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Atta Ullah
Muhammad Jamil Yousaf
Hifzar Ullah
Imran Ali Babber
Junaid Ahmed
Saira Farman
Panhwer Sana Noor
Momina Sami Khan
Syed Meesam Raza
Jamal Muhammad Khan


Laryngeal cancer (LC), Bradford Hill criteria, Human papillomavirus (HPV)


The role of human papillomavirus (HPV) in Laryngeal cancer (LC) has been extensively investigated globally, yielding conflicting results. Despite numerous attempts by different research groups to explore the potential association of HPV with LC using statistical metaanalysis, the findings remain controversial due to inherent limitations in meta-analytical approaches. Therefore, this study was conducted to investigate the potential link between HPV and LC using an alternative method, the Bradford Hill criteria, to provide a clearer perspective. Initially, we conducted a comprehensive search on PubMed to gather all studies associating HPV with LC. Subsequently, we examined the available data on HPV in LC and normal/benign samples, applying the major Bradford Hill criteria postulates to assess the potential association. Additionally, to enhance the reliability of our findings, we critically evaluated the methodologies of the identified studies to assess the risk of false-negative and false-positive results. Following a meticulous assessment of previous studies against the Bradford Hill criteria postulates, it was observed that not all major postulates were fulfilled. Consequently, our findings suggest no causal association between HPV and LC.

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1. Almadori G, Bussu F, Cadoni G, Galli J, Paludetti G, Maurizi M. Molecular markers in laryngeal squamous cell carcinoma: towards an integrated clinicobiological approach. European Journal of Cancer. 2005;41(5):683-93.
2. Tsimplaki E, Argyri E, Sakellaridis A, Kyrodimos E, Xesfyngi D, Panotopoulou E. Oropharyngeal and laryngeal but not oral cancers are strongly associated with high‐risk human papillomavirus in 172 Greek patients. Journal of medical virology. 2017;89(1):170-6.
3. Carozzi F, Lombardi F, Zendron P, Confortini M, Sani C, Bisanzi S, et al. Association of human papillomavirus with prostate cancer: analysis of a consecutive series of prostate biopsies. The International journal of biological markers. 2004;19(4):257-61.
4. Araujo-Neto AP, Ferreira-Fernandes H, Amaral CM, Santos LG, Freitas AC, Silva-Neto JC, et al. Lack of detection of human papillomavirus DNA in prostate carcinomas in patients from northeastern Brazil. Genet Mol Biol. 2016;39(1):24-9.
5. McNicol P, Dodd J. Detection of human papillomavirus DNA in prostate gland tissue by using the polymerase chain reaction amplification assay. Journal of clinical microbiology. 1990;28(3):409-12.
6. Ma XL, Ueno K, Pan ZM, Hi SZ, Ohyama M, Eizuru YJJomv. Human papillomavirus DNA sequences and p53 over‐expression in laryngeal squamous cell carcinomas in Northeast China. 1998;54(3):186-91.
7. Xu Y, Liu S, Yi H, Wang J, Dong P, Li X, et al. Human papillomavirus infection in 674 Chinese patients with laryngeal squamous cell carcinoma. 2014;9(12):e115914.
8. Lu Z, Li Y, Xu M, Chen L, Luo X, Huang YJJPM. The infection and integration status of high-risk human papillomavirus 16/18 in laryngeal cancer. 2016;32:1422-4.
9. Wang H, Mu Z, Zhou X, Zhou XJCJG. Relationship between high risk human papillomavirus E7 mRNA and laryngeal lesions. 2017;37:2875-7.
10. Guan L, Sun N, Sun G, Fang Q, Meng Y, Zhao XJJoCOH, et al. Analysis of subtypes of HPV infection in laryngeal squamous cell carcinoma and precancerous lesions and its clinical significance. 2015;29:1549-52.
11. Wang H, Sun R, Weihan HJCR, Clinic. Human papillomavirus infection and HRAS, PIK3CA mutations analysis in patients with early laryngeal carcinoma. 2014;26(6):361-5,72.
12. Liu B, Lu Z, Wang P, Basang Z, Rao XJN. Prevalence of high-risk human papillomavirus types (HPV-16, HPV-18) and their physical status in primary laryngeal squamous cell carcinoma. 2010;57(6):594.
13. Tong F, Geng J, Yan B, Lou H, Chen X, Duan C, et al. Prevalence and prognostic significance of HPV in laryngeal squamous cell carcinoma in Northeast China. 2018;49(1):206-16.
14. Wang H, Zhang Z, Sun R, Lin H, Gong L, Fang M, et al. HPV infection and anemia status stratify the survival of early T2 laryngeal squamous cell carcinoma. 2015;29(3):356-62.
15. Li J, Yang J, Yi Z, Lin Y, Zhou AJZebyhkzz. Human papilloma virus infection and expression of p16 protein in laryngeal papilloma and laryngeal carcinoma. 2001;36(1):51-4.
16. Chen X, Gao L, Sturgis E, Liang Z, Zhu Y, Xia X, et al. HPV16 DNA and integration in normal and malignant epithelium: implications for the etiology of laryngeal squamous cell carcinoma. 2017;28(5):1105-10.
17. Yang S-M, Wu M, Han F-Y, Sun Y-M, Yang J-Q, Liu H-XJIJoC, et al. Role of HPV status and PD-L1 expression in prognosis of laryngeal squamous cell carcinoma. 2021;14(1):107.
18. Wang P, Rao X, Yong L, Ning T, Liu BJCR, Clinic. Detection of high-risk human papillomavirus types-16 and-18 in laryngeal squamous cell carcinoma. 2011;23(1):14-7.
19. Cui L, Qu C, Liu HJCO. Association study of cell cycle proteins and human papillomavirus in laryngeal cancer in Chinese population. 2019;44(3):323-9.
20. Ben Elhadj M, Amine OE, Mokni Baizig N, Ben Ayoub W, Goucha A, El May M-V, et al. Expression Profile of Survivin and p16 in Laryngeal Squamous Cell Carcinoma: Contribution of Tunisian Patients. 2019:0145561319855644.
21. Sánchez Barrueco A, González Galán F, Lora Pablos D, Villacampa Aubá JM, Ballestín Carcavilla C, Cenjor Español C, et al. HPV in larynx squamous cell carcinoma: new serotypes and survival study within 10-year follow-up. 2017;156(4):677-82.
22. Duray A, Descamps G, Arafa M, Decaestecker C, Remmelink M, Sirtaine N, et al. High incidence of high-risk HPV in benign and malignant lesions of the larynx. 2011;39(1):51-9.
23. Dogantemur S, Ozdemir S, Uguz A, Surmelioglu O, Dagkiran M, Tarkan O, et al. Assessment of HPV 16, HPV 18, p16 expression in advanced stage laryngeal cancer patients and prognostic significance. 2020;86(3):351-7.
24. Celebi OO, Sener E, Hosal S, Cengiz M, Gullu I, Tezel GGJBc. Human papillomavirus infection in patients with laryngeal carcinoma. 2018;18(1):1-5.
25. Güvenç MG, Midilli K, Özdoğan A, İnci E, Tahamiler R, Enver Ö, et al. Detection of HHV-8 and HPV in laryngeal carcinoma. 2008;35(3):357-62.
26. Gungor A, Cincik H, Baloglu H, Cekin E, Dogru S, Dursun EJTJol, et al. Human papilloma virus prevalence in laryngeal squamous cell carcinoma. 2007;121(8):772.
27. Erkul E, Yilmaz I, Narli G, Babayigit MA, Gungor A, Demirel DJEAoO-R-L. The presence and prognostic significance of human papillomavirus in squamous cell carcinoma of the larynx. 2017;274(7):2921-6.
28. Stumbrytė-Kaminskienė A, Gudlevičienė Ž, Dabkevičienė D, Mackevičienė IJM. Combined effect of HPV and several gene SNPs in laryngeal cancer. 2020;56(2):81.
29. Castellsagué X, Alemany L, Quer M, Halec G, Quirós B, Tous S, et al. HPV involvement in head and neck cancers: comprehensive assessment of biomarkers in 3680 patients. 2016;108(6):djv403.
30. Rodrigo JP, Hermsen MA, Fresno MF, Brakenhoff RH, García-Velasco F, Snijders PJ, et al. Prevalence of human papillomavirus in laryngeal and hypopharyngeal squamous cell carcinomas in northern Spain. 2015;39(1):37-41.
31. Young R, Urban D, Angel C, Corry J, Lyons B, Vallance N, et al. Frequency and prognostic significance of p16 INK4A protein overexpression and transcriptionally active human papillomavirus infection in laryngeal squamous cell carcinoma. 2015;112(6):1098-104.
32. Atighechi S, Meybodian M, Dadgarnia MH, Baradaranfar MH, Behniafard NJIjoo. Investigating the prevalence of human papilloma virus in squamous cell carcinoma of the larynx and its correlation with disease prognosis. 2016;28(86):197.
33. Dahm V, Haitel A, Kaider A, Stanisz I, Beer A, Lill CJEAoO-R-L. Cancer stage and pack-years, but not p16 or HPV, are relevant for survival in hypopharyngeal and laryngeal squamous cell carcinomas. 2018;275(7):1837-43.
34. Drop B, Strycharz-Dudziak M, Kliszczewska E, Polz-Dacewicz MJIjoms. Coinfection with Epstein–barr Virus (EBV), Human Papilloma Virus (HPV) and Polyoma BK Virus (BKPyV) in laryngeal, oropharyngeal and oral cavity cancer. 2017;18(12):2752.
35. Polz-Gruszka D, Stec A, Dworzański J, Polz-Dacewicz MJAr. EBV, HSV, CMV and HPV in laryngeal and oropharyngeal carcinoma in Polish patients. 2015;35(3):1657-61.
36. Morshed K, Polz-Dacewicz M, Szymański M, Polz DJEaoo-r-l. Short-fragment PCR assay for highly sensitive broad-spectrum detection of human papillomaviruses in laryngeal squamous cell carcinoma and normal mucosa: clinico-pathological evaluation. 2008;265(1):89-96.
37. Patel KR, Chernock RD, Zhang TR, Wang X, El-Mofty SK, Lewis Jr JSJHp. Verrucous carcinomas of the head and neck, including those with associated squamous cell carcinoma, lack transcriptionally active high-risk human papillomavirus. 2013;44(11):2385-92.
38. Hernandez BY, Goodman MT, Lynch CF, Cozen W, Unger ER, Steinau M, et al. Human papillomavirus prevalence in invasive laryngeal cancer in the United States. 2014;9(12):e115931.
39. Baumann JL, Cohen S, Evjen AN, Law JH, Vadivelu S, Attia A, et al. Human papillomavirus in early laryngeal carcinoma. 2009;119(8):1531-7.
40. Andrews E, Seaman WT, Webster-Cyriaque JJOo. Oropharyngeal carcinoma in non-smokers and non-drinkers: a role for HPV. 2009;45(6):486-91.
41. Stephen JK, Chen KM, Shah V, Havard S, Lu M, Schweitzer VP, et al. Human papillomavirus outcomes in an access-to-care laryngeal cancer cohort. 2012;146(5):730-8.
42. Lewis Jr JS, Ukpo OC, Ma XJ, Flanagan JJ, Luo Y, Thorstad WL, et al. Transcriptionally‐active high‐risk human papillomavirus is rare in oral cavity and laryngeal/hypopharyngeal squamous cell carcinomas–a tissue microarray study utilizing E6/E7 mRNA in situ hybridization. 2012;60(6):982-91.
43. Rivera-Peña B, Ruíz-Fullana FJ, Vélez-Reyes GL, Rodriguez-Benitez RJ, Marcos-Martínez MJ, Trinidad-Pinedo J, et al. HPV-16 infection modifies overall survival of Puerto Rican HNSCC patients. 2016;11(1):1-9.
44. Shaughnessy JN, Farghaly H, Wilson L, Redman R, Potts K, Bumpous J, et al. HPV: a factor in organ preservation for locally advanced larynx and hypopharynx cancer? 2014;35(1):19-24.
45. Halec G, Holzinger D, Schmitt M, Flechtenmacher C, Dyckhoff G, Lloveras B, et al. Biological evidence for a causal role of HPV16 in a small fraction of laryngeal squamous cell carcinoma. 2013;109(1):172-83.
46. Arndt O, Johannes A, Zeise K, Brock JJL-r-o. High-risk HPV types in oral and laryngeal papilloma and leukoplakia. 1997;76(3):142-9.
47. Chen W-C, Chuang H-C, Lin Y-T, Huang C-C, Chien C-YJP. Clinical impact of human papillomavirus in laryngeal squamous cell carcinoma: a retrospective study. 2017;5:e3395.
48. Huang C-G, Lee L-A, Fang T-J, Li H-Y, Liao C-T, Kang C-J, et al. Human papillomavirus infection is not associated with laryngeal squamous cell carcinoma in Taiwan. 2020;53(1):79-86.
49. Chitose S-i, Sakazaki T, Fukahori M, Ono M, Maeda A, Umeno H, et al. Immunological responses against human papilloma virus and human papilloma virus induced laryngeal cancer. 2010;22(2):83-7.
50. Orita Y, Gion Y, Tachibana T, Ikegami K, Marunaka H, Makihara S, et al. Laryngeal squamous cell papilloma is highly associated with human papillomavirus. Jpn J Clin Oncol. 2018;48(4):350-5.
51. Gorgoulis VG, Zacharatos P, Kotsinas A, Kyroudi A, Rassidakis AN, Ikonomopoulos JA, et al. Human papilloma virus (HPV) is possibly involved in laryngeal but not in lung carcinogenesis. 1999;30(3):274-83.
52. Baboci L, Holzinger D, Boscolo-Rizzo P, Tirelli G, Spinato R, Lupato V, et al. Low prevalence of HPV-driven head and neck squamous cell carcinoma in North-East Italy. 2016;2:133-40.
53. Cattani P, Hohaus S, Bellacosa A, Genuardi M, Cavallo S, Rovella V, et al. Association between cyclin D1 (CCND1) gene amplification and human papillomavirus infection in human laryngeal squamous cell carcinoma. 1998;4(11):2585-9.
54. Peralta R, Garcia P, Valdivia A, Lopez A, Apresa T, Hernandez DM, et al. HPV Could be a potential factor of survival in laryngeal cancer: a preliminary study in Mexican patients. 2018;19(6):1711.
55. Lindeberg H, Krogdahl AJCl. Laryngeal cancer and human papillomavirus: HPV is absent in the majority of laryngeal carcinomas. 1999;146(1):9-13.
56. Narisawa‐Saito M, Kiyono T. Basic mechanisms of high‐risk human papillomavirus‐induced carcinogenesis: Roles of E6 and E7 proteins. Cancer science. 2007;98(10):1505-11.
57. Malik SS, Batool R, Masood N, Yasmin A. Risk factors for prostate cancer: A multifactorial case-control study. Current problems in cancer. 2018;42(3):337-43.
58. Whitaker NJ, Glenn WK, Sahrudin A, Orde MM, Delprado W, Lawson JS. Human papillomavirus and Epstein Barr virus in prostate cancer: Koilocytes indicate potential oncogenic influences of human papillomavirus in prostate cancer. The Prostate. 2013;73(3):236-41.
59. Anzivino E, Rodio DM, Mischitelli M, Bellizzi A, Sciarra A, Salciccia S, et al. High frequency of JCV DNA detection in prostate cancer tissues. Cancer Genomics-Proteomics. 2015;12(4):189-200.
60. Zammarchi F, Pistello M, Piersigilli A, Murr R, Cristofano CD, Naccarato AG, et al. MMTV‐like sequences in human breast cancer: a fluorescent PCR/laser microdissection approach. The Journal of Pathology: A Journal of the Pathological Society of Great Britain and Ireland. 2006;209(4):436-44.
61. Al Dossary R, Alkharsah KR, Kussaibi H. Prevalence of Mouse Mammary Tumor Virus (MMTV)-like sequences in human breast cancer tissues and adjacent normal breast tissues in Saudi Arabia. BMC cancer. 2018;18(1):1-10.
62. Awadh A, Chughtai AA, Dyda A, Sheikh M, Heslop DJ, MacIntyre CR. Does Zika virus cause microcephaly-applying the Bradford Hill viewpoints. PLoS currents. 2017;9.
63. Song D, Li H, Li H, Dai J. Effect of human papillomavirus infection on the immune system and its role in the course of cervical cancer. Oncology letters. 2015;10(2):600-6.

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