The role of human papillomavirus marker p16 in identifying the primary focus in patients with metastases of squamous cell carcinoma from an undiagnosed primary focus

Introduction. Squamous cell carcinoma of the oropharynx associated with Human papilloma virus (Hpv) has been identified as a distinct nosological unit among squamous cell carcinoma of the head and neck. This is due to the peculiarities of the disease and localization (the tumor mainly occurs in the palatine or lingual tonsils). primary squamous cell carcinoma of the oropharynx often debuts in the form of cancer metastases from an undiagnosed primary focus.

Aim. To show relationship between presence of the Hpv marker p16 in patients with metastases from an undiagnosed primary focus with primary squamous cell carcinoma of the oropharynx.

Materials and methods. The retrospective study included 151 patients with cervical lymph node metastases from an undiagnosed primary focus, treated from 2014 to 2024 in the Oncology Department of Surgical methods of Treatment No. 10 of the N. N. Blokhin National medical Center of Oncology, 83 of whom were found to have p16 – a surrogate marker of Hpv.

Results. The findings suggest a strong relationship between the presence of Hpv in the metastatic focus and oropharyngeal squamous cell carcinoma. The difficulty of identifying the primary focus is most likely due to the small size of this focus and its submucosal location, as well as with early metastasis to the lymph nodes.

Conclusion. In order not to miss clinically latent squamous cell carcinoma of the oropharynx, interdisciplinary collaboration and conduct of thorough immunohistological study, especially a surrogate marker test for Hpv p16, are needed.

1. Adelstein D.J., Ridge J.A. et al. Head and neck squamous cell cancer and the human papillomavirus: summary of a National Cancer Institute State of the Science Meeting, November 9–10, 2008, Washington, D.C. Head Neck 2009;31(11):1393–422. DOI: 10.1002/hed.21269

2. Fakhry C., Westra W.H., Li S. et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 2008;100(4):261–9. DOI: 10.1093/jnci/djn01

3. Ragin C.C., Taioli E. Survival of squamous cell carcinoma of the head and neck in relation to human papillomavirus infection: review and meta-analysis. Int J Cancer 2007;121(8):1813–20. DOI: 10.1002/ijc.22851

4. Shiboski C.H., Schmidt B.L., Jordan R.C. Tongue and tonsil carcinoma: increasing trends in the U.S. population ages 20–44 years. Cancer 2005;103(9):1843–9. DOI: 10.1002/cncr.20998

5. D’Souza G., Kreimer A.R., Viscidi R. et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 2007;356(19):1944–56. DOI: 10.1056/NEJMoa065497

6. D’Souza G., Agrawal Y., Halpern J. et al. Oral sexual behaviors associated with prevalent oral human papillomavirus infection. J Infect Dis 2009;199(9):1263–9. DOI: 10.1086/597755

7. Schwartz S.M., Daling J.R., Doody D.R. et al. Oral cancer risk in relation to sexual history and evidence of human papillomavirus infection. J Natl Cancer Inst 1998;90(21):1626–36. DOI: 10.1093/jnci/90.21.1626

8. Termine N., Panzarella V., Falaschini S. et al. HPV in oral squamous cell carcinoma vs head and neck squamous cell carcinoma biopsies: a meta-analysis (1988–2007). Ann Oncol 2008;19(10):1681–90. DOI: 10.1093/annonc/mdn37

9. Kumar B., Cordell K.G., Lee J.S. et al. EGFR, p16, HPV titer, Bcl-xL and p53, sex, and smoking as indicators of response to therapy and survival in oropharyngeal cancer. J Clin Oncol 2008;26(19):3128–37. DOI: 10.1200/JCO.2007.12.7662

10. Hafkamp H.C., Manni J.J., Haesevoets A. et al. Marked differences in survival rate between smokers and nonsmokers with HPV 16- associated tonsillar carcinomas. Int J Cancer 2008;122(12):2656–64. DOI: 10.1002/ijc.23458

11. Chernock R.D., El-Mofty S.K., Thorstad W.L. et al. HPV-related nonkeratinizing squamous cell carcinoma of the oropharynx: utility of microscopic features in predicting patient outcome. Head Neck Pathol 2009;3(3):186–94. DOI: 10.1007/s12105-009-0126-1

12. Adelstein D.J. Concurrent chemoradiotherapy in the management of squamous cell cancer of the oropharynx: current standards and future directions. Int J Radiat Oncol Biol Phys 2007;69(Suppl 2):S37–9. DOI: 10.1016/j.ijrobp.2007.04.086

13. Nasman A., Attner P., Hammarstedt L. et al. Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma? Int J Cancer 2009;125(2):362–6. DOI: 10.1002/ijc.24339

14. Chaturvedi A.K., Engels E.A., Pfeiffer R.M. et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol 2011;29(32):4294–301. DOI: 10.1200/JCO.2011.36.4596

15. Fischer C.A., Zlobec I., Green E. et al. Is the improved prognosis of p16 positive oropharyngeal squamous cell carcinoma dependent of the treatment modality? Int J Cancer 2010;126(5):1256–62. DOI: 10.1002/ijc.24842

16. Guo M., Gong Y., Deavers M. et al. Evaluation of a commercialized in situ hybridization assay for detecting human papillomavirus DNA in tissue specimens from patients with cervical intraepithelial neoplasia and cervical carcinoma. J Clin Microbiol 2008;46(1): 274–80. DOI: 10.1128/JCM.01299-07

17. Westra W. The changing face of head and neck cancer in the 21st century: the impact of HPV on the epidemiology and pathology of oral cancer. Head Neck Pathol 2009;3:78–81. DOI: 10.1007/s12105-009-0100-y

18. Zur Hausen H. Papillomaviruses in human cancers. Proc Assoc Am Physicians 1999;111(6):581–7. DOI: 10.1046/j.1525-1381.1999.99723.x

19. Andl T., Kahn T., Pfuhl A. et al. Etiological involvement of oncogenic human papillomavirus in tonsillar squamous cell carcinomas lacking retinoblastoma cell cycle control. Cancer Res 1998;58(1):5–13.

20. Munger K., Basile J.R., Duensing S. et al. Biological activities and molecular targets of the human papillomavirus E7 oncoprotein. Oncogene 2001;20(54):7888–98. DOI: 10.1038/sj.onc.1204860

21. Vent J., Haidle B., Wedemeyer I. et al. p16 expression in carcinoma of unknown primary: diagnostic indicator and prognostic marker. Head Neck 2013;35(11):1521–6. DOI: 10.1002/hed.23190

22. Lewis J.S. p16 immunohistochemistry as a standalone test for risk stratification in oropharyngeal squamous cell carcinoma. Head Neck Pathol 2012;6(Suppl 1):S75–82. DOI: 10.1007/s12105-012-0369-0

23. Chernock R.D., Wang X., Gao G. et al. Detection and significance of human papillomavirus, CDKN2A(p16) and CDKN1A(p21) expression in squamous cell carcinoma of the larynx. Mod Pathol 2013;26(2):223–31. DOI: 10.1038/modpathol.2012.159

24. Beadle B.M., William W.N. Jr, McLemore M.S. et al. p16 expression in cutaneous squamous carcinomas with neck metastases: a potential pitfall in identifying unknown primaries of the head and neck. Head Neck 2013;35(11):1527–33. DOI: 10.1002/hed.23188

25. Chang S.Y., Keeney M., Law M. et al. (2015). Detection of human papillomavirus in non-small cell carcinoma of the lung. Human Pathol 2015;46(11):1592–7. DOI: 10.1016/j.humpath.2015.07.012

26. Bishop J.A., Ogawa T., Chang X. et al. HPV analysis in distinguishing second primary tumors from lung metastases in patients with head and neck squamous cell carcinoma. Am J Surg Pathol 2012;36(1):142–8. DOI: 10.1097/pas.0b013e3182395c7b

27. Cianchetti M., Mancuso A., Amdur R. et al. Diagnostic evaluation of squamous cell carcinoma metastatic to cervical lymph nodes from an unknown head and neck primary site. Laryngoscope 2009;119(12):2348–54. DOI: 10.1002/lary.20638

28. Perry M.E. The specialised structure of crypt epithelium in the human palatine tonsil and its functional significance. J Anat 1994;185(Pt 1):111–27.

29. Begum S., Cao D., Gillison M. et al. Tissue distribution of human papillomavirus 16 DNA integration in patients with tonsillar carcinoma. Clin Cancer Res 2005;11(16):5694–9. DOI: 10.1158/1078-0432.CCR-05-0587

30. Rischin D., Young R., Fisher R. et al. Prognostic significance of HPV and p16 status in patients with oropharyngeal cancer treated on a large international phase III trial. J Clin Oncol 2009;28(27):4142–8. DOI: 10.1200/JCO.2010.29.2904