Main Article Content

Kinza Khan
Rizwana Sultan
Syed Qaswar Ali Shah
Zahid Farooq
Najeeb Ur Rehman
Hafsa Munir
Jamal Muhammad Khan


Head and neck cancer (HNC), Bradford Hill criteria, Human papillomavirus (HPV)


The involvement of human papillomavirus (HPV) has effectively been decoded in Head and neck cancer (HNC) worldwide with contradicting findings. Although the different groups of researchers explored the potential association of HPV with HNC using statistical meta-analysis, however, the association remained still controversial due to the major shortcomings of meta-analysis. Therefore, we arranged the present study to investigate a potential link of HPV with HNC using an additional method (Bradford Hill criteria) which helps to get a more clear picture. Methodology: Initially using PubMed, we extracted all of the studies that associated HPV to HNC. Then, to assess the potential association of HPV with HNC, an examination of the available data on HPV in HNC, normal/benign samples was done using all the major Bradford Hill criteria postulates. Furthermore, to improve the authenticity of our findings, we have also critically evaluated the methodologies of the identified studies to check the possibility of false-negative and false-positive results. Results: After a careful assessment of the previous studies against Bradford Hill criteria postulates, we observed that all the major postulates were not fulfilled. Conclusion: Therefore, our findings recommended no casual association of HPV with HNC.

Abstract 117 | pdf Downloads 55


1. Pfeiffer J, Wiech T, Maier W, Ridder GJ, Laszig R, Birkenhäger R. Head and neck cancer in young adults and nonsmokers: Study of cancer susceptibility by genome-wide high-density SNP microarray mapping. Acta oto-laryngologica. 2011;131(10):1091-8.
2. Khan M, Hameed Y. Discovery of novel six genes-based cervical cancer-associated biomarkers that are capable to break the heterogeneity barrier and applicable at the global level. Journal of Cancer Research and Therapeutics. 9000.
3. Usman M, Hameed Y, Ahmad M. Does human papillomavirus cause human colorectal cancer? Applying Bradford Hill criteria postulates. ecancermedicalscience. 2020;14.
4. Pai SI, Westra WH. Molecular pathology of head and neck cancer: implications for diagnosis, prognosis, and treatment. Annual Review of Pathology: Mechanisms of Disease. 2009;4:49-70.
5. Yasir M, Nawaz A, Ghazanfar S, Okla M, Chaudhary A, Al WH, et al. Anti-bacterial activity of essential oils against multidrug-resistant foodborne pathogens isolated from raw milk. Brazilian Journal of Biology. 2022;84:e259449.
6. Khalil T, Okla M, Al-Qahtani W, Ali F, Zahra M, Shakeela Q, et al. Tracing probiotic producing bacterial species from gut of buffalo (Bubalus bubalis), South-East-Asia. Brazilian Journal of Biology. 2022;84:e259094.
7. Aboagye E, Agyemang-Yeboah F, Duduyemi BM, Obirikorang C. Human papillomavirus detection in head and neck squamous cell carcinomas at a tertiary hospital in sub-Saharan Africa. The Scientific World Journal. 2019;2019.
8. Zhang L, Sahar A, Li C, Chaudhary A, Yousaf I, Saeedah M, et al. A detailed multi-omics analysis of GNB2 gene in human cancers. Brazilian Journal of Biology. 2022;84.
9. Hameed Y, Ejaz S. TP53 lacks tetramerization and N-terminal domains due to novel inactivating mutations detected in leukemia patients. Journal of Cancer Research and Therapeutics. 2021;17(4):931-7.
10. Ullah L, Hameed Y, Ejaz S, Raashid A, Iqbal J, Ullah I, et al. Detection of novel infiltrating ductal carcinoma-associated BReast CAncer gene 2 mutations which alter the deoxyribonucleic acid-binding ability of BReast CAncer gene 2 protein. Journal of Cancer Research and Therapeutics. 2020;16(6):1402-7.
11. Hameed Y, Usman M, Liang S, Ejaz S. Novel diagnostic and prognostic biomarkers of colorectal cancer: capable to overcome the heterogeneity-specific barrier and valid for global applications. Plos one. 2021;16(9):e0256020.
12. Zhu X, Tang L, Mao J, Hameed Y, Zhang J, Li N, et al. Decoding the mechanism behind the pathogenesis of the focal segmental glomerulosclerosis. Computational and Mathematical Methods in Medicine.2022.
13. Usman M, Hameed Y, Ahmad M, Iqbal MJ, Maryam A, Mazhar A, et al. SHMT2 is associated with tumor purity, CD8+ T immune cells infiltration, and a novel therapeutic target in four different human cancers. Current Molecular Medicine. 2023;23(2):161-76.
14. de Abreu PM, Có ACG, Azevedo PL, do Valle IB, de Oliveira KG, Gouvea SA, et al. Frequency of HPV in oral cavity squamous cell carcinoma. BMC cancer. 2018;18(1):1-8.
15. Attner P, Du J, Näsman A, Hammarstedt L, Ramqvist T, Lindholm J, et al. The role of human papillomavirus in the increased incidence of base of tongue cancer. International journal of cancer. 2010;126(12):2879-84.
16. Baig S, Zaman U, Lucky MH. Human papilloma virus 16/18: Fabricator of trouble in oral squamous cell carcinoma. International Journal of Infectious Diseases. 2018;69:115-9.
17. García-Milián R, Hernández H, Panadé L, Rodríguez C, González N, Valenzuela C, et al. Detection and typing of human papillomavirus DNA in benign and malignant tumours of laryngeal epithelium. Acta Otolaryngol. 1998 Sep;118(5):754-8.
18. Hameed Y, Usman M, Ahmad M. Does mouse mammary tumor-like virus cause human breast cancer? Applying Bradford Hill criteria postulates. Bulletin of the National Research Centre. 2020;44(1):1-13.
19. Mao J, Huang X, Okla MK, Abdel-Maksoud MA, Mubarak A, Hameed Z, et al. Risk Factors for TERT promoter mutations with papillary thyroid carcinoma patients: a meta-analysis and systematic review. Computational and Mathematical Methods in Medicine.2022.
20. Sial N, Rehman JU, Saeed S, Ahmad M, Hameed Y, Atif M, et al. Integrative analysis reveals methylenetetrahydrofolate dehydrogenase 1-like as an independent shared diagnostic and prognostic biomarker in five different human cancers. Bioscience Reports. 2022;42(1):BSR20211783.
21. Hameed A, Condò C, Tauseef I, Idrees M, Ghazanfar S, Farid A, et al. Isolation and characterization of a cholesterol-lowering bacteria from Bubalus bubalis raw milk. Fermentation. 2022;8(4):163.
22. Ahmad M, Hameed Y, Khan M, Usman M, Rehman A, Abid U, et al. Up-regulation of GINS1 highlighted a good diagnostic and prognostic potential of survival in three different subtypes of human cancer. Brazilian Journal of Biology. 2021;84.
23. Fedak KM, Bernal A, Capshaw ZA, Gross S. Applying the Bradford Hill criteria in the 21st century: how data integration has changed causal inference in molecular epidemiology. Emerging themes in epidemiology. 2015;12(1):1-9.
24. Anaya-Saavedra G, Ramírez-Amador V, Irigoyen-Camacho ME, García-Cuellar CM, Guido-Jiménez M, Méndez-Martínez R, et al. High association of human papillomavirus infection with oral cancer: a case-control study. Archives of medical research. 2008;39(2):189-97.
25. Balaram P, Nalinakumari KR, Abraham E, Balan A, Hareendran NK, Bernard HU, et al. Human papillomaviruses in 91 oral cancers from Indian betel quid chewers--high prevalence and multiplicity of infections. Int J Cancer. 1995;61(4):450-4.
26. Boy S, Rensburg EJV, Engelbrecht S, Dreyer L, Van Heerden M, Van Heerden W. HPV detection in primary intra‐oral squamous cell carcinomas–commensal, aetiological agent or contamination? Journal of oral pathology & medicine. 2006;35(2):86-90.
27. Cao J, Zhang ZY, Patima, Zhang YX, Chen WT. Human papillomavirus infection and p53 alteration in oral squamous cell carcinoma. Chin J Dent Res. 2000;3(3):44-9.
28. Charfi L, Jouffroy T, de Cremoux P, Le Peltier N, Thioux M, Fréneaux P, et al. Two types of squamous cell carcinoma of the palatine tonsil characterized by distinct etiology, molecular features and outcome. Cancer letters. 2008;260(1-2):72-8.
29. Chaudhary AK, Pandya S, Mehrotra R, Bharti AC, Singh M, Singh M. Comparative study between the Hybrid Capture II test and PCR based assay for the detection of human papillomavirus DNA in oral submucous fibrosis and oral squamous cell carcinoma. Virology Journal. 2010;7(1):253.
30. Chen F, Yan L, Liu F, Huang J, Liu F, Wu J, et al. Oral human papillomavirus infection, sexual behaviors and risk of oral squamous cell carcinoma in southeast of China: a case-control study. Journal of clinical virology. 2016;85:7-12.
31. Chernock RD, Zhang Q, El-Mofty SK, Thorstad WL, Lewis JS. Human papillomavirus–related squamous cell carcinoma of the oropharynx: a comparative study in whites and African Americans. Archives of Otolaryngology–Head & Neck Surgery. 2011;137(2):163-9.
32. Dillner J, Knekt P, Schiller J, Hakulinen T. Prospective seroepidemiological evidence that human papillomavirus type 16 infection is a risk factor for oesophageal squamous cell carcinoma. Bmj. 1995;311(7016):1346.
33. Elango KJ, Suresh A, Erode EM, Subhadradevi L, Ravindran HK, Iyer SK, et al. Role of human papilloma virus in oral tongue squamous cell carcinoma. Asian Pac J Cancer Prev. 2011;12(4):889-96.
34. Gan L-L, Zhang H, Guo J-H, Fan M-W. Prevalence of human papillomavirus infection in oral squamous cell carcinoma: a case-control study in Wuhan, China. Asian Pac J Cancer Prev. 2014;15(14):5861-5.
35. Hannisdal K, Schjølberg A, De Angelis PM, Boysen M, Clausen OPF. Human papillomavirus (HPV)-positive tonsillar carcinomas are frequent and have a favourable prognosis in males in Norway. Acta oto-laryngologica. 2010;130(2):293-9.
36. Hansson BG, Rosenquist K, Antonsson A, Wennerberg J, Schildt E-B, Bladström A, et al. Strong association between infection with human papillomavirus and oral and oropharyngeal squamous cell carcinoma: a population-based case-control study in southern Sweden. Acta oto-laryngologica. 2005;125(12):1337-44.
37. Ibieta BR, Lizano M, Frı́as-Mendivil M, Barrera JL, Carrillo A, Ruı́z-Godoy LM, et al. Human papilloma virus in oral squamous cell carcinoma in a Mexican population. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology. 2005;99(3):311-5.
38. Jalouli J, Ibrahim SO, Sapkota D, Jalouli MM, Vasstrand EN, Hirsch JM, et al. Presence of human papilloma virus, herpes simplex virus and Epstein–Barr virus DNA in oral biopsies from Sudanese patients with regard to toombak use. Journal of oral pathology & medicine. 2010;39(8):599-604.
39. Kane S, Patil V, Joshi A, Noronha V, Muddu V, Dhumal S, et al. Neoadjuvant Chemotherapy in Technically Unresectable Oral Cancers: Does Human Papillomavirus Make a Difference? Clinical oncology (Royal College of Radiologists (Great Britain)). 2015;27(12):751.
40. Kouketsu A, Sato I, Abe S, Oikawa M, Shimizu Y, Takahashi T, et al. Detection of human papillomavirus infection in oral squamous cell carcinoma: a cohort study of Japanese patients. Journal of oral pathology & medicine. 2016;45(8):565-72.
41. Kozomara R, Jović N, Magić Z, Branković-Magić M, Minić V. p53 mutations and human papillomavirus infection in oral squamous cell carcinomas: correlation with overall survival. Journal of Cranio-Maxillofacial Surgery. 2005;33(5):342-8.
42. Kulkarni SS, Kulkarni SS, Vastrad PP, Kulkarni BB, Markande AR, Kadakol G, et al. Prevalence and distribution of high risk human papillomavirus (HPV) types 16 and 18 in carcinoma of cervix, saliva of patients with oral squamous cell carcinoma and in the general population in Karnataka, India. Asian Pac J Cancer Prev. 2011;12(3):645-8.
43. Kumar RV, Kadkol S, Daniel R, Shenoy A, Shah K. Human papillomavirus, p53 and cyclin D1 expression in oropharyngeal carcinoma. International journal of oral and maxillofacial surgery. 2003;32(5):539-43.
44. Kuo K-T, Hsiao C-H, Lin C-H, Kuo L-T, Huang S-H, Lin M-C. The biomarkers of human papillomavirus infection in tonsillar squamous cell carcinoma—molecular basis and predicting favorable outcome. Modern Pathology. 2008;21(4):376-86.
45. Lai K, Killingsworth M, Matthews S, Caixeiro N, Evangelista C, Wu X, et al. Differences in survival outcome between oropharyngeal and oral cavity squamous cell carcinoma in relation to HPV status. Journal of oral pathology & medicine. 2017;46(8):574-82.
46. Lau HY, Brar S, Klimowicz AC, Petrillo SK, Hao D, Brockton NT, et al. Prognostic significance of p16 in locally advanced squamous cell carcinoma of the head and neck treated with concurrent cisplatin and radiotherapy. Head & neck. 2011;33(2):251-6.
47. Lee L-A, Huang C-G, Tsao K-C, Liao C-T, Kang C-J, Chang K-P, et al. Human papillomavirus infections are common and predict mortality in a retrospective cohort study of taiwanese patients with oral cavity cancer. Medicine. 2015;94(47).
48. Lee S, Cho N, Choi E, Baek S, Kim W, Shin D, et al. Relevance of human papilloma virus (HPV) infection to carcinogenesis of oral tongue cancer. International journal of oral and maxillofacial surgery. 2010;39(7):678-83.
49. Lindquist D, Romanitan M, Hammarstedt L, Näsman A, Dahlstrand H, Lindholm J, et al. Human papillomavirus is a favourable prognostic factor in tonsillar cancer and its oncogenic role is supported by the expression of E6 and E7. Molecular Oncology. 2007;1(3):350-5.
50. Lingen MW, Xiao W, Schmitt A, Jiang B, Pickard R, Kreinbrink P, et al. Low etiologic fraction for high-risk human papillomavirus in oral cavity squamous cell carcinomas. Oral oncology. 2013;49(1):1-8.
51. Mathew A, Mody R, Patait MR, Razooki AA, Varghese NT, Saraf K. Prevalence and relationship of human papilloma virus type 16 and type 18 with oral squamous cell carcinoma and oral leukoplakia in fresh scrappings: A PCR study. Indian journal of medical sciences. 2011;65(5).
52. Mellin H, Friesland S, Lewensohn R, Dalianis T, Munck‐Wikland E. Human papillomavirus (HPV) DNA in tonsillar cancer: clinical correlates, risk of relapse, and survival. International journal of cancer. 2000;89(3):300-4.
53. Nagpal JK, Patnaik S, Das BR. Prevalence of high-risk human papilloma virus types and its association with P53 codon 72 polymorphism in tobacco addicted oral squamous cell carcinoma (OSCC) patients of Eastern India. Int J Cancer. 2002;97(5):649-53.
54. Nemes JA, Deli L, Nemes Z, Márton IJ. Expression of p16INK4A, p53, and Rb proteins are independent from the presence of human papillomavirus genes in oral squamous cell carcinoma. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology. 2006;102(3):344-52.
55. Niedobitek G, Pitteroff S, Herbst H, Shepherd P, Finn T, Anagnostopoulos I, et al. Detection of human papillomavirus type 16 DNA in carcinomas of the palatine tonsil. Journal of clinical pathology. 1990;43(11):918-21.
56. Nishioka KF, Kazunori Nishizaki, Mehmet Gunduz, Susumu Tominaga, Motoharu Fukazawa, Nobuya Monden, Shuichi Watanabe, Yu Masuda, Hajime Ogura, Shinji. Human papillomavirus as a risk factor for head and neck cancers-a case-control study. Acta Oto-Laryngologica. 1999;119(540):77-80.
57. PALLESEN G, AUER G, LINDHOLM J, LINDE A, ÅBERG B, RUBIO C, et al. Involvement of Aberrant p53 Expression and Human Papillo-mavirus in Carcinoma of the Head, Neck and Esophagus. Anticancer research. 1994;14:1281-6.
58. Palve V, Bagwan J, Krishnan NM, Pareek M, Chandola U, Suresh A, et al. Detection of high-risk human papillomavirus in oral cavity squamous cell carcinoma using multiple analytes and their role in patient survival. Journal of global oncology. 2018;4:1-33.
59. Pillai MR, Phanidhara A, Kesari AL, Nair P, Nair MK. Cellular manifestations of human papillomavirus infection in the oral mucosa. J Surg Oncol. 1999;71(1):10-5.
60. Premoli-De-Percoco G, Ramirez JL. High risk human papillomavirus in oral squamous carcinoma: evidence of risk factors in a Venezuelan rural population. Preliminary report. J Oral Pathol Med. 2001;30(6):355-61.
61. Premoli-De-Percoco G, Ramírez JL, Galindo I. Correlation between HPV types associated with oral squamous cell carcinoma and cervicovaginal cytology: An in situ hybridization study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1998;86(1):77-81.
62. Ritchie JM, Smith EM, Summersgill KF, Hoffman HT, Wang D, Klussmann JP, et al. Human papillomavirus infection as a prognostic factor in carcinomas of the oral cavity and oropharynx. International journal of cancer. 2003;104(3):336-44.
63. Smith EM, Summersgill KF, McCulloch T, Allen J, Turek LP, Hoffman HT, et al. Human papillomavirus and risk of laryngeal cancer. Annals of Otology, Rhinology & Laryngology. 2000;109(11):1069-76.
64. Snijders PJ, Cromme FV, Van Brule AJD, Schrijnemakers HF, Snow GB, Meijer CJ, et al. Prevalence and expression of human papillomavirus in tonsillar carcinomas, indicating a possible viral etiology. International journal of cancer. 1992;51(6):845-50.
65. Strome SE, Savva A, Brissett AE, Gostout BS, Lewis J, Clayton AC, et al. Squamous cell carcinoma of the tonsils: a molecular analysis of HPV associations. Clinical Cancer Research. 2002;8(4):1093-100.
66. Sugiyama M, Bhawal UK, Kawamura M, Ishioka Y, Shigeishi H, Higashikawa K, et al. Human papillomavirus-16 in oral squamous cell carcinoma: clinical correlates and 5-year survival. British Journal of Oral and Maxillofacial Surgery. 2007;45(2):116-22.
67. Syrjänen S, Syrjänen K, Happonen RP. Human papillomavirus (HPV) DNA sequences in oral precancerous lesions and squamous cell carcinoma demonstrated by in situ hybridization. Journal of oral pathology & medicine. 1988;17(6):273-8.
68. Tang X, Jia L, Ouyang J, Takagi M. Comparative study of HPV prevalence in Japanese and North‐east Chinese oral carcinoma. Journal of oral pathology & medicine. 2003;32(7):393-8.
69. Tsuhako K, Nakazato I, Miyagi J, Iwamasa T, Arasaki A, Hiratsuka H, et al. Comparative study of oral squamous cell carcinoma in Okinawa, Southern Japan and Sapporo in Hokkaido, Northern Japan; with special reference to human papillomavirus and Epstein‐Barr virus infection. Journal of oral pathology & medicine. 2000;29(2):70-9.
70. Xue J, Chen H, Fan M, Zhu F, Diao L, Chen X, et al. Use of quantum dots to detect human papillomavirus in oral squamous cell carcinoma. Journal of oral pathology & medicine. 2009;38(8):668-71.
71. Zhang Z-Y, Sdek P, Cao J, Chen W-T. Human papillomavirus type 16 and 18 DNA in oral squamous cell carcinoma and normal mucosa. International journal of oral and maxillofacial surgery. 2004;33(1):71-4.
72. 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.
73. Galbiatti ALS, Padovani-Junior JA, Maníglia JV, Rodrigues CDS, Pavarino ÉC, Goloni-Bertollo EM. Head and neck cancer: causes, prevention and treatment. Brazilian journal of otorhinolaryngology. 2013;79(2):239-47.
74. Al-Thawadi H, Gupta I, Jabeen A, Skenderi F, Aboulkassim T, Yasmeen A, et al. Co-presence of human papillomaviruses and Epstein–Barr virus is linked with advanced tumor stage: a tissue microarray study in head and neck cancer patients. Cancer Cell International. 2020;20(1):1-13.
75. Deng Z, Uehara T, Maeda H, Hasegawa M, Matayoshi S, Kiyuna A, et al. Epstein-Barr virus and human papillomavirus infections and genotype distribution in head and neck cancers. PLoS One. 2014;9(11):e113702.
76. Kutsuna T, Zheng H, Abdel-Aziz HO, Murai Y, Tsuneyama K, Furuta I, et al. High JC virus load in tongue carcinomas may be a risk factor for tongue tumorigenesis. Virchows Arch. 2008;452(4):405-10.
77. 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.
78. 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.
79. 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.
80. 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.

Most read articles by the same author(s)