33.7415
19. Kudela E, Kudelova E, Kozubík E, et al. HPV-associated breast cancer: myth or fact? Pathogens. 2022;11(12):1510. doi:10.3390/pathogens11121510
20. Li YJ, Tsai YC, Chen YC, Christiani DC. Human papilloma virus and female lung adenocarcinoma. Semin Oncol. 2009;36(6):542–552. doi:10.1053/j.seminoncol.2009.10.002
21. Li Z, Liu P, Wang Z, et al. Prevalence of human papillomavirus DNA and p16(INK4a) positivity in vulvar cancer and vulvar intraepithelial neoplasia: a systematic review and meta-analysis. Lancet Oncol. 2023;24(4):403–414. doi:10.1016/S1470-2045(23)00066-9
22. Tumban E. A current update on human papillomavirus-associated head and neck cancers. Viruses. 2019;11(10):922. doi:10.3390/v11100922
23. Deshmukh AA, Suk R, Shiels MS, et al. Incidence trends and burden of human papillomavirus-associated cancers among women in the United States, 2001–2017. J Natl Cancer Inst. 2021;113(6):792–796. doi:10.1093/jnci/djaa128
24. Guo F, Chang M, Scholl M, McKinnon B, Berenson AB. Trends in oropharyngeal cancer incidence among adult men and women in the United States from 2001 to 2018. Front Oncol. 2022;12:926555. doi:10.3389/fonc.2022.926555
25. Hsu CH, Lin YJ, Chen YC, et al. Human papillomavirus and risk of colorectal cancer: an analysis of nationwide claims data. Medicina. 2022;58(10). doi:10.3390/medicina58101461
26. Ibragimova MK, Tsyganov MM, Litviakov NV. Human papillomavirus and colorectal cancer. Med Oncol. 2018;35(11):140. doi:10.1007/s12032-018-1201-9
27. Mix JM, Saraiya M, Thompson TD, et al. Prevalence of human papillomavirus genotypes in high-grade cervical precancer and invasive cervical cancer from cancer registries before and after vaccine introduction in the United States. Cancer. 2021;127(19):3614–3621. doi:10.1002/cncr.33582
28. de Sanjose S, Quint WG, Alemany L, et al. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol. 2010;11(11):1048–1056. doi:10.1016/S1470-2045(10)70230-8
29. Lin Y, Lin WY, Lin TW, et al. Trend of HPV molecular epidemiology in the post-vaccine Era: a 10-year study. Viruses. 2023;15(10):2015. doi:10.3390/v15102015
30. Castellsagué X, Alemany L, Quer M, et al. HPV involvement in head and neck cancers: comprehensive assessment of biomarkers in 3680 patients. J Natl Cancer Inst. 2016;108(6):djv403. doi:10.1093/jnci/djv403
31. Wang CP, Chen TC, Hsu WL, et al. Rising incidence of HPV positive oropharyngeal cancer in Taiwan between 1999 and 2014 where betel nut chewing is common. BMC Cancer. 2022;22(1):296. doi:10.1186/s12885-022-09407-5
32. Hwang TZ, Hsiao JR, Tsai CR, Chang JS. Incidence trends of human papillomavirus-related head and neck cancer in Taiwan, 1995–2009. Int J Cancer. 2015;137(2):395–408. doi:10.1002/ijc.29330
33. Cufi P, Soussan P, Truffault F, et al. Thymoma-associated myasthenia gravis: on the search for a pathogen signature. J Autoimmun. 2014;52:29–35. doi:10.1016/j.jaut.2013.12.018
34. Huang HJ, Huang SL, Lin CY, et al. Human papillomavirus genotyping by a polymerase chain reaction-based genechip method in cervical carcinoma treated with neoadjuvant chemotherapy plus radical surgery. Int J Gynecol Cancer. 2004;14(4):639–649. doi:10.1136/ijgc-00009577-200407000-00012
35. Malcolm KM, Gill J, Leggatt GR, Boyd R, Lambert P, Frazer IH. Expression of the HPV16E7 oncoprotein by thymic epithelium is accompanied by disrupted T cell maturation and a failure of the thymus to involute with age. Clin Dev Immunol. 2003;10(2–4):91–103. doi:10.1080/10446670310001626562
36. Lin CY, Chen HC, Lin RW, et al. Quality assurance of genotyping array for detection and typing of human papillomavirus. J Virol Methods. 2007;140(1–2):1–9. doi:10.1016/j.jviromet.2006.10.004
37. Lin CY, Chao A, Yang YC, et al. Human papillomavirus typing with a polymerase chain reaction-based genotyping array compared with type-specific PCR. J Clin Virol. 2008;42(4):361–367. doi:10.1016/j.jcv.2008.03.018
38. Egawa N, Doorbar J. The low-risk papillomaviruses. Virus Res. 2017;231:119–127. doi:10.1016/j.virusres.2016.12.017
39. Jeng CJ, Ko ML, Ling QD, et al. Prevalence of cervical human papillomavirus in Taiwanese women. Clin Invest Med. 2005;28(5):261–266.
40. Onuki M, Matsumoto K, Iwata T, et al. Human papillomavirus genotype contribution to cervical cancer and precancer: implications for screening and vaccination in Japan. Cancer Sci. 2020;111(7):2546–2557. doi:10.1111/cas.14445
41. Lorenzatti Hiles G, Chang KP, Bellile EL, et al. Understanding the impact of high-risk human papillomavirus on oropharyngeal squamous cell carcinomas in Taiwan: a retrospective cohort study. PLoS One. 2021;16(4):e0250530. doi:10.1371/journal.pone.0250530
42. Hussen BM, Ahmadi G, Marzban H, et al. The role of HPV gene expression and selected cellular MiRNAs in lung cancer development. Microb Pathog. 2021;150:104692. doi:10.1016/j.micpath.2020.104692
43. Sarchianaki E, Derdas SP, Ntaoukakis M, et al. Detection and genotype analysis of human papillomavirus in non-small cell lung cancer patients. Tumour Biol. 2014;35(4):3203–3209. doi:10.1007/s13277-013-1419-2
44. Syrjänen KJ. Condylomatous changes in neoplastic bronchial epithelium. Report of a case. Respiration. 1979;38(5):299–304. doi:10.1159/000194095
45. Pao CC, Hor JJ, Yang FP, Lin CY, Tseng CJ. Detection of human papillomavirus mRNA and cervical cancer cells in peripheral blood of cervical cancer patients with metastasis. J Clin Oncol. 1997;15(3):1008–1012. doi:10.1200/JCO.1997.15.3.1008
46. Tseng CJ, Pao CC, Lin JD, Soong YK, Hong JH, Hsueh S. Detection of human papillomavirus types 16 and 18 mRNA in peripheral blood of advanced cervical cancer patients and its association with prognosis. J Clin Oncol. 1999;17(5):1391–1396. doi:10.1200/JCO.1999.17.5.1391
47. Kostov S, Dzhenkov D, Metodiev D, et al. A case of human papillomavirus infection and vulvar cancer in a young patient – “hit and run” theory. Gynecol Oncol Rep. 2021;36:100760. doi:10.1016/j.gore.2021.100760
48. De Carolis S, Storci G, Ceccarelli C, et al. HPV DNA associates with breast cancer malignancy and it is transferred to breast cancer stromal cells by extracellular vesicles. Front Oncol. 2019;9:860. doi:10.3389/fonc.2019.00860